Genetic Sensitivity to Peer Behaviors: "5HTTLPR", Smoking, and Alcohol Consumption

ERIC Educational Resources Information Center

Daw, Jonathan; Shanahan, Michael; Harris, Kathleen Mullan; Smolen, Andrew; Haberstick, Brett; Boardman, Jason D.

2013-01-01

We investigate whether the serotonin transporter-linked polymorphic region ("5HTTLPR"), a gene associated with environmental sensitivity, moderates the association between smoking and drinking patterns at adolescents' schools and their corresponding risk for smoking and drinking themselves. Drawing on the school-based design of the National…

Differences in MCT1 A1470T polymorphism prevalence between runners and swimmers.

PubMed

Ben-Zaken, S; Eliakim, A; Nemet, D; Rabinovich, M; Kassem, E; Meckel, Y

2015-06-01

Skeletal muscle is the major producer and user of lactate in the body. Therefore, transport of lactate across cells' membrane is of considerable importance. Lactate transport is mediated by proton-linked monocarboxylate transporter (MCT1). The A1470T polymorphism (rs1049434) in MCT1 gene influences lactate transport, with T allele associated with reduction of lactate transport rate and elevation in blood lactate levels. The aim of the current study was to compare allelic and genotype frequencies of MCT1 A1470T polymorphism among Israeli track-and-field athletes, swimmers, and non-athletes. Genomic DNA was extracted from 173 track-and-field athletes (age 17-50), 80 swimmers (age 16-49), and 128 non-athletes (age 19-29). Track-and-field athletes were assigned to three subgroups: long-distance runners, middle-distance runners, and power event athletes. Swimmers were assigned to two subgroups: long-distance swimmers and short-distance swimmers. Genotyping was performed using polymerase chain reaction. T-allele frequency was significantly higher among long-distance swimmers (45%) compared with long- and middle-distance runners (27% and 30%, respectively; P < 0.01). In addition, T-allele frequency was significantly higher among short-distance swimmers (40%) compared with power event athletes (25%, P < 0.01). Overall, T-allele frequency was significantly higher among swimmers (42%) compared with runners (27%, P < 0.001). More research is needed to clarify whether this polymorphism displays advantage for swimming performance. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Serotonin transporter genotype (5-HTTLPR) and electrocortical responses indicating the sensitivity to negative emotional cues.

PubMed

Papousek, Ilona; Reiser, Eva M; Schulter, Günter; Fink, Andreas; Holmes, Emily A; Niederstätter, Harald; Nagl, Simone; Parson, Walther; Weiss, Elisabeth M

2013-12-01

Growing literature indicates that emotional reactivity and regulation are strongly linked to genetic modulation of serotonergic neurotransmission. However, until now, most studies have focused on the relationship between genotypic markers, in particular the serotonin transporter-linked polymorphic region (5-HTTLPR), and neural structures using MRI. The current study aimed to bridge the gap between the relevant MRI literature on the effects of the 5-HTTLPR genotype and the research tradition focusing on transient lateralized changes of electrocortical activity in the prefrontal cortex using electroencephalography (EEG). Lateral shifts of EEG alpha asymmetry in response to an aversive film consisting of scenes of real injury and death were assessed in healthy participants (n = 165). To evaluate the specificity of the 5-HTTLPR effect, participants were also tested for the COMT Val158Met polymorphism which is linked to dopamine inactivation. While viewing the film, individuals homozygous for the 5-HTTLPR short allele displayed a clear lateral shift of dorsolateral frontal activity to the right, which was virtually absent in participants carrying the long allele. The heightened electrocortical response to the aversive stimulation and its direction indicates a greater propensity of s/s homozygotes to experience withdrawal oriented affect in response to negative emotion cues in the environment. Moreover, together with previous research the findings support the notion of a link between the serotonergic system and self-regulation related to avoidance motivation, and a link between the dopaminergic system and self-regulation related to approach motivation.

An examination of the association between the 5-HTT promoter region polymorphism and depressogenic attributional styles in childhood

PubMed Central

Sheikh, Haroon I.; Hayden, Elizabeth P.; Singh, Shiva M.; Dougherty, Lea R.; Olino, Thomas M.; Durbin, C. Emily; Klein, Daniel N.

2008-01-01

Although a vast literature examining the role of attributional styles in depression has accumulated, the origins of such cognitions remain poorly understood. Investigators are increasingly interested in whether cognitive vulnerability to depression is linked to genetic variation. As a preliminary test of this hypothesis, we examined whether the serotonin transporter promoter polymorphism (5-HTTLPR) was associated with attributional styles in children. Thirty-eight children completed a self-report measure of attributional styles, the Child Attributional Style Questionnaire-Revised (CASQ-R). Children were also genotyped for the 5-HTTLPR polymorphism, including the single nucleotide polymorphism (SNP) rs25531 in the long allele of the 5-HTTLPR. The short alleles of the 5-HTTLPR and their putative functional equivalents were associated with increased levels of depressogenic attributions for negative events, as measured by the CASQ-R, lending support to the role of 5-HTTLPR polymorphisms in cognitive vulnerability to depression. PMID:19122845

Biallelic and Triallelic 5-Hydroxytyramine Transporter Gene-Linked Polymorphic Region (5-HTTLPR) Polymorphisms and Their Relationship with Lifelong Premature Ejaculation: A Case-Control Study in a Chinese Population

PubMed Central

Huang, Yuanyuan; Zhang, Xiansheng; Gao, Jingjing; Tang, Dongdong; Gao, Pan; Li, Chao; Liu, Weiqun; Liang, Chaozhao

2016-01-01

Background This study aimed to explore the relationship between premature ejaculation (PE) and the serotonin transporter gene-linked polymorphic region (5-HTTLPR) with respect to the biallelic and triallelic classifications. Material/Methods A total of 115 outpatients who complained of ejaculating prematurely and who were diagnosed as having lifelong premature ejaculation (LPE) and 101 controls without PE complaint were recruited. All subjects completed a detailed questionnaire and were genotyped for 5-HTTLPR polymorphism using PCR-based technology. We evaluated the associations between 5-HTTLPR allelic and genotypic frequencies and their association with LPE, as well as the intravaginal ejaculation latency time (IELT) of different 5-HTTLPR genotypes among LPE patients. Results The patients and controls did not differ significantly in terms of any characteristic except age. The results showed no significant difference regarding biallelic 5-HTTLPR. According to the triallelic classification, no significant difference was found when comparing the genotypic distribution (P=0.091). However, the distribution of the S, LG, and LA alleles in the cases was significantly different from the controls (P=0.018). We found a significantly lower frequency of LA allele and higher frequency of LG allele in patients. Based on another classification by expression, we found a significantly lower frequency of the L’L’ genotype (OR=0.37; 95%CI=0.15–0.91, P=0.025) in patients with LPE. No significant association was detected between IELT of LPE and different genotypes. Conclusions Contrary to the general classification based on S/L alleles, triallelic 5-HTTLPR was associated with LPE. Triallelic 5-HTTLPR may be a promising field for genetic research in PE to avoid false-negative results in future studies. PMID:27311544

Comparing photoelectrochemical water oxidation, recombination kinetics and charge trapping in the three polymorphs of TiO2.

PubMed

Moss, Benjamin; Lim, Kee Kean; Beltram, Alessandro; Moniz, Savio; Tang, Junwang; Fornasiero, Paolo; Barnes, Piers; Durrant, James; Kafizas, Andreas

2017-06-07

In this article we present the first comparative study of the transient decay dynamics of photo-generated charges for the three polymorphs of TiO 2 . To our knowledge, this is the first such study of the brookite phase of TiO 2 over timescales relevant to the kinetics of water splitting. We find that the behavior of brookite, both in the dynamics of relaxation of photo-generated charges and in energetic distribution, is similar to the anatase phase of TiO 2 . Moreover, links between the rate of recombination of charge carriers, their energetic distribution and the mode of transport are made in light of our findings and used to account for the differences in water splitting efficiency observed across the three polymorphs.

The Serotonin Transporter Promoter Polymorphism and Childhood Positive and Negative Emotionality

PubMed Central

Hayden, Elizabeth P.; Klein, Daniel N.; Sheikh, Haroon I.; Olino, Thomas M.; Dougherty, Lea R.; Dyson, Margaret W.; Durbin, C. Emily; Singh, Shiva M.

2011-01-01

Association studies of the serotonin transporter promoter polymorphism (5-HTTLPR) and negative emotionality (NE) are inconclusive. However, emerging evidence suggests that the association between this polymorphism and NE may be influenced by levels of another temperament trait, positive emotionality (PE). Therefore, this study examined whether the association between the 5-HTTLPR and NE was moderated by PE. A community sample of 413 three-year-old children completed a standardized battery of laboratory tasks designed to tap temperamental emotionality. Children were also genotyped for the 5-HTTLPR. No direct association between 5-HTTLPR genotype and NE was found. However, the interaction of child PE and NE predicted 5-HTTLPR genotype. Furthermore, children with a short allele who were also low in PE had significantly greater NE than children without a short allele or children with high PE. Our findings suggest that the short allele of the 5-HTTLPR is associated with NE only in the context of low PE. Inconsistent links between NE and this gene in previous research may stem from the failure to consider other temperament traits that moderate associations. PMID:21038952

Investigating the genetic basis of attention to facial expressions: the role of the norepinephrine transporter gene.

PubMed

Yang, Xing; Ru, Wenzhao; Wang, Bei; Gao, Xiaocai; Yang, Lu; Li, She; Xi, Shoumin; Gong, Pingyuan

2016-12-01

Levels of norepinephrine (NE) in the brain are related to attention ability in animals and risk of attention-deficit hyperactivity disorder in humans. Given the modulation of the norepinephrine transporter (NET) on NE levels in the brain and the link between NE and attention impairment of attention-deficit hyperactivity disorder, it was possible that the NET gene underpinned individual differences in attention processes in healthy populations. To investigate to what extent NET could modulate one's attention orientation to facial expressions, we categorized individuals according to the genotypes of the -182 T/C (rs2242446) polymorphism and measured individuals' attention orientation with the spatial cueing task. Our results indicated that the -182 T/C polymorphism significantly modulated attention orientation to facial expressions, of which the CC genotype facilitated attention reorientation to the locations where cued faces were previously presented. However, this polymorphism showed no significant effects on the regulations of emotional cues on attention orientation. Our findings suggest that the NET gene modulates the individual difference in attention to facial expressions, which provides new insights into the roles of NE in social interactions.

A study of blood serotonin and serotonin transporter promoter variant (5-HTTLPR) polymorphism in Egyptian autistic children.

PubMed

Meguid, Nagwa A; Gebril, Ola H; Khalil, Rehab O

2015-01-01

Autism spectrum disorder (ASD) is a complex, heterogeneous neurodevelopmental disorder with onset during early childhood. Most studies have reported an elevation in platelet serotonin in persons with autism. The serotonin (5-hydroxytryptamine; 5-HT) transporter in the brain uptakes 5-HT from extracellular spaces. It is also present in platelets, where it takes up 5-HT from plasma. Polymorphisms in serotonin transporter gene (SLC6A4) were frequently studied in many neuropsychiatric disorders. We have measured the plasma 5-HT levels in 20 autistic male children and 20 control male children by the enzyme-linked immunosorbent assay (ELISA) method. In addition, the SLC6A4 promoter region (5-HTTLPR) insertion/deletion (I/D) polymorphism was studied, using whole genomic DNA. Plasma serotonin was significantly low in autistic children compared to control (P = 0.001), although correlation to severity of autism was not significant. The frequency of short (S) allele in autism cases was 10% and in the control group it was absent. Our study demonstrated an increased prevalence of 5-HTTLPR S allele in autism subjects. Significantly decreased plasma serotonin was detected in autism subjects, with no significant relationship between 5-HTTLPR genotype and plasma 5-HT being evident.

A study of blood serotonin and serotonin transporter promoter variant (5-HTTLPR) polymorphism in Egyptian autistic children

PubMed Central

Meguid, Nagwa A.; Gebril, Ola H.; Khalil, Rehab O.

2015-01-01

Background: Autism spectrum disorder (ASD) is a complex, heterogeneous neurodevelopmental disorder with onset during early childhood. Most studies have reported an elevation in platelet serotonin in persons with autism. The serotonin (5-hydroxytryptamine; 5-HT) transporter in the brain uptakes 5-HT from extracellular spaces. It is also present in platelets, where it takes up 5-HT from plasma. Polymorphisms in serotonin transporter gene (SLC6A4) were frequently studied in many neuropsychiatric disorders. Materials and Methods: We have measured the plasma 5-HT levels in 20 autistic male children and 20 control male children by the enzyme-linked immunosorbent assay (ELISA) method. In addition, the SLC6A4 promoter region (5-HTTLPR) insertion/deletion (I/D) polymorphism was studied, using whole genomic DNA. Results: Plasma serotonin was significantly low in autistic children compared to control (P = 0.001), although correlation to severity of autism was not significant. The frequency of short (S) allele in autism cases was 10% and in the control group it was absent. Conclusion: Our study demonstrated an increased prevalence of 5-HTTLPR S allele in autism subjects. Significantly decreased plasma serotonin was detected in autism subjects, with no significant relationship between 5-HTTLPR genotype and plasma 5-HT being evident. PMID:26015920

Genetic polymorphisms of serotonin transporter and receptor 1A could influence success during embryo implantation and maintenance of pregnancy.

PubMed

Palomares, Arturo R; Lendínez-Ramírez, Ana M; Pérez-Nevot, Beatriz; Cortés-Rodríguez, Miriam; Martínez, Francisco; Garrido, Nicolás; Ruiz-Galdón, Maximiliano; Reyes-Engel, Armando

2013-06-01

To explore whether serotonin-related gene polymorphisms influence clinical outcomes of IVF treatment in recipients using donated oocytes. Nested case-control study. University-affiliated infertility clinic. Two hundred forty-five women undergoing IVF treatment with donated oocytes. None. Genotype and haplotype analysis of the serotonin transporter-linked polymorphic region (5-HTTLPR), rs1800532, rs6295, rs6313, and rs3813929, between recipients grouped according to the results of the oocyte donation for IVF treatment. No differences were found between genotype distribution of the tryptophan hydroxylase 1, serotonin receptor 2A, and serotonin receptor 2C polymorphisms. Recipients carrying the LL genotype for 5-HTTLPR had lower clinical pregnancy rates (PR) and higher biochemical pregnancy loss (BPL) events. Lower implantation rates were found in CC carriers for 5-HT1A.rs6295 who also presented higher BPL rates. A lower incidence of clinical pregnancy was observed for LC haplotypes, corresponding to an increase in BPL rates. A strong association was found between early pregnancy loss and recipients carrying the 5-HTTLPR and rs6295 genetic variants. Identifying biological processes involving serotonin and embryo implantation may help to understand the dynamics of the maternal-embryo dialogue. Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Comparative analysis of response to selection with three insecticides in the dengue mosquito Aedes aegypti using mRNA sequencing

PubMed Central

2014-01-01

Background Mosquito control programmes using chemical insecticides are increasingly threatened by the development of resistance. Such resistance can be the consequence of changes in proteins targeted by insecticides (target site mediated resistance), increased insecticide biodegradation (metabolic resistance), altered transport, sequestration or other mechanisms. As opposed to target site resistance, other mechanisms are far from being fully understood. Indeed, insecticide selection often affects a large number of genes and various biological processes can hypothetically confer resistance. In this context, the aim of the present study was to use RNA sequencing (RNA-seq) for comparing transcription level and polymorphism variations associated with adaptation to chemical insecticides in the mosquito Aedes aegypti. Biological materials consisted of a parental susceptible strain together with three child strains selected across multiple generations with three insecticides from different classes: the pyrethroid permethrin, the neonicotinoid imidacloprid and the carbamate propoxur. Results After ten generations, insecticide-selected strains showed elevated resistance levels to the insecticides used for selection. RNA-seq data allowed detecting over 13,000 transcripts, of which 413 were differentially transcribed in insecticide-selected strains as compared to the susceptible strain. Among them, a significant enrichment of transcripts encoding cuticle proteins, transporters and enzymes was observed. Polymorphism analysis revealed over 2500 SNPs showing > 50% allele frequency variations in insecticide-selected strains as compared to the susceptible strain, affecting over 1000 transcripts. Comparing gene transcription and polymorphism patterns revealed marked differences among strains. While imidacloprid selection was linked to the over transcription of many genes, permethrin selection was rather linked to polymorphism variations. Focusing on detoxification enzymes revealed that permethrin selection strongly affected the polymorphism of several transcripts encoding cytochrome P450 monooxygenases likely involved in insecticide biodegradation. Conclusions The present study confirmed the power of RNA-seq for identifying concomitantly quantitative and qualitative transcriptome changes associated with insecticide resistance in mosquitoes. Our results suggest that transcriptome modifications can be selected rapidly by insecticides and affect multiple biological functions. Previously neglected by molecular screenings, polymorphism variations of detoxification enzymes may play an important role in the adaptive response of mosquitoes to insecticides. PMID:24593293

Comparative analysis of response to selection with three insecticides in the dengue mosquito Aedes aegypti using mRNA sequencing.

PubMed

David, Jean-Philippe; Faucon, Frédéric; Chandor-Proust, Alexia; Poupardin, Rodolphe; Riaz, Muhammad Asam; Bonin, Aurélie; Navratil, Vincent; Reynaud, Stéphane

2014-03-05

Mosquito control programmes using chemical insecticides are increasingly threatened by the development of resistance. Such resistance can be the consequence of changes in proteins targeted by insecticides (target site mediated resistance), increased insecticide biodegradation (metabolic resistance), altered transport, sequestration or other mechanisms. As opposed to target site resistance, other mechanisms are far from being fully understood. Indeed, insecticide selection often affects a large number of genes and various biological processes can hypothetically confer resistance. In this context, the aim of the present study was to use RNA sequencing (RNA-seq) for comparing transcription level and polymorphism variations associated with adaptation to chemical insecticides in the mosquito Aedes aegypti. Biological materials consisted of a parental susceptible strain together with three child strains selected across multiple generations with three insecticides from different classes: the pyrethroid permethrin, the neonicotinoid imidacloprid and the carbamate propoxur. After ten generations, insecticide-selected strains showed elevated resistance levels to the insecticides used for selection. RNA-seq data allowed detecting over 13,000 transcripts, of which 413 were differentially transcribed in insecticide-selected strains as compared to the susceptible strain. Among them, a significant enrichment of transcripts encoding cuticle proteins, transporters and enzymes was observed. Polymorphism analysis revealed over 2500 SNPs showing > 50% allele frequency variations in insecticide-selected strains as compared to the susceptible strain, affecting over 1000 transcripts. Comparing gene transcription and polymorphism patterns revealed marked differences among strains. While imidacloprid selection was linked to the over transcription of many genes, permethrin selection was rather linked to polymorphism variations. Focusing on detoxification enzymes revealed that permethrin selection strongly affected the polymorphism of several transcripts encoding cytochrome P450 monooxygenases likely involved in insecticide biodegradation. The present study confirmed the power of RNA-seq for identifying concomitantly quantitative and qualitative transcriptome changes associated with insecticide resistance in mosquitoes. Our results suggest that transcriptome modifications can be selected rapidly by insecticides and affect multiple biological functions. Previously neglected by molecular screenings, polymorphism variations of detoxification enzymes may play an important role in the adaptive response of mosquitoes to insecticides.

Serotonin Transporter Gene (SLC6A4) Polymorphism and Mucosal Serotonin Levels in Southeastern Iranian Patients with Irritable Bowel Syndrome

PubMed Central

Mohammadi, Mojgan; Tahmasebi Abdar, Hossein; Mollaei, Hamid Reza; Hajghani, Hossein; Baneshi, Mohammad Reza; Hayatbakhsh, Mohammad Mahdi

2017-01-01

BACKGROUND Irritable bowel syndrome (IBS) is a digestive system disorder with an unknown etiology. Serotonin has a key role in the secretion and motility of the intestine. Polymorphism in serotonin re-uptake transporter (SERT or SLC6A4) gene may have a functional role in the gut of patients with IBS. The aims of the present study were to investigate the association between SLC6A4 gene polymorphism and IBS and to detect the correlation between rectal serotonin levels and IBS sub-types. METHODS SLC6A4 gene polymorphism in 131 patients with IBS and 211 healthy controls were analysed using the quantitative polymerase chain reaction high-resolution melting (qPCR-HRM) curve technique. Serotonin was measured in rectal biopsies of patients with IBS using the enzyme-linked immunosorbent assay (ELISA) method. RESULTS The patients were categorized into three groups: IBS with diarrhoea (IBS-D): 70 patients, IBS with constipation (IBS-C): 18 patients, and IBS with mixed symptoms (IBS-M): 43 patients. The frequency of SLC6A4 s/s and l/s genotypes was significantly higher in IBS-C than IBS-D, IBS-M, and controls (p=0.036). Serotonin levels were similar in IBS sub-types. CONCLUSION SLC6A4 polymorphism is a possible candidate gene associated with the pathogenesis of IBS-C. Although serotonin levels did not differ in rectal biopsies of IBS sub-types, further investigation is recommended. PMID:28316763

Association of the serotonin transporter-linked polymorphic region genotype with lower bone mineral density.

PubMed

Lapid, M I; Kung, S; Frye, M A; Biernacka, J M; Geske, J R; Drake, M T; Jankowski, M D; Clarke, B L

2017-08-22

The serotonin transporter-linked polymorphic region (5-HTTLPR) of the serotonin transporter gene (SLC6A4) S allele is linked to pathogenesis of depression and slower response to selective serotonin reuptake inhibitors (SSRIs); depression and SSRIs are independently associated with bone loss. We aimed to determine whether 5-HTTLPR was associated with bone loss. This cross-sectional study included psychiatric patients with both 5-HTTLPR analysis and bone mineral density (BMD) assessment (hip and spine Z-scores if age <50 years and T-scores if ⩾50 years). BMD association with 5-HTTLPR was evaluated under models with additive allele effects and dominant S allele effects using linear regression models. Patients were stratified by age (<50 and ⩾50 years) and sex. Of 3016 patients with 5-HTTLPR genotyping, 239 had BMD assessments. Among the younger patients, the S allele was associated with lower Z-scores at the hip (P=0.002, dominant S allele effects; P=0.004, additive allele effects) and spine (P=0.0006, dominant S allele effects; P=0.01, additive allele effects). In sex-stratified analyses, the association of the S allele with lower BMD in the younger patients was also significant in the subset of women (P⩽0.003 for both hip and spine BMD under the additive allele effect model). In the small group of men younger than 50 years, the S allele was marginally associated with higher spine BMD (P=0.05). BMD T-scores were not associated with 5-HTTLPR genotypes in patients 50 years or older. The 5-HTTLPR variants may modify serotonin effects on bone with sex-specific effects.

Association of the serotonin transporter-linked polymorphic region genotype with lower bone mineral density

PubMed Central

Lapid, M I; Kung, S; Frye, M A; Biernacka, J M; Geske, J R; Drake, M T; Jankowski, M D; Clarke, B L

2017-01-01

The serotonin transporter-linked polymorphic region (5-HTTLPR) of the serotonin transporter gene (SLC6A4) S allele is linked to pathogenesis of depression and slower response to selective serotonin reuptake inhibitors (SSRIs); depression and SSRIs are independently associated with bone loss. We aimed to determine whether 5-HTTLPR was associated with bone loss. This cross-sectional study included psychiatric patients with both 5-HTTLPR analysis and bone mineral density (BMD) assessment (hip and spine Z-scores if age <50 years and T-scores if ⩾50 years). BMD association with 5-HTTLPR was evaluated under models with additive allele effects and dominant S allele effects using linear regression models. Patients were stratified by age (<50 and ⩾50 years) and sex. Of 3016 patients with 5-HTTLPR genotyping, 239 had BMD assessments. Among the younger patients, the S allele was associated with lower Z-scores at the hip (P=0.002, dominant S allele effects; P=0.004, additive allele effects) and spine (P=0.0006, dominant S allele effects; P=0.01, additive allele effects). In sex-stratified analyses, the association of the S allele with lower BMD in the younger patients was also significant in the subset of women (P⩽0.003 for both hip and spine BMD under the additive allele effect model). In the small group of men younger than 50 years, the S allele was marginally associated with higher spine BMD (P=0.05). BMD T-scores were not associated with 5-HTTLPR genotypes in patients 50 years or older. The 5-HTTLPR variants may modify serotonin effects on bone with sex-specific effects. PMID:28892067

Does the Incredible Years reduce child externalizing problems through improved parenting? The role of child negative affectivity and serotonin transporter linked polymorphic region (5-HTTLPR) genotype.

PubMed

Weeland, Joyce; Chhangur, Rabia R; Jaffee, Sara R; Van Der Giessen, Danielle; Matthys, Walter; Orobio De Castro, Bram; Overbeek, Geertjan

2018-02-01

In a randomized controlled trial, the Observational Randomized Controlled Trial of Childhood Differential Susceptibility (ORCHIDS study), we tested whether observed parental affect and observed and reported parenting behavior are mechanisms of change underlying the effects of the behavioral parent training program the Incredible Years (IY). Furthermore, we tested whether some children are more susceptible to these change mechanisms because of their temperamental negative affectivity and/or serotonin transporter linked polymorphic region (5-HTTLPR) genotype. Participants were 387 Dutch children between 4 and 8 years of age (M age = 6.31, SD = 1.33; 55.3% boys) and their parents. Results showed that although IY was successful in improving parenting behavior and increasing parental positive affect, these effects did not explain the significant decreases in child externalizing problems. We therefore found no evidence for changes in parenting behavior or parental affect being the putative mechanisms of IY effectiveness. Furthermore, intervention effects on child externalizing behavior were not moderated by child negative affectivity or 5-HTTLPR genotype. However, child 5-HTTLPR genotype did moderate intervention effects on negative parenting behavior. This suggests that in research on behavioral parent training programs, "what works for which parents" might also be an important question.

Prenatal maternal depression and child serotonin transporter linked polymorphic region (5-HTTLPR) and dopamine receptor D4 (DRD4) genotype predict negative emotionality from 3 to 36 months.

PubMed

Green, Cathryn Gordon; Babineau, Vanessa; Jolicoeur-Martineau, Alexia; Bouvette-Turcot, Andrée-Anne; Minde, Klaus; Sassi, Roberto; St-André, Martin; Carrey, Normand; Atkinson, Leslie; Kennedy, James L; Steiner, Meir; Lydon, John; Gaudreau, Helene; Burack, Jacob A; Levitan, Robert; Meaney, Michael J; Wazana, Ashley

2017-08-01

Prenatal maternal depression and a multilocus genetic profile of two susceptibility genes implicated in the stress response were examined in an interaction model predicting negative emotionality in the first 3 years. In 179 mother-infant dyads from the Maternal Adversity, Vulnerability, and Neurodevelopment cohort, prenatal depression (Center for Epidemiologic Studies Depressions Scale) was assessed at 24 to 36 weeks. The multilocus genetic profile score consisted of the number of susceptibility alleles from the serotonin transporter linked polymorphic region gene (5-HTTLPR): no long-rs25531(A) (LA: short/short, short/long-rs25531(G) [LG], or LG/LG] vs. any LA) and the dopamine receptor D4 gene (six to eight repeats vs. two to five repeats). Negative emotionality was extracted from the Infant Behaviour Questionnaire-Revised at 3 and 6 months and the Early Child Behavior Questionnaire at 18 and 36 months. Mixed and confirmatory regression analyses indicated that prenatal depression and the multilocus genetic profile interacted to predict negative emotionality from 3 to 36 months. The results were characterized by a differential susceptibility model at 3 and 6 months and by a diathesis-stress model at 36 months.

The influence of TAP1 and TAP2 gene polymorphisms on TAP function and its inhibition by viral immune evasion proteins.

PubMed

Praest, P; Luteijn, R D; Brak-Boer, I G J; Lanfermeijer, J; Hoelen, H; Ijgosse, L; Costa, A I; Gorham, R D; Lebbink, R J; Wiertz, E J H J

2018-06-04

Herpesviruses encode numerous immune evasion molecules that interfere with the immune system, particularly with certain stages in the MHC class I antigen presentation pathway. In this pathway, the transporter associated with antigen processing (TAP) is a frequent target of viral immune evasion strategies. This ER-resident transporter is composed of the proteins TAP1 and TAP2, and plays a crucial role in the loading of viral peptides onto MHC class I molecules. Several variants of TAP1 and TAP2 occur in the human population, some of which are linked to autoimmune disorders and susceptibility to infections. Here, we assessed the influence of naturally occurring TAP variants on peptide transport and MHC class I expression. In addition, we tested the inhibitory capacity of three viral immune evasion proteins, the TAP inhibitors US6 from human cytomegalovirus, ICP47 from herpes simplex virus type 1 and BNLF2a from Epstein-Barr virus, for a series of TAP1 and TAP2 variants. Our results suggest that these TAP polymorphisms have no or limited effect on peptide transport or MHC class I expression. Furthermore, our study indicates that the herpesvirus-encoded TAP inhibitors target a broad spectrum of TAP variants; inhibition of TAP is not affected by the naturally occurring polymorphisms of TAP tested in this study. Our findings suggest that the long-term coevolution of herpesviruses and their host did not result in selection of inhibitor-resistant TAP variants in the human population. Copyright © 2018. Published by Elsevier Ltd.

Association of serotonin transporter promoter regulatory region polymorphism and cerebral activity to visual presentation of food.

PubMed

Kaurijoki, Salla; Kuikka, Jyrki T; Niskanen, Eini; Carlson, Synnöve; Pietiläinen, Kirsi H; Pesonen, Ullamari; Kaprio, Jaakko M; Rissanen, Aila; Tiihonen, Jari; Karhunen, Leila

2008-07-01

Recent functional magnetic resonance imaging (fMRI) studies have revealed links between genetic polymorphisms and cognitive and behavioural processes. Serotonin is a classical neurotransmitter of central nervous system, and it is connected to the control of appetite and satiety. In this study, the relationship between the functional variation in the serotonin transporter gene and the activity in the left posterior cingulate cortex (PCC), a brain area activated by visual food stimuli was explored. Thirty subjects underwent serial fMRI studies and provided DNA for genetic analyses. Subjects homozygous for the long allele exhibited greater left PCC activity in the comparison food > non-food compared with individuals heterozygous or homozygous for the short allele. The association between genotype and activation was linear, the subjects with two copies of the long allele variant having the strongest activation. These results demonstrate the possible genetically driven variation in the response of the left PCC to visual presentation of food in humans.

Rat MHC-linked peptide transporter alleles strongly influence peptide binding by HLA-B27 but not B27-associated inflammatory disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Simmons, W.A.; Satumtira, Nimman; Taurog, J.D.

1996-02-15

Rats transgenic for the human MHC molecule HLA-B27 were used to study the effect of two alleles, cim{sup a} and cim{sup b}, which are associated with peptide transport by the MHC-encoded Tap2 transporter, on the function of HLA-B27 as a restriction element for CTL recognition of the male H-Y minor H Ag and on the multisystem inflammatory disease characteristic of B27 transgenic rats. Anti-H-Y CTL generated in cim{sup a} B27 transgenic rats lysed male B27 cim{sup b/b} targets significantly less well than cim{sup a/a} or cim{sup a/b} targets. Addition of exogenous H-Y peptides to male B27 cim{sup b/b} targets increasedmore » susceptibility to lysis to the level of cim{sup a/a} targets sensitized with exogenous H-Y peptides. {sup 3}H-labeled peptides eluted from B27 molecules of lymphoblasts from rats of two cim{sup b} and three cim{sup a} RT1 haplotypes showed that the cim{sup b} peptide pool favors comparatively longer and/or more hydrophobic peptides. These results indicate that RT1-linked Tap2 polymorphism in the rat strongly influences peptide loading of HLA-B27. Nonetheless, the prevalence and severity of multisystem inflammatory lesions were comparable in backcross rats bearing either cim{sup a/b} or cim{sup b/b}. It thus appears either that binding of specific peptides to B27 is unimportant in the pathogenesis of B27-associated disease or that the critical peptides, unlike H-Y and many others, are not influenced by Tap transporter polymorphism. 42 refs., 6 figs., 3 tabs.« less

Serotonin transporter promoter region (5-HTTLPR) polymorphism is associated with the intravaginal ejaculation latency time in Dutch men with lifelong premature ejaculation.

PubMed

Janssen, Paddy K C; Bakker, Steven C; Réthelyi, Janos; Zwinderman, Aeilko H; Touw, Daan J; Olivier, Berend; Waldinger, Marcel D

2009-01-01

Lifelong premature ejaculation (LPE) is characterized by persistent intravaginal ejaculation latency times (IELTs) of less than 1 minute, and has been postulated as a neurobiological dysfunction with genetic vulnerability for the short IELTs, related to disturbances of central serotonin (5-hydroxytryptamine [5-HT]) neurotransmission and 5-HT receptor functioning. To investigate the relationship between 5-HT transporter gene-linked polymorphism (5-HTTLPR) and short IELTs in men with lifelong PE. A prospective study was conducted in 89 Dutch Caucasian men with lifelong PE. IELT during coitus was assessed by stopwatch over a 1-month period. Controls consisted of 92 Dutch Caucasian men. All men with LPE were genotyped for a 5-HTT-promoter polymorphism. Allele frequencies and genotypes of short (S) and long (L) variants of 5-HTTLPR polymorphism were compared between patients and controls. Association between LL, SL, and SS genotypes, and the natural logarithm of the IELT in men with LPE was investigated. IELT measured by stopwatch, 5-HTTLPR polymorphism. In men with lifelong PE, the geometric mean, median, and natural mean IELTs were 21, 26, and 32 seconds, respectively. There were no significant differences in the 5-HTT polymorphism alleles and genotypes between 89 Dutch Caucasian men with LPE (S 47%, L 53%/LL 29%, SL 48%, SS 22%) and 92 Dutch Caucasian controls (S 48%, L 52%/LL 29%, SL 45%, SS 26%). In men with lifelong PE there was a statistically significant difference between LL, SL, and SS genotypes in their geometric mean IELT (P < or = 0.027); the LL genotypes had significantly shorter IELTs than the SS and SL genotypes. The 5-HTTLPR polymorphism is associated with significant effects on the latency to ejaculate in men with lifelong PE. Men with SS and SL genotypes have 100% and 90% longer ejaculation time, respectively than men with LL genotypes.

Association Study of Serotonin Transporter Gene Polymorphisms with Obstructive Sleep Apnea Syndrome in Chinese Han Population

PubMed Central

Yue, Weihua; Liu, Huiguo; Zhang, Jishui; Zhang, Xianghui; Wang, Xiaoping; Liu, Tieqiao; Liu, Pozi; Hao, Wei

2008-01-01

Background: Since the serotonin (5-HT) is associated with circadian rhythm and breathing regulation, the serotonin transporter (5-HTT), which plays an important role in serotoninergic transmission, might be a strong candidate gene in the pathogenesis of obstructive sleep apnea syndrome (OSAS). Objective: To investigate the association of 5-HTT gene polymorphisms with OSAS and clinical characteristics. Methods: We genotyped the 5-HTT gene linked polymorphic region (5-HTTLPR) and a variable number of tandem repeats at intron 2 (STin2.VNTR) in 254 OSAS patients and 338 healthy controls in Chinese Han population. Results: In total sample, the 10-repeat allele of STin2.VNTR was significantly associated with OSAS (P = 0.007, OR = 1.72, 95% CI = 1.15~2.58), but no association was found in 5-HTTLPR. In male subjects, both polymorphisms showed significant association with OSAS (Allele L: P = 0.005, OR = 1.44, 95% CI = 1.11 to 1.87; Allele 10: P = 0.002, OR = 1.94, 95% CI = 1.26 to 3.00). Two haplotypes, S-12 and L-10, constructed by the above polymorphisms also revealed significant associations with OSAS (global P-values were 0.020 for total sample and 0.0006 for male subjects, respectively). Male patients carrying the haplotype S-12 showed a significantly lower apnea / hypopnea index (AHI), depressive factor, plasma 5-HT level and 5-hydroxyindolacetic acid (5-HIAA) levels, but higher episodic memory, when compared with non-S-12 carriers (P < 0.05). However, no significant differences were found in excessive daytime sleepiness or other psychological function across haplotype carriers (P > 0.05). Conclusions: These findings support that 5-HTT gene may be involved in susceptibility to OSAS, especially with sex-dependent effect. Citation: Yue W; Liu H; Zhang J; Zhang X; Wang X; Liu T; Liu P; Hao W. Association study of serotonin transporter gene polymorphisms with obstructive sleep apnea syndrome in chinese han population. SLEEP 2008;31(11):1535–1541. PMID:19014073

Serotonin Transporter Promoter Region (5-HTTLPR) Polymorphism Is Not Associated With Paroxetine-Induced Ejaculation Delay in Dutch Men With Lifelong Premature Ejaculation

PubMed Central

Janssen, Paddy K.C.; Zwinderman, Aeilko H.; Olivier, Berend

2014-01-01

Purpose To investigate the association between the 5-HT-transporter-gene-linked promoter region (5-HTTLPR) polymorphism and 20-mg paroxetine-induced ejaculation delay in men with lifelong premature ejaculation (LPE). Materials and Methods This was a prospective study of 10 weeks of paroxetine treatment in 54 men with LPE. Intravaginal ejaculation latency time (IELT) was measured by stopwatch. Controls consisted of 92 Caucasian men. All men with LPE were genotyped for the 5-HTTLPR polymorphism. Allele frequencies and genotypes of short (S) and long (L) variants of the polymorphism were compared between patients and controls. Associations between the LL, SL, and SS genotypes and fold increase of mean IELT were investigated. Results Of the 54 patients, 43 (79.6%) responded to 20-mg paroxetine treatment with an ejaculation delay, whereas 11 patients (20.4%) did not respond; 44%, 18%, and 18% of the patients showed a fold increase in mean IELT of 2-10, 10-20, and more than 20, respectively. Of the 54 men, 14 (25.9%) had the LL genotype, 29 (53.7%) had the SL genotype, and 11 (20.4%) had the SS genotype. In the 92 controls, the LL, SL, and SS genotypes were present in 27 (29.3%), 41 (44.6%), and 24 (26.1%), respectively. No statistically significant differences were found in 5-HTTLPR allelic variations or in 5-HTTLPR gene variations. In all men treated with 20 mg paroxetine, analysis of variance of the natural logarithm of fold increase in the IELT showed no statistically significant difference according to genotype (p=0.83). Conclusions The 5-HTTLPR polymorphism is not associated with daily 20-mg paroxetine treatment-induced ejaculation delay in men with LPE. PMID:24578810

Association study of serotonin transporter gene polymorphisms with obstructive sleep apnea syndrome in Chinese Han population.

PubMed

Yue, Weihua; Liu, Huiguo; Zhang, Jishui; Zhang, Xianghui; Wang, Xiaoping; Liu, Tieqiao; Liu, Pozi; Hao, Wei

2008-11-01

Since the serotonin (5-HT) is associated with circadian rhythm and breathing regulation, the serotonin transporter (5-HTT), which plays an important role in serotoninergic transmission, might be a strong candidate gene in the pathogenesis of obstructive sleep apnea syndrome (OSAS). To investigate the association of 5-HTT gene polymorphisms with OSAS and clinical characteristics. We genotyped the 5-HTT gene linked polymorphic region (5-HTTLPR) and a variable number of tandem repeats at intron 2 (STin2.VNTR) in 254 OSAS patients and 338 healthy controls in Chinese Han population. In total sample, the 10-repeat allele of STin2.VNTR was significantly associated with OSAS (P = 0.007, OR = 1.72, 95% CI = 1.15-2.58), but no association was found in 5-HTTLPR. In male subjects, both polymorphisms showed significant association with OSAS (Allele L: P = 0.005, OR = 1.44, 95% CI = 1.11 to 1.87; Allele 10: P = 0.002, OR= 1.94, 95% CI = 1.26 to 3.00). Two haplotypes, S-12 and L-10, constructed by the above polymorphisms also revealed significant associations with OSAS (global P-values were 0.020 for total sample and 0.0006 for male subjects, respectively). Male patients carrying the haplotype S-12 showed a significantly lower apnea / hypopnea index (AHI), depressive factor, plasma 5-HT level and 5-hydroxyindolacetic acid (5-HIAA) levels, but higher episodic memory, when compared with non-S-12 carriers (P < 0.05). However, no significant differences were found in excessive daytime sleepiness or other psychological function across haplotype carriers (P > 0.05). These findings support that 5-HTT gene may be involved in susceptibility to OSAS, especially with sex-dependent effect.

The influence of 5-HTTLPR transporter genotype on amygdala-subgenual anterior cingulate cortex connectivity in autism spectrum disorder.

PubMed

Velasquez, Francisco; Wiggins, Jillian Lee; Mattson, Whitney I; Martin, Donna M; Lord, Catherine; Monk, Christopher S

2017-04-01

Social deficits in autism spectrum disorder (ASD) are linked to amygdala functioning and functional connection between the amygdala and subgenual anterior cingulate cortex (sACC) is involved in the modulation of amygdala activity. Impairments in behavioral symptoms and amygdala activation and connectivity with the sACC seem to vary by serotonin transporter-linked polymorphic region (5-HTTLPR) variant genotype in diverse populations. The current preliminary investigation examines whether amygdala-sACC connectivity differs by 5-HTTLPR genotype and relates to social functioning in ASD. A sample of 108 children and adolescents (44 ASD) completed an fMRI face-processing task. Youth with ASD and low expressing 5-HTTLPR genotypes showed significantly greater connectivity than youth with ASD and higher expressing genotypes as well as typically developing (TD) individuals with both low and higher expressing genotypes, in the comparison of happy vs. baseline faces and happy vs. neutral faces. Moreover, individuals with ASD and higher expressing genotypes exhibit a negative relationship between amygdala-sACC connectivity and social dysfunction. Altered amygdala-sACC coupling based on 5-HTTLPR genotype may help explain some of the heterogeneity in neural and social function observed in ASD. This is the first ASD study to combine genetic polymorphism analyses and functional connectivity in the context of a social task. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

The serotonin transporter 5-HTTLPR polymorphism in the association between sleep quality and affect.

PubMed

Hartmann, Jessica A; Wichers, Marieke; van Bemmel, Alex L; Derom, Catherine; Thiery, Evert; Jacobs, Nele; van Os, Jim; Simons, Claudia J P

2014-07-01

A link between sleep and affect is well-known. Serotonin (5-HT) is associated with the regulation of affective as well as sleep-related processes. A functional polymorphism in the serotonin transporter gene (5-HTTLPR) has been associated with serotonergic functioning. The present study investigated whether allelic variation of this gene moderates the association between nighttime subjective sleep quality and affect the following day. A population-based sample of 361 ethnically homogenous adult female twins underwent a five day protocol based on the experience sampling method (ESM), assessing momentary negative affect, positive affect, and subjective sleep quality repeatedly and prospectively. There was a significant interaction between sleep quality and genotype in predicting positive affect the next day: carriers of one (n=167) or two S-alleles (n=78) had a significantly steeper slope compared to LL carriers (n=116) (χ(2)=4.16, p=.042 and χ(2)=3.90, p=.048 respectively). The association between subjective sleep quality and positive affect the next day varied as a function of 5-HTTLPR: it was stronger in carriers of at least one copy of the S-allele compared to homozygous L-carriers, supporting a link between sleep and affect regulation, in which serotonin may play a role. However, these results are preliminary and require replication. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

A case-control study on association of proteasome subunit beta 8 (PSMB8) and transporter associated with antigen processing 1 (TAP1) polymorphisms and their transcript levels in vitiligo from Gujarat.

PubMed

Jadeja, Shahnawaz D; Mansuri, Mohmmad Shoab; Singh, Mala; Dwivedi, Mitesh; Laddha, Naresh C; Begum, Rasheedunnisa

2017-01-01

Autoimmunity has been implicated in the destruction of melanocytes from vitiligo skin. Major histocompatibility complex (MHC) class-II linked genes proteasome subunit beta 8 (PSMB8) and transporter associated with antigen processing 1 (TAP1), involved in antigen processing and presentation have been reported to be associated with several autoimmune diseases including vitiligo. To explore PSMB8 rs2071464 and TAP1 rs1135216 single nucleotide polymorphisms and to estimate the expression of PSMB8 and TAP1 in patients with vitiligo and unaffected controls from Gujarat. PSMB8 rs2071464 polymorphism was genotyped using polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) and TAP1 rs1135216 polymorphism was genotyped by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) in 378 patients with vitiligo and 509 controls. Transcript levels of PSMB8 and TAP1 were measured in the PBMCs of 91 patients and 96 controls by using qPCR. Protein levels of PSMB8 were also determined by Western blot analysis. The frequency of 'TT' genotype of PSMB8 polymorphism was significantly lowered in patients with generalized and active vitiligo (p = 0.019 and p = 0.005) as compared to controls suggesting its association with the activity of the disease. However, TAP1 polymorphism was not associated with vitiligo susceptibility. A significant decrease in expression of PSMB8 at both transcript level (p = 0.002) as well as protein level (p = 0.0460) was observed in vitiligo patients as compared to controls. No significant difference was observed between patients and controls for TAP1 transcripts (p = 0.553). Interestingly, individuals with the susceptible CC genotype of PSMB8 polymorphism showed significantly reduced PSMB8 transcript level as compared to that of CT and TT genotypes (p = 0.009 and p = 0.003 respectively). PSMB8 rs2071464 was associated with generalized and active vitiligo from Gujarat whereas TAP1 rs1135216 showed no association. The down-regulation of PSMB8 in patients with risk genotype 'CC' advocates the vital role of PSMB8 in the autoimmune basis of vitiligo.

Children's 5-HTTLPR genotype moderates the link between maternal criticism and attentional biases specifically for facial displays of anger.

PubMed

Gibb, Brandon E; Johnson, Ashley L; Benas, Jessica S; Uhrlass, Dorothy J; Knopik, Valerie S; McGeary, John E

2011-09-01

Theorists have proposed that negative experiences in childhood may contribute to the development of experience-specific information-processing biases, including attentional biases. There are also clear genetic influences on cognitive processes, with evidence that polymorphisms in specific candidate genes may moderate the impact of environmental stress on attentional biases (e.g., a functional polymorphism in the serotonin transporter gene; 5-HTTLPR). In the current study, we tested a gene×environment (G×E) model of risk for attentional biases. We hypothesised that children whose mothers exhibit high levels of expressed emotion criticism (EE-Crit) would display attentional biases specifically for angry, but not happy or sad, faces, and that this link would be stronger among children carrying one or two copies of the 5-HTTLPR short allele than among those homozygous for the long allele. Results generally supported these hypotheses, though we found that carriers of the 5-HTTLPR short allele who also had a critical mother exhibited attentional avoidance of angry faces rather than preferential attention.

Children’s 5-HTTLPR genotype moderates the link between maternal criticism and attentional biases specifically for facial displays of anger

PubMed Central

Gibb, Brandon E.; Johnson, Ashley L.; Benas, Jessica S.; Uhrlass, Dorothy J.; Knopik, Valerie S.; McGeary, John E.

2011-01-01

Theorists have proposed that negative experiences in childhood may contribute to the development of experience-specific information-processing biases, including attentional biases. There are also clear genetic influences on cognitive processes, with evidence that polymorphisms in specific candidate genes may moderate the impact of environmental stress on attentional biases (e.g., a functional polymorphism in the serotonin transporter gene [5-HTTLPR]). In the current study, we tested a gene × environment (G × E) model of risk for attentional biases. We hypothesized that children whose mothers exhibit high levels of expressed emotion criticism (EE-Crit) would display attentional biases specifically for angry, but not happy or sad, faces, and that this link would be stronger among children carrying one or two copies of the 5-HTTLPR short allele than among those homozygous for the long allele. Results generally supported these hypotheses, though we found that carriers of the 5-HTTLPR short allele who also had a critical mother exhibited attentional avoidance of angry faces rather than preferential attention. PMID:21895572

[Genomics of type I diabetes mellitus and its late complications].

PubMed

Nosikov, V V

2004-01-01

In ethnic Russians, MHC (HLA) was shown to be the major locus determining the predisposition to type 1 diabetes mellitus (T1DM). To map the regions linked to T1DM, families with concordant or discordant sib pairs were selected from the Russian population of Moscow. With these families, linkage to T1DM was demonstrated for CTLA4 (IDDM12, 2q32.1-q33), which codes for a T-cell surface antigen, and PDCD2 (IDDM8, 6q25-q27), which is homologous to the mouse programmed cell death activator gene. With polymorphic microsatellites, regions 3q21-q25 (IDDM9) and 10p12.2 (IDDM10) were also linked to T1DM. Case/control and family studies of the polymorphic markers from region 11p13 revealed a new T1DM-associated locus in the vicinity of the catalase gene (CAT); linkage to this locus was not reported earlier for other populations. Diabetic polyneuropathy (DPN) proved to be associated with single-nucleotide polymorphisms Ala(-9)Val (SOD2), Arg213Gly (SOD3), and T(-262)C (CAT) and with a polymorphic microsatellite of the NOS2 promoter. Hence oxidative stress, which results from hyperglycemia, increased mitochondrial production of superoxide radicals, and insufficient activities of antioxidative enzymes, was assumed to play an important part in DPN development in T1DM. Diabetic nephropathy (DN) showed no association with the antioxidative enzyme genes. However, the association was observed for the insertion/deletion (I/D) polymorphism of ACE and the ecNOS34a/4b polymorphism of NOS3, two genes involved in controlling vascular tonicity, and for the I/D polymorphism of APOB and the epsilon 2/epsilon 3/epsilon 4 polymorphism of APOE, two genes involved in lipid transport. In addition, polymorphic microsatellites of chromosome 3q21-q25 proved to be closely associated with DN. The tightest association was established for D3S1550, carriers of allele 12 or genotype 12/14 having high risk of DN (OR = 4.85 and 6.25, respectively). Region 3q21-q25 was assumed to contain a major gene determining DN development, while the other DN-associated genes mostly affect the progression of DN.

The effects of acute tryptophan depletion and serotonin transporter polymorphism on emotional processing in memory and attention.

PubMed

Roiser, Jonathan P; Müller, Ulrich; Clark, Luke; Sahakian, Barbara J

2007-08-01

Polymorphism at the serotonin transporter linked polymorphic region (5-HTTLPR) has been associated with neuroticism, increased risk for affective disorders and greater vulnerability to mood change following serotonin (5-HT) depletion. The aim of the present study was to investigate whether the cognitive effects of 5-HT depletion were differentially affected by genotype at the 5-HTTLPR polymorphism, using neuropsychological measures of memory and attention. We utilized the acute tryptophan depletion (ATD) technique to temporarily reduce 5-HT synthesis in two groups of healthy volunteers pre-selected on the basis of 5-HTTLPR genotype, 15 of the ll genotype and 15 of the ss genotype, in a double-blind, placebo-controlled crossover design. As expected, ATD resulted in a robust reduction in plasma tryptophan concentration in both genotype groups. However, the genotype groups differed in terms of the effect of ATD on cognitive performance. The ss genotype group showed impaired verbal recall following depletion, while episodic memory was unimpaired by ATD in the ll genotype group. Averaging across depletion condition, the ss genotype group outperformed the ll genotype group on tests of episodic memory and attention. Neither group was significantly affected by ATD on measures of emotional state. These data confirm previous reports that ss individuals are particularly vulnerable to 5-HT depletion, but extend these findings to the cognitive domain. The unexpected finding that ss volunteers showed improved memory and attention relative to ll volunteers suggests a possible evolutionary advantage to possession of the s allele, which may offset the disadvantage of vulnerability to depression following stressful life events.

5-HTTLPR polymorphism is linked to neural mechanisms of selective attention in preschoolers from lower socioeconomic status backgrounds.

PubMed

Isbell, Elif; Stevens, Courtney; Hampton Wray, Amanda; Bell, Theodore; Neville, Helen J

2016-12-01

While a growing body of research has identified experiential factors associated with differences in selective attention, relatively little is known about the contribution of genetic factors to the skill of sustained selective attention, especially in early childhood. Here, we assessed the association between the serotonin transporter linked polymorphic region (5-HTTLPR) genotypes and the neural mechanisms of selective attention in young children from lower socioeconomic status (SES) backgrounds. Event-related potentials (ERPs) were recorded during a dichotic listening task from 121 children (76 females, aged 40-67 months), who were also genotyped for the short and long allele of 5-HTTLPR. The effect of selective attention was measured as the difference in ERP mean amplitudes elicited by identical probe stimuli embedded in stories when they were attended versus unattended. Compared to children homozygous for the long allele, children who carried at least one copy of the short allele showed larger effects of selective attention on neural processing. These findings link the short allele of the 5-HTTLPR to enhanced neural mechanisms of selective attention and lay the groundwork for future studies of gene-by-environment interactions in the context of key cognitive skills. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Interaction between serotonin transporter gene-linked polymorphic region (5-HTTLPR) and job-related stress in insomnia: a cross-sectional study in Sichuan, China.

PubMed

Huang, Chan; Li, Ju; Lu, Lingeng; Ren, Xiaohui; Li, Yongru; Huang, Qian; Lan, Yajia; Wang, Yongwei

2014-10-01

Insomnia, a widely occurring sleep disorder in modern society, has a large impact on life quality and work safety. A cross-sectional study was conducted to explore the possible link between serotonin transporter-linked polymorphic region (5-HTTLPR), job-related stress, and insomnia in West China. Of the total 462 workers recruited, 177 had insomnia according to the Athens Insomnia Scale (AIS-5). The 5-HTTLPR genotypes were determined by polymerase chain reaction. Job-related stress was assessed for each participant by the General Job Stress Questionnaire. Unconditional logistic regression models showed that the 5-HTTLPR genotype was significantly associated with insomnia, and >80% increased risk per S allele was observed. High job-related stress had a higher risk for insomnia than low job-related stress (odds ratio [OR], 6.14; 95% confidence interval [CI], 3.94-9.59). Crossover analysis found significant job-related stress × 5-HTTLPR interaction. Compared to individuals with both low job-related stress and SL/LL genotype, those with both higher job-related stress and SS genotype had a higher risk of insomnia (OR, 5.16; 95% CI, 3.13-8.54), whereas those with both low job-related stress and SS genotype showed a lower risk of insomnia (OR, 0.26; 95% CI, 0.08-0.74). The interaction remained statistically significant after adjusting for potential confounding factors. The findings indicated that 5-HTTLPR could modify the effect of job-related stress on employees' insomnia, suggesting that a work environment-based personalized intervention may be applied to prevent employees' insomnia by alleviating job-related stress in the workplace. Copyright © 2014. Published by Elsevier B.V.

No association between the serotonin transporter linked polymorphic region polymorphism and severity of posttraumatic stress disorder symptoms in combat veterans with or without comorbid depression.

PubMed

Kovacic Petrovic, Zrnka; Nedic Erjavec, Gordana; Nikolac Perkovic, Matea; Peraica, Tina; Pivac, Nela

2016-10-30

Since both posttraumatic stress disorder (PTSD) and depression are associated with disturbances in the serotoninergic system, the aim of the study was to determine the association between severity of PTSD symptoms, serotonin transporter polymorphism (5-HTTLPR) and platelet serotonin (5-HT) concentration, in male combat veterans with PTSD (n = 325), who were subdivided according to presence of comorbid depression. The methodological approach included the psychiatric diagnostic interviews and rating scales (SCID for DSM-IV, HDRS, CAPS), polymerase chain reaction for 5-HTTLPR genotyping and spectrophotofluorometric method for measuring the platelet 5-HT concentration. PTSD veterans without depression had more severe PTSD symptoms, and less severe depressive symptoms, than PTSD veterans with depression. 5-HTTLPR genotype frequencies did not differ between veterans with mild, moderate and severe PTSD symptoms, and between depressed and non-depressed PTSD veterans. No significant association was found between the severity of PTSD symptoms and 5-HTTLPR genotype. Platelet 5-HT concentration was similar in PTSD veterans, with or without comorbid depression, and between two groups subdivided according to the severity of PTSD symptoms or 5-HTTLPR genotype. The study confirmed, on ethnically homogenous groups of veterans with matched combat experience, a lack of association between the PTSD symptoms severity and 5-HTTLPR or platelet 5-HT concentration. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Association of Polymorphisms of Serotonin Transporter (5HTTLPR) and 5-HT2C Receptor Genes with Criminal Behavior in Russian Criminal Offenders

PubMed Central

Toshchakova, Valentina A.; Bakhtiari, Yalda; Kulikov, Alexander V.; Gusev, Sergey I.; Trofimova, Marina V.; Fedorenko, Olga Yu.; Mikhalitskaya, Ekaterina V.; Popova, Nina K.; Bokhan, Nikolay A.; Hovens, Johannes E.; Loonen, Anton J.M.; Wilffert, Bob; Ivanova, Svetlana A.

2018-01-01

Background Human aggression is a heterogeneous behavior with biological, psychological, and social backgrounds. As the biological mechanisms that regulate aggression are components of both reward-seeking and adversity-fleeing behavior, these phenomena are difficult to disentangle into separate neurochemical processes. Nevertheless, evidence exists linking some forms of aggression to aberrant serotonergic neurotransmission. We determined possible associations between 6 serotonergic neurotransmission-related gene variants and severe criminal offenses. Methods Male Russian prisoners who were convicted for murder (n = 117) or theft (n = 77) were genotyped for variants of the serotonin transporter (5HTTLPR), tryptophan hydroxylase, tryptophan-2,3-dioxygenase, or type 2C (5-HT2C) receptor genes and compared with general-population male controls (n = 161). Prisoners were psychologically phenotyped using the Buss-Durkee Hostility Inventory and the Beck Depression Inventory. Results No differences were found between murderers and thieves either concerning genotypes or concerning psychological measures. Comparison of polymorphism distribution between groups of prisoners and controls revealed highly significant associations of 5HTTLPR and 5-HTR2C (rs6318) gene polymorphisms with being convicted for criminal behavior. Conclusions The lack of biological differences between the 2 groups of prisoners indicates that the studied 5HT-related genes do not differentiate between the types of crimes committed. PMID:29621775

Neighborhood × Serotonin Transporter Linked Polymorphic Region (5-HTTLPR) interactions for substance use from ages 10 to 24 years using a harmonized data set of African American children.

PubMed

Windle, Michael; Kogan, Steven M; Lee, Sunbok; Chen, Yi-Fu; Lei, Karlo Mankit; Brody, Gene H; Beach, Steven R H; Yu, Tianyi

2016-05-01

This study investigated the influences of neighborhood factors (residential stability and neighborhood disadvantage) and variants of the serotonin transporter linked polymorphic region (5-HTTLPR) genotype on the development of substance use among African American children aged 10-24 years. To accomplish this, a harmonized data set of five longitudinal studies was created via pooling overlapping age cohorts to establish a database with 2,689 children and 12,474 data points to span ages 10-24 years. A description of steps used in the development of the harmonized data set is provided, including how issues such as the measurement equivalence of constructs were addressed. A sequence of multilevel models was specified to evaluate Gene × Environment effects on growth of substance use across time. Findings indicated that residential instability was associated with higher levels and a steeper gradient of growth in substance use across time. The inclusion of the 5-HTTLPR genotype provided greater precision to the relationships in that higher residential instability, in conjunction with the risk variant of 5-HTTLPR (i.e., the short allele), was associated with the highest level and steepest gradient of growth in substance use across ages 10-24 years. The findings demonstrated how the creation of a harmonized data set increased statistical power to test Gene × Environment interactions for an under studied sample.

The dopamine-related polymorphisms BDNF, COMT, DRD2, DRD3, and DRD4 are not linked with changes in CSF dopamine levels and frequency of HIV infection.

PubMed

Horn, Anne; Scheller, C; du Plessis, S; Burger, R; Arendt, G; Joska, J; Sopper, S; Maschke, C M; Obermann, M; Husstedt, I W; Hain, J; Riederer, P; Koutsilieri, E

2017-04-01

We showed previously that higher levels in CSF dopamine in HIV patients are associated with the presence of the dopamine transporter (DAT) 10/10-repeat allele which was also detected more frequently in HIV-infected individuals compared to uninfected subjects. In the current study, we investigated further whether other genetic dopamine (DA)-related polymorphisms may be related with changes in CSF DA levels and frequency of HIV infection in HIV-infected subjects. Specifically, we studied genetic polymorphisms of brain-derived neurotrophic factor, catechol-O-methyltransferase, and dopamine receptors DRD2, DRD3, and DRD4 genetic polymorphisms in uninfected and HIV-infected people in two different ethnical groups, a German cohort (Caucasian, 72 individuals with HIV infection and 22 individuals without HIV infection) and a South African cohort (Xhosan, 54 individuals with HIV infection and 19 individuals without HIV infection). We correlated the polymorphisms with CSF DA levels, HIV dementia score, CD4 + T cell counts, and HIV viral load. None of the investigated DA-related polymorphisms was associated with altered CSF DA levels, CD4 + T cell count, viral load, and HIV dementia score. The respective allele frequencies were equally distributed between HIV-infected patients and controls. Our findings do not show any influence of the studied genetic polymorphisms on CSF DA levels and HIV infection. This is in contrast to what we found previously for the DAT 3'UTR VNTR and highlights the specific role of the DAT VNTR in HIV infection and disease.

A case-control study on association of proteasome subunit beta 8 (PSMB8) and transporter associated with antigen processing 1 (TAP1) polymorphisms and their transcript levels in vitiligo from Gujarat

PubMed Central

Jadeja, Shahnawaz D.; Mansuri, Mohmmad Shoab; Singh, Mala; Dwivedi, Mitesh; Laddha, Naresh C.

2017-01-01

Background Autoimmunity has been implicated in the destruction of melanocytes from vitiligo skin. Major histocompatibility complex (MHC) class-II linked genes proteasome subunit beta 8 (PSMB8) and transporter associated with antigen processing 1 (TAP1), involved in antigen processing and presentation have been reported to be associated with several autoimmune diseases including vitiligo. Objectives To explore PSMB8 rs2071464 and TAP1 rs1135216 single nucleotide polymorphisms and to estimate the expression of PSMB8 and TAP1 in patients with vitiligo and unaffected controls from Gujarat. Methods PSMB8 rs2071464 polymorphism was genotyped using polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) and TAP1 rs1135216 polymorphism was genotyped by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) in 378 patients with vitiligo and 509 controls. Transcript levels of PSMB8 and TAP1 were measured in the PBMCs of 91 patients and 96 controls by using qPCR. Protein levels of PSMB8 were also determined by Western blot analysis. Results The frequency of ‘TT’ genotype of PSMB8 polymorphism was significantly lowered in patients with generalized and active vitiligo (p = 0.019 and p = 0.005) as compared to controls suggesting its association with the activity of the disease. However, TAP1 polymorphism was not associated with vitiligo susceptibility. A significant decrease in expression of PSMB8 at both transcript level (p = 0.002) as well as protein level (p = 0.0460) was observed in vitiligo patients as compared to controls. No significant difference was observed between patients and controls for TAP1 transcripts (p = 0.553). Interestingly, individuals with the susceptible CC genotype of PSMB8 polymorphism showed significantly reduced PSMB8 transcript level as compared to that of CT and TT genotypes (p = 0.009 and p = 0.003 respectively). Conclusions PSMB8 rs2071464 was associated with generalized and active vitiligo from Gujarat whereas TAP1 rs1135216 showed no association. The down-regulation of PSMB8 in patients with risk genotype ‘CC’ advocates the vital role of PSMB8 in the autoimmune basis of vitiligo. PMID:28700671

Androgen Receptor Gene Polymorphism, Aggression, and Reproduction in Tanzanian Foragers and Pastoralists

PubMed Central

Butovskaya, Marina L.; Lazebny, Oleg E.; Vasilyev, Vasiliy A.; Dronova, Daria A.; Karelin, Dmitri V.; Mabulla, Audax Z. P.; Shibalev, Dmitri V.; Shackelford, Todd K.; Fink, Bernhard; Ryskov, Alexey P.

2015-01-01

The androgen receptor (AR) gene polymorphism in humans is linked to aggression and may also be linked to reproduction. Here we report associations between AR gene polymorphism and aggression and reproduction in two small-scale societies in northern Tanzania (Africa)—the Hadza (monogamous foragers) and the Datoga (polygynous pastoralists). We secured self-reports of aggression and assessed genetic polymorphism of the number of CAG repeats for the AR gene for 210 Hadza men and 229 Datoga men (aged 17–70 years). We conducted structural equation modeling to identify links between AR gene polymorphism, aggression, and number of children born, and included age and ethnicity as covariates. Fewer AR CAG repeats predicted greater aggression, and Datoga men reported more aggression than did Hadza men. In addition, aggression mediated the identified negative relationship between CAG repeats and number of children born. PMID:26291982

Influence of DAT1 and COMT variants on neural activation during response inhibition in adolescents with attention-deficit/hyperactivity disorder and healthy controls.

PubMed

van Rooij, D; Hoekstra, P J; Bralten, J; Hakobjan, M; Oosterlaan, J; Franke, B; Rommelse, N; Buitelaar, J K; Hartman, C A

2015-11-01

Impairment of response inhibition has been implicated in attention-deficit/hyperactivity disorder (ADHD). Dopamine neurotransmission has been linked to the behavioural and neural correlates of response inhibition. The current study aimed to investigate the relationship of polymorphisms in two dopamine-related genes, the catechol-O-methyltransferase gene (COMT) and the dopamine transporter gene (SLC6A3 or DAT1), with the neural and behavioural correlates of response inhibition. Behavioural and neural measures of response inhibition were obtained in 185 adolescents with ADHD, 111 of their unaffected siblings and 124 healthy controls (mean age 16.9 years). We investigated the association of DAT1 and COMT variants on task performance and whole-brain neural activation during response inhibition in a hypothesis-free manner. Additionally, we attempted to explain variance in previously found ADHD effects on neural activation during response inhibition using these DAT1 and COMT polymorphisms. The whole-brain analyses demonstrated large-scale neural activation changes in the medial and lateral prefrontal, subcortical and parietal regions of the response inhibition network in relation to DAT1 and COMT polymorphisms. Although these neural activation changes were associated with different task performance measures, no relationship was found between DAT1 or COMT variants and ADHD, nor did variants in these genes explain variance in the effects of ADHD on neural activation. These results suggest that dopamine-related genes play a role in the neurobiology of response inhibition. The limited associations between gene polymorphisms and task performance further indicate the added value of neural measures in linking genetic factors and behavioural measures.

A polymorphism in a transporter of testosterone is a determinant of androgen independence in prostate cancer.

PubMed

Sharifi, Nima; Hamada, Akinobu; Sissung, Tristan; Danesi, Romano; Venzon, David; Baum, Caitlin; Gulley, James L; Price, Douglas K; Dahut, William L; Figg, William D

2008-08-05

To determine if patients with advanced prostate cancer carrying a polymorphism that codes for a more active testosterone transporter have less durable responses to androgen-deprivation therapy (ADT) than patients not carrying this polymorphism. We previously determined that a polymorphism in SLCO1B3 affects testosterone transport and that those men who have at least one wild-type T allele at the 334 T > G polymorphism in this gene have a shorter survival. We hypothesized that the T allele which increases testosterone transport would be associated with a shorter interval from ADT to androgen independence. We examined the association between this SLCO1B3 polymorphism and time from ADT to androgen independence, ADT to prostate-specific antigen (PSA) nadir and PSA nadir to androgen independence in 68 Caucasian patients with advanced prostate cancer who were treated with ADT with metastatic disease (D2) or biochemical failure with no metastatic disease (D0). When examined separately, patients in the individual stages tended to have a shorter time to androgen independence with the T allele in the D0 (P = 0.11) and D2 (P = 0.18) groups. Combining these groups and stratifying by stage yielded a statistically significant shorter time to androgen independence with the T allele (P = 0.048). A polymorphism in a transporter that increases testosterone import is associated with a shorter time to androgen independence in patients with prostate cancer who are treated with ADT.

Candidate genes for aggression and antisocial behavior: a meta-analysis of association studies of the 5HTTLPR and MAOA-uVNTR.

PubMed

Ficks, Courtney A; Waldman, Irwin D

2014-09-01

Variation in central serotonin levels due to genetic mutations or experimental modifications has been associated with the manifestation of aggression in humans and animals. Many studies have examined whether common variants in serotonergic genes are implicated in aggressive or antisocial behaviors (ASB) in human samples. The two most commonly studied polymorphisms have been the serotonin transporter linked polymorphic region of the serotonin transporter gene (5HTTLPR) and the 30 base pair variable number of tandem repeats of the monoamine oxidase A gene (MAOA-uVNTR). Despite the aforementioned theoretical justification for these polymorphisms, findings across studies have been mixed and are thus difficult to interpret. A meta-analysis of associations of the 5HTTLPR and MAOA-uVNTR with ASB was conducted to determine: (1) the overall magnitude of effects for each polymorphism, (2) the extent of heterogeneity in effect sizes across studies and the likelihood of publication bias, and (3) whether sample-level or study-level characteristics could explain observed heterogeneity across studies. Both the 5HTTLPR and the MAOA-uVNTR were significantly associated with ASB across studies. There was also significant and substantial heterogeneity in the effect sizes for both markers, but this heterogeneity was not explained by any sample-level or study-level characteristics examined. We did not find any evidence for publication bias across studies for the MAOA-uVNTR, but there was evidence for an oversampling of statistically significant effect sizes for the 5HTTLPR. These findings provide support for the modest role of common serotonergic variants in ASB. Implications regarding the role of serotonin in antisocial behavior and the conceptualization of antisocial and aggressive phenotypes are discussed.

Gender differences in association between serotonin transporter gene polymorphism and resting-state EEG activity.

PubMed

Volf, N V; Belousova, L V; Knyazev, G G; Kulikov, A V

2015-01-22

Human brain oscillations represent important features of information processing and are highly heritable. Gender has been observed to affect association between the 5-HTTLPR (serotonin-transporter-linked polymorphic region) polymorphism and various endophenotypes. This study aimed to investigate the effects of 5-HTTLPR on the spontaneous electroencephalography (EEG) activity in healthy male and female subjects. DNA samples extracted from buccal swabs and resting EEG recorded at 60 standard leads were collected from 210 (101 men and 109 women) volunteers. Spectral EEG power estimates and cortical sources of EEG activity were investigated. It was shown that effects of 5-HTTLPR polymorphism on electrical activity of the brain vary as a function of gender. Women with the S/L genotype had greater global EEG power compared to men with the same genotype. In men, current source density was markedly different among genotype groups in only alpha 2 and alpha 3 frequency ranges: S/S allele carriers had higher current source density estimates in the left inferior parietal lobule in comparison with the L/L group. In women, genotype difference in global power asymmetry was found in the central-temporal region. Contrasting L/L and S/L genotype carriers also yielded significant effects in the right hemisphere inferior parietal lobule and the right postcentral gyrus with L/L genotype carriers showing lower current source density estimates than S/L genotype carriers in all but gamma bands. So, in women, the effects of 5-HTTLPR polymorphism were associated with modulation of the EEG activity in a wide range of EEG frequencies. The significance of the results lies in the demonstration of gene by sex interaction with resting EEG that has implications for understanding sex-related differences in affective states, emotion and cognition. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Dopaminergic Polymorphisms, Academic Achievement, and Violent Delinquency.

PubMed

Yun, Ilhong; Lee, Julak; Kim, Seung-Gon

2015-12-01

Recent research in the field of educational psychology points to the salience of self-control in accounting for the variance in students' report card grades. At the same time, a novel empirical study from molecular genetics drawing on the National Longitudinal Study of Adolescent Health (Add Health) data has revealed that polymorphisms in three dopaminergic genes (dopamine transporter [DAT1], dopamine D2 receptor [DRD2], and dopamine D4 receptor [DRD4]) are also linked to adolescents' grade point averages (GPAs). Juxtaposing these two lines of research, the current study reanalyzed the Add Health genetic subsample to assess the relative effects of these dopaminergic genes and self-control on GPAs. The results showed that the effects of the latter were far stronger than those of the former. The interaction effects between the dopaminergic genes and a set of environmental factors on academic performance were also examined, producing findings that are aligned with the "social push hypothesis" in behavioral genetics. Finally, based on the criminological literature on the link between academic performance and delinquency, we tested whether dopaminergic effects on violent delinquency were mediated by GPAs. The results demonstrated that academic performance fully mediated the linkage between these genes and violent delinquency. © The Author(s) 2014.

Effect of common polymorphisms of the farnesoid X receptor and bile acid transporters on the pharmacokinetics of ursodeoxycholic acid.

PubMed

Hu, Miao; Fok, Benny S P; Wo, Siu-Kwan; Lee, Vincent H L; Zuo, Zhong; Tomlinson, Brian

2016-01-01

Ursodeoxycholic acid (UDCA), a natural, dihydroxy bile acid, promotes gallstone dissolution and has been attributed with several other beneficial effects. The farnesoid X receptor (FXR) may influence the pharmacokinetics of UDCA by modulating the expression of bile acid transporters. This exploratory study examined whether common functional polymorphisms in FXR and in bile acid transporter genes affect the pharmacokinetics of exogenous UDCA. Polymorphisms in genes for transporters involved in bile acid transport, solute carrier organic anion 1B1 (SLCO1B1) 388A>G and 521T>C, solute carrier 10A1 (SLC10A1) 800 C>T and ATP-binding cassette B11 (ABCB11) 1331T>C, and the FXR -1G>T polymorphism were genotyped in 26 male Chinese subjects who ingested single oral 500-mg doses of UDCA. Plasma concentrations of UDCA and its major conjugate metabolite glycoursodeoxycholic acid (GUDCA) were determined. The mean systemic exposure of UDCA was higher in the five subjects with one copy of the FXR -1G>T variant allele than in those homozygous for the wild-type allele (n = 21) (AUC0-24 h : 38.5 ± 28.2 vs. 20.9 ± 8.0 μg h/mL, P = 0.021), but this difference appeared mainly due to one outlier with the -1GT genotype and elevated baseline and post-treatment UDCA concentrations. After excluding the outlier, body weight was the only factor associated with plasma concentrations of UDCA and there were no significant associations with the other polymorphisms examined. None of the polymorphisms affected the pharmacokinetics of GUDCA. This study showed that the common polymorphisms in bile acid transporters had no significant effect on the pharmacokinetics of exogenous UDCA but an effect of the FXR polymorphism cannot be excluded. © 2015 Wiley Publishing Asia Pty Ltd.

The GLUT-1 XbaI gene polymorphism is associated with vascular calcifications in nondiabetic uremic patients.

PubMed

Rufino, Margarita; Hernández, Domingo; Barrios, Ysamar; Salido, Eduardo

2008-01-01

Glucose transporters mediate the facilitative uptake of glucose into cells, with GLUT-1 being the predominant isoform in vascular smooth muscle cell (VSMC). Clones of human cells overexpressing the GLUT-1 transporter showed a high increase in intracellular glucose concentrations, mimicking the diabetic milieu. It is possible that high intracellular glucose together with uremic factors may play an important role in vascular calcification by transforming VSMC into osteoblast-like cells. The XbaI polymorphism in the GLUT-1 gene has been linked to variations in GLUT-1 expression, with consequent changes in intracellular glucose concentration. To assess the association between the GLUT-1 XbaI gene polymorphism and the presence of VC in nondiabetic uremic patients, a total of 105 nondiabetic patients on hemodialysis were studied. VC were evaluated by conventional simple X-ray. Mean values of serum calcium, phosphorous, cholesterol, triglycerides, HbA1c, PTH and insulin were measured. Height, weight, BMI and waist circumference were also determined. The GLUT-1 XbaI polymorphism in the second intron of the gene was ascertained by means of the polymerase chain reaction and restriction fragment length polymorphism analysis on DNA isolated from peripheral blood DNA. In the absence of an XbaI site, a fragment of 305 bp was seen (so-called x allele), whereas fragments of 232 and 73 bp were generated if the XbaI site was present (X allele). Genotype distribution in all patients was similar to the Caucasian population. However, when the patients were grouped according to the presence or absence of VC, there were marked differences in the frequency of the GLUT1 genotypes: the xx GLUT-1 genotype was more prevalent in the group with VC (30.7 vs. 4.5%, p = 0.001). Stepwise logistic regression demonstrated that the xx GLUT-1 genotype was independently associated with the presence of VC after adjusting for other variables such as age, calcium x phosphrus product, BMI and time on dialysis (OR 7.68; 95% CI 1.28-45.7). GLUT-1 XbaI gene polymorphism is associated with vascular calcifications in nondiabetic uremic patients. Copyright 2008 S. Karger AG, Basel.

Reward dependence is related to norepinephrine transporter T-182C gene polymorphism in a Korean population.

PubMed

Ham, Byung-Joo; Choi, Myoung-Jin; Lee, Heon-Jeong; Kang, Rhee-Hun; Lee, Min-Soo

2005-06-01

It is well established that approximately 50% of the variance in personality traits is genetic. The goal of this study was to investigate a relationship between personality traits and the T-182C polymorphism in the norepinephrine transporter gene. The participants included 115 healthy adults with no history of psychiatric disorders and other physical illness during the past 6 months. All participants were tested with the Temperament and Character Inventory and genotyped norepinephrine transporter gene polymorphism. Differences on the Temperament and Character Inventory dimensions among three groups were examined with one-way analysis of variance. Our study suggests that the norepinephrine transporter T-182C gene polymorphism is associated with reward dependence in Koreans, but the small number of study participants and their sex and age heterogeneity limits generalization of our results. Further studies are necessary with a larger number of homogeneous participants to confirm whether the norepinephrine transporter gene is related to personality traits.

Relationship between 5-HTTLPR polymorphism and post-stroke depression.

PubMed

Guo, W Y; Zhang, Z H; Mu, J L; Liu, D; Zhao, L; Yao, Z Y; Song, J G

2016-02-19

Post-stroke depression (PSD) is a mental illness characterized by subjective feelings of depression, cognitive dysfunction, and decreased interest. The serotoninergic system is involved in the pathogenesis of depressive disorders and is regulated by the serotonin transporter gene. The serotonin transporter-linked polymorphic region (5-HTTLPR) has been examined as a factor associated with depression and other mental disorders. This study was performed to explore the relationship between 5-HTTLPR and PSD in a Han Chinese population. In total, 199 patients with PSD and 202 unrelated non-PSD patients were recruited from psychiatric hospitals. Depression was diagnosed using the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition. Blood samples were collected from all patients for 5-HTTLPR genotyping. Genotype and allele frequencies were compared between the two groups. SS genotype frequency was significantly higher in the PSD group than in the non-PSD group. LL genotype frequency was significantly higher in the non-PSD group than in the PSD group (P < 0.01). This study describes a positive association between 5-HTTLPR and PSD in a Han Chinese population and provides genetic evidence to support the genetic susceptibility of PSD.

The short (S) allele of the serotonin transporter polymorphism and acute tryptophan depletion both increase impulsivity in men.

PubMed

Walderhaug, Espen; Herman, Aryeh Isaac; Magnusson, Andres; Morgan, Michael John; Landrø, Nils Inge

2010-04-12

Reduced serotonergic neurotransmission is implicated in impulsive behavior. We studied the triallelic system of the serotonin transporter gene linked polymorphic region (5-HTTLPR) and acute manipulation of serotonin together to further delineate the mechanisms by which serotonergic neurotransmission affects impulsivity. Fifty-two healthy participants (38 men and 14 women) underwent acute tryptophan depletion (ATD) or placebo in a randomized, double-blind, parallel group experiment. Impulsive response style was measured on two versions of the Continuous Performance Task (CPT), and calculated using signal detection theory. We observed a dose-dependent effect for the short (S') allele of the 5-HTTLPR on impulsive response style. Individuals who had the S'/S' genotype were more impulsive than individuals with the L/S' genotype. Participants with the L/S' genotype were more impulsive than those with the L/L genotype. ATD increased impulsivity in men, and decreased impulsivity in women. These data demonstrate for the first time that reduced serotonergic tone as a result of either 5-HTTLPR genotype, or experimental ATD, are both independently and additively, associated with elevated impulsive response style in Caucasian men. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

Pharmacogenetics of tacrolimus and sirolimus in renal transplant patients: from retrospective analyses to prospective studies.

PubMed

Anglicheau, D; Legendre, C; Thervet, E

2007-09-01

The promises of pharmacogenetics are to elucidate the inherited basis of differences between individual responses to drugs in order to identify the right drug and dose for each patient. The recent identification of genetic polymorphisms in drug-metabolizing enzymes and drug transporters led to the hypothesis that genetic factors may be implicated in the interindividual variability of the pharmacokinetic or pharmacodynamic characteristics of immunosuppressive drugs, major side effects, and efficacy. The purpose of this study was to provide a short overview of recent results obtained in the field of pharmacogenetics of tacrolimus and sirolimus, both substrates of the cytochrome P450 3A (CYP3A) enzymes and of the efflux pump P-glycoprotein, the product of the Multidrug Resistance-1 (MDR1) genes. A number of retrospective studies that demonstrated a link between the polymorphisms governing the CYP3A5 protein expression, with more conflicting results with the MDR1 gene polymorphisms, related to the daily dose necessary to achieve adequate blood tacrolimus levels. The CYP3A5 polymorphisms have also been associated with sirolimus pharmacokinetics. One challenge is to investigate the combined effect of a number of different polymorphisms in various genes to define genetic backgrounds with different pharmacokinetic profiles using high throughput technologies. Another challenge is to move toward prospective randomized studies to explore whether a pharmacogenetic approach, taking into account a limited number of polymorphisms prior to drug treatment, could be used on an individual basis to guide initial dosing of a given drug. The last challenge is based on "target" pharmacogenetics to investigate the role of the polymorphisms of other genes implicated in the efficacy and/or safety of the drug.

Genetic polymorphisms in the amino acid transporters LAT1 and LAT2 in relation to the pharmacokinetics and side effects of melphalan.

PubMed

Kühne, Annett; Kaiser, Rolf; Schirmer, Markus; Heider, Ulrike; Muhlke, Sabine; Niere, Wiebke; Overbeck, Tobias; Hohloch, Karin; Trümper, Lorenz; Sezer, Orhan; Brockmöller, Jürgen

2007-07-01

Melphalan is widely used in the treatment of multiple myeloma. Pharmacokinetics of this alkylating drug shows high inter-individual variability. As melphalan is a phenylalanine derivative, the pharmacokinetic variability may be determined by genetic polymorphisms in the L-type amino acid transporters LAT1 (SLC7A5) and LAT2 (SLC7A8). Pharmacokinetics were analysed in 64 patients after first administration of intravenous melphalan. Severity of side effects was documented according to WHO criteria. Genomic DNA was analysed for polymorphisms in LAT1 and LAT2 by sequencing of the entire coding region, intron-exon boundaries and 2 kb upstream promoter region. Selected polymorphisms in the common heavy chain of both transporters, the protein 4F2hc (SLC3A2), were analysed by single nucleotide primer extension. Melphalan pharmacokinetics was highly variable with up to 6.2-fold differences in total clearance. A total of 44 polymorphisms were identified in LAT1 and 21 polymorphisms in LAT2. From all variants, only five were in the coding region and only one heterozygous non-synonymous polymorphism (Ala94Thr) was found in LAT2. Numerous polymorphisms were found in the LAT1 and LAT2 5'-flanking regions but did not correlate with expression of the respective genes. No significant correlations could be observed between the polymorphisms in 4F2hc, LAT1, and LAT2 with melphalan pharmacokinetics or with melphalan side effects. The study confirmed that these transporter genes are highly conserved, particularly in the coding sequences. Genetic variation in 4F2hc, LAT1, and LAT2 does not appear to be a major cause of inter-individual variability in pharmacokinetics and of adverse reactions to melphalan.

Genetic mutation underlying orthostatic intolerance and diagnostic and therapeutic methods relating thereto

NASA Technical Reports Server (NTRS)

Blakely, Randy D. (Inventor); Robertson, David (Inventor)

2006-01-01

Isolated polynucleotide molecules and peptides encoded by these molecules are used in the analysis of human norepinephrine (NE) transporter variants, as well as in diagnostic and therapeutic applications, relating to a human NE transporter polymorphism. By analyzing genomic DNA or amplified genomic DNA, or amplified cDNA derived from mRNA, it is possible to type a human NE transporter with regard to the human NE transporter polymorphism, for example, in the context of diagnosing and treating NE transport impairments, and disorders associated with NE transport impairments, such as orthostatic intolerance.

Possible role of IL-6 and TIE2 gene polymorphisms in predicting the initial high transport status in patients with peritoneal dialysis: an observational study.

PubMed

Ding, Li; Shao, Xinghua; Cao, Liou; Fang, Wei; Yan, Hao; Huang, Jiaying; Gu, Aiping; Yu, Zanzhe; Qi, Chaojun; Chang, Xinbei; Ni, Zhaohui

2016-10-26

The aim of this study was to investigate the effect of interleukin (IL)-6 and TIE2 gene polymorphisms on baseline peritoneal transport property. An observational study. Renji Hospital in Shanghai, China. This study included 220 patients with continuous ambulatory peritoneal dialysis (PD). Patients were divided into 2 groups based on the results of an initial peritoneal equilibration test performed within 3 months of starting PD therapy: group 1 consisted of low/low average transporters (n=123), and group 2 consisted of high/high average transporters (n=97). We genotyped TIE2 and IL-6 polymorphisms and analysed their effects on baseline transport status. The genotype AT in IL-6 Rs13306435 and the genotype CC in TIE2 Rs639225 were both negatively associated with a higher initial peritoneal transport status (IL-6 Rs13306435: OR=0.408, 95% CI 0.227 to 0.736; TIE2 Rs639225: OR=0.188, 95% CI 0.044 to 0.806). IL-6 and TIE2 polymorphisms are associated with baseline peritoneal transport property. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Genotype and Ancestry Modulate Brain's DAT Availability in Healthy Humans

PubMed Central

Shumay, Elena; Chen, John; Fowler, Joanna S.; Volkow, Nora D.

2011-01-01

The dopamine transporter (DAT) is a principal regulator of dopaminergic neurotransmission and its gene (the SLC6A3) is a strong biological candidate gene for various behavioral- and neurological disorders. Intense investigation of the link between the SLC6A3 polymorphisms and behavioral phenotypes yielded inconsistent and even contradictory results. Reliance on objective brain phenotype measures, for example, those afforded by brain imaging, might critically improve detection of DAT genotype-phenotype association. Here, we tested the relationship between the DAT brain availability and the SLC6A3 genotypes using an aggregate sample of 95 healthy participants of several imaging studies. These studies employed positron emission tomography (PET) with [11C]cocaine wherein the DAT availability was estimated as Bmax/Kd; while the genotype values were obtained on two repeat polymorphisms - 3-UTR- and intron 8- VNTRs. The main findings are the following: 1) both polymorphisms analyzed as single genetic markers and in combination (haplotype) modulate DAT density in midbrain; 2) ethnic background and age influence the strength of these associations; and 3) age-related changes in DAT availability differ in the 3-UTR and intron8 – genotype groups. PMID:21826203

Genotype and ancestry modulate brain's DAT availability in healthy humans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shumay, E.; Shumay, E.; Chen, J.

2011-08-01

The dopamine transporter (DAT) is a principal regulator of dopaminergic neurotransmission and its gene (the SLC6A3) is a strong biological candidate gene for various behavioral- and neurological disorders. Intense investigation of the link between the SLC6A3 polymorphisms and behavioral phenotypes yielded inconsistent and even contradictory results. Reliance on objective brain phenotype measures, for example, those afforded by brain imaging, might critically improve detection of DAT genotype-phenotype association. Here, we tested the relationship between the DAT brain availability and the SLC6A3 genotypes using an aggregate sample of 95 healthy participants of several imaging studies. These studies employed positron emission tomography (PET)more » with [{sup 11}C] cocaine wherein the DAT availability was estimated as Bmax/Kd; while the genotype values were obtained on two repeat polymorphisms - 3-UTR- and intron 8- VNTRs. The main findings are the following: (1) both polymorphisms analyzed as single genetic markers and in combination (haplotype) modulate DAT density in midbrain; (2) ethnic background and age influence the strength of these associations; and (3) age-related changes in DAT availability differ in the 3-UTR and intron8 - genotype groups.« less

DAT1 Polymorphism Determines L-DOPA Effects on Learning about Others’ Prosociality

PubMed Central

Rieskamp, Jörg; Zehnder, Christian; Ebstein, Richard; Fehr, Ernst; Knoch, Daria

2013-01-01

Despite that a wealth of evidence links striatal dopamine to individualś reward learning performance in non-social environments, the neurochemical underpinnings of such learning during social interaction are unknown. Here, we show that the administration of 300 mg of the dopamine precursor L-DOPA to 200 healthy male subjects influences learning about a partners’ prosocial preferences in a novel social interaction task, which is akin to a repeated trust game. We found learning to be modulated by a well-established genetic marker of striatal dopamine levels, the 40-bp variable number tandem repeats polymorphism of the dopamine transporter (DAT1 polymorphism). In particular, we found that L-DOPA improves learning in 10/10R genoype subjects, who are assumed to have lower endogenous striatal dopamine levels and impairs learning in 9/10R genotype subjects, who are assumed to have higher endogenous dopamine levels. These findings provide first evidence for a critical role of dopamine in learning whether an interaction partner has a prosocial or a selfish personality. The applied pharmacogenetic approach may open doors to new ways of studying psychiatric disorders such as psychosis, which is characterized by distorted perceptions of others’ prosocial attitudes. PMID:23861813

Tumor Necrosis Factor-Alpha Gene Promoter Region Polymorphism and the Risk of Coronary Heart Disease

PubMed Central

Asifa, Gul Zareen; Kazmi, Syed Ali Raza; Javed, Qamar

2013-01-01

Background. Tumor necrosis factor-alpha (TNF-α) gene polymorphisms have been implicated in the manifestation of atherosclerosis. Controversy exists regarding the link between the cytokine's variant genotype and CHD among different ethnic groups. There have been fewer studies on the TNF-α gene −1031T>C and −863C>A polymorphisms in relation to CHD. Therefore, the current study was designed to investigate the association of the TNF-α gene −1031T>C and −863C>A polymorphisms with CHD in a Pakistani population. Methods. Patients with CHD (n = 310) and healthy individuals (n = 310) were enrolled in this study. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results. A significant difference was observed in the −863C>A polymorphism between patients with CHD and control subjects (P < 0.0001). CHD risk was positively associated with the variant allele −863A (P < 0.0001) in the study subjects. There was no significant link between the −1031T>C polymorphism and CHD risk in the study population. Haplotypes A-T and A-C of the TNF-alpha gene loci at −863 and −1031 showed higher frequency in the patient group compared with controls (P < 0.05). Conclusion. The TNF-α  −863C>A gene polymorphism was associated with the pathogenesis of CHD while the −1031T>C polymorphism did not show any link with the disease in a Pakistani population. PMID:24381514

Association of Functional Polymorphisms from Brain-Derived Neurotrophic Factor and Serotonin-Related Genes with Depressive Symptoms after a Medical Stressor in Older Adults

PubMed Central

Rawson, Kerri S.; Dixon, David; Nowotny, Petra; Ricci, William M.; Binder, Ellen F.; Rodebaugh, Thomas L.; Wendleton, Leah; Doré, Peter; Lenze, Eric J.

2015-01-01

Depressive symptoms are common in older adults after a disabling medical event and interfere with rehabilitation and recovery from the disability. This prospective study examined the role of genetic polymorphisms implicated in synaptic integrity and stress-associated depression as predictors of depressive symptoms after hip fracture. We recruited healthy comparisons from the community and participants with hip fracture after surgical fixation from Saint Louis, Missouri hospitals. We examined the valine (Val) to methionine (Met) polymorphism in brain-derived neurotrophic factor (BDNF), serotonin 1A receptor (5HT1a-rs6295) polymorphism, and the serotonin transporter-linked polymorphic region (5HTTLPR) interaction with the rs25531 A to G single nucleotide polymorphism (5HTTLPR-rs25531) as predictors of depressive symptoms. We also examined whether depressive symptoms mediate the influence of BDNF genotype on functional recovery. Among 429 participants with hip fracture, BDNF Met/Met carriers developed significantly more depressive symptoms than Val/Val carriers during a four-week period after the fracture (p=.012). BDNF genotype also predicted functional recovery over the ensuing year, mediated by its effects on depressive symptoms (CI: 0.07-3.37). Unlike prior studies of stressful life events, the S′ 5HTTLPR-rs25531 variant did not predict higher levels of depressive symptoms; instead, we report an exploratory finding of an epistatic effect between BDNF and 5HTTLPR-rs25531 whereby the compounded effects of two LA alleles and BDNF Met/Met genotype elevate risk of depressive symptoms after hip fracture (p=.006). No differences between 5HT1a genotypes were found. Our findings suggest plasticity-related genetic factors contribute to the neural mechanisms of mental and functional well-being after a disabling medical stressor. PMID:25781924

Effect of the 5-HTTLPR polymorphism on affective temperament, depression and body mass index in obesity.

PubMed

Borkowska, A; Bieliński, M; Szczęsny, W; Szwed, K; Tomaszewska, M; Kałwa, A; Lesiewska, N; Junik, R; Gołębiewski, M; Sikora, M; Tretyn, A; Akiskal, K; Akiskal, H

2015-09-15

Many studies show high prevalence of affective disorders in obese patients. Affective temperament is a subclinical manifestation of such conditions. The 5-HTT gene encoding the serotonin transporter may be involved in both mood and eating dysregulation. The aim of this study was to investigate the influence of a polymorphism in the 5-HTT gene on affective temperament types, depressive symptoms and Body Mass Index (BMI) in obese patients. This study involved 390 patients (237 females, and 153 males) with obesity. The TEMPS-A questionnaire, Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HDRS) were used to evaluate affective temperaments and prevalence of depression. DNA was obtained for serotonin transporter gene-linked polymorphism (5-HTTLPR) genotyping. In obese patients S/S genotype was associated with depressive and L/L with cyclothymic temperament. Subjects with L/L genotype presented significantly higher BMI and greater intensity of depressive symptoms in BDI and HDRS. Females scored higher in anxious and depressive, while males in hyperthymic, cyclothymic and irritable temperaments. Females scored higher in BDI (subjective depression) while males in HDRS (objective depression). TEMPS-A, BDI and HDRS are frequently used in studies on affective disorders. However, these methods do not examine all dimensions of mood and personality. In obese patients S allele of 5-HTTLPR was associated with development of depressive temperament while L allele corresponded with greater obesity and prevalence of depression. Different mechanisms may be involved in manifestation of depression in males and females with obesity. Copyright © 2015 Elsevier B.V. All rights reserved.

Cholesterol metabolism and transport in the pathogenesis of Alzheimer's disease.

PubMed

Martins, Ian J; Berger, Tamar; Sharman, Matthew J; Verdile, Giuseppe; Fuller, Stephanie J; Martins, Ralph N

2009-12-01

Alzheimer's disease (AD) is the most common neurodegenerative disorder, affecting millions of people worldwide. Apart from age, the major risk factor identified so far for the sporadic form of AD is possession of the epsilon4 allele of apolipoprotein E (APOE), which is also a risk factor for coronary artery disease (CAD). Other apolipoproteins known to play an important role in CAD such as apolipoprotein B are now gaining attention for their role in AD as well. AD and CAD share other risk factors, such as altered cholesterol levels, particularly high levels of low density lipoproteins together with low levels of high density lipoproteins. Statins--drugs that have been used to lower cholesterol levels in CAD, have been shown to protect against AD, although the protective mechanism(s) involved are still under debate. Enzymatic production of the beta amyloid peptide, the peptide thought to play a major role in AD pathogenesis, is affected by membrane cholesterol levels. In addition, polymorphisms in several proteins and enzymes involved in cholesterol and lipoprotein transport and metabolism have been linked to risk of AD. Taken together, these findings provide strong evidence that changes in cholesterol metabolism are intimately involved in AD pathogenic processes. This paper reviews cholesterol metabolism and transport, as well as those aspects of cholesterol metabolism that have been linked with AD.

Genetic moderation of multiple pathways linking early cumulative socioeconomic adversity and young adults' cardiometabolic disease risk.

PubMed

Wickrama, Kandauda A S; Lee, Tae Kyoung; O'Neal, Catherine Walker

2018-02-01

Recent research suggests that psychosocial resources and life stressors are mediating pathways explaining socioeconomic variation in young adults' health risks. However, less research has examined both these pathways simultaneously and their genetic moderation. A nationally representative sample of 11,030 respondents with prospective data collected over 13 years from the National Study of Adolescent to Adult Health was examined. First, the association between early cumulative socioeconomic adversity and young adults' (ages 25-34) cardiometabolic disease risk, as measured by 10 biomarkers, through psychosocial resources (educational attainment) and life stressors (accelerated transition to adulthood) was examined. Second, moderation of these pathways by the serotonin transporter linked polymorphic region gene (5-HTTLPR) was examined. There was evidence for the association between early socioeconomic adversity and young adults' cardiometabolic disease risk directly and indirectly through educational attainment and accelerated transitions. These direct and mediating pathways were amplified by the 5-HTTLPR polymorphism. These findings elucidate how early adversity can have an enduring influence on young adults' cardiometabolic disease risk directly and indirectly through psychosocial resources and life stressors and their genetic moderation. This information suggests that effective intervention and prevention programs should focus on early adversity, youth educational attainment, and their transition to young adulthood.

Ethanol-Associated Changes in Glutamate Reward Neurocircuitry: A Minireview of Clinical and Preclinical Genetic Findings

PubMed Central

Bell, Richard L.; Hauser, Sheketha R.; McClintick, Jeanette; Rahman, Shafiqur; Edenberg, Howard J.; Szumlinski, Karen K.; McBride, William J.

2016-01-01

Herein, we have reviewed the role of glutamate, the major excitatory neurotransmitter in the brain, in a number of neurochemical, -physiological, and -behavioral processes mediating the development of alcohol dependence. The findings discussed include results from both preclinical as well as neuroimaging and postmortem clinical studies. Expression levels for a number of glutamate-associated genes and/or proteins are modulated by alcohol abuse and dependence. These changes in expression include metabotropic receptors and ionotropic receptor subunits as well as different glutamate transporters. Moreover, these changes in gene expression parallel the pharmacologic manipulation of these same receptors and transporters. Some of these gene expression changes may have predated alcohol abuse and dependence because a number of glutamate-associated polymorphisms are related to a genetic predisposition to develop alcohol dependence. Other glutamate-associated polymorphisms are linked to age at the onset of alcohol-dependence and initial level of response/sensitivity to alcohol. Finally, findings of innate and/or ethanol-induced glutamate-associated gene expression differences/changes observed in a genetic animal model of alcoholism, the P rat, are summarized. Overall, the existing literature indicates that changes in glutamate receptors, transporters, enzymes, and scaffolding proteins are crucial for the development of alcohol dependence and there is a substantial genetic component to these effects. This indicates that continued research into the genetic underpinnings of these glutamate-associated effects will provide important novel molecular targets for treating alcohol abuse and dependence. PMID:26809998

The relationship of polymorphisms in ABCC2 and SLCO1B3 with docetaxel pharmacokinetics and neutropenia: CALGB 60805 (Alliance).

PubMed

Lewis, Lionel D; Miller, Antonius A; Owzar, Kouros; Bies, Robert R; Markova, Svetlana; Jiang, Chen; Kroetz, Deanna L; Egorin, Merrill J; McLeod, Howard L; Ratain, Mark J

2013-01-01

Docetaxel-related neutropenia was associated with polymorphisms in the drug transporters ABCC2 and SLCO1B3 in Japanese cancer patients. We hypothesized that this association is because of reduced docetaxel clearance, associated with polymorphisms in those genes. We studied 64 US cancer patients who received a single cycle of 75 mg/m of docetaxel monotherapy. We found that the ABCC2 polymorphism at rs-12762549 trended to show a relationship with reduced docetaxel clearance (P=0.048), but not with neutropenia. There was no significant association of the SLCO1B3 polymorphisms with docetaxel clearance or neutropenia. We conclude that the relationship between docetaxel-associated neutropenia and polymorphisms in drug transporters identified in Japanese patients was not confirmed in this cohort of US cancer patients. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

The 5-HTTLPR confers susceptibility to anorexia nervosa in Han Chinese: evidence from a case-control and family-based study.

PubMed

Chen, Jue; Kang, Qing; Jiang, Wenhui; Fan, Juan; Zhang, Mingdao; Yu, Shunying; Zhang, Chen

2015-01-01

Accumulating evidence has implied that serotonin system dysfunction may be involved in the etiology of anorexia nervosa (AN). Serotonin-transporter-linked promoter region (5-HTTLPR) polymorphism is the genetic variant coding for the serotonin transporter and has a modulatory effect on its expression. This study aimed to investigate the possible association between the 5-HTTLPR and the susceptibility and severity of AN in Han Chinese using a case-control (255 patients and 351 controls) and family based study (198 trios). Eating disorder examination was used to measure the severity of AN behavioral symptoms. For the case-control study, the 5-HTTLPR showed significant association with AN in our sample (genotypic P = 0.03). The frequency of S allele was significantly higher in patients than that in controls (OR = 1.38, 95%CI: 1.06-1.79, P = 0.017). For the family-based study, the S allele of 5-HTTLPR was preferentially transmitted rather than non-transmitted from the parents to affected offspring (P = 0.013). The results of ANCOVA test revealed no significant association between the 5-HTTLPR polymorphism and severity of AN. Our findings suggested that 5-HTTLPR is able to confer susceptibility to AN in Han Chinese.

Serotonin transporter 5-HTTLPR genotype is associated with intrusion and avoidance symptoms of DSM-5 posttraumatic stress disorder (PTSD) in Chinese earthquake survivors.

PubMed

Liu, Luobing; Wang, Li; Cao, Chengqi; Cao, Xing; Zhu, Ye; Liu, Ping; Luo, Shu; Zhang, Jianxin

2018-05-01

Prior studies have found that the serotonin transporter gene-linked polymorphic region (5-HTTLPR) interacts with trauma exposure to increase general risk for Posttraumatic Stress Disorder (PTSD). However, there is little knowledge about the effects of the interaction on distinct symptom clusters of PTSD. This study aimed to investigate the relation between the interaction of 5-HTTLPR and earthquake-related exposures and a contemporary phenotypic model of DSM-5 PTSD symptoms in a traumatised adult sample from China. A cross-sectional design with gene-environment interaction (G × E) approach was adopted. Participants were 1131 survivors who experienced 2008 Wenchuan earthquake. PTSD symptoms were assessed with the PTSD Checklist for DSM-5 (PCL-5). The 5-HTTLPR polymorphism was genotyped with capillary electrophoresis (CE) in ABI 3730xl genetic Analyzer. Although there was no significant interaction between 5-HTTLPR and traumatic exposure on total PTSD symptoms, respondents with the LL genotype of 5-HTTLPR who were highly exposed to the earthquake experienced lower intrusion and avoidance symptoms than those with the S-allele carriers. The findings suggest that the 5-HTTLPR may have an important impact on the development of PTSD and add to the extant knowledge on understanding and treating of posttraumatic psychopathology.

The 5-HTTLPR and BDNF polymorphisms moderate the association between uncinate fasciculus connectivity and antidepressants treatment response in major depression.

PubMed

Tatham, Erica L; Hall, Geoff B C; Clark, Darren; Foster, Jane; Ramasubbu, Rajamannar

2017-03-01

Symptom improvement in depression due to antidepressant treatment is highly variable and clinically unpredictable. Linking neuronal connectivity and genetic risk factors in predicting antidepressant response has clinical implications. Our investigation assessed whether indices of white matter integrity, serotonin transporter-linked polymorphism (5-HTTLPR) and brain-derived neurotrophic factor (BDNF) val66met polymorphism predicted magnitude of depression symptom change following antidepressant treatment. Fractional anisotropy (FA) was used as an indicator of white matter integrity and was assessed in the uncinate fasciculus and superior longitudinal fasciculus using tract-based spatial statistics (TBSS) and probabilistic tractography. Forty-six medication-free patients with major depressive disorder participated in a diffusion tensor imaging scan prior to completing an 8-week treatment regime with citalopram or quetiapine XR. Indexed improvements in Hamilton Depression Rating Scale score from baseline to 8-week endpoint were used as an indicator of depression improvement. Carriers of the BDNF met allele exhibited lower FA values in the left uncinate fasciculus relative to val/val individuals [F(1, 40) = 7.314, p = 0.009]. Probabilistic tractography identified that higher FA in the left uncinate fasciculus predicted percent change in depression severity, with BDNF moderating this association [F(3, 30) = 3.923, p = 0.018]. An interaction between FA in the right uncinate fasciculus and 5-HTTLPR also predicted percent change in depression severity [F(5, 25) = 5.315, p = 0.002]. Uncorrected TBSS results revealed significantly higher FA in hippocampal portions of the cingulum bundle in responders compared to non-responders (p = 0.016). The predictive value of prefrontal and amygdala/hippocampal WM connectivity on antidepressant treatment response may be influenced by 5-HTTLPR and BDNF polymorphisms in MDD.

The influence of psychiatric screening in healthy populations selection: a new study and meta-analysis of functional 5-HTTLPR and rs25531 polymorphisms and anxiety-related personality traits.

PubMed

Minelli, Alessandra; Bonvicini, Cristian; Scassellati, Catia; Sartori, Riccardo; Gennarelli, Massimo

2011-03-31

A genetic liability for anxiety-related personality traits in healthy subjects has been associated with the functional serotonin transporter promoter polymorphism (5-HTTLPR), although the data are somewhat conflicting. Moreover, only one study has investigated the functional significance of the 5-HTTLPR/rs25531 haplotypes in relation to anxiety traits in healthy subjects. We tested whether the 5-HTTLPR polymorphism and the 5-HTTLPR/rs25531 haplotypes are linked to Harm Avoidance (HA) using an association study (STUDY I) and a meta-analytic approach (STUDY II). STUDY I: A total of 287 unrelated Italian volunteers were screened for DSM-IV Axis I disorders and genotyped for the 5-HTTLPR and rs25531 (A/G) polymorphisms. Different functional haplotype combinations were also analyzed. STUDY II: A total of 44 studies were chosen for a meta-analysis of the putative association between 5-HTTLPR and anxiety-related personality traits. STUDY I: In the whole sample of 287 volunteers, we found that the SS genotype and S'S' haplotypes were associated with higher scores on HA. However, because the screening assessed by Mini-International Neuropsychiatric Interview (M.I.N.I.) showed the presence of 55 volunteers affected by depression or anxiety disorders, we analyzed the two groups ("disordered" and "healthy") separately. The data obtained did indeed confirm that in the "healthy" group, the significant effects of the SS genotype and S'S' haplotypes were lost, but they remained in the "disordered" group. STUDY II: The results of the 5-HTTLPR meta-analysis with anxiety-related traits in the whole sample confirmed the association of the SS genotype with higher anxiety-related traits scores in Caucasoids; however, when we analyzed only those studies that used structured psychiatric screening, no association was found. This study demonstrates the relevance to perform analyses on personality traits only in DSM-IV axis I disorder-free subjects. Furthermore, we did not find an association between functional serotonin transporter gene polymorphisms and anxiety traits in healthy subjects screened through a structured psychiatric interview.

Interaction effects between the 5-hydroxy tryptamine transporter-linked polymorphic region (5-HTTLPR) genotype and family conflict on adolescent alcohol use and misuse.

PubMed

Kim, Jueun; Park, Aesoon; Glatt, Stephen J; Eckert, Tanya L; Vanable, Peter A; Scott-Sheldon, Lori A J; Carey, Kate B; Ewart, Craig K; Carey, Michael P

2015-02-01

To investigate whether the effects of family conflict on adolescent drinking differed as a function of 5-hydroxy tryptamine transporter-linked polymorphic region (5-HTTLPR) genotype cross-sectionally and prospectively in two independent samples of adolescents. Path analysis and multi-group analysis of two prospective datasets were conducted. United States and United Kingdom. Sample 1 was 175 adolescents in the United States (mean age = 15 at times 1 and 2 with a 6-month interval); Sample 2 was 4916 adolescents in the United Kingdon (mean age = 12 at time 1 and 15 at time 2). In both samples, demographics, tri-allelic 5-HTTLPR genotype and perceived family conflict were assessed at time 1. Alcohol use (frequency of drinking) and alcohol misuse (frequency of intoxication, frequency of drinking three or more drinks, maximum number of drinks) were assessed at times 1 and 2. A significant gene-environment interaction on alcohol misuse at time 1 was found in both sample 1 (β = 0.57, P = 0.001) and sample 2 (β = 0.19, P = 0.01), indicating that the 5-HTTLPR low-activity allele carriers exposed to higher levels of family conflict were more likely to engage in alcohol misuse than non-carriers. A significant gene-environment interaction effect on change in alcohol misuse over time was found only in sample 1 (β = 0.48, P = 0.04) but not in sample 2. Compared with non-carriers, adolescents carrying the 5-HTTLPR low-activity allele are more susceptible to the effects of family conflict on alcohol misuse. © 2014 Society for the Study of Addiction.

Association of Anxiety Symptoms in Offspring of Bipolar Parents with Serotonin Transporter-Linked Polymorphic Region (5-HTTLPR) Genotype

PubMed Central

Park, Min-Hyeon; Sanders, Erica; Howe, Meghan; Singh, Manpreet; Hallmayer, Joachim; Kim, Eunjoo

2015-01-01

Abstract Objective: Offspring of parents with bipolar disorder (BD) have been shown to be at high risk for BD. Anxiety symptoms, even at subclinical levels, have been associated with increased risk for BD in these youth. The s-allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) has been implicated in the pathophysiology of both BD and anxiety disorders and has been associated with pharmacological treatment response and increased risk for antidepressant side effects. Therefore, we aimed to explore 1) whether anxiety symptoms in offspring of BD parents were associated with presence of the 5-HTTLPR s-allele and 2) whether anxiety symptoms in the offspring of BD parents according to the 5-HTTLPR genotypes are related to antianxiety medication status. Methods: A total of 64 offspring of BD parents (mean age: 13.7 years) and 51 healthy controls (HC) (mean age: 13.7 years) were compared genetically and on the Multidimensional Anxiety Scale for Children (MASC). Results: Offspring of BD parents showed higher levels of overall anxiety than did the HC group. Only antianxiety medication naïve offspring of BD parents were found to have an association between 5-HTTLPR genotypes and anxiety symptoms. The antianxiety medication naïve offspring of BD parents with the s-allele showed higher level of overall anxiety than offspring of BD parents with the l/l genotype. No significant differences in anxiety symptoms or their association with the 5-HTTLPR genotype were found in the HC group. Conclusions: This study indicated that there may be an association between 5-HTTLPR genotypes and anxiety symptoms in offspring of BD parents, and that antianxiety medication status may affect anxiety symptoms in the offspring of BD patients according to genotype. PMID:26218602

Serotonin transporter promoter variants: Analysis in Indian autistic and control population.

PubMed

Guhathakurta, Subhrangshu; Ghosh, Sagarmoy; Sinha, Swagata; Chatterjee, Anindita; Ahmed, Shabina; Chowdhury, Susanta Roy; Gangopadhyay, Prasanta Kumar; Ghosh, Saurabh; Singh, Manoranjan; Usha, Rajamma

2006-05-30

Serotonin transporter (5-HTT) is a transmembrane protein belonging to Na+/Cl- dependent membrane transporter family and transports 5-HT across the membranes of presynaptic neurons. 5-HTT-linked polymorphic region (5-HTTLPR) gained much interest because of the differential regulation of expression and activity of 5-HTT by its various genotypes. A population-based study has been conducted on 5-HTTLPR with 358 individuals, which included 79 autistic probands, 136 parents, and 143 controls from two subpopulations of east and northeast regions of India. The genotypic frequencies of all the groups conform to Hardy-Weinberg equilibrium. With the finding of efficacy of serotonin reuptake inhibitors in ameliorating ritualistic behavior in autistic disorder, 5-HTT emerged as a putative candidate gene for autism and association studies have been carried out in different ethnic populations. But these studies were inconclusive due to conflicting results on association. Because such a study has never been performed in the Indian population, we have tested the possible involvement of 5-HTTLPR polymorphism with autism. The present study failed to establish any association or linkage of 5-HTTLPR with autism in the Indian population by case-control studies (chi2 = 1.314, P = 0.63) and family-based approaches (TDT chi2 = 0.22, P = 0.64 and HHRR-chi2 = 0.25, P = 0.61). However, when a meta-analysis of all the available TDT data, inclusive of the present study is carried out, we observed a significant preferential transmission of S-allele from parents to the affected offspring (chi2 = 7.51, P = 0.006) indicating an association of 5-HTTLPR with autism.

Recognition of Scared Faces and the Serotonin Transporter Gene in Young Children: The Generation R Study

ERIC Educational Resources Information Center

Szekely, Eszter; Herba, Catherine M.; Arp, Pascal P.; Uitterlinden, Andre G.; Jaddoe, Vincent W. V.; Hofman, Albert; Verhulst, Frank C.; Hudziak, James J.; Tiemeier, Henning

2011-01-01

Background: Previous research highlights the significance of a functional polymorphism located in the promoter region (5-HTTLPR) of the serotonin transporter gene in emotional behaviour. This study examined the effect of the 5-HTTLPR polymorphism on emotion processing in a large number of healthy preschoolers. Methods: The 5-HTTLPR genotype was…

Genetic polymorphisms of genes involved in DNA repair and metabolism influence micronucleus frequencies in human peripheral blood lymphocytes.

PubMed

Dhillon, Varinderpal S; Thomas, Philip; Iarmarcovai, G; Kirsch-Volders, Micheline; Bonassi, Stefano; Fenech, Michael

2011-01-01

The cytokinesis-block micronucleus cytome (CBMNCyt) assay is a widely used technique for measuring DNA damage in human populations. The formation of micronuclei (MN) in dividing cells can result from chromosome breakage due to unrepaired or mis-repaired DNA lesions or chromosome malsegregation due to mitotic malfunction. The sensitivity of the MN assay to polymorphisms in various genes involved in DNA repair, activation/deactivation of carcinogens/chemicals/drugs/alcohol, folate metabolism pathway and micronutrient transport has been extensively reported in the literature. MN frequency is also an important index for determining DNA repair efficiency phenotype (including mis-repair), response to environmental exposure and identifying various dietary factors required for optimal genome stability. The aim of the present study is to review the reported in vivo associations between genotype and MN frequency in humans taking into considerations the presence of interactions with nutrients levels and/or exposure to genotoxins. One hundred and eleven publications linking MN frequency in peripheral blood lymphocytes to gene polymorphism were retrieved from PubMed. After applying exclusion criteria, only 37 studies were evaluated in the present review. Polymorphisms in XRCC1 (Arg280His), ERCC2 (Lys751Gln), CYP2E1 (c1/c2) and MTR (A2756G) were consistently associated with the MN formation. These results contribute substantial evidence to the hypothesis that genotype may influence MN frequency in human cells.

Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample.

PubMed

Greenberg, B D; Li, Q; Lucas, F R; Hu, S; Sirota, L A; Benjamin, J; Lesch, K P; Hamer, D; Murphy, D L

2000-04-03

The serotonin transporter (5-HTT) regulates serotonergic neurotransmission and is thought to influence emotion. A 5-HTT-linked polymorphic region (5-HTTLPR) has two common variants, short (s) and long (l). We previously found population and within-family associations between the lower-expressing s allele and neuroticism, a trait related to anxiety, hostility, and depression, on a standard measure (the NEO Personality Inventory, Revised [NEO-PI-R]) in a primarily male population (n=505), and that the s allele was dominant. We investigated this association in a new sample (n=397, 84% female, primarily sib-pairs). The results robustly replicated the 5-HTTLPR neuroticism association, and the dominance of the s allele. Combined data from the two studies (n=902) showed a highly significant association between the s allele and higher NEO Neuroticism both across individuals and within families. Association between genotype and a related measure, Anxiety on the 16PF inventory, was replicated in the new population and within families in the combined sample. Association to another trait, estimated TPQ Harm Avoidance, was not replicated in the new sample but found only within the combined sibship group. Another association found in our original study, between the s allele and lower scores on NEO-PI-R Agreeableness, was also replicated and was more robust in the current and the combined samples. Associations between the functional 5-HTTLPR polymorphism were similar in women and men. These results help to define specific personality features reproducibly associated with 5-HTTLPR genotype. Such associations were strongest for traits defined by the NEO, enhancing the attractiveness of the five-factor personality model in genetic research on complex behavioral dimensions. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:202-216, 2000. Published 2000 Wiley-Liss, Inc.

The tricks of the trait: neural implementation of personality varies with genotype-dependent serotonin levels.

PubMed

Hahn, Tim; Heinzel, Sebastian; Notebaert, Karolien; Dresler, Thomas; Reif, Andreas; Lesch, Klaus-Peter; Jakob, Peter M; Windmann, Sabine; Fallgatter, Andreas J

2013-11-01

Gray's Reinforcement Sensitivity Theory (RST) has developed into one of the most prominent personality theories of the last decades. The RST postulates a Behavioral Inhibition System (BIS) modulating the reaction to stimuli indicating aversive events. A number of psychiatric disorders including depression, anxiety disorders, and psychosomatic illnesses have been associated with extreme BIS responsiveness. In recent years, neuroimaging studies have implicated the amygdala-septo-hippocampal circuit as an important neural substrate of the BIS. However, the neurogenetic basis of the regulation of this behaviorally and clinically essential system remains unclear. Investigating the effects of two functional genetic polymorphisms (tryptophan hydroxylase-2, G-703T, and serotonin transporter, serotonin transporter gene-linked polymorphic region) in 89 human participants, we find significantly different patterns of associations between BIS scores and amygdala-hippocampus connectivity during loss anticipation for genotype groups regarding both polymorphisms. Specifically, the correlation between amygdala-hippocampus connectivity and Gray's trait anxiety scores is positive in individuals homozygous for the TPH2 G-allele, while carriers of at least one T-allele show a negative association. Likewise, individuals homozygous for the 5-HTTLPR L(A) variant display a positive association while carriers of the S/L(G) allele show a trend towards a negative association. Thus, we show converging evidence of different neural implementation of the BIS depending on genotype-dependent levels of serotonin. We provide evidence suggesting that genotype-dependent serotonin levels and thus putative changes in the efficiency of serotonergic neurotransmission might not only alter brain activation levels directly, but also more fundamentally impact the neural implementation of personality traits. We outline the direct clinical implications arising from this finding and discuss the complex interplay of neural responses, genes and personality traits in this context. Copyright © 2013 Elsevier Inc. All rights reserved.

Effects of methamphetamine abuse and serotonin transporter gene variants on aggression and emotion-processing neurocircuitry

PubMed Central

Payer, D E; Nurmi, E L; Wilson, S A; McCracken, J T; London, E D

2012-01-01

Individuals who abuse methamphetamine (MA) exhibit heightened aggression, but the neurobiological underpinnings are poorly understood. As variability in the serotonin transporter (SERT) gene can influence aggression, this study assessed possible contributions of this gene to MA-related aggression. In all, 53 MA-dependent and 47 control participants provided self-reports of aggression, and underwent functional magnetic resonance imaging while viewing pictures of faces. Participants were genotyped at two functional polymorphic loci in the SERT gene: the SERT-linked polymorphic region (SERT-LPR) and the intron 2 variable number tandem repeat polymorphism (STin2 VNTR); participants were then classified as having high or low risk for aggression according to individual SERT risk allele combinations. Comparison of SERT risk allele loads between groups showed no difference between MA-dependent and control participants. Comparison of self-report scores showed greater aggression in MA-dependent than control participants, and in high genetic risk than low-risk participants. Signal change in the amygdala was lower in high genetic risk than low-risk participants, but showed no main effect of MA abuse; however, signal change correlated negatively with MA use measures. Whole-brain differences in activation were observed between MA-dependent and control groups in the occipital and prefrontal cortex, and between genetic high- and low-risk groups in the occipital, fusiform, supramarginal and prefrontal cortex, with effects overlapping in a small region in the right ventrolateral prefrontal cortex. The findings suggest that the investigated SERT risk allele loads are comparable between MA-dependent and healthy individuals, and that MA and genetic risk influence aggression independently, with minimal overlap in associated neural substrates. PMID:22832817

Serotonin transporter gene promoter polymorphism and autism: a family-based genetic association study in Japanese population.

PubMed

Koishi, Shinko; Yamamoto, Kenji; Matsumoto, Hideo; Koishi, Seiji; Enseki, Youichi; Oya, Akitoshi; Asakura, Arata; Aoki, Yutaka; Atsumi, Mariko; Iga, Tomiei; Inomata, Jyoji; Inoko, Hidetoshi; Sasaki, Tsukasa; Nanba, Eiji; Kato, Nobumasa; Ishii, Tetsuo; Yamazaki, Kosuke

2006-05-01

Autism is now widely accepted as a biological disorder which, by and large, starts before birth. It has been shown that serotonin (5-HT) is associated with several psychological processes and hyperserotoninemia is observed in some autistic patients. The results of previous reports about family-based association studies between the serotonin transporter (5-HTT) gene promoter polymorphism and autism are controversial. In this study, an analysis using the transmission/disequilibrium test (TDT) between the 5-HTT gene promoter polymorphism and autism in 104 trios, all ethnically Japanese, showed no significant linkage disequilibrium (P=0.17). Recently, it has been reported that some haplotypes at the serotonin transporter locus may be associated with the pathogenesis of autism. Therefore, further investigations by haplotype analyses are necessary to confirm the implications of genetic variants of the serotonin transporter in the etiology of autism.

Vitamin C transporter gene polymorphisms, dietary vitamin C and serum ascorbic acid.

PubMed

Cahill, Leah E; El-Sohemy, Ahmed

2009-01-01

Vitamin C transporter proteins SVCT1 and SVCT2 are required for the absorption and transport of vitamin C in humans. This study aims to determine whether common SVCT genotypes modify the association between dietary vitamin C and serum ascorbic acid. Non-smoking men and women (n=1,046) aged 20-29 were participants of the Toronto Nutrigenomics and Health Study. Overnight fasting blood samples were collected to determine serum ascorbic acid concentrations by HPLC and to genotype for two SVCT1 (rs4257763 and rs6596473) and two SVCT2 (rs6139591 and rs2681116) polymorphisms. No diet-gene interactions were observed for the vitamin C transporter polymorphisms, however, the average (mean+/-SE) serum ascorbic acid concentrations differed between rs4257763 genotypes (GG: 24.4+/-1.3, GA: 26.8+/-1.1, AA: 29.7+/-1.4 micromol/l; p=0.002). For this polymorphism, the correlation between dietary vitamin C and serum ascorbic acid was only significant in subjects with a G allele. The SVCT2 polymorphisms also appeared to modify the strength of the diet-serum correlation. Our findings demonstrate that genetic variation in SVCT1 can influence serum ascorbic acid concentrations and that SVCT1 and SVCT2 genotypes modify the strength of the correlation between dietary vitamin C and serum ascorbic acid. Copyright © 2010 S. Karger AG, Basel.

[The analysis of the polymorphic variations of the dopamine gen transporter (DAT1) and the serotonin transporter (5-HTTLPR) in patients with alcohol dependence syndrome with inclusion of the phenotypic feature of sweet liking preference].

PubMed

Jasiewicz, Andrzej; Grzywacz, Anna; Jabłoński, Marcin; Bieńkowski, Przemysław; Samochowiec, Agnieszka; Samochowiec, Jerzy

2014-01-01

The purpose of this study was to determine the relationship between sweet-liking phenotype and the variation of the gene sequence of the dopaminergic and serotonergic system. The study recruited 100 probands. The participants were interviewed for addiction (SSAGA-Semi Structured Assessment for the Genetics of Alcoholism) and assessed with the questionnaires: MMSE, Beck Depression Inventory and Hamilton Anxiety, Snaith-Hamilton Pleasure Scale. The taste was analyzed with tests to assess sensitivity to sweet taste and also smell tests were performed. Patients preferring the highest glucose volumes were called sweet likers. Statistical analyses were performed (SPSS- Statistical Package for the Social Sciences). Links between sweet liking phenotype and polymorphic variant of DAT1 gene were determined. The presence of DAT1 9/10 genotype increased three fold time sweet liking phenotype (p = 0.015, odds ratio-3.00), the presence of DAT1 10/10 decreased two fold time the chance being sweet liker (p = 0.051, odds ratio-0.43). Genotype 10/10 was significantly more common among sweet dislikers 10/10 (68.18% vs 47.92%) i 9/9 (6.82% vs 2.08%). CONCLUSIONS; A genetically significant association between the presence of 9/10 DAT1 VNTR genotype and a sweet-liking phenotype in probands was determined.

Genetic Polymorphisms Associated to Folate Transport as Predictors of Increased Risk for Acute Lymphoblastic Leukemia in Mexican Children.

PubMed

Zaruma-Torres, Fausto; Lares-Asseff, Ismael; Lima, Aurea; Reyes-Espinoza, Aarón; Loera-Castañeda, Verónica; Sosa-Macías, Martha; Galaviz-Hernández, Carlos; Arias-Peláez, María C; Reyes-López, Miguel A; Quiñones, Luis A

2016-01-01

Acute lymphoblastic leukemia (ALL) is a frequent neoplasia occurring in children. The most commonly used drug for the treatment of ALL is methotrexate (MTX), an anti-folate agent. Previous studies suggest that folate transporters play a role in ALL prognosis and that genetic polymorphism of genes encoding folate transporters may increase the risk of ALL. Therefore, the main goal of this study was to determine the associations among six genetic polymorphisms in four genes related with the folate transporter pathway to determine a relationship with the occurrence of ALL in Mexican children. A case-control study was performed in 73 ALL children and 133 healthy children from Northern and Northwestern Mexico. COL18A1 (rs2274808), SLC19A1 (rs2838956), ABCB1 (rs1045642 and rs1128503), and ABCC5 (rs9838667 and rs3792585). Polymorphisms were assayed through qPCR. Our results showed an increased ALL risk in children carrying CT genotype (OR = 2.55, CI 95% 1.11-5.83, p = 0.0001) and TT genotype (OR = 21.05, CI 95% 5.62-78.87, p < 0.0001) of COL18A1 rs2274808; in SLC19A1 rs2838956 AG carriers (OR = 44.69, CI 95% 10.42-191.63, p = 0.0001); in ABCB1 rs1045642 TT carriers (OR = 13.76, CI 95% 5.94-31.88, p = 0.0001); in ABCC5 rs9838667 AC carriers (OR = 2.61, CI 95% 1.05-6.48, p < 0.05); and in ABCC5 rs3792585 CC carriers (OR = 9.99, CI 95% 3.19-31.28, p = 0.004). Moreover, several combinations of genetic polymorphisms were found to be significantly associated with a risk for ALL. Finally, two combinations of ABCC5 polymorphisms resulted in protection from this neoplasia. In conclusion, certain genetic polymorphisms related to the folate transport pathway, particularly COL18A1 rs2274808, SLC19A1 rs2838956, ABCB1 rs1045642, and ABCC5 rs3792585, were associated with an increased risk for ALL in Mexican children.

Antigenic and functional properties of the human red blood cell urea transporter hUT-B1.

PubMed

Lucien, Nicole; Sidoux-Walter, Frédéric; Roudier, Nathalie; Ripoche, Pierre; Huet, Martine; Trinh-Trang-Tan, Marie-Marcelle; Cartron, Jean-Pierre; Bailly, Pascal

2002-09-13

The Kidd (JK) blood group locus encodes the urea transporter hUT-B1, which is expressed on human red blood cells and other tissues. The common JK*A/JK*B blood group polymorphism is caused by a single nucleotide transition G838A changing Asp-280 to Asn-280 on the polypeptide, and transfection of erythroleukemic K562 cells with hUT-B1 cDNAs carrying either the G838 or the A838 nucleotide substitutions resulted in the isolation of stable clones that expressed the Jk(a) or Jk(b) antigens, respectively, thus providing the first direct demonstration that the hUT-B1 gene encodes the Kidd blood group antigens. In addition, immunochemical analysis of red blood cells demonstrated that hUT-B1 also exhibits ABO determinants attached to the single N-linked sugar chain at Asn-211. Moreover, immunoadsorption studies, using inside-out and right-side-out red cell membrane vesicles as competing antigen, demonstrated that the C- and N-terminal ends of hUT-B1 are oriented intracellularly. Mutagenesis and functional studies by expression in Xenopus oocytes revealed that both cysteines Cys-25 and Cys-30 (but not alone) are essential for plasma membrane addressing. Conversely, the transport function was not affected by the JK*A/JK*B polymorphism, C-terminal deletion (residues 360-389), or mutation of the extracellular N-glycosylation consensus site and remains poorly para-chloromercuribenzene sulfonate (pCMBS)-sensitive. However, transport studies by stopped flow light scattering using Jk-K562 transfectants demonstrated that the hUT-B1-mediated urea transport is pCMBS-sensitive in an erythroid context, as reported previously for the transporter of human red blood cells. Mutagenesis analysis also indicated that Cys-151 and Cys-236, at least alone, are not involved in pCMBS inhibition. Altogether, these antigenic, topologic, and functional properties might have implications into the physiology of hUT-B1 and other members of the urea transporter family.

Meiotic drive influences the outcome of sexually antagonistic selection at a linked locus.

PubMed

Patten, M M

2014-11-01

Most meiotic drivers, such as the t-haplotype in Mus and the segregation distorter (SD) in Drosophila, act in a sex-specific manner, gaining a transmission advantage through one sex although suffering only the fitness costs associated with the driver in the other. Their inheritance is thus more likely through one of the two sexes, a property they share with sexually antagonistic alleles. Previous theory has shown that pairs of linked loci segregating for sexually antagonistic alleles are more likely to remain polymorphic and that linkage disequilibrium accrues between them. I probe this similarity between drive and sexual antagonism and examine the evolution of chromosomes experiencing these selection pressures simultaneously. Reminiscent of previous theory, I find that: the opportunity for polymorphism increases for a sexually antagonistic locus that is physically linked to a driving locus; the opportunity for polymorphism at a driving locus also increases when linked to a sexually antagonistic locus; and stable linkage disequilibrium accompanies any polymorphic equilibrium. Additionally, I find that drive at a linked locus favours the fixation of sexually antagonistic alleles that benefit the sex in which drive occurs. Further, I show that under certain conditions reduced recombination between these two loci is selectively favoured. These theoretical results provide clear, testable predictions about the nature of sexually antagonistic variation on driving chromosomes and have implications for the evolution of genomic architecture. © 2014 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2014 European Society For Evolutionary Biology.

Brief Report: Glutamate Transporter Gene ("SLC1A1") Single Nucleotide Polymorphism (rs301430) and Repetitive Behaviors and Anxiety in Children with Autism Spectrum Disorder

ERIC Educational Resources Information Center

Gadow, Kenneth D.; Roohi, Jasmin; DeVincent, Carla J.; Kirsch, Sarah; Hatchwell, Eli

2010-01-01

Investigated association of single nucleotide polymorphism (SNP) rs301430 in glutamate transporter gene ("SLC1A1") with severity of repetitive behaviors (obsessive-compulsive behaviors, tics) and anxiety in children with autism spectrum disorder (ASD). Mothers and/or teachers completed a validated DSM-IV-referenced rating scale for 67 children…

Mapping the x-linked lymphoproliferative syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Skare, J.C.; Milunsky, A.; Byron, K.S.

1987-04-01

The X-linked lymphoproliferative syndrome is triggered by Epstein-Barr virus infection and results in fatal mononucleosis, immunodeficiency, and lymphoproliferative disorders. This study shows that the mutation responsible for X-linked lymphoproliferative syndrome is genetically linked to a restriction fragment length polymorphism detected with the DXS42 probe (from Xq24-q27). The most likely recombination frequency between the loci is 4%, and the associated logarithm of the odds is 5.26. Haplotype analysis using flanking restriction fragment length polymorphism markers indicates that the locus for X-linked lymphoproliferative syndrome is distal to probe DXS42 but proximal to probe DXS99 (from Xq26-q27). It is now possible to predictmore » which members of a family with X-linked lymphoproliferative syndrome are carrier females and to diagnose the syndrome prenatally.« less

Interaction of IFNL3 with insulin resistance, steatosis and lipid metabolism in chronic hepatitis C virus infection.

PubMed

Eslam, Mohammed; Booth, David R; George, Jacob; Ahlenstiel, Golo

2013-11-07

Metabolic changes are inextricably linked to chronic hepatitis C (CHC). Recently polymorphisms in the IFNL3 (IL28B) region have been shown to be strongly associated with spontaneous and treatment induced recovery from hepatitis C virus (HCV) infection. Further, circumstantial evidence suggests a link between IFNL3 single nucleotide polymorphisms and lipid metabolism, steatosis and insulin resistance in CHC. The emerging picture suggests that the responder genotypes of IFNL3 polymorphisms are associated with a higher serum lipid profile, and less frequent steatosis and insulin resistance. This review analyzes the current data regarding this interaction and its meaning for HCV pathogenesis and disease progression.

[Polymorphism in the Serotonin Transporter Gene (SLC6A4) and Emotional Bipolar Disorder in Two Regional Mental Health Centers from the Eje Cafetero (Colombia)].

PubMed

Ramos, Lucero Rengifo; Arias, Duverney Gaviria; Salazar, Liliana Salazar; Vélez, Juan Pablo; Pardo, Stella Lozano

2012-03-01

The indel polymorphisms in the promoting region and the 2(nd) intron polymorphisms in the serotonin transporter gene (SLC6A4) have been associated to bipolar disorder 1 (BD1) in several population studies. The objective was to analyze the genotypic and allelic frequencies in both gene regions in a study of cases and controls with individuals from Risaralda and Quindío (Colombia) so as to establish possible associations to BD1, and compare results with previous and similar studies. 133 patients and 120 controls were studied. L and S indel polymorphisms in the promoting region were analyzed by PCR, together with VNTR STin2.10 and STin 2.12 VNTRs polymorphisms in the 2(nd) intron of the SL-C6A4 gene Genotypic and allelic frequencies for the S and L polymorphisms were similar both in cases and controls. However, the LL genotype was significantly increased both in BD1 population (OR=1.89; CI95%=1.1-3.68), and when discriminated by gender. This particular genotype in general population is OR=2.22; IC95%=1.04-5.66 for women, and OR=1.62; IC 95%=0.71-4.39 for men. No significant genotypic and allelic differences were found for VNTR STin2.10 and STin 2.12. polymorphisms. No association was found between polymorphisms of 5-HTTLPR polymorphisms and the 2(nd) intron of the serotonin transporting gene in general patients with BD1, nor when compared by gender. Our results are similar to those reported for Caucasian populations and differ from those of Asian and Brazilian populations. Copyright © 2012 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

Polymorphisms and linkage analysis for ICAM-1 and the selectin gene cluster

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vora, D.K.; Rosenbloom, C.L.; Cottingham, R.W.

1994-06-01

Genetic polymorphisms in leukocyte and endothelial cell adhesion molecules may be important variables with regard to susceptibility to multifactorial disease processes that include an inflammatory component. For this reason, polymorphisms were sought for intercellular adhesion molecule-1 (ICAM-1; gene symbol ICAM1) and for the three genes in the selectin cluster, P-selectin, L-selectin, and E-selectin (gene symbols SELP, SELL, and SELE, respectively). Two amino acid polymorphisms were identified for ICAM-1; Gly or Arg at codon 241 and Lys or Glu at codon 469. Dinucleotide repeat polymorphisms were identified in the 3{prime}-untranslated region for ICAM-1 and in intron 9 for P-selectin. Restriction fragmentmore » length polymorphisms were found using cDNAs for each of the three selectin genes as probes; E-selectin with BglII, P-selectin with ScaI, and L-selectin with HincII. Linkage analysis was performed for the selectin gene cluster and for ICAM-1 using the CEPH families; ICAM-1 is very tightly linked to the LDL receptor on chromosome 19, and the selectin cluster is linked to markers at chromosome 1q23. 41 refs., 2 tabs.« less

Infectious mononucleosis-linked HLA class I single nucleotide polymorphism is associated with multiple sclerosis.

PubMed

Jafari, Naghmeh; Broer, Linda; Hoppenbrouwers, Ilse A; van Duijn, Cornelia M; Hintzen, Rogier Q

2010-11-01

Multiple sclerosis is a presumed autoimmune disease associated with genetic and environmental risk factors such as infectious mononucleosis. Recent research has shown infectious mononucleosis to be associated with a specific HLA class I polymorphism. Our aim was to test if the infectious mononucleosis-linked HLA class I single nucleotide polymorphism (rs6457110) is also associated with multiple sclerosis. Genotyping of the HLA-A single nucleotide polymorphism rs6457110 using TaqMan was performed in 591 multiple sclerosis cases and 600 controls. The association of multiple sclerosis with the HLA-A single nucleotide polymorphism was tested using logistic regression adjusted for age, sex and HLA-DRB1*1501. HLA-A minor allele (A) is associated with multiple sclerosis (OR = 0.68; p = 4.08 × 10( -5)). After stratification for HLA-DRB1*1501 risk allele (T) carrier we showed a significant OR of 0.70 (p = 0.003) for HLA-A. HLA class I single nucleotide polymorphism rs6457110 is associated with infectious mononucleosis and multiple sclerosis, independent of the major class II allele, supporting the hypothesis that shared genetics may contribute to the association between infectious mononucleosis and multiple sclerosis.

5-HTTLPR moderates the association between attention away from angry faces and prospective depression among youth.

PubMed

Jenness, Jessica L; Young, Jami F; Hankin, Benjamin L

2017-08-01

Attention bias to emotion has been studied as a risk factor associated with depression. No study has examined whether attention bias within the context of measured genetic risk leads to increased risk for clinical depressive episodes over time. The current study investigated whether genetic risk, as indexed by the serotonin-transporter-linked polymorphic region (5-HTTLPR), moderated the relationship between attention bias to emotional faces and clinical depression onset prospectively across 18-months in a community sample of youth (n = 428; mean age = 11.97, SD = 2.28; 59% girls). Youth who attended away from angry emotional faces and were homozygous for the S allele of the 5-HTTLPR polymorphism were at greater risk for prospective depressive episode onset. The current study's findings highlight the importance of examining risk for depression across multiple levels of analysis and demonstrate attention away from threat as a possible point of intervention related to attention bias modification and depression treatment among youth. Copyright © 2017 Elsevier Ltd. All rights reserved.

Possible roles for products of polymorphic MHC and linked olfactory receptor genes during selection processes in reproduction.

PubMed

Ziegler, Andreas; Dohr, Gotrfried; Uchanska-Ziegler, Barbara

2002-07-01

Polymorphic genes of the human major histocompatibility complex [MHC; human leukocyte antigen (HLA)] are probably important in determining resistance to parasites and avoidance of inbreeding. We investigated whether HLA-associated sexual selection could also involve HLA-linked olfactory receptor (OR) genes, which might not only participate in olfaction-guided mate choice, but also in selection processes within the testis. The testicular expression status of HLA class I molecules (by immunohistology) and HLA-linked OR genes (by transcriptional analysis) was determined. Various HLA class I heavy chains, but not beta2-microglobulin (beta2m), were expressed, mainly at the spermatocyte I stage. Of 17 HLA-linked OR genes analyzed, eight were found to be transcribed in the testis. They exhibited varying numbers of 5'- or 3'-non-coding exons as well as differential splicing. We suggest that testis-expressed polymorphic HLA and OR proteins are functionally connected and serve the selection of spermatozoa, enabling them to distinguish 'self from 'non-self [the sperm-receptor-selection (SRS) hypothesis].

Interleukin-18 (rs187238) and glucose transporter 4 (rs5435) polymorphisms in Euro-Brazilians with type 1 diabetes.

PubMed

Al-Lahham, Y; Mendes, A K B; Souza, E M; Alberton, D; Rego, F G M; Valdameri, G; Picheth, G

2017-09-21

Type 1 diabetes (T1D) is an autoimmune disease with a strong genetic component that has been associated with several genetic loci. Interleukin 18 (IL-18) is a potent proinflammatory cytokine, which is involved in the innate and adaptive immune responses, and in the pathogenesis of various diseases including T1D. Glucose transporter 4 (GLUT4) is known to be an insulin-responsive glucose transporter and has been associated with various diseases, including diabetes mellitus. We investigated the association of the polymorphisms rs187238 (IL-18) and rs5435 (GLUT4) in a case-control study in Euro-Brazilians with T1D (N = 136) and healthy subjects (N = 144). Real-time PCR with TaqMan ® fluorescent probes were applied for genotyping. All polymorphisms were in Hardy-Weinberg equilibrium. The minor allele frequencies for the G-allele (rs187238; IL-18) in healthy and T1D groups were 28.5% [95%CI = 23-34%] vs 31.6% [95%CI = 26-37%], P = 0.416, and for the T-allele (rs5435, GLUT4) were 33% [95%CI = 28-39] vs 27% [95%CI = 23-33%], P = 0.167, respectively. Genotype comparisons for both polymorphisms showed no significant differences (P > 0.05). The polymorphisms rs187238 and rs5435 were not associated with T1D in the studied population. The minor allele frequencies for both polymorphisms were similar to those of other Caucasian populations.

Lack of association between serotonin transporter gene polymorphism 5-HTTLPR and smoking among Polish population: a case-control study

PubMed Central

Sieminska, Alicja; Buczkowski, Krzysztof; Jassem, Ewa; Tkacz, Ewa

2008-01-01

Background A better understanding of the genetic determinants of tobacco smoking might help in developing more effective cessation therapies, tailored to smokers' genotype. Insertion/deletion polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) has been linked to vulnerability to smoking and ability to quit. We aimed to determine whether 5-HTTLPR genotype is associated with smoking behavior in Caucasians from Northern Poland and to investigate other risk factors for tobacco smoking. Methods 5-HTTLPR genotypes were determined in 149 ever smokers (66 females; mean age 53.0 years) and 158 gender and ethnicity matched never smoking controls (79 females; mean age 45.0 years) to evaluate the association of this polymorphism with ever smoking status. Analysis of smokers was performed to evaluate the role of 5-HTTLPR in the age of starting regular smoking, the number of cigarettes smoked daily, pack-years, FTND score, duration of smoking, and the mean length of the longest abstinence on quitting. Genotype was classified according to the presence or absence of the short (S) allele vs. the long (L) allele of 5-HTTLPR (i.e., S/S + S/L vs. L/L). Logistic regression analysis was also used to evaluate correlation between ever smoking and several selected variables. Results We found no significant differences in the rates of S allele carriers in ever smokers and never smokers, and no relationship was observed between any quantitative measures of smoking and the polymorphism. Multivariate analysis demonstrated significant association between the older age (OR = 4.03; 95% CI: 2.33–6.99) and alcohol dependence (OR = 10.23; 95% CI: 2.09–50.18) and smoking. Conclusion 5-HTTLPR seems to be not a major factor determining cigarette smoking in Poles. Probably, the risk of smoking results from a large number of genes, each contributing a small part of the overall risk, while numerous non-genetic factors might strongly influence these genetic undergrounds of susceptibility to smoking. PMID:18691405

Impact of serotonin transporter gene polymorphism on brain activation by colorectal distention.

PubMed

Fukudo, S; Kanazawa, M; Mizuno, T; Hamaguchi, T; Kano, M; Watanabe, S; Sagami, Y; Shoji, T; Endo, Y; Hongo, M; Itoyama, Y; Yanai, K; Tashiro, M; Aoki, M

2009-09-01

Determining the gene that plays a key role in brain-gut interactions is a crucial step for clarifying the pathophysiology of irritable bowel syndrome (IBS). We previously reported that the 5-hydroxytryptamine transporter gene-linked polymorphic region (5-HTTLPR) is related to anxiety in subjects with IBS. The amygdala is more activated during fearful face recognition in individuals with the s allele of 5-HTTLPR. Here, we tested our hypothesis that 5-HTTLPR differentially activates brain regions with colorectal distention in humans. We enrolled 28 subjects without any organic disease. The study was approved by the Ethics Committee and all subjects gave written informed consent. DNA was extracted from the peripheral blood. The genotype of 5-HTTLPR was determined using polymerase chain reaction. Age, sex, diagnosis-matched individuals with the s/s genotype (n=14) and individuals with the l allele (genotypes l/s, l/l, l/extra-l, n=14) were compared. A barostat bag was inserted to the colorectum and was intermittently inflated with no (0 mm Hg), mild (20 mm Hg), or intense (40 mm Hg) stimulation on a random order. Radioactive H2[(15-)O] saline was injected at bag inflation and then positron emission tomography was performed. Changes in rCBF were analyzed using statistical parametric mapping. Individuals with the s/s genotype showed a significantly larger increase in rCBF by colorectal distention from 0 mm Hg to 40 mm Hg than individuals with the l allele. The significantly more activated brain regions in individuals with the s/s genotype were the left anterior cingulate cortex and right parahippocampal gyrus (p<0.0001). The increase in rCBF by colorectal distention of 20 mm Hg compared with 0 mm Hg was significantly larger in the left orbitofrontal cortex of individuals with the s/s genotype than that of individuals with the l allele (p<0.0001). These data suggest that individuals with a weak function of serotonin transporter respond to gut signals more in emotion-regulating brain regions. Functional gene polymorphism may partially predict the individual effect of a selective serotonin reuptake inhibitor on visceral pain.

Functional Characterization of 5-Oxoproline Transport via SLC16A1/MCT1*

PubMed Central

Sasaki, Shotaro; Futagi, Yuya; Kobayashi, Masaki; Ogura, Jiro; Iseki, Ken

2015-01-01

Thyrotropin-releasing hormone is a tripeptide that consists of 5-oxoproline, histidine, and proline. The peptide is rapidly metabolized by various enzymes. 5-Oxoproline is produced by enzymatic hydrolysis in a variety of peptides. Previous studies showed that 5-oxoproline could become a possible biomarker for autism spectrum disorders. Here we demonstrate the involvement of SLC16A1 in the transport of 5-oxoproline. An SLC16A1 polymorphism (rs1049434) was recently identified. However, there is no information about the effect of the polymorphism on SLC16A1 function. In this study, the polymorphism caused an observable change in 5-oxoproline and lactate transport via SLC16A1. The Michaelis constant (Km) was increased in an SLC16A1 mutant compared with that in the wild type. In addition, the proton concentration required to produce half-maximal activation of transport activity (K0.5, H+) was increased in the SLC16A1 mutant compared with that in the wild type. Furthermore, we examined the transport of 5-oxoproline in T98G cells as an astrocyte cell model. Despite the fact that 5-oxoproline is an amino acid derivative, Na+-dependent and amino acid transport systems scarcely contributed to 5-oxoproline transport. Based on our findings, we conclude that H+-coupled 5-oxoproline transport is mediated solely by SLC16A1 in the cells. PMID:25371203

Epistasis between 5-HTTLPR and ADRA2B polymorphisms influences attentional bias for emotional information in healthy volunteers.

PubMed

Naudts, Kris H; Azevedo, Ruben T; David, Anthony S; van Heeringen, Kees; Gibbs, Ayana A

2012-09-01

Individual differences in emotional processing are likely to contribute to vulnerability and resilience to emotional disorders such as depression and anxiety. Genetic variation is known to contribute to these differences but they remain incompletely understood. The serotonin transporter (5-HTTLPR) and α2B-adrenergic autoreceptor (ADRA2B) insertion/deletion polymorphisms impact on two separate but interacting monaminergic signalling mechanisms that have been implicated in both emotional processing and emotional disorders. Recent studies suggest that the 5-HTTLPR s allele is associated with a negative attentional bias and an increased risk of emotional disorders. However, such complex behavioural traits are likely to exhibit polygenicity, including epistasis. This study examined the contribution of the 5-HTTLPR and ADRA2B insertion/deletion polymorphisms to attentional biases for aversive information in 94 healthy male volunteers and found evidence of a significant epistatic effect (p<0.001). Specifically, in the presence of the 5-HTTLPR s allele, the attentional bias for aversive information was attenuated by possession of the ADRA2B deletion variant whereas in the absence of the s allele, the bias was enhanced. These data identify a cognitive mechanism linking genotype-dependent serotonergic and noradrenergic signalling that is likely to have implications for the development of cognitive markers for depression/anxiety as well as therapeutic drug effects and personalized approaches to treatment.

Association between norepinephrine transporter gene (SLC6A2) polymorphisms and suicide in patients with major depressive disorder.

PubMed

Kim, Yong-Ku; Hwang, Jung-A; Lee, Heon-Jeong; Yoon, Ho-Kyoung; Ko, Young-Hoon; Lee, Bun-Hee; Jung, Han-Yong; Hahn, Sang-Woo; Na, Kyoung-Sae

2014-04-01

Although several studies have investigated possible associations between norepinephrine neurotransmitter transporter gene (SLC6A2) polymorphisms and depression, few studies have examined associations between SLC6A2 polymorphisms and suicide. Three single-nucleotide polymorphisms (rs2242446, rs28386840, and rs5569) were measured in 550 patients: 201 with major depressive disorder (MDD) and suicide attempt/s, 160 with MDD without suicide attempts, and 189 healthy controls. Analysis of single-nucleotide polymorphisms (SNPs) and haplotype was conducted for the three groups. Subsequently, multivariate logistic regression analysis adjusting for age and gender was conducted to identify independent influences of each SNP. A possible association between suicide lethality and SLC6A2 polymorphisms was also investigated. In the genotype and allele frequency analysis, there were significant differences in rs28386840 between suicidal MDD patients and healthy controls. In the haplotype analysis, TAA (rs2242446-rs28386840-rs5569, from left to right) was associated with suicide attempts in MDD, although the significance (p=0.043) disappeared after Bonferroni correction. There were no relationships between lethality scores and SLC6A2 polymorphisms in suicidal MDD. Modest sample size and a single type of neurotransmitter analyzed (norepinephrine) are the primary limitations. Our results suggest that SLC6A2 polymorphisms were associated with suicide risk in patients with MDD. Future studies are warranted to elucidate possible mechanisms by which SLC6A2 polymorphisms influence suicide risk. Copyright © 2014 Elsevier B.V. All rights reserved.

Dopamine transporter gene variation modulates activation of striatum in youth with ADHD

PubMed Central

Bédard, Anne-Claude; Schulz, Kurt P.; Cook, Edwin H.; Fan, Jin; Clerkin, Suzanne M.; Ivanov, Iliyan; Halperin, Jeffrey M.; Newcorn, Jeffrey H.

2009-01-01

Polymorphisms in the 3′ UTR variable number tandem repeat (VNTR) of exon 15 of the dopamine transporter gene (DAT1) have been linked to attention-deficit hyperactivity disorder (ADHD); moreover, variability in DAT1 3′UTR genotype may contribute to both heterogeneity of the ADHD phenotype and differences in response to stimulant medications. The impact of this VNTR on neuronal function in individuals with ADHD remains unclear despite evidence that the polymorphisms influence dopamine transporter expression. Thus, we used event-related functional magnetic resonance imaging to examine the impact of DAT1 3′UTR genotype on brain activation during response inhibition in unmedicated children and adolescents with ADHD. Twenty-one youth with ADHD who were homozygous for the 10-repeat (10R) allele of the DAT1 3′UTR and 12 youth who were carriers of the 9-repeat (9R) allele were scanned while they performed a Go/No-Go task. Response inhibition was modeled by contrasting activation during correct No-Go trials versus correct Go trials. Participants who were homozygous for the DAT1 3′UTR 10R allele and those who had a single 9R allele did not differ on percent of trials with successful inhibition, which was the primary measure of inhibitory control. Yet, youth with the DAT1 3′UTR 10R/10R genotype had significantly greater inhibitory control-related activation than those with one 9R allele in the left striatum, right dorsal premotor cortex, and bilaterally in the temporoparietal cortical junction. These findings provide preliminary evidence that neural activity related to inhibitory control may differ as a function of DAT1 3′UTR genotype in youth with ADHD. PMID:20026227

Dopamine transporter gene variation modulates activation of striatum in youth with ADHD.

PubMed

Bédard, Anne-Claude; Schulz, Kurt P; Cook, Edwin H; Fan, Jin; Clerkin, Suzanne M; Ivanov, Iliyan; Halperin, Jeffrey M; Newcorn, Jeffrey H

2010-11-15

Polymorphisms in the 3'UTR variable number tandem repeat (VNTR) of exon 15 of the dopamine transporter gene (DAT1) have been linked to attention-deficit hyperactivity disorder (ADHD); moreover, variability in DAT1 3'UTR genotype may contribute to both heterogeneity of the ADHD phenotype and differences in response to stimulant medications. The impact of this VNTR on neuronal function in individuals with ADHD remains unclear despite evidence that the polymorphisms influence dopamine transporter expression. Thus, we used event-related functional magnetic resonance imaging to examine the impact of DAT1 3'UTR genotype on brain activation during response inhibition in unmedicated children and adolescents with ADHD. Twenty-one youth with ADHD who were homozygous for the 10-repeat (10R) allele of the DAT1 3'UTR and 12 youth who were carriers of the 9-repeat (9R) allele were scanned while they performed a Go/No-Go task. Response inhibition was modeled by contrasting activation during correct No-Go trials versus correct Go trials. Participants who were homozygous for the DAT1 3'UTR 10R allele and those who had a single 9R allele did not differ on percent of trials with successful inhibition, which was the primary measure of inhibitory control. Yet, youth with the DAT1 3'UTR 10R/10R genotype had significantly greater inhibitory control-related activation than those with one 9R allele in the left striatum, right dorsal premotor cortex, and bilaterally in the temporoparietal cortical junction. These findings provide preliminary evidence that neural activity related to inhibitory control may differ as a function of DAT1 3'UTR genotype in youth with ADHD. Copyright 2009 Elsevier Inc. All rights reserved.

Pharmacogenetics of adverse reactions to antiepileptic drugs.

PubMed

Fricke-Galindo, I; Jung-Cook, H; LLerena, A; López-López, M

2018-04-01

Adverse drug reactions (ADRs) are a major public health concern and a leading cause of morbidity and mortality in the world. In the case of antiepileptic drugs (AEDs), ADRs constitute a barrier to successful treatment since they decrease treatment adherence and impact patients' quality of life of patients. Pharmacogenetics aims to identify genetic polymorphisms associated with drug safety. This article presents a review of genes coding for drug metabolising enzymes and drug transporters, and HLA system genes that have been linked to AED-induced ADRs. To date, several genetic variations associated with drug safety have been reported: CYP2C9*2 and *3 alleles, which code for enzymes with decreased activity, have been linked to phenytoin (PHT)-induced neurotoxicity; GSTM1 null alleles with hepatotoxicity induced by carbamazepine (CBZ) and valproic acid (VPA); EPHX1 polymorphisms with teratogenesis; ABCC2 genetic variations with CBZ- and VPA-induced neurological ADRs; and HLA alleles (e.g. HLA-B*15:02, -A*31:01, -B*15:11, -C*08:01) with cutaneous ADRs. Published findings show that there are ADRs with a pharmacogenetic basis and a high interethnic variability, which indicates a need for future studies in different populations to gather more useful results for larger number of patients. The search for biomarkers that would allow predicting ADRs to AEDs could improve pharmacotherapy for epilepsy. Copyright © 2014 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Frequency of 3' VNTR Polymorphism in the Dopamine Transporter Gene SLC6A3 in Humans Predisposed to Antisocial Behavior.

PubMed

Cherepkova, E V; Aftanas, L I; Maksimov, N; Menshanov, P N

2016-11-01

Predisposition to antisocial behavior can be related to the presence of certain polymorphic variants of genes encoding dopaminergic system proteins. We studied the frequencies of allele variants and genotypes of variable number tandem repeat polymorphism in 3' untranslated region (3' VTNR) of the dopaminergic transporter SLC6A3 gene in Caucasian men committed socially dangerous violent and non-violent crimes. Alleles with 9 and 10 repeats were most frequent in both the control group and group of men predisposed to antisocial behavior. At the same time, the 10/10 genotype was more frequently observed in the group of men prone to antisocial non-violent behavior. Hence, the presence of certain variants of 3' VTNR polymorphism of SLC6A3 gene in men is associated with predisposition to certain forms of antisocial behavior.

Identification and functional characterization of genetic variants of human organic cation transporters in a Korean population.

PubMed

Kang, Ho-Jin; Song, Im-Sook; Shin, Ho Jung; Kim, Woo-Young; Lee, Choong-Hee; Shim, Joo-Cheol; Zhou, Hong-Hao; Lee, Sang Seop; Shin, Jae-Gook

2007-04-01

Genetic variants of three human organic cation transporter genes (hOCTs) were extensively explored in a Korean population. The functional changes of hOCT2 variants were evaluated in vitro, and those genetic polymorphisms of hOCTs were compared among different ethnic populations. From direct DNA sequencing, 7 of 13 coding variants were nonsynonymous single-nucleotide polymorphisms (SNPs), including four variants from hOCT1 (F160L, P283L, P341L, and M408V) and three from hOCT2 (T199I, T201M, and A270S), whereas 6 were synonymous SNPs. The linkage disequilibrium analysis presented for three independent LD blocks for each hOCT gene showed no significant linkage among all three hOCT genes. The transporter activities of MDCK cells that overexpress the hOCT2-T199I, -T201M, and -A270S variants showed significantly decreased uptake of [(3)H]methyl-4-phenylpyridinium acetate (MPP(+)) or [(14)C]tetraethylammonium compared with those cells that overexpress wild-type hOCT2, and the estimated kinetic parameters of these variants for [(3)H]MPP(+) uptake in oocytes showed a 2- to 5-fold increase in K(m) values and a 10- to 20-fold decrease in V(max) values. The allele frequencies of the five functional variants hOCT1-P283L, -P341L, and hOCT2-T199I, -T201M, and -A270S were 1.3, 17, 0.7, 0.7, and 11%, respectively, in a Korean population; the frequency distributions of these variants were not significantly different from those of Chinese and Vietnamese populations. These findings suggest that genetic variants of hOCTs are not linked among three genes in a Korean population, and several of the hOCT genetic variants cause decreased transport activity in vitro compared with the wild type, although the clinical relevance of these variants remains to be evaluated.

Differential effects of tri-allelic 5-HTTLPR polymorphisms in healthy subjects on mood and stress performance after tryptophan challenge.

PubMed

Markus, C Rob; Firk, Christine

2009-12-01

Earlier data suggest that a polymorphism at the serotonin (5-HT) transporter gene (5-HTTLPR) may affect depression particularly in the face of stress due to interactions between 5-HT vulnerability and stress exposure. However, this interaction between 5-HT transporter-linked transcriptional promoter region (5-HTTLPR), 5-HT vulnerability and the affective effects of stress exposure has not yet been investigated. As participants with short-allele 5-HTTLPR genotypes may exhibit enhanced 5-HT vulnerability, this study examines the effects of tryptophan challenge on stress reactivity and performance in healthy participants with S'/S' vs L'/L' genotypes. Sixteen healthy subjects with homozygotic short alleles (S'/S'=S/L(G,) L(G)/L(G)) and 14 subjects with homozygotic long alleles (L'/L'=L(A)/L(A)) of the 5-HTTLPR were tested in a double-blind placebo-controlled design under acute stress exposure following tryptophan challenge or placebo. Although there were no 5-HTTLPR-related differences in stress responses, significant beneficial effects of tryptophan challenge on mood and stress performance were exclusively found in participants with S'/S' genotypes. These findings suggest greater brain 5-HT vulnerability to tryptophan manipulations in participants with S'/S' as compared with L'/L' 5-HTTLPR genotypes. This apparent genetic 5-HT vulnerability may become a meaningful risk factor for depression when brain 5-HT falls below functional need in the face of real severe stressful life events.

Association of serotonin transporter gene polymorphism with obstructive sleep apnea syndrome.

PubMed

Ylmaz, Metin; Bayazit, Yildirim A; Ciftci, Tansu Ulukavak; Erdal, M Emin; Urhan, Meral; Kokturk, Oguz; Kemaloglu, Yusuf K; Inal, Erdogan

2005-05-01

Obstructive sleep apnea syndrome (OSAS) is a common condition characterized by repetitive pharyngeal collapse during sleep and daytime sleepiness. There is genetic predisposition to sleep disorders. Serotonin is involved in the regulation of sleep. The synaptic 5-hydroxytryptamine (HT) is inactivated by presynaptic reuptake, which is mediated by the serotonin transporter. Blockage of the serotonin transporter leads to increased extracellular 5-HT. Polymorphism of the serotonin transporter gene (STG) leads to alterations in serotonin level and may be important in OSAS. In this study, we aimed to assess the role of STG polymorphism in OSAS. Twenty-seven OSAS patients and 162 healthy volunteers were involved in the study. STG polymorphism was investigated using leukocytes obtained from peripheral blood. There was no difference between the genotypes and allele frequencies of the patients and controls regarding VNTR and HTTLPR polymorphisms (P > .05). The VNTR and HTTLPR variants and the frequencies of 12/12, 12/10, L, and S alleles were not significantly different between male and female control subjects (P > .05). The 12/12 and SS genotypes were over-represented in the female patients, whereas 12/10 and LL genotypes were over-represented in the male patients (P < .05). The genotypes 12 to 12 were over-represented in the male controls, whereas the genotypes 12 to 10 and L/S were over-represented in the male patients (P < .05). The alleles 10 and L were more frequent in the male patients than male controls (P < .05). The genotypes of female patients and female controls were not significantly different (P > .05). The allele 10 and L were less frequent in the female patients than female controls with Fisher's exact testing (P < .05). There was no relation between genotypes and clinical data of the patients (P > .05). STG polymorphism appears to be associated with the occurrence of OSAS, especially in male patients. Absence of association of between genetic variants and polysomnography findings may suggest that some mechanisms other than STG polymorphism are involved in OSAS pathophysiology. Our results need confirmation in a larger group of patients with OSAS.

Effects of genetic polymorphisms on the OCT1 and OCT2-mediated uptake of ranitidine.

PubMed

Meyer, Marleen Julia; Seitz, Tina; Brockmöller, Jürgen; Tzvetkov, Mladen Vassilev

2017-01-01

Ranitidine (Zantac®) is a H2-receptor antagonist commonly used for the treatment of acid-related gastrointestinal diseases. Ranitidine was reported to be a substrate of the organic cation transporters OCT1 and OCT2. The hepatic transporter OCT1 is highly genetically variable. Twelve major alleles confer partial or complete loss of OCT1 activity. The effects of these polymorphisms are highly substrate-specific and therefore difficult to predict. The renal transporter OCT2 has a common polymorphism, Ala270Ser, which was reported to affect OCT2 activity. In this study we analyzed the effects of genetic polymorphisms in OCT1 and OCT2 on the uptake of ranitidine and on its potency to inhibit uptake of other drugs. We characterized ranitidine uptake using HEK293 and CHO cells stably transfected to overexpress wild type OCT1, OCT2, or their naturally occurring allelic variants. Ranitidine was transported by wild-type OCT1 with a Km of 62.9 μM and a vmax of 1125 pmol/min/mg protein. Alleles OCT1*5, *6, *12, and *13 completely lacked ranitidine uptake. Alleles OCT1*2, *3, *4, and *10 had vmax values decreased by more than 50%. In contrast, OCT1*8 showed an increase of vmax by 25%. The effects of OCT1 alleles on ranitidine uptake strongly correlated with the effects on morphine uptake suggesting common interaction mechanisms of both drugs with OCT1. Ranitidine inhibited the OCT1-mediated uptake of metformin and morphine at clinically relevant concentrations. The inhibitory potency for morphine uptake was affected by the OCT1*2 allele. OCT2 showed only a limited uptake of ranitidine that was not significantly affected by the Ala270Ser polymorphism. We confirmed ranitidine as an OCT1 substrate and demonstrated that common genetic polymorphisms in OCT1 strongly affect ranitidine uptake and modulate ranitidine's potential to cause drug-drug interactions. The effects of the frequent OCT1 polymorphisms on ranitidine pharmacokinetics in humans remain to be analyzed.

Effects of genetic polymorphisms on the OCT1 and OCT2-mediated uptake of ranitidine

PubMed Central

Meyer, Marleen Julia; Seitz, Tina; Brockmöller, Jürgen

2017-01-01

Background Ranitidine (Zantac®) is a H2-receptor antagonist commonly used for the treatment of acid-related gastrointestinal diseases. Ranitidine was reported to be a substrate of the organic cation transporters OCT1 and OCT2. The hepatic transporter OCT1 is highly genetically variable. Twelve major alleles confer partial or complete loss of OCT1 activity. The effects of these polymorphisms are highly substrate-specific and therefore difficult to predict. The renal transporter OCT2 has a common polymorphism, Ala270Ser, which was reported to affect OCT2 activity. Aim In this study we analyzed the effects of genetic polymorphisms in OCT1 and OCT2 on the uptake of ranitidine and on its potency to inhibit uptake of other drugs. Methods and results We characterized ranitidine uptake using HEK293 and CHO cells stably transfected to overexpress wild type OCT1, OCT2, or their naturally occurring allelic variants. Ranitidine was transported by wild-type OCT1 with a Km of 62.9 μM and a vmax of 1125 pmol/min/mg protein. Alleles OCT1*5, *6, *12, and *13 completely lacked ranitidine uptake. Alleles OCT1*2, *3, *4, and *10 had vmax values decreased by more than 50%. In contrast, OCT1*8 showed an increase of vmax by 25%. The effects of OCT1 alleles on ranitidine uptake strongly correlated with the effects on morphine uptake suggesting common interaction mechanisms of both drugs with OCT1. Ranitidine inhibited the OCT1-mediated uptake of metformin and morphine at clinically relevant concentrations. The inhibitory potency for morphine uptake was affected by the OCT1*2 allele. OCT2 showed only a limited uptake of ranitidine that was not significantly affected by the Ala270Ser polymorphism. Conclusions We confirmed ranitidine as an OCT1 substrate and demonstrated that common genetic polymorphisms in OCT1 strongly affect ranitidine uptake and modulate ranitidine’s potential to cause drug-drug interactions. The effects of the frequent OCT1 polymorphisms on ranitidine pharmacokinetics in humans remain to be analyzed. PMID:29236753

Poecilia picta, a Close Relative to the Guppy, Exhibits Red Male Coloration Polymorphism: A System for Phylogenetic Comparisons

PubMed Central

Lindholm, Anna K.; Sandkam, Ben; Pohl, Kristina; Breden, Felix

2015-01-01

Studies on the evolution of female preference and male color polymorphism frequently focus on single species since traits and preferences are thought to co-evolve. The guppy, Poecilia reticulata, has long been a premier model for such studies because female preferences and orange coloration are well known to covary, especially in upstream/downstream pairs of populations. However, focused single species studies lack the explanatory power of the comparative method, which requires detailed knowledge of multiple species with known evolutionary relationships. Here we describe a red color polymorphism in Poecilia picta, a close relative to guppies. We show that this polymorphism is restricted to males and is maintained in natural populations of mainland South America. Using tests of female preference we show female P. picta are not more attracted to red males, despite preferences for red/orange in closely related species, such as P. reticulata and P. parae. Male color patterns in these closely related species are different from P. picta in that they occur in discrete patches and are frequently Y chromosome-linked. P. reticulata have an almost infinite number of male patterns, while P. parae males occur in discrete morphs. We show the red male polymorphism in P. picta extends continuously throughout the body and is not a Y-linked trait despite the theoretical prediction that sexually-selected characters should often be linked to the heterogametic sex chromosome. The presence/absence of red male coloration of P. picta described here makes this an ideal system for phylogenetic comparisons that could reveal the evolutionary forces maintaining mate choice and color polymorphisms in this speciose group. PMID:26529081

Radiological sacroiliitis, a hallmark of spondylitis, is linked with CARD15 gene polymorphisms in patients with Crohn's disease

PubMed Central

Peeters, H; Vander, C; Laukens, D; Coucke, P; Marichal, D; Van Den Berghe, M; Cuvelier, C; Remaut, E; Mielants, H; De Keyser, F; Vos, M

2004-01-01

Background: Sacroiliitis is a common extraintestinal manifestation of Crohn's disease but its association with the HLA-B27 phenotype is less evident. Polymorphisms in the CARD15 gene have been linked to higher susceptibility for Crohn's disease. In particular, associations have been found with ileal and fibrostenosing disease, young age at onset of disease, and familial cases. Objectives: To investigate whether the presence of sacroiliitis in patients with Crohn's disease is linked to the carriage of CARD15 polymorphisms. Methods: 102 consecutive patients with Crohn's disease were clinically evaluated by a rheumatologist. Radiographs of the sacroiliac joints were taken and assessed blindly by two investigators. The RFLP-PCR technique was used to genotype all patients for three single nucleotide polymorphisms (SNP) in the CARD15 gene. Every SNP was verified by direct sequencing. The HLA-B27 phenotype was determined. Results: Radiological evidence of sacroiliitis with or without ankylosing spondylitis was found in 23 patients (23%), of whom only three were HLA-B27 positive. In contrast, 78% of patients with sacroiliitis carried a CARD15 variant v 48% of those without sacroiliitis (p = 0.01; odds ratio 3.8 (95% confidence interval, 1.3 to 11.5)). Multivariate analysis (logistic regression) showed that the association between sacroiliitis and CARD15 polymorphisms was independent of other CARD15 related phenotypes (ileal and fibrostenosing disease, young age at onset of disease, familial Crohn's disease) (p = 0.039). Conclusions: CARD15 variants were identified as genetic predictors of Crohn's disease related sacroiliitis. An association was demonstrated between these polymorphisms and an extraintestinal manifestation of Crohn's disease. PMID:15308523

Pharmacogenetic screening for polymorphisms in drug-metabolizing enzymes and drug transporters in a Dutch population.

PubMed

Bosch, T M; Doodeman, V D; Smits, P H M; Meijerman, I; Schellens, J H M; Beijnen, J H

2006-01-01

A possible explanation for the wide interindividual variability in toxicity and efficacy of drug therapy is variation in genes encoding drug-metabolizing enzymes and drug transporters. The allelic frequency of these genetic variants, linkage disequilibrium (LD), and haplotype of these polymorphisms are important parameters in determining the genetic differences between patients. The aim of this study was to explore the frequencies of polymorphisms in drug-metabolizing enzymes (CYP1A1, CYP2C9, CYP2C19, CYP3A4, CYP2D6, CYP3A5, DPYD, UGT1A1, GSTM1, GSTP1, GSTT1) and drug transporters (ABCB1[MDR1] and ABCC2[MRP2]), and to investigate the LD and perform haplotype analysis of these polymorphisms in a Dutch population. Blood samples were obtained from 100 healthy volunteers and genomic DNA was isolated and amplified by PCR. The amplification products were sequenced and analyzed for the presence of polymorphisms by sequence alignment. In the study population, we identified 13 new single nucleotide polymorphisms (SNPs) in Caucasians and three new SNPs in non-Caucasians, in addition to previously recognized SNPs. Three of the new SNPs were found within exons, of which two resulted in amino acid changes (A428T in CYP2C9 resulting in the amino acid substitution D143V; and C4461T in ABCC2 in a non-Caucasian producing the amino acid change T1476M). Several LDs and haplotypes were found in the Caucasian individuals. In this Dutch population, the frequencies of 16 new SNPs and those of previously recognized SNPs were determined in genes coding for drug-metabolizing enzymes and drug transporters. Several LDs and haplotypes were also inferred. These data are important for further research to help explain the interindividual pharmacokinetic and pharmacodynamic variability in response to drug therapy.

Cortisol responses to chronic stress in adult macaques: moderation by a polymorphism in the serotonin transporter gene.

PubMed

Qin, Dongdong; Rizak, Joshua; Feng, Xiaoli; Yang, Shangchuan; Yang, Lichuan; Fan, Xiaona; Lü, Longbao; Chen, Lin; Hu, Xintian

2015-02-01

Accumulating evidence has shown that a polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) moderates the association between stress and depressive symptoms. However, the exact etiologies underlying this moderation are not well understood. Here it is reported that among adult female rhesus macaques, an orthologous polymorphism (rh5-HTTLPR) exerted an influence on cortisol responses to chronic stress. It was found that females with two copies of the short allele were associated with increased cortisol responses to chronic stress in comparison to their counterparts who have one or two copies of the long allele. In the absence of stress, no differences related to genotype were observed in these females. This genetic moderation was found without a genetic influence on exposure to stressful situations. Rather it was found to be a genetic modulation of cortisol responses to chronic stress. These findings indicate that the rh5-HTTLPR polymorphism is closely related to hypothalamus-pituitary-adrenal (HPA) axis reactivity, which may increase susceptibility to depression in females with low serotonin transporter efficiency and a history of stress. Copyright © 2014 Elsevier B.V. All rights reserved.

The serotonin transporter promoter variant (5-HTTLPR) and childhood adversity are associated with the personality trait openness to experience.

PubMed

Rahman, Md Shafiqur; Guban, Peter; Wang, Mei; Melas, Philippe A; Forsell, Yvonne; Lavebratt, Catharina

2017-11-01

There is evidence supporting an association between the serotonin-transporter-linked polymorphic region (5-HTTLPR) and the Five Factor Model (FFM) of human personality. 5-HTTLPR has also been found to interact with stressful life events to increase risk of psychopathology. In the present study, by taking into account stressful life events in the form of childhood adversity, we examined the association between 5-HTTLPR and FFM traits using an adult Swedish cohort (N = 3112). We found that 5-HTTLPR was significantly associated with openness (to experience). Specifically, homozygote carriers of the short allele had lower levels of openness compared to carriers of the long allele. In addition, childhood adversity was found to influence openness. These findings support a previously reported association of 5-HTTLPR with openness in a younger cohort and may provide insights into the neurobiological basis of human personality. Copyright © 2017 Elsevier B.V. All rights reserved.

Association of human hippocampal neurochemistry, serotonin transporter genetic variation, and anxiety.

PubMed

Gallinat, Jürgen; Ströhle, Andreas; Lang, Undine E; Bajbouj, Malek; Kalus, Peter; Montag, Christiane; Seifert, Frank; Wernicke, Catrin; Rommelspacher, Hans; Rinneberg, Herbert; Schubert, Florian

2005-05-15

The impact of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) on anxiety-related behavior and related cerebral activation has facilitated the understanding of neurobiological mechanisms of anxiety. However, the influence of the 5-HTTLPR genotype on hippocampal neuronal development and neurochemistry, which is relevant to anxiety behavior, has not been investigated. In 38 healthy subjects, absolute concentrations of N-acetylaspartate (NAA) were measured as a main surrogate parameter for hippocampal neurochemistry on a 3-T scanner. A significantly lower hippocampal NAA concentration in s allele carriers was observed as compared to l/l genotype. Other metabolites (choline, creatine + phosphocreatine, glutamate) were unaffected by genotype. The hippocampal NAA concentration was negatively correlated with trait anxiety scores (STAI). Metabolites measured in the anterior cingulate cortex (reference region) were not associated with genotype. The results are in accordance with the recently reported relationship between hippocampal neuronal development and anxiety behavior in adult animals and show an association between human limbic neurochemistry and genetically driven serotonergic neurotransmission relevant to anxiety.

Pharmacogenomics of high-density lipoprotein-cholesterol-raising therapies

PubMed Central

Aslibekyan, Stella; Straka, Robert J.; Irvin, Marguerite R.; Claas, Steven A.; Arnett, Donna K.

2017-01-01

High levels of HDL cholesterol (HDL-C) have traditionally been linked to lower incidence of cardiovascular disease, prompting the search for effective and safe HDL-C raising pharmaceutical agents. Although drugs such as niacin and fibrates represent established therapeutic approaches, HDL-C response to such therapies is variable and heritable, suggesting a role for pharmacogenomic determinants. Multiple genetic polymorphisms, located primarily in genes encoding lipoproteins, cholesteryl ester transfer protein, transporters and CYP450 genes have been shown to associate with HDL-C drug response in vitro and in epidemiologic studies. However, few of the pharmacogenomic findings have been independently validated, precluding the development of clinical tools that can be used to predict HDL-C response and leaving the goal of personalized medicine to future efforts. PMID:23469915

Functional characterization of 5-oxoproline transport via SLC16A1/MCT1.

PubMed

Sasaki, Shotaro; Futagi, Yuya; Kobayashi, Masaki; Ogura, Jiro; Iseki, Ken

2015-01-23

Thyrotropin-releasing hormone is a tripeptide that consists of 5-oxoproline, histidine, and proline. The peptide is rapidly metabolized by various enzymes. 5-Oxoproline is produced by enzymatic hydrolysis in a variety of peptides. Previous studies showed that 5-oxoproline could become a possible biomarker for autism spectrum disorders. Here we demonstrate the involvement of SLC16A1 in the transport of 5-oxoproline. An SLC16A1 polymorphism (rs1049434) was recently identified. However, there is no information about the effect of the polymorphism on SLC16A1 function. In this study, the polymorphism caused an observable change in 5-oxoproline and lactate transport via SLC16A1. The Michaelis constant (Km) was increased in an SLC16A1 mutant compared with that in the wild type. In addition, the proton concentration required to produce half-maximal activation of transport activity (K0.5, H (+)) was increased in the SLC16A1 mutant compared with that in the wild type. Furthermore, we examined the transport of 5-oxoproline in T98G cells as an astrocyte cell model. Despite the fact that 5-oxoproline is an amino acid derivative, Na(+)-dependent and amino acid transport systems scarcely contributed to 5-oxoproline transport. Based on our findings, we conclude that H(+)-coupled 5-oxoproline transport is mediated solely by SLC16A1 in the cells. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

The translocator protein gene is associated with symptom severity and cerebral pain processing in fibromyalgia.

PubMed

Kosek, Eva; Martinsen, Sofia; Gerdle, Björn; Mannerkorpi, Kaisa; Löfgren, Monika; Bileviciute-Ljungar, Indre; Fransson, Peter; Schalling, Martin; Ingvar, Martin; Ernberg, Malin; Jensen, Karin B

2016-11-01

The translocator protein (TSPO) is upregulated during glia activation in chronic pain patients. TSPO constitutes the rate-limiting step in neurosteroid synthesis, thus modulating synaptic transmission. Related serotonergic mechanisms influence if pro- or anti-nociceptive neurosteroids are produced. This study investigated the effects of a functional genetic polymorphism regulating the binding affinity to the TSPO, thus affecting symptom severity and cerebral pain processing in fibromyalgia patients. Gene-to-gene interactions with a functional polymorphism of the serotonin transporter gene were assessed. Fibromyalgia patients (n=126) were genotyped regarding the polymorphisms of the TSPO (rs6971) and the serotonin transporter (5-HTTLPR/rs25531). Functional magnetic resonance imaging (n=24) was used to study brain activation during individually calibrated pressure pain. Compared to mixed/low TSPO affinity binders, the high TSPO affinity binders rated more severe pain (p=0.016) and fibromyalgia symptoms (p=0.02). A significant interaction was found between the TSPO and the serotonin transporter polymorphisms regarding pain severity (p<0.0001). Functional connectivity analyses revealed that the TSPO high affinity binding group had more pronounced pain-evoked functional connectivity in the right frontoparietal network, between the dorsolateral prefrontal area and the parietal cortex. In conclusion, fibromyalgia patients with the TSPO high affinity binding genotype reported a higher pain intensity and more severe fibromyalgia symptoms compared to mixed/low affinity binders, and this was modulated by interaction with the serotonin transporter gene. To our knowledge this is the first evidence of functional genetic polymorphisms affecting pain severity in FM and our findings are in line with proposed glia-related mechanisms. Furthermore, the functional magnetic resonance findings indicated an effect of translocator protein on the affective-motivational components of pain perception. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Amygdala Volume in Offspring from Multiplex for Alcohol Dependence Families: The Moderating Influence of Childhood Environment and 5-HTTLPR Variation.

PubMed

Hill, Shirley Y; Wang, Shuhui; Carter, Howard; McDermott, Michael D; Zezza, Nicholas; Stiffler, Scott

2013-12-12

The increased susceptibility for developing alcohol dependence seen in offspring from families with alcohol dependence may be related to structural and functional differences in brain circuits that influence emotional processing. Early childhood environment, genetic variation in the serotonin transporter-linked polymorphic region (5-HTTLPR) of the SLCA4 gene and allelic variation in the Brain Derived Neurotrophic Factor (BDNF) gene have each been reported to be related to volumetric differences in the temporal lobe especially the amygdala. Magnetic resonance imaging was used to obtain amygdala volumes for 129 adolescent/young adult individuals who were either High-Risk (HR) offspring from families with multiple cases of alcohol dependence (N=71) or Low-Risk (LR) controls (N=58). Childhood family environment was measured prospectively using age-appropriate versions of the Family Environment Scale during a longitudinal follow-up study. The subjects were genotyped for Brain-Derived Neurotrophic Factor (BDNF) Val66Met and the serotonin transporter polymorphism (5-HTTLPR). Two family environment scale scores (Cohesion and Conflict), genotypic variation, and their interaction were tested for their association with amygdala volumes. Personal and prenatal exposure to alcohol and drugs were considered in statistical analyses in order to more accurately determine the effects of familial risk group differences. Amygdala volume was reduced in offspring from families with multiple alcohol dependent members in comparison to offspring from control families. High-Risk offspring who were carriers of the S variant of the 5-HTTLPR polymorphism had reduced amygdala volume in comparison to those with an LL genotype. Larger amygdala volume was associated with greater family cohesion but only in Low-Risk control offspring. Familial risk for alcohol dependence is an important predictor of amygdala volume even when removing cases with significant personal exposure and covarying for prenatal exposure effects. The present study provides new evidence that amygdala volume is modified by 5-HTTLPR variation in High-Risk families.

Combination of polymorphic variants in serotonin transporter and monoamine oxidase-A genes may influence the risk for early-onset alcoholism.

PubMed

Bordukalo-Niksic, Tatjana; Stefulj, Jasminka; Matosic, Ana; Mokrovic, Gordana; Cicin-Sain, Lipa

2012-12-30

The combinatory effect of polymorphisms in serotonin transporter and monoamine oxidase-A genes on the aetiopathogenesis of alcoholism was investigated in a sample of 714 individuals. Increased frequency of subjects having three 'suspected' genotypes (5-HTTLPR-LL, STin2-1010 and MAO-A 3-repeat allele) was found among type-2 alcoholic patients (P=0.0189). Results highlight serotonergic/genetic contribution to early-onset alcoholism. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Identification of new polymorphisms of the angiotensin I-converting enzyme (ACE) gene, and study of their relationship to plasma ACE levels by two-QTL segregation-linkage analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Villard, E.; Soubrier, F.; Tiret, L.

1996-06-01

Plasma angiotensin I-converting enzyme (ACE) levels are highly genetically determined. A previous segregation-linkage analysis suggested the existence of a functional mutation located within or close to the ACE locus, in almost complete linkage disequilibrium (LD) with the ACE insertion/deletion (I/D) polymorphism and accounting for half the ACE variance. In order to identify the functional variant at the molecular level, we compared ACE gene sequences between four subjects selected for having contrasted ACE levels and I/D genotypes. We identified 10 new polymorphisms, among which 8 were genotyped in 95 healthy nuclear families, in addition to the I/D polymorphism. These polymorphisms couldmore » be divided into two groups: five polymorphisms in the 5{prime} region and three in the coding sequence and the 3{prime} UTR. Within each group, polymorphisms were in nearly complete association, whereas polymorphisms from the two groups were in strong negative LD. After adjustment for the I/D polymorphism, all polymorphisms of the 5{prime} group remained significantly associated with ACE levels, which suggests the existence of two quantitative trait loci (QTL) acting additively on ACE levels. Segregation-linkage analyses including one or two ACE-linked QTLs in LD with two ACE markers were performed to test this hypothesis. The two QTLs and the two markers were assumed to be in complete LD. Results supported the existence of two ACE-linked QTLs, which would explain 38% and 49% of the ACE variance in parents and offspring, respectively. One of these QTLs might be the I/D polymorphism itself or the newly characterized 4656(CT){sub 2/3} polymorphism. The second QTL would have a frequency of {approximately}.20, which is incompatible with any of the yet-identified polymorphisms. More extensive sequencing and extended analyses in larger samples and in other populations will be necessary to characterize definitely the functional variants. 30 refs., 1 fig., 6 tabs.« less

Disposed to distraction: Genetic variation in the cholinergic system influences distractibility but not time-on-task effects

PubMed Central

Berry, Anne S.; Demeter, Elise; Sabhapathy, Surya; English, Brett A.; Blakely, Randy D.; Sarter, Martin; Lustig, Cindy

2015-01-01

Both the passage of time and external distraction make it difficult to keep attention on the task at hand. We tested the hypothesis that time-on-task and external distraction pose independent challenges to attention, and that the brain’s cholinergic system selectively modulates our ability to resist distraction. Participants with a polymorphism limiting cholinergic capacity (Ile89Val variant (rs1013940) of the choline transporter gene SLC5A7) and matched controls completed self-report measures of attention and a laboratory task that measured decrements in sustained attention with and without distraction. We found evidence that distraction and time-on-task effects are independent and that the cholinergic system is strongly linked to greater vulnerability to distraction. Ile89Val participants reported more distraction during everyday life than controls, and their task performance was more severely impacted by the presence of an ecologically valid video distractor (similar to a television playing in the background). These results are the first to demonstrate a specific impairment in cognitive control associated with the Ile89Val polymorphism, and add to behavioral and cognitive neuroscience studies indicating the cholinergic system’s critical role in overcoming distraction. PMID:24666128

Gender Interacts with Opioid Receptor Polymorphism A118G and Serotonin Receptor Polymorphism -1438 A/G on Speed-Dating Success.

PubMed

Wu, Karen; Chen, Chuansheng; Moyzis, Robert K; Greenberger, Ellen; Yu, Zhaoxia

2016-09-01

We examined an understudied but potentially important source of romantic attraction-genetics-using a speed-dating paradigm. The mu opioid receptor (OPRM1) polymorphism A118G (rs1799971) and the serotonin receptor (HTR2A) polymorphism -1438 A/G (rs6311) were studied because they have been implicated in social affiliation. Guided by the social role theory of mate selection and prior genetic evidence, we examined these polymorphisms' gender-specific associations with speed-dating success (i.e., date offers, mate desirability). A total of 262 single Asian Americans went on speed-dates with members of the opposite gender and completed interaction questionnaires about their partners. Consistent with our prediction, significant gender-by-genotype interactions were found for speed-dating success. Specifically, the minor variant of A118G (G-allele), which has been linked to submissiveness/social sensitivity, predicted greater speed-dating success for women, whereas the minor variant of -1438 A/G (G-allele), which has been linked to leadership/social dominance, predicted greater speed-dating success for men. For both polymorphisms, reverse "dampening" effects of minor variants were found for opposite-gender counterparts. These results support previous research on the importance of the opioid and serotonergic systems in social affiliation, indicating that their influence extends to dating success, with opposite, yet gender-norm consistent, effects for men and women.

[Effect of promoter polymorphism of organic cation transporter OCTN1/2 on the susceptibility to Crohns disease: a Meta-analysis].

PubMed

Ma, Mu-yuan; Ma, Zhi-bin; Xu, Hong-yu; Zhao, Jing-bo; Li, Ying; Gao, Meng

2013-03-01

To investigate the associations between polymorphisms of organic cation transporter OCTN1/2 (organic cation transporter 1/2) and the susceptibility of Crohn's disease (CD) through a meta-analysis. Databases of PubMed, EMBASE, MedLine, and CNKI (Chinese), Wanfang (Chinese) were searched for published case control studies on the association between polymorphisms of OCTN1/2 gene and the susceptibility of CD which were published before September 2012. The meta-analysis was applied with Review Manager 4.2 software and Stata 10.0 software. Nineteen eligible studies, including 14 from Europeans, 3 from Asians, 1 from Oceania, and 1 from the US were included in the meta-analysis. In total, significant associations were found between OCTN1/2 polymorphisms and the susceptibility of CD for all genetic models. In subgroup analyses, significant associations were found in the European population for OCTN1/2. Associations were not significant in the non-European population for OCTN1 (TT vs. CT: OR = 1.25, 95%CI: 0.75 - 1.98, P = 0.34; TT vs. CC + CT: OR = 1.48, 95%CI: 0.95 - 2.29, P = 0.08) and for OCTN2 (CC vs. GC: OR = 1.03, 95%CI: 0.68 - 1.56, P = 0.89; CC vs. GG + GC: OR = 1.23, 95%CI: 0.83 - 1.82, P = 0.31). However, there were significant associations found between OCTN1/2 (TT vs. CC, TT + CT vs. CC, CC vs. GG, CC + GC vs. GG) polymorphisms and the susceptibility of CD found in the non-European population. Results from this meta-analysis suggested that OCTN1/2 polymorphisms were associated with the susceptibility of CD in the European population. Associations between OCTN1/2 polymorphisms and the susceptibility of CD in the non-European population required searching for large samples to confirm the findings.

Application of a Physiologically Based Pharmacokinetic Model to Predict OATP1B1-Related Variability in Pharmacodynamics of Rosuvastatin

PubMed Central

Rose, R H; Neuhoff, S; Abduljalil, K; Chetty, M; Rostami-Hodjegan, A; Jamei, M

2014-01-01

Typically, pharmacokinetic–pharmacodynamic (PK/PD) models use plasma concentration as the input that drives the PD model. However, interindividual variability in uptake transporter activity can lead to variable drug concentrations in plasma without discernible impact on the effect site organ concentration. A physiologically based PK/PD model for rosuvastatin was developed that linked the predicted liver concentration to the PD response model. The model was then applied to predict the effect of genotype-dependent uptake by the organic anion-transporting polypeptide 1B1 (OATP1B1) transporter on the pharmacological response. The area under the plasma concentration–time curve (AUC0–∞) was increased by 63 and 111% for the c.521TC and c.521CC genotypes vs. the c.521TT genotype, while the PD response remained relatively unchanged (3.1 and 5.8% reduction). Using local concentration at the effect site to drive the PD response enabled us to explain the observed disconnect between the effect of the OATP1B1 c521T>C polymorphism on rosuvastatin plasma concentration and the cholesterol synthesis response. PMID:25006781

Breast cancer resistance protein (BCRP)-mediated glyburide transport: effect of the C421A/Q141K BCRP single-nucleotide polymorphism.

PubMed

Pollex, Erika K; Anger, Gregory; Hutson, Janine; Koren, Gideon; Piquette-Miller, Micheline

2010-05-01

The antidiabetic agent glyburide (glibenclamide) is frequently used for the treatment of type II diabetes and is increasingly being used for the treatment of gestational diabetes. Evidence suggests that breast cancer resistance protein/ATP-binding cassette, subfamily G, member 2 (ABCG2) expressed in the placenta protects the fetus against the accumulation of glyburide. A number of studies have investigated the significance of several single-nucleotide polymorphisms (SNPs) in the ABCG2 gene. Associations between the Q141K (C421A) SNP and ABCG2 protein expression, membrane surface translocation, efflux activity, or ATPase activity have been shown. Therefore, alterations in glyburide transport across the placenta, resulting in increased fetal glyburide exposure, may be seen in individuals carrying the C421A allele. The purpose of this study is to investigate whether the Q141K SNP causes alterations in ABCG2-mediated glyburide transport. Glyburide accumulation assays were carried out with stably transfected human embryonic kidney (HEK)-293 cells expressing wild-type ABCG2 (Arg482) and polymorphic ABCG2 (Q141K). Glyburide kinetic parameters were determined for comparison of wild-type and SNP ABCG2 activity by simultaneously fitting data for ABCG2-expressing cells (saturable transport) and empty vector-expressing cells (nonsaturable transport) by nonlinear regression analysis. The apparent K(t) and V(max) values for the transfected HEK-293 cells expressing the polymorphic variant (Q141K) of ABCG2 were significantly higher than those values determined for the wild-type ABCG2-expressing cells (p < 0.05). Our results indicate that the Q141K variant of ABCG2 may have the potential to alter the placental pharmacokinetics of glyburide used in pregnancy.

Cystic fibrosis transmembrane regulator haplotypes in households of patients with cystic fibrosis.

PubMed

Furgeri, Daniela Tenório; Marson, Fernando Augusto Lima; Correia, Cyntia Arivabeni Araújo; Ribeiro, José Dirceu; Bertuzzo, Carmen Sílvia

2018-01-30

Nearly 2000 mutations in the cystic fibrosis transmembrane regulator (CFTR) gene have been reported. The F508del mutation occurs in approximately 50-65% of patients with cystic fibrosis (CF). However, molecular diagnosis is not always possible. Therefore, silent polymorphisms can be used to label the mutant allele in households of patients with CF. To verify the haplotypes of four polymorphisms at the CFTR locus in households of patients with CF for pre-fertilization, pre-implantation, and prenatal indirect mutation diagnosis to provide better genetic counseling for families and patients with CF and to associate the genotypes/haplotypes with the F508del mutation screening. GATT polymorphism analysis was performed using direct polymerase chain reaction amplification, and the MP6-D9, TUB09 and TUB18 polymorphism analyses were performed using restriction fragment length polymorphism. Nine haplotypes were found in 37 CFTR alleles, and of those, 24 were linked with the F508del mutation and 13 with other CFTR mutations. The 6 (GATT), C (MP6-D9), G (TUB09), and C (TUB18) haplotypes showed the highest prevalence (48%) of the mutant CFTR allele and were linked to the F508del mutation (64%). In 43% of households analyzed, at least one informative polymorphism can be used for the indirect diagnostic test. CFTR polymorphisms are genetic markers that are useful for identifying the mutant CFTR alleles in households of patients with CF when it is not possible to establish the complete CFTR genotype. Moreover, the polymorphisms can be used for indirect CFTR mutation identification in cases of pre-fertilization, pre-implantation and prenatal analysis. Copyright © 2017 Elsevier B.V. All rights reserved.

Polymorphism of SLC25A32, the folate transporter gene, is associated with plasma folate levels and bone fractures in Japanese postmenopausal women.

PubMed

Urano, Tomohiko; Shiraki, Masataka; Saito, Mitsuru; Sasaki, Noriko; Ouchi, Yasuyoshi; Inoue, Satoshi

2014-10-01

Elevation of homocysteine is associated with an increased risk for bone fractures. We previously reported that the methylenetetrahydrofolate reductase (MTHFR) gene polymorphism is associated with homocysteine levels and fracture. The association between the fracture and folate levels or their related gene polymorphisms is not completely clear. We speculated that the SLC25A32 gene, the mitochondrial inner membrane folate transporter, also could be implicated in the regulation of folate metabolism and fracture. A total of 851 Japanese postmenopausal women participated in the association study between the single nucleotide polymorphism genotype and plasma homocysteine or folate. We also tested the association between the candidate single nucleotide polymorphism and 663 postmenopausal women. The AA genotype of rs2241777 single nucleotide polymorphism at the 3'UTR region in the SLC25A32 gene was associated with lower plasma folate concentration compared with the other genotypes in 851 postmenopausal women. A total of 674 postmenopausal ambulatory Japanese women were followed up for 5.5 ± 0.1 years (mean ± SE). The AA genotype groups also showed an apparently higher rate and earlier onset of incident fractures than the other genotypes. A total of 407 participants had >70% young-adult mean bone mineral density at the start of the observation. These results show that the SLC25A32 gene polymorphism could be a risk factor for lower folate concentration and future fracture. © 2013 Japan Geriatrics Society.

Understanding polymorphism in organic semiconductor thin films through nanoconfinement.

PubMed

Diao, Ying; Lenn, Kristina M; Lee, Wen-Ya; Blood-Forsythe, Martin A; Xu, Jie; Mao, Yisha; Kim, Yeongin; Reinspach, Julia A; Park, Steve; Aspuru-Guzik, Alán; Xue, Gi; Clancy, Paulette; Bao, Zhenan; Mannsfeld, Stefan C B

2014-12-10

Understanding crystal polymorphism is a long-standing challenge relevant to many fields, such as pharmaceuticals, organic semiconductors, pigments, food, and explosives. Controlling polymorphism of organic semiconductors (OSCs) in thin films is particularly important given that such films form the active layer in most organic electronics devices and that dramatic changes in the electronic properties can be induced even by small changes in the molecular packing. However, there are very few polymorphic OSCs for which the structure-property relationships have been elucidated so far. The major challenges lie in the transient nature of metastable forms and the preparation of phase-pure, highly crystalline thin films for resolving the crystal structures and evaluating the charge transport properties. Here we demonstrate that the nanoconfinement effect combined with the flow-enhanced crystal engineering technique is a powerful and likely material-agnostic method to identify existing polymorphs in OSC materials and to prepare the individual pure forms in thin films at ambient conditions. With this method we prepared high quality crystal polymorphs and resolved crystal structures of 6,13-bis(triisopropylsilylethynyl)pentacene (TIPS-pentacene), including a new polymorph discovered via in situ grazing incidence X-ray diffraction and confirmed by molecular mechanic simulations. We further correlated molecular packing with charge transport properties using quantum chemical calculations and charge carrier mobility measurements. In addition, we applied our methodology to a [1]benzothieno[3,2-b][1]1benzothiophene (BTBT) derivative and successfully stabilized its metastable form.

Ploidally antagonistic selection maintains stable genetic polymorphism.

PubMed

Immler, Simone; Arnqvist, Göran; Otto, Sarah Perin

2012-01-01

Understanding the maintenance of genetic variation in the face of selection remains a key issue in evolutionary biology. One potential mechanism for the maintenance of genetic variation is opposing selection during the diploid and haploid stages of biphasic life cycles universal among eukaryotic sexual organisms. If haploid and diploid gene expression both occur, selection can act in each phase, potentially in opposing directions. In addition, sex-specific selection during haploid phases is likely simply because male and female gametophytes/gametes tend to have contrasting life histories. We explored the potential for the maintenance of a stable polymorphism under ploidally antagonistic as well as sex-specific selection. Furthermore, we examined the role of the chromosomal location of alleles (autosomal or sex-linked). Our analyses show that the most permissible conditions for the maintenance of polymorphism occur under negative ploidy-by-sex interactions, where stronger selection for an allele in female than male diploids is coupled with weaker selection against the allele in female than male haploids. Such ploidy-by-sex interactions also promote allele frequency differences between the sexes. With constant fitness, ploidally antagonistic selection can maintain stable polymorphisms for autosomal and X-linked genes but not for Y-linked genes. We discuss the implications of our results and outline a number of biological settings where the scenarios modeled may apply. © 2011 The Author(s). Evolution © 2011 The Society for the Study of Evolution.

BDNF Val66Met is Associated with Introversion and Interacts with 5-HTTLPR to Influence Neuroticism

PubMed Central

Terracciano, Antonio; Tanaka, Toshiko; Sutin, Angelina R; Deiana, Barbara; Balaci, Lenuta; Sanna, Serena; Olla, Nazario; Maschio, Andrea; Uda, Manuela; Ferrucci, Luigi; Schlessinger, David; Costa, Paul T

2010-01-01

Brain-derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurotransmission, and has been linked to neuroticism, a major risk factor for psychiatric disorders. A recent genome-wide association (GWA) scan, however, found the BDNF Val66Met polymorphism (rs6265) associated with extraversion but not with neuroticism. In this study, we examine the links between BDNF and personality traits, assessed using the Revised NEO Personality Inventory (NEO-PI-R), in a sample from SardiNIA (n=1560) and the Baltimore Longitudinal Study of Aging (BLSA; n=1131). Consistent with GWA results, we found that BDNF Met carriers were more introverted. By contrast, in both samples and in a meta-analysis inclusive of published data (n=15251), we found no evidence for a main effect of BDNF Val66Met on neuroticism. Finally, on the basis of recent reports of an epistatic effect between BDNF and the serotonin transporter, we explored a Val66Met × 5-HTTLPR interaction in a larger SardiNIA sample (n=2333). We found that 5-HTTLPR LL carriers scored lower on neuroticism in the presence of the BDNF Val variant, but scored higher on neuroticism in the presence of the BDNF Met variant. Our findings support the association between the BDNF Met variant and introversion and suggest that BDNF interacts with the serotonin transporter gene to influence neuroticism. PMID:20042999

Differential perinatal risk factors in children with attention-deficit/hyperactivity disorder by subtype.

PubMed

Park, Subin; Cho, Soo-Churl; Kim, Jae-Won; Shin, Min-Sup; Yoo, Hee-Jeong; Oh, Seung Min; Han, Doug Hyun; Cheong, Jae Hoon; Kim, Bung-Nyun

2014-11-30

We compared the attention-deficit/hyperactivity disorder(ADHD) combined subtype (ADHD-C) to the ADHD inattentive subtype (ADHD-I) in terms of genetic, perinatal, and developmental risk factors as well as clinical and neuropsychological characteristics. A total of 147 children diagnosed with ADHD between the ages of 6 and 15 years participated in this study. The parents of the children completed the structured diagnostic interview, the ADHD Rating Scale-IV, the Children's Behavior Checklist, and structured questionnaires on perinatal risk factors, and the children underwent a neuropsychological test and were genotyped. A total of 502 children without ADHD were recruited from the community as a healthy control group. The ADHD-C children showed more severe externalizing symptoms, showed more deficits in a continuous performance test, and were more likely to have comorbid disorders. Maternal stress during pregnancy, postpartum depression, and changes in the primary caretaker during first 3 years were significantly associated with both ADHD-I and ADHD-C. The ADHD-I group was less likely to have received regular prenatal check-ups and more likely to have had postnatal medical illness than the ADHD-C group. There were no significant differences in the genotype frequencies of the dopamine transporter (DAT1) and the serotonin transporter -linked polymorphic region (5-HTTLPR) polymorphisms between ADHD-I and ADHD-C groups. This study shows that the inattentive subtype of ADHD is different from the combined subtype in many parameters including severity of symptoms, comorbidity, neuropsychological characteristics, and environmental risk factors. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Effect of Dopamine Transporter Gene (SLC6A3) Variation on Dorsal Anterior Cingulate Function in Attention-Deficit/Hyperactivity Disorder

PubMed Central

Brown, Ariel B.; Biederman, Joseph; Valera, Eve M.; Doyle, Alysa E.; Bush, George; Spencer, Thomas; Monuteaux, Michael C.; Mick, Eric; Whitfield-Gabrieli, Susan; Makris, Nikos; LaViolette, Peter S.; Oscar-Berman, Marlene; Faraone, Stephen V.; Seidman, Larry J.

2010-01-01

Objective - Although Attention-Deficit/Hyperactivity Disorder (ADHD) is associated both with brain alterations in attention and executive function (EF) circuitry and with genetic variations within the dopamine system (including the dopamine transporter gene [SLC6A3]), few studies have directly investigated how genetic variations are linked to brain alterations. We sought to examine how a polymorphism in the 3’ untranslated region (UTR) of SLC6A3, associated with ADHD in meta-analysis, might contribute to variation in dorsal anterior cingulate cortex (dACC) function in subjects with ADHD. Method - We collected fMRI scans of 42 individuals with ADHD, all of European descent and over the age of 17, while they performed the Multi-Source Interference Task (MSIT), a cognitive task shown to activate dACC. SLC6A3 3’ UTR variable number tandem repeat (VNTR) polymorphisms were genotyped and brain activity was compared for groups based on allele status. Results - ADHD individuals homozygous for the 10R allele showed significant hypoactivation in the left dACC compared to 9R-carriers. Exploratory analysis also showed trends toward hypoactivation in the 10R homozygotes in left cerebellar vermis and right lateral prefrontal cortex. Further breakdown of genotype groups showed similar activation in individuals heterozygous and homozygous for the 9R allele. Conclusions - Alterations in activation of attention and EF networks found previously to be involved in ADHD are likely influenced by SLC6A3 genotype. This genotype may contribute to heterogeneity of brain alterations found within ADHD samples. PMID:19676101

Balance between transmitted HLA preadapted and nonassociated polymorphisms is a major determinant of HIV-1 disease progression.

PubMed

Mónaco, Daniela C; Dilernia, Dario A; Fiore-Gartland, Andrew; Yu, Tianwei; Prince, Jessica L; Dennis, Kristine K; Qin, Kai; Schaefer, Malinda; Claiborne, Daniel T; Kilembe, William; Tang, Jianming; Price, Matt A; Farmer, Paul; Gilmour, Jill; Bansal, Anju; Allen, Susan; Goepfert, Paul; Hunter, Eric

2016-09-19

HIV-1 adapts to a new host through mutations that facilitate immune escape. Here, we evaluate the impact on viral control and disease progression of transmitted polymorphisms that were either preadapted to or nonassociated with the new host's HLA. In a cohort of 169 Zambian heterosexual transmission pairs, we found that almost one-third of possible HLA-linked target sites in the transmitted virus Gag protein are already adapted, and that this transmitted preadaptation significantly reduced early immune recognition of epitopes. Transmitted preadapted and nonassociated polymorphisms showed opposing effects on set-point VL and the balance between the two was significantly associated with higher set-point VLs in a multivariable model including other risk factors. Transmitted preadaptation was also significantly associated with faster CD4 decline (<350 cells/µl) and this association was stronger after accounting for nonassociated polymorphisms, which were linked with slower CD4 decline. Overall, the relative ratio of the two classes of polymorphisms was found to be the major determinant of CD4 decline in a multivariable model including other risk factors. This study reveals that, even before an immune response is mounted in the new host, the balance of these opposing factors can significantly influence the outcome of HIV-1 infection. © 2016 Mónaco et al.

Evidence for adaptation from standing genetic variation on an antimicrobial peptide gene in the mussel Mytilus edulis.

PubMed

Gosset, Célia C; Do Nascimento, Joana; Augé, Marie-Thérèse; Bierne, Nicolas

2014-06-01

Genome scans of population differentiation identify candidate loci for adaptation but provide little information on how selection has influenced the genetic structure of these loci. Following a genome scan, we investigated the nature of the selection responsible for the outlying differentiation observed between populations of the marine mussel Mytilus edulis at a leucine/arginine polymorphism (L31R) in the antimicrobial peptide MGD2. We analysed DNA sequence polymorphisms, allele frequencies and population differentiation of polymorphisms closely linked to L31R, and pairwise and third-order linkage disequilibria. An outlying level of population differentiation was observed at L31R only, while no departure from panmixia was observed at linked loci surrounding L31R, as in most of the genome. Selection therefore seems to affect L31R directly. Three hypotheses can explain the lack of differentiation in the chromosomal region close to L31R: (i) hitchhiking has occurred but migration and recombination subsequently erased the signal, (ii) selection was weak enough and recombination strong enough to limit the hitchhiking effect to a very small chromosomal region or (iii) selection acted on a pre-existing polymorphism (i.e. standing variation) at linkage equilibrium with its background. Linkage equilibrium was observed between L31R and linked polymorphisms in every population analysed, as expected under the three hypotheses. However, linkage disequilibrium was observed in some populations between pairs of loci located upstream and downstream to L31R, generating a complex pattern of third-order linkage disequilibria which is best explained by the hypothesis of selection on a pre-existing polymorphism. We hypothesise that selection could be either balanced, maintaining alleles at different frequencies depending on the pathogen community encountered locally by mussels, or intermittent, resulting in sporadic fluctuations in allele frequency. © 2014 John Wiley & Sons Ltd.

A common polymorphism of the MCT1 gene and athletic performance.

PubMed

Fedotovskaya, Olga N; Mustafina, Leysan J; Popov, Daniil V; Vinogradova, Olga L; Ahmetov, Ildus I

2014-01-01

In red skeletal muscle, monocarboxylate transporter 1 (MCT1) is required for lactate to enter the myocytes for oxidation. The A1470T polymorphism (rs1049434) in the MCT1 gene was shown to be associated with lactate transport rates in human skeletal muscles. The aim of the study was to compare genotype and allele frequencies of the MCT1 gene polymorphism in 323 Russian athletes and 467 nonathletic controls and to investigate the association of the MCT1 gene A1470T polymorphism with maximal oxygen consumption and maximal lactate concentration in rowers (n = 79). Genotyping for the A1470T MCT1 polymorphism was performed by PCR-RFLP method. Physiological measurements of 79 Russian rowers of national competitive standard were determined during an incremental test to exhaustion on a rowing ergometer. Frequencies of the A allele (71.8% vs 62.5%, P < .0001) and AA genotype (59.8% vs 39.4%, P < .0001) were significantly higher in endurance-oriented athletes (n = 142) than in the control group. Mean blood lactate concentration was higher in male rowers with the T allele (AT+TT 10.26 ± 1.89 mmol/L, AA 8.75 ± 1.69 mmol/L, P = .005). MCT1 gene A1470T polymorphism is associated with endurance athlete status and blood lactate level after intensive exercise.

ADIPOQ rs266729 G/C gene polymorphism and plasmatic adipocytokines connect metabolic syndrome to colorectal cancer

PubMed Central

Divella, Rosa; Daniele, Antonella; Mazzocca, Antonio; Abbate, Ines; Casamassima, Porzia; Caliandro, Cosimo; Ruggeri, Eustachio; Naglieri, Emanuele; Sabbà, Carlo; De Luca, Raffaele

2017-01-01

Background: ADIPOQ gene, which encode for Adiponectin (APN), is sited on chromosome 3q27 and linked to a susceptibility locus for metabolic syndrome (MetS). The ADIPOQ rs266729 G/C gene polymorphism is significantly associated with low APN levels and linked to susceptibility to develop cancer. In addition, decreased APN serum levels are linked with tumor development and progression and inversely associated with markers of inflammation. Here, we investigate the influence of APN rs266729 G/C polymorphism on adipocytokine circulating levels and their association with MetS in colorectal cancer patients (CRC). Methods: Blood samples from 105 CRC patients (50 women and 55 men) with and without MetS were genotyped for APN rs266729 G/C polymorphism by TETRA ARMS PCR. ELISA assay was used to measure plasma levels of APN and inflammatory TNF-α cytokine. Biochemical and anthropometric parameters of MetS were also analyzed. Results: We found that CRC patients (N=75) with genotype rs266729G/C or carriers of G allele were associated with a significantly increased risk of MetS development (OR =2.9) compared to those with CC genotype (N=30). Also, CG/GG genotypes were associated with significantly lower plasma APN levels and higher TNF-α levels in comparison to CC genotype (P=0.034) and APN levels were decreased in relation to BMI increases (P=0.001). Conclusions: Our findings show that APN rs266729 G/C polymorphism is associated with lower APN levels in CRC patients, indicating that decreased circulating levels of APN may be a determinant risk factor for CRC in MetS patients. PMID:28529612

A Polymorphism in the Retinol Binding Protein 4 Gene is Not Associated with Gestational Diabetes Mellitus in Several Different Ethnic Groups

PubMed Central

Urschitz, Johann; Sultan, Omar; Ward, Kenneth

2011-01-01

Objective Various Asian and Pacifific Islander groups have higher prevalence rates of type 2 diabetes and gestational diabetes. This increased incidence is likely to include genetic factors. Single nucleotide polymorphisms in the retinol binding protein 4 gene have been linked to the occurrence of type 2 diabetes. Hypothesizing a link between retinol binding protein 4 and gestational diabetes, we performed a candidate gene study to look for an association between an important retinol binding protein gene polymorphism (rs3758539) and gestational diabetes. Study Design Blood was collected from Caucasian, Asian, and Pacific Islander women diagnosed with gestational diabetes and from ethnically matched non-diabetic controls. DNA was extracted and real time PCR technology (TaqMan, Applied Biosystems) used to screen for the rs3758539 single nucleotide polymorphism located 5′ of exon 1 of the retinol binding protein 4 gene. Results Genotype and allele frequencies in the controls and gestational diabetes cases were tested using chi-square contingency tests. Genotype frequencies were in Hardy-Weinberg equilibrium. There was no association between the rs3758539 retinol binding protein 4 single nucleotide polymorphism and gestational diabetes in the Caucasian, Filipino, or Pacific Islander groups. Conclusion Interestingly, the rs3758539 retinol binding protein 4 single nucleotide polymorphism was not found to be associated with gestational diabetes. The absence of association suggests that gestational and type 2 diabetes may have more divergent molecular pathophysiology than previously suspected. PMID:21886308

Comparison of CYP2C9, CYP2C19, CYP2D6, ABCB1, and SLCO1B1 gene-polymorphism frequency in Russian and Nanai populations

PubMed Central

Sychev, Dmitrij Alekseevitch; Shuev, Grigorij Nikolaevich; Suleymanov, Salavat Shejhovich; Ryzhikova, Kristina Anatol’evna; Mirzaev, Karin Badavievich; Grishina, Elena Anatol’evna; Snalina, Natalia Evgenievna; Sozaeva, Zhannet Alimovna; Grabuzdov, Anton Mikhailovich; Matsneva, Irina Andreevna

2017-01-01

Background The efficiency and safety of drug therapy depends on the peculiarities of functioning of the P450 cytochrome group and transporting proteins. There are significant differences for single-nucleotide polymorphism (SNP) frequency. Materials and methods We studied the peculiarities of P450 cytochrome polymorphisms, SLCO1B1 transporting protein, and P-glycoprotein carriage in healthy volunteers in the Nanai ethnic group living in Russia, and compared them to the carriage of SNPs in the Russian population according to literature data. Results After performing the real-time polymerase chain reactions on the samples from 70 healthy volunteers from the Nanai group, for the CYP2C9*2C430T polymorphism we determined 70 CC-genotype carriers. As for the CYP2C9*3A1075C polymorphism, we found 62 AA-genotype carriers and eight AC-genotype carriers. For the CYP2C19*2G681A polymorphism, we determined 39 GG-genotype carriers and 28 GA-genotype carriers, for the CYP2C19*3G636A polymorphism 58 GG-genotype carriers and 12 GA-genotype carriers, and for the CYP2C19*17C806T polymorphism 67 CC-genotype carriers and three CT-genotype carriers. For the CYP2D6*4G1846A polymorphism, the GG genotype had 68 carriers, and the GA genotype two carriers. For the ABCB1*6C3435T polymorphism, there were 19 CC-genotype carriers and 39 CT-genotype carriers. For the SLCO1B1*5T521C polymorphism, the TT genotype had 41 carriers and the CT genotype 25 carriers. The distribution of genotypes fitted the Hardy–Weinberg equilibrium for all the polymorphisms, except those of CYP2C9*2. There were also significant differences in allele frequencies for some polymorphisms between the Nanais and the Russians. Conclusion In the Nanai population, there are polymorphisms connected with the decrease in safety and efficiency of drug therapy. Studying the ethnic differences might influence the determination of priority in the introduction of pharmacogenetic tests in clinical practice in different regions of Russia. PMID:28435307

Lack of association of the serotonin transporter polymorphism with the sudden infant death syndrome in the San Diego Dataset.

PubMed

Paterson, David S; Rivera, Keith D; Broadbelt, Kevin G; Trachtenberg, Felicia L; Belliveau, Richard A; Holm, Ingrid A; Haas, Elisabeth A; Stanley, Christina; Krous, Henry F; Kinney, Hannah C; Markianos, Kyriacos

2010-11-01

Dysfunction of medullary serotonin (5-HT)-mediated respiratory and autonomic function is postulated to underlie the pathogenesis of the majority of sudden infant death syndrome (SIDS) cases. Several studies have reported an increased frequency of the LL genotype and L allele of the 5-HT transporter (5-HTT) gene promoter polymorphism (5-HTTLPR), which is associated with increased transcriptional activity and 5-HT transport in vitro, in SIDS cases compared with controls. These findings raise the possibility that this polymorphism contributes to or exacerbates existing medullary 5-HT dysfunction in SIDS. In this study, we tested the hypothesis that the frequency of LL genotype and L allele are higher in 179 SIDS cases compared with 139 controls of multiple ethnicities in the San Diego SIDS Dataset. We observed no significant association of genotype or allele with SIDS cases either in the total cohort or on stratification for ethnicity. These observations do not support previous findings that the L allele and/or LL genotype of the 5-HTTLPR are associated with SIDS.

Effects of paroxetine on intravaginal ejaculatory latency time in Egyptian patients with lifelong premature ejaculation as a function of serotonin transporter polymorphism.

PubMed

Salem, A M; Kamel, I I; Rashed, L A; GamalEl Din, S F

2017-01-01

Premature ejaculation (PE) is a common ejaculatory complaint. The estimated rates among Turkish men reached 20%, although the severest type of PE (lifelong PE) usually does not exceed 2.3%. This could be seen in line with two survey studies involving five nations. They revealed that 2.5% of men had an intravaginal ejaculation latency time of <1 min and 6% of <2 min. Rapid ejaculation may be treated pharmacologically with a variety of different medications that act either centrally or locally to delay ejaculation and subsequent orgasm. Antidepressants, particularly members of the selective serotonin reuptake inhibitor class, retard ejaculation significantly. Recently, it was postulated that men with lifelong PE might result from a combination of polymorphisms of the serotonergic transporter and receptors, and other neurotransmitters and/or receptors. Our findings augment the significant effect of paroxetine in delaying ejaculation in the responders (P<0.001). Meanwhile, the findings do not suggest a positive association between such response and serotonin transporter gene promoter polymorphism.

Lack of Association of the Serotonin Transporter Polymorphism With the Sudden Infant Death Syndrome in the San Diego Dataset

PubMed Central

Paterson, David S.; Rivera, Keith D.; Broadbelt, Kevin G.; Trachtenberg, Felicia L.; Belliveau, Richard A.; Holm, Ingrid A.; Haas, Elisabeth A.; Stanley, Christina; Krous, Henry F.; Kinney, Hannah C.; Markianos, Kyriacos

2011-01-01

Dysfunction of medullary serotonin (5-HT)-mediated respiratory and autonomic function is postulated to underlie the pathogenesis of the majority of sudden infant death syndrome (SIDS) cases. Several studies have reported an increased frequency of the LL genotype and L allele of the 5-HT transporter (5-HTT) gene promoter polymorphism (5-HTTLPR), which is associated with increased transcriptional activity and 5-HT transport in vitro, in SIDS cases compared with controls. These findings raise the possibility that this polymorphism contributes to or exacerbates existing medullary 5-HT dysfunction in SIDS. In this study, we tested the hypothesis that the frequency of LL genotype and L allele are higher in 179 SIDS cases compared with 139 controls of multiple ethnicities in the San Diego SIDS Dataset. We observed no significant association of genotype or allele with SIDS cases either in the total cohort or on stratification for ethnicity. These observations do not support previous findings that the L allele and/or LL genotype of the 5-HTTLPR are associated with SIDS. PMID:20661167

[Polymorphic loci and polymorphism analysis of short tandem repeats within XNP gene].

PubMed

Liu, Qi-Ji; Gong, Yao-Qin; Guo, Chen-Hong; Chen, Bing-Xi; Li, Jiang-Xia; Guo, Yi-Shou

2002-01-01

To select polymorphic short tandem repeat markers within X-linked nuclear protein (XNP) gene, genomic clones which contain XNP gene were recognized by homologous analysis with XNP cDNA. By comparing the cDNA with genomic DNA, non-exonic sequences were identified, and short tandem repeats were selected from non-exonic sequences by using BCM search Launcher. Polymorphisms of the short tandem repeats in Chinese population were evaluated by PCR amplification and PAGE. Five short tandem repeats were identified from XNP gene, two of which were polymorphic. Four and 11 alleles were observed in Chinese population for XNPSTR1 and XNPSTR4, respectively. Heterozygosities were 47% for XNPSTR1 and 70% for XNPSTR4. XNPSTR1 and XNPSTR4 localized within 3' end and intron 10, respectively. Two polymorphic short tandem repeats have been identified within XNP gene and will be useful for linkage analysis and gene diagnosis of XNP gene.

Gray Matter Volume in Adolescent Anxiety: An Impact of the Brain-Derived Neurotrophic Factor Val[superscript 66]Met Polymorphism?

ERIC Educational Resources Information Center

Mueller, Sven C.; Aouidad, Aveline; Gorodetsky, Elena; Goldman, David; Pine, Daniel S.; Ernst, Monique

2013-01-01

Objective: Minimal research links anxiety disorders in adolescents to regional gray matter volume (GMV) abnormalities and their modulation by genetic factors. Prior research suggests that a brain-derived neurotrophic factor (BNDF) Val[superscript 66]Met polymorphism may modulate such brain morphometry profiles. Method: Using voxel-based…

Randomly amplified polymorphic DNA linkage relationships in different Norway spruce populations

Treesearch

M. Troggio; Thomas L. Kubisiak; G. Bucci; P. Menozzi

2001-01-01

We tested the constancy of linkage relationships of randomly amplified polymorphic DNA (RAPD) marker loci used to construct a population-based consensus map in material from an Italian stand of Picea abies (L.) Karst. in 29 individuals from three Norwegian populations. Thirteen marker loci linked in the Italian stand did show a consistent locus...

Serotonin transporter polymorphism modifies the association between depressive symptoms and sleep onset latency complaint in elderly people: results from the 'InveCe.Ab' study.

PubMed

Polito, Letizia; Davin, Annalisa; Vaccaro, Roberta; Abbondanza, Simona; Govoni, Stefano; Racchi, Marco; Guaita, Antonio

2015-04-01

Previous studies have documented the involvement of the central nervous system serotonin in promoting wakefulness. There are few and conflicting results over whether there is an actual association between bearing the short allele of serotonin transporter promoter polymorphism (5-HTTLPR) and worse sleep quality. This study examined whether sleep onset latency complaint is associated with the 5-HTTLPR triallelic polymorphism in the SLC6A4 gene promoter and whether this polymorphism influences the relationship between sleep onset latency complaint and depressive symptoms in elderly people. A total of 1321 community-dwelling individuals aged 70-74 years were interviewed for sleep onset latency complaint and for sleep medication consumption. Participants' genomic DNA was typed for 5-HTTLPR and rs25531 polymorphisms. Depressive symptoms were evaluated with the Geriatric Depression Scale Short form and general medical comorbidity was assessed by the Cumulative Illness Rating Scale. The presence of a past history of depression was recorded. The S' allele of the 5-HTTLPR triallelic polymorphism was associated with sleep onset latency complaint. This association was maintained after adjusting for depressive symptoms, sex, age, history of depression and medical comorbidity. After stratification for 5-HTTLPR/rs25531, only in S'S' individuals high depressive symptoms were actually associated with sleep onset latency complaint. These data indicate that the low-expressing 5-HTTLPR triallelic polymorphism is an independent risk factor for sleep onset latency disturbance. Furthermore, the 5-HTTLPR genotype influences the association between depressive symptoms and sleep onset latency complaint. © 2014 European Sleep Research Society.

Assessment of the rs4340 ACE gene polymorphism in acute coronary syndrome in a Western Mexican population.

PubMed

Valdez-Haro, A; Valle, Y; Valdes-Alvarado, E; Casillas-Muñoz, F; Muñoz-Valle, J F; Reynoso-Villalpando, G L; Flores-Salinas, H E; Padilla-Gutiérrez, J R

2017-09-27

Acute coronary syndrome (ACS) is considered one of the main causes of death worldwide. Contradictory findings concerning the impact of the angiotensin-converting enzyme (ACE) gene on cardiovascular diseases have been reported. Previous conclusions point out that the variability in results depends on ethnicity and genetic polymorphisms to determine the association of rs4340 polymorphisms of the ACE gene and ACE circulating levels in ACS. Genotyping of rs4340 polymorphisms was performed in a total of 600 individuals from Western Mexico divided into two groups: the ACS and the control group (CG). The polymorphisms were identified by polymerase chain reaction. Serum ACE concentration was determined by enzyme-linked immunosorbent assay. D/D carriers had higher ACE levels than I/I carriers (3.6 vs 2.8 ng/mL, P < 0.0021) in the CG. The D/D genotype of the rs4340 polymorphism is associated with higher ACE concentration levels; however, the polymorphism was not associated with ACS.

MTHFR 677C-->T and 1298A-->C polymorphisms in children with Down syndrome and acute myeloid leukemia in Brazil.

PubMed

Amorim, Marcia R; Zanrosso, Crisiane Wais; Magalhães, Isis Q; Pereira, Simone C; Figueiredo, Alexandre; Emerenciano, Mariana; Pinheiro, Vitoria Regia; d'Andréa, Maria Lydia; Orioli, Ieda M; Koifman, Sergio; Pombo-de-Oliveira, Maria S

2008-12-01

Down syndrome (DS) is an important risk factor associated with acute leukemia (AL). The presence of polymorphisms that reduce 5,10-methylenetetrahydrofolate reductase (MTHFR) activity has been linked to the multifactorial leukemogenic process. The authors have conducted a study to test whether 677C-->T and/or 1298A-->C polymorphisms of MTHFR would play an additional role in susceptibility of acute myeloid leukemia (AML) in DS children. They also verified whether any polymorphism in the MTHFR gene was associated with the risk of DS. Genetic polymorphisms determination was carried out in 248 samples from healthy individuals as controls and a total of 115 DS children (65 without leukemia and 50 with AML). The present study failed to reveal any association between these polymorphisms and risk of AML in DS children. The data also indicate that MTHFR polymorphisms are not associated with risk of being a DS child.

Inherent X-Linked Genetic Variability and Cellular Mosaicism Unique to Females Contribute to Sex-Related Differences in the Innate Immune Response.

PubMed

Spolarics, Zoltan; Peña, Geber; Qin, Yong; Donnelly, Robert J; Livingston, David H

2017-01-01

Females have a longer lifespan and better general health than males. Considerable number of studies also demonstrated that, after trauma and sepsis, females present better outcomes as compared to males indicating sex-related differences in the innate immune response. The current notion is that differences in the immuno-modulatory effects of sex hormones are the underlying causative mechanism. However, the field remains controversial and the exclusive role of sex hormones has been challenged. Here, we propose that polymorphic X-linked immune competent genes, which are abundant in the population are important players in sex-based immuno-modulation and play a key role in causing sex-related outcome differences following trauma or sepsis. We describe the differences in X chromosome (ChrX) regulation between males and females and its consequences in the context of common X-linked polymorphisms at the individual as well as population level. We also discuss the potential pathophysiological and immune-modulatory aspects of ChrX cellular mosaicism, which is unique to females and how this may contribute to sex-biased immune-modulation. The potential confounding effects of ChrX skewing of cell progenitors at the bone marrow is also presented together with aspects of acute trauma-induced de novo ChrX skewing at the periphery. In support of the hypothesis, novel observations indicating ChrX skewing in a female trauma cohort as well as case studies depicting the temporal relationship between trauma-induced cellular skewing and the clinical course are also described. Finally, we list and discuss a selected set of polymorphic X-linked genes, which are frequent in the population and have key regulatory or metabolic functions in the innate immune response and, therefore, are primary candidates for mediating sex-biased immune responses. We conclude that sex-related differences in a variety of disease processes including the innate inflammatory response to injury and infection may be related to the abundance of X-linked polymorphic immune-competent genes, differences in ChrX regulation, and inheritance patterns between the sexes and the presence of X-linked cellular mosaicism, which is unique to females.

Boys' serotonin transporter genotype affects maternal behavior through self-control: a case of evocative gene-environment correlation.

PubMed

Pener-Tessler, Roni; Avinun, Reut; Uzefovsky, Florina; Edelman, Shany; Ebstein, Richard P; Knafo, Ariel

2013-02-01

Self-control, involving processes such as delaying gratification, concentrating, planning, following instructions, and adapting emotions and behavior to situational requirements and social norms, may have a profound impact on children's adjustment. The importance of self-control suggests that parents are likely to modify their parenting based on children's ability for self-control. We study the effect of children's self-control, a trait partially molded by genetics, on their mothers' parenting, a process of evocative gene-environment correlation. Israeli 3.5-year-old twins (N = 320) participated in a lab session in which their mothers' parenting was observed. DNA was available from most children (N = 228). Mothers described children's self-control in a questionnaire. Boys were lower in self-control and received less positive parenting from their mothers, in comparison with girls. For boys, and not for girls, the serotonin transporter linked polymorphic region gene predicted mothers' levels of positive parenting, an effect mediated by boys' self-control. The implications of this evocative gene-environment correlation and the observed sex differences are discussed.

Relationships between FTO rs9939609, MC4R rs17782313, and PPARγ rs1801282 polymorphisms and the occurrence of selected metabolic and hormonal disorders in middle-aged and elderly men - a preliminary study.

PubMed

Rotter, Iwona; Skonieczna-Żydecka, Karolina; Kosik-Bogacka, Danuta; Adler, Grażyna; Rył, Aleksandra; Laszczyńska, Maria

2016-01-01

Metabolic disorders, including MetS, obesity, and lipid disorders, may be related to genetic factors. Metabolic disorders are associated with decreased TS levels in aging men. The aim of this study was to evaluate the relationship between FTO rs9939609, MC4R rs17782313, and PPARγ rs1801282 polymorphisms and the presence of MetS and its components, the concurrent lipid disorders, as well as sex hormone concentrations. This study involved 272 men of Caucasian descent aged 50-75 years. Lipid profile, including TCh, LDL, HDL, and TG, was evaluated by spectrophotometric method. Anthropometric measurements concerned WC and blood pressure. MetS was diagnosed according to the criteria of the IDF. Sex hormone profile, including TST, FTS, E 2 , DHEAS, and SHBG, was examined using enzyme-linked immunosorbent assay. Polymorphisms within FTO , MC4R , and PPARγ genes were identified using polymerase chain reaction-restriction fragments length polymorphism. This study did not show links between the analyzed genetic polymorphisms and the presence of MetS, T2DM, HT, and obesity. However, higher concentrations of TCh and LDL were found in men with the FTO rs9939609 polymorphism in the recessive mode of inheritance ( P =0.03 and P =0.05, respectively). Lower WC was found to be associated with MC4R rs17782313 gene inherited in the same model ( P =0.005). FTO rs9939609, MC4R rs17782313, and PPARγ rs1801282 polymorphisms seem to have little effect on the incidence of metabolic malfunctions and no effect on androgen-related disorders in the examined middle-aged and elderly men.

Promoter Polymorphism G-6A, which Modulates Angiotensinogen Gene Expression, Is Associated with Non-Familial Sick Sinus Syndrome

PubMed Central

Chen, Jan-Yow; Liou, Ying-Ming; Wu, Hong-Dar Isaac; Lin, Kuo-Hung; Chang, Kuan-Cheng

2012-01-01

Background It is well known that familial sick sinus syndrome (SSS) is caused by functional alterations of ion channels and gap junction. Limited information is available on the mechanism of age-related non-familial SSS. Although evidence shows a close link between arrhythmia and the renin-angiotensin system (RAS), it remains to be determined whether the RAS is involved in the pathogenesis of non-familial SSS. Methods In this study, 113 patients with documented non-familial SSS and 125 controls were screened for angiotensinogen (AGT) and gap junction protein-connexin 40 (Cx40) promoter polymorphisms by gene sequencing, followed by an association study. A luciferase assay was used to determine the transcriptional activity of the promoter polymorphism. The interaction between nuclear factors and the promoter polymorphism was characterized by an electrophoretic mobility shift assay (EMSA). Results Association study showed the Cx40 -44/+71 polymorphisms are not associated with non-familial SSS; however, it indicated that four polymorphic sites at positions -6, -20, -152, and -217 in the AGT promoter are linked to non-familial SSS. Compared to controls, SSS patients had a lower frequency of the G-6A AA genotype (OR 2.88, 95% CI 1.58–5.22, P = 0.001) and a higher frequency of the G allele at -6 position (OR 2.65, 95% CI 1.54–4.57, P = 0.0003). EMSA and luciferase assays confirmed that nucleotide G at position -6 modulates the binding affinity with nuclear factors and yields a lower transcriptional activity than nucleotide A (P<0.01). Conclusion G-6A polymorphism, which modulates the transcriptional activity of the AGT promoter, may contribute to non-familial SSS susceptibility. PMID:22242192

BDNF polymorphism predicts the rate of decline in skilled task performance and hippocampal volume in healthy individuals

PubMed Central

Sanchez, M Millan; Das, D; Taylor, J L; Noda, A; Yesavage, J A; Salehi, A

2011-01-01

Numerous studies have indicated a link between the presence of polymorphism in brain-derived neurotrophic factor (BDNF) and cognitive and affective disorders. However, only a few have studied these effects longitudinally along with structural changes in the brain. This study was carried out to investigate whether valine-to-methionine substitution at position 66 (val66met) of pro-BDNF could be linked to alterations in the rate of decline in skilled task performance and structural changes in hippocampal volume. Participants consisted of 144 healthy Caucasian pilots (aged 40–69 years) who completed a minimum of 3 consecutive annual visits. Standardized flight simulator score (SFSS) was measured as a reliable and quantifiable indicator for skilled task performance. In addition, a subset of these individuals was assessed for hippocampal volume alterations using magnetic resonance imaging. We found that val66met substitution in BDNF correlated longitudinally with the rate of decline in SFSS. Structurally, age-dependent hippocampal volume changes were also significantly altered by this substitution. Our study suggests that val66met polymorphism in BDNF can be linked to the rate of decline in skilled task performance. Furthermore, this polymorphism could be used as a predictor of the effects of age on the structure of the hippocampus in healthy individuals. Such results have implications for understanding possible disabilities in older adults performing skilled tasks who are at a higher risk for cognitive and affective disorders. PMID:22833197

Genomic signatures of selection at linked sites: unifying the disparity among species

PubMed Central

Cutter, Asher D.; Payseur, Bret A.

2014-01-01

Population genetics theory supplies powerful predictions about how natural selection interacts with genetic linkage to sculpt the genomic landscape of nucleotide polymorphism. Both the spread of beneficial mutations and removal of deleterious mutations act to depress polymorphism levels, especially in low-recombination regions. However, empiricists have documented extreme disparities among species. Here we characterize the dominant features that could drive variation in linked selection among species, including roles for selective sweeps being ‘hard’ or ‘soft’, and concealing by demography and genomic confounds. We advocate targeted studies of close relatives to unify our understanding of how selection and linkage interact to shape genome evolution. PMID:23478346

Antisense expression of the peptide transport gene AtPTR2-B delays flowering and arrests seed development in transgenic Arabidopsis plants.

PubMed Central

Song, W; Koh, S; Czako, M; Marton, L; Drenkard, E; Becker, J M; Stacey, G

1997-01-01

Previously, we identified a peptide transport gene, AtPTR2-B, from Arabidopsis thaliana that was constitutively expressed in all plant organs, suggesting an important physiological role in plant growth and development. To evaluate the function of this transporter, transgenic Arabidopsis plants were constructed expressing antisense or sense AtPTR2-B. Genomic Southern analysis indicated that four independent antisense and three independent sense AtPTR2-B transgenic lines were obtained, which was confirmed by analysis of the segregation of the kanamycin resistance gene carried on the T-DNA. RNA blot data showed that the endogenous AtPTR2-B mRNA levels were significantly reduced in transgenic leaves and flowers, but not in transgenic roots. Consistent with this reduction in endogenous AtPTR2-B mRNA levels, all four antisense lines and one sense line exhibited significant phenotypic changes, including late flowering and arrested seed development. These phenotypic changes could be explained by a defect in nitrogen nutrition due to the reduced peptide transport activity conferred by AtPTR2-B. These results suggest that AtPTR2-B may play a general role in plant nutrition. The AtPTR2-B gene was mapped to chromosome 2, which is closely linked to the restriction fragment length polymorphism marker m246. PMID:9232875

Contact lens fitting in a patient with Alport syndrome and posterior polymorphous corneal dystrophy: a case report.

PubMed

Rosa, Juliana Maria da Silva; Andrade Sobrinho, Marcelo Vicente de; Lipener, César

2016-02-01

Alport Syndrome is a hereditary disease that is caused by a gene mutation and affects the production of collagen in basement membranes; this condition causes hemorrhagic nephritis associated with deafness and ocular changes. The X-linked form of this disease is the most common and mainly affects males. Typical ocular findings are dot-and-fleck retinopathy, anterior lenticonus, and posterior polymorphous corneal dystrophy. Some cases involving polymorphous corneal dystrophy and corneal ectasia have been previously described. Here we present a case report of a 33-year-old female with Alport syndrome, posterior polymorphous corneal dystrophy, and irregular astigmatism, whose visual acuity improved with a rigid gas permeable contact lens.

[THE INFLUENCE OF SEROTONIN TRANSPORTER AND MONOAMINE OXIDASE A GENES POLYMORPHISM ON PSYCHO-EMOTION AND KARYOLOGICAL STABILITY OF ATHLETES].

PubMed

Kalaev, V N; Nechaeva, M S; Korneeva, O S; Cherenkov, D A

2015-11-01

The influence of polymorphism of the serotonin transporter and monoamine oxidase A genes, associated with man's aggressiveness on the psycho-emotional state and karyological status of single combat athletes. It was revealed that the carriers of less active ("short"), monoamine oxidase A gene variant have a high motivation to succeed and less rigidity and frustrated, compared to the carriers of more active ("long") version of the gene. Heterozygote carriers of less active ("short") variant of the serotonin transporter gene 5-HTTL had more physical aggression, guilt and were less frustrated compared with carriers of two long alleles. It has been revealed the association of studied genes with the karyological status of athletes. So fighters who are carriers of the short and long alleles of the serotonin transporter gene had more cells with nuclear abnormalities in the buccal epithelium than single combat athletes which both alleles were long.

Functional genetic variants in the vesicular monoamine transporter 1 modulate emotion processing.

PubMed

Lohoff, F W; Hodge, R; Narasimhan, S; Nall, A; Ferraro, T N; Mickey, B J; Heitzeg, M M; Langenecker, S A; Zubieta, J-K; Bogdan, R; Nikolova, Y S; Drabant, E; Hariri, A R; Bevilacqua, L; Goldman, D; Doyle, G A

2014-01-01

Emotional behavior is in part heritable and often disrupted in psychopathology. Identification of specific genetic variants that drive this heritability may provide important new insight into molecular and neurobiological mechanisms involved in emotionality. Our results demonstrate that the presynaptic vesicular monoamine transporter 1 (VMAT1) Thr136Ile (rs1390938) polymorphism is functional in vitro, with the Ile allele leading to increased monoamine transport into presynaptic vesicles. Moreover, we show that the Thr136Ile variant predicts differential responses in emotional brain circuits consistent with its effects in vitro. Lastly, deep sequencing of bipolar disorder (BPD) patients and controls identified several rare novel VMAT1 variants. The variant Phe84Ser was only present in individuals with BPD and leads to marked increase monoamine transport in vitro. Taken together, our data show that VMAT1 polymorphisms influence monoamine signaling, the functional response of emotional brain circuits and risk for psychopathology.

Pharmacogenetics of taxanes: impact of gene polymorphisms of drug transporters on pharmacokinetics and toxicity.

PubMed

Jabir, Rafid Salim; Naidu, Rakesh; Annuar, Muhammad Azrif Bin Ahmad; Ho, Gwo Fuang; Munisamy, Murali; Stanslas, Johnson

2012-12-01

Interindividual variability in drug response and the emergence of adverse drug effects are the main causes of treatment failure in cancer therapy. Functional membrane drug transporters play important roles in altering pharmacokinetic profile, resistance to treatment, toxicity and patient survival. Pharmacogenetic studies of these transporters are expected to provide new approaches for optimizing therapy. Taxanes are approved for the treatment of various cancers. Circulating taxanes are taken up by SLCO1B3 into hepatocytes. The CYP450 enzymes CYP3A4, CYP3A5 and CYP2C8 are responsible for the conversion of taxanes into their metabolites. Ultimately, ABCB1 and ABCC2 will dispose the metabolites into bile canaliculi. Polymorphisms of genes encoding for proteins involved in the transport and clearance of taxanes reduce excretion of the drugs, leading to development of toxicity in patients. This review addresses current knowledge on genetic variations of transporters affecting taxanes pharmacokinetics and toxicity, and provides insights into future direction for personalized medicine.

[Associations between chronotype, road accidents and polymorphisms in genes linked with biological clock and dopaminergic system].

PubMed

Taranov, A O; Puchkova, A N; Slominsky, P A; Tupitsyna, T V; Dementiyenko, V V; Dorokhov, V B

2017-01-01

Public transport driving is a highly demanding activity requiring high skills and responsibility. Shift work, problems with regular sleep schedule negatively impact psychomotor reactions, cognitive functions and ability to react appropriately to the changing environment. For professional drivers all these factors may lead to the increased risk of a road accident. Individual differences in chronotype, cognitive and emotional control are partially genetically determined. Our study aimed to investigate the possible associations between chronotype parameters, traffic accident history and single nucleotide polymorphisms (SNPs) in a number of genes: RORA (rs1159814), CLOCK (rs12649507), PER3 (rs2640909), NPSR1 (rs324981), NPAS2 (rs4851377), DRD3 (rs6280), SLC6A3 (rs6347), DBH (rs1611125). We have studied 303 professional bus drivers working on rolling shifts in the Moscow region who had a recorded history of road accidents. The studied group was genotyped on selected SNPs and has filled out two chronotype questionnaires: MCTQ and shortened SWPAQ (Putilov A.A, 2014). A mixed chronotype with high levels of morning and evening alertness prevailed in the group. A prominent social jetlag caused by shift work was found. For SNP in PER3 gene there was an association with morning activation. SNP in CLOCK gene was associated with social jetlag and the risk to cause a crash. Minor alleles of SNPs in NPSR1and SLC6A3 correlated with later chronotype and increased risk of a road accident. We suppose that these polymorphisms may be amongst the genetic factors connecting chronotype and road accident risk.

Serotonin's Complex Role in Alcoholism: Implications for Treatment and Future Research.

PubMed

Marcinkiewcz, Catherine A; Lowery-Gionta, Emily G; Kash, Thomas L

2016-06-01

Current pharmacological treatments for alcohol dependence have focused on reducing alcohol consumption, but to date there are few treatments that also address the negative affective symptoms during acute and protracted alcohol withdrawal which are often exacerbated in people with comorbid anxiety and depression. Selective serotonin reuptake inhibitors (SSRIs) are sometimes prescribed to ameliorate these symptoms but can exacerbate anxiety and cravings in a select group of patients. In this critical review, we discuss recent literature describing an association between alcohol dependence, the SERT linked polymorphic region (5-HTTLPR), and pharmacological response to SSRIs. Given the heterogeneity in responsiveness to serotonergic drugs across the spectrum of alcoholic subtypes, we assess the contribution of specific 5-HT circuits to discrete endophenotypes of alcohol dependence. 5-HT circuits play a distinctive role in reward, stress, and executive function which may account for the variation in response to serotonergic drugs. New optogenetic and chemogenetic methods for dissecting 5-HT circuits in alcohol dependence may provide clues leading to more effective pharmacotherapies. Although our current understanding of the role of 5-HT systems in alcohol dependence is incomplete, there is some evidence to suggest that 5-HT3 receptor antagonists are effective in people with the L/L genotype of the 5-HTTLPR polymorphism while SSRIs may be more beneficial to people with the S/L or S/S genotype. Studies that assess the impact of serotonin transporter polymorphisms on 5-HT circuit function and the subsequent development of alcohol use disorders will be an important step forward in treating alcohol dependence. Copyright © 2016 by the Research Society on Alcoholism.

Association between a serotonin transporter promoter polymorphism (5HTTLPR) and personality disorder traits in a community sample.

PubMed

Blom, Rianne M; Samuels, Jack F; Riddle, Mark A; Joseph Bienvenu, O; Grados, Marco A; Reti, Irving M; Eaton, William W; Liang, Kung-Yee; Nestadt, Gerald

2011-09-01

The serotonin transporter (SERT) polymorphism (5HTTLPR) has been reported to be associated with several psychiatric conditions. Specific personality disorders could be intermediate factors in the known relationship between 5HTTLPR and psychiatric disorders. This is the first study to test the association between this polymorphism and dimensions of all DSM-IV personality disorders in a community sample. 374 white participants were assessed by clinical psychologists using the International Personality Disorder Examination (IPDE). Associations between dimensions of each DSM-IV personality disorder and the long (l) and short (s) alleles of the 5HTTLPR were evaluated using non-parametric tests and regression models. The s allele of the 5HTTLPR polymorphism was significantly associated with higher avoidant personality trait scores in the whole sample. Males with the s allele had a significantly lower likelihood of higher obsessive-compulsive personality disorder (OCPD) trait scores, whereas females with the s allele were likely to have higher OCPD personality trait scores. This paper provides preliminary data on the relationship between personality disorders and the 5HTTLPR polymorphism. The relationship of the s allele and avoidant PD is consistent with findings of a nonspecific relationship of this polymorphism to anxiety and depressive disorders. Concerning the unusual sexual dimorphic result with OCPD, several hypotheses are presented. These findings need further replication, including a more detailed study of additional variants in SERT. Copyright © 2011 Elsevier Ltd. All rights reserved.

Association between a serotonin transporter promoter polymorphism (5-HTTLPR) and personality disorder traits in a community sample

PubMed Central

Blom, Rianne M.; Samuels, Jack F.; Riddle, Mark A.; Bienvenu, O. Joseph; Grados, Marco A.; Reti, Irving M.; Eaton, William W.; Liang, Kung-Yee; Nestadt, Gerald

2011-01-01

Background The serotonin transporter (SERT) polymorphism (5HTTLPR) has been reported to be associated with several psychiatric conditions. Specific personality disorders could be intermediate factors in the known relationship between 5HTTLPR and psychiatric disorders. This is the first study to test the association between this polymorphism and dimensions of all DSM-IV personality disorders in a community sample. Methods 374 white participants were assessed by clinical psychologists using the International Personality Disorder Examination (IPDE). Associations between dimensions of each DSM-IV personality disorder and the long (l) and short (s) alleles of the 5HTTLPR were evaluated using nonparametric tests and regression models. Results The s allele of the 5HTTLPR polymorphism was significantly associated with higher avoidant personality trait scores in the whole sample. Males with the s allele had a significantly lower likelihood of higher obsessive-compulsive personality disorder (OCPD) trait scores, whereas females with the s allele were likely to have higher OCPD personality trait scores. Conclusion This paper provides preliminary data on the relationship between personality disorders and the 5HTTLPR polymorphism. The relationship of the s allele and avoidant PD is consistent with findings of a nonspecific relationship of this polymorphism to anxiety and depressive disorders. Concerning the unusual sexual dimorphic result with OCPD, several hypotheses are presented. These findings need further replication, including a more detailed study of additional variants in SERT. PMID:21450307

Possible effect of norepinephrine transporter polymorphisms on methylphenidate-induced changes in neuropsychological function in attention-deficit hyperactivity disorder.

PubMed

Park, Subin; Kim, Jae-Won; Yang, Young-Hui; Hong, Soon-Beom; Park, Min-Hyeon; Kim, Boong-Nyun; Shin, Min-Sup; Yoo, Hee-Jeong; Cho, Soo-Churl

2012-05-16

Dysregulation of noradrenergic system may play important roles in pathophysiology of attention-deficit/hyperactivity disorder (ADHD). We examined the relationship between polymorphisms in the norepinephrine transporter SLC6A2 gene and attentional performance before and after medication in children with ADHD. Fifty-three medication-naïve children with ADHD were genotyped and evaluated using the continuous performance test (CPT). After 8-weeks of methylphenidate treatment, these children were evaluated by CPT again. We compared the baseline CPT measures and the post-treatment changes in the CPT measures based on the G1287A and the A-3081T polymorphisms of SLC6A2. There was no significant difference in the baseline CPT measures associated with the G1287A or A-3081T polymorphisms. After medication, however, ADHD subjects with the G/G genotype at the G1287A polymorphism showed a greater decrease in the mean omission error scores (p = 0.006) than subjects with the G/A or A/A genotypes, and subjects with the T allele at the A-3081T polymorphism (T/T or A/T) showed a greater decrease in the mean commission error scores (p = 0.003) than those with the A/A genotypes. Our results provide evidence for the possible role of the G1287A and A-3081T genotypes of SLC6A2 in methylphenidate-induced improvement in attentional performance and support the noradrenergic hypothesis for the pathophysiology of ADHD.

Polymorphisms in methotrexate transporters and their relationship to plasma methotrexate levels, toxicity of high-dose methotrexate, and outcome of pediatric acute lymphoblastic leukemia.

PubMed

Liu, Shu-Guang; Gao, Chao; Zhang, Rui-Dong; Zhao, Xiao-Xi; Cui, Lei; Li, Wei-Jing; Chen, Zhen-Ping; Yue, Zhi-Xia; Zhang, Yuan-Yuan; Wu, Min-Yuan; Wang, Jian-Xiang; Li, Zhi-Gang; Zheng, Hu-Yong

2017-06-06

High-dose methotrexate (HDMTX) plays an important role in the treatment of acute lymphoblastic leukemia (ALL) although there is great inter-patient variability in the efficacy and toxicity of MTX. The relationship between polymorphisms in genes encoding MTX transporters and MTX response is controversial. In the present study, 322 Chinese children with standard- and intermediate-risk ALL were genotyped for 12 polymorphisms. SLCO1B1 rs10841753 showed a significant association with plasma MTX levels at 48 h (P = 0.017). Patients who had the ABCB1 rs1128503 C allele had longer duration of hospitalization than did those with the TT genotype (P = 0.006). No association was found between oral mucositis and any polymorphism. Long-term outcome was worse in patients with the SLCO1B1 rs4149056 CC genotype than in patients with TT or TC (5-year event-free survival [EFS] 33.3 ± 19.2% vs. 90.5 ± 1.7%, P < 0.001), and was worse in patients with the SCL19A1 rs2838958 AA genotype than in patients with AG or GG (5-year EFS 78.5 ± 4.6% vs. 92.2 ± 1.8%, P = 0.008). Multiple Cox regression analyses revealed associations of minimal residual disease (MRD) at day 33 (hazard ratio 3.458; P = 0.002), MRD at day 78 (hazard ratio 6.330; P = 0.001), SLCO1B1 rs4149056 (hazard ratio 12.242; P < 0.001), and SCL19A1 rs2838958 (hazard ratio 2.324; P = 0.019) with EFS. Our findings show that polymorphisms in genes encoding MTX transporters substantially influence the kinetics and response to HDMTX therapy in childhood ALL.

Identification of promoter polymorphisms in the cytochrome P450 CYP6AY1 linked with insecticide resistance in the brown planthopper, Nilaparvata lugens.

PubMed

Pang, R; Li, Y; Dong, Y; Liang, Z; Zhang, Y; Zhang, W

2014-12-01

Imidacloprid resistance in the brown planthopper, Nilaparvata lugens, is primarily the result of the over-expression of cytochrome P450 monooxygenases. Here, a field-collected strain of N. lugens was shown to be highly resistant to both imidacloprid and buprofezin. Insecticide exposure and quantitative real-time PCR revealed that its resistance was mainly associated with a cytochrome P450 gene, CYP6AY1. CYP6AY1 is known to metabolize imidacloprid but its effect on buprofezin is unclear. In the 5'-untranslated region of CYP6AY1, a novel alternative splicing was detected. After a 1990-bp promoter region was cloned, its basal luciferase activity was assessed. Furthermore, genotyping studies identified 12 variations in the promoter region that discriminated between the field-collected and control strain. Finally, survival bioassays revealed a single nucleotide polymorphism and an insertion-deletion polymorphism linked to buprofezin and imidacloprid resistance. Mutagenesis of these sites enhanced the promoter activity of CYP6AY1. These results suggest that promoter polymorphisms may affect P450-mediated multiple insecticide resistance of pests. © 2014 The Royal Entomological Society.

Evaluation of the effect of divalent metal transporter 1 gene polymorphism on blood iron, lead and cadmium levels

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kayaaltı, Zeliha, E-mail: kayaalti@ankara.edu.tr; Akyüzlü, Dilek Kaya; Söylemezoğlu, Tülin

Divalent metal transporter 1 (DMT1), a member of the proton-coupled metal ion transporter family, mediates transport of ferrous iron from the lumen of the intestine into the enterocyte and export of iron from endocytic vesicles. It has an affinity not only for iron but also for other divalent cations including manganese, cobalt, nickel, cadmium, lead, copper, and zinc. DMT1 is encoded by the SLC11a2 gene that is located on chromosome 12q13 in humans and express four major mammalian isoforms (1A/+IRE, 1A/-IRE, 2/+IRE and 2/-IRE). Mutations or polymorphisms of DMT1 gene may have an impact on human health by disturbing metalmore » trafficking. To study the possible association of DMT1 gene with the blood levels of some divalent cations such as iron, lead and cadmium, a single nucleotide polymorphism (SNP) (IVS4+44C/A) in DMT1 gene was investigated in 486 unrelated and healthy individuals in a Turkish population by method of polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). The genotype frequencies were found as 49.8% homozygote typical (CC), 38.3% heterozygote (CA) and 11.9% homozygote atypical (AA). Metal levels were analyzed by dual atomic absorption spectrometer system and the average levels of iron, lead and cadmium in the blood samples were 446.01±81.87 ppm, 35.59±17.72 ppb and 1.25±0.87 ppb, respectively. Individuals with the CC genotype had higher blood iron, lead and cadmium levels than those with AA and CA genotypes. Highly statistically significant associations were detected between IVS4+44 C/A polymorphism in the DMT1 gene and iron and lead levels (p=0.001 and p=0.036, respectively), but no association was found with cadmium level (p=0.344). This study suggested that DMT1 IVS4+44 C/A polymorphism is associated with inter-individual variations in blood iron, lead and cadmium levels. - Highlights: • DMT1 IVS4+44 C/A polymorphism is associated with inter-individual variations in blood iron, cadmium and lead levels. • Individuals with the DMT1 IVS4+44 CC genotype had higher blood iron, lead and cadmium levels. • Individuals with DMT1 IVS4+44 CC genotype may be more susceptible for metal toxicity.« less

Transcobalamin 776C-->G polymorphism is associated with peripheral neuropathy in elderly with high folate intake

USDA-ARS?s Scientific Manuscript database

Background: The 776C-->G polymorphism of the vitamin B-12 transport protein transcobalamin gene (TCN2) (rs1801198; Pro259Arg) is associated with a lower holotranscobalamin concentration in plasma. This effect may reduce the availability of vitamin B-12 to tissues even when vitamin B-12 intake is ade...

Pharmacogenomic Variants May Influence the Urinary Excretion of Novel Kidney Injury Biomarkers in Patients Receiving Cisplatin.

PubMed

Chang, Cara; Hu, Yichun; Hogan, Susan L; Mercke, Nickie; Gomez, Madeleine; O'Bryant, Cindy; Bowles, Daniel W; George, Blessy; Wen, Xia; Aleksunes, Lauren M; Joy, Melanie S

2017-06-22

Nephrotoxicity is a dose limiting side effect associated with the use of cisplatin in the treatment of solid tumors. The degree of nephrotoxicity is dictated by the selective accumulation of cisplatin in renal tubule cells due to: (1) uptake by organic cation transporter 2 (OCT2) and copper transporter 1 (CTR1); (2) metabolism by glutathione S-transferases (GSTs) and γ-glutamyltransferase 1 (GGT1); and (3) efflux by multidrug resistance-associated protein 2 (MRP2) and multidrug and toxin extrusion protein 1 (MATE1). The purpose of this study was to determine the significance of single nucleotide polymorphisms that regulate the expression and function of transporters and metabolism genes implicated in development of acute kidney injury (AKI) in cisplatin treated patients. Changes in the kidney function were assessed using novel urinary protein biomarkers and traditional markers. Genotyping was conducted by the QuantStudio 12K Flex Real-Time PCR System using a custom open array chip with metabolism, transport, and transcription factor polymorphisms of interest to cisplatin disposition and toxicity. Traditional and novel biomarker assays for kidney toxicity were assessed for differences according to genotype by ANOVA. Allele and genotype frequencies were determined based on Caucasian population frequencies. The polymorphisms rs596881 ( SLC22A2 /OCT2), and rs12686377 and rs7851395 ( SLC31A1 /CTR1) were associated with renoprotection and maintenance of estimated glomerular filtration rate (eGFR). Polymorphisms in SLC22A2 /OCT2, SLC31A1 /CTRI, SLC47A1 /MATE1, ABCC2 /MRP2, and GSTP1 were significantly associated with increases in the urinary excretion of novel AKI biomarkers: KIM-1, TFF3, MCP1, NGAL, clusterin, cystatin C, and calbindin. Knowledge concerning which genotypes in drug transporters are associated with cisplatin-induced nephrotoxicity may help to identify at-risk patients and initiate strategies, such as using lower or fractionated cisplatin doses or avoiding cisplatin altogether, in order to prevent AKI.

Pharmacogenomic Variants May Influence the Urinary Excretion of Novel Kidney Injury Biomarkers in Patients Receiving Cisplatin

PubMed Central

Chang, Cara; Hu, Yichun; Hogan, Susan L.; Mercke, Nickie; Gomez, Madeleine; O’Bryant, Cindy; Bowles, Daniel W.; George, Blessy; Wen, Xia; Aleksunes, Lauren M.; Joy, Melanie S.

2017-01-01

Nephrotoxicity is a dose limiting side effect associated with the use of cisplatin in the treatment of solid tumors. The degree of nephrotoxicity is dictated by the selective accumulation of cisplatin in renal tubule cells due to: (1) uptake by organic cation transporter 2 (OCT2) and copper transporter 1 (CTR1); (2) metabolism by glutathione S-transferases (GSTs) and γ-glutamyltransferase 1 (GGT1); and (3) efflux by multidrug resistance-associated protein 2 (MRP2) and multidrug and toxin extrusion protein 1 (MATE1). The purpose of this study was to determine the significance of single nucleotide polymorphisms that regulate the expression and function of transporters and metabolism genes implicated in development of acute kidney injury (AKI) in cisplatin treated patients. Changes in the kidney function were assessed using novel urinary protein biomarkers and traditional markers. Genotyping was conducted by the QuantStudio 12K Flex Real-Time PCR System using a custom open array chip with metabolism, transport, and transcription factor polymorphisms of interest to cisplatin disposition and toxicity. Traditional and novel biomarker assays for kidney toxicity were assessed for differences according to genotype by ANOVA. Allele and genotype frequencies were determined based on Caucasian population frequencies. The polymorphisms rs596881 (SLC22A2/OCT2), and rs12686377 and rs7851395 (SLC31A1/CTR1) were associated with renoprotection and maintenance of estimated glomerular filtration rate (eGFR). Polymorphisms in SLC22A2/OCT2, SLC31A1/CTRI, SLC47A1/MATE1, ABCC2/MRP2, and GSTP1 were significantly associated with increases in the urinary excretion of novel AKI biomarkers: KIM-1, TFF3, MCP1, NGAL, clusterin, cystatin C, and calbindin. Knowledge concerning which genotypes in drug transporters are associated with cisplatin-induced nephrotoxicity may help to identify at-risk patients and initiate strategies, such as using lower or fractionated cisplatin doses or avoiding cisplatin altogether, in order to prevent AKI. PMID:28640195

Gene polymorphism linked to increased asthma and IBD risk alters gasdermin-B structure, a sulfatide and phosphoinositide binding protein.

PubMed

Chao, Kinlin L; Kulakova, Liudmila; Herzberg, Osnat

2017-02-14

The exact function of human gasdermin-B (GSDMB), which regulates differentiation and growth of epithelial cells, is yet to be elucidated. In human epidermal growth factor receptor 2 (HER2)-positive breast cancer, GSDMB gene amplification and protein overexpression indicate a poor response to HER2-targeted therapy. Genome-wide association studies revealed a correlation between GSDMB SNPs and an increased susceptibility to Crohn's disease, ulcerative colitis, and asthma. The N- and C-terminal domains of all gasdermins possess lipid-binding and regulatory activities, respectively. Inflammatory caspases cleave gasdermin-D in the interdomain linker but not GSDMB. The cleaved N-terminal domain binds phosphoinositides and cardiolipin, forms membrane-disrupting pores, and executes pyroptosis. We show that both full-length GSDMB and the N-terminal domain bind to nitrocellulose membranes immobilized with phosphoinositides or sulfatide, but not with cardiolipin. In addition, the GSDMB N-terminal domain binds liposomes containing sulfatide. The crystal structure of the GSDMB C-terminal domain reveals the structural impact of the amino acids encoded by SNPs that are linked to asthma and inflammatory bowel disease (IBD). A loop that carries the polymorphism amino acids corresponding to healthy individuals (Gly299:Pro306) exhibits high conformational flexibility, whereas the loop carrying amino acids found in individuals with increased disease risk (Arg299:Ser306) exhibits a well-defined conformation and higher positive surface charge. Apoptotic executioner caspase-3, -6, and -7, but not the inflammatory caspases, cleave GSDMB at 88 DNVD 91 within the N-terminal domain. Selective sulfatide binding may indicate possible function for GSDMB in the cellular sulfatide transport.

Gene polymorphism linked to increased asthma and IBD risk alters gasdermin-B structure, a sulfatide and phosphoinositide binding protein

PubMed Central

Chao, Kinlin L.; Kulakova, Liudmila; Herzberg, Osnat

2017-01-01

The exact function of human gasdermin-B (GSDMB), which regulates differentiation and growth of epithelial cells, is yet to be elucidated. In human epidermal growth factor receptor 2 (HER2)-positive breast cancer, GSDMB gene amplification and protein overexpression indicate a poor response to HER2-targeted therapy. Genome-wide association studies revealed a correlation between GSDMB SNPs and an increased susceptibility to Crohn’s disease, ulcerative colitis, and asthma. The N- and C-terminal domains of all gasdermins possess lipid-binding and regulatory activities, respectively. Inflammatory caspases cleave gasdermin-D in the interdomain linker but not GSDMB. The cleaved N-terminal domain binds phosphoinositides and cardiolipin, forms membrane-disrupting pores, and executes pyroptosis. We show that both full-length GSDMB and the N-terminal domain bind to nitrocellulose membranes immobilized with phosphoinositides or sulfatide, but not with cardiolipin. In addition, the GSDMB N-terminal domain binds liposomes containing sulfatide. The crystal structure of the GSDMB C-terminal domain reveals the structural impact of the amino acids encoded by SNPs that are linked to asthma and inflammatory bowel disease (IBD). A loop that carries the polymorphism amino acids corresponding to healthy individuals (Gly299:Pro306) exhibits high conformational flexibility, whereas the loop carrying amino acids found in individuals with increased disease risk (Arg299:Ser306) exhibits a well-defined conformation and higher positive surface charge. Apoptotic executioner caspase-3, -6, and -7, but not the inflammatory caspases, cleave GSDMB at 88DNVD91 within the N-terminal domain. Selective sulfatide binding may indicate possible function for GSDMB in the cellular sulfatide transport. PMID:28154144

Lack of association between temporal lobe epilepsy and a novel polymorphism in the alpha 2 subunit gene (ATP1A2) of the sodium potassium transporting ATPase.

PubMed

Buono, R J; Ferraro, T N; O'Connor, M J; Sperling, M R; Abbey, M; Finanger, E; Lohoff, F; Mulholland, N; Berrettini, W H

2000-02-07

Genetic linkage studies in rodents and humans have identified specific chromosomal regions harboring seizure susceptibility genes. We have identified a novel polymorphism in the human alpha 2 subunit gene (ATP1A2) of the sodium potassium transporting ATPase (NaK-pump), a candidate gene for human temporal lobe epilepsy (TLE) based on its chromosomal location and function in ion homeostasis. The polymorphism consists of a four base pair insertion 12 base pairs upstream of the start of exon 2. We performed an association study between this polymorphism and TLE. Our study did not find a significant difference in the frequency of this polymorphism between TLE patients and controls, indicating that this variation is not a major susceptibility factor. However, since the number of patients studied so far is small and the functional consequence of the polymorphism is unknown, the variation may yet be found to play a minor role in increased risk for seizure susceptibility. In contrast to the findings in TLE patients and controls, we did find a significant difference in the frequency of the variation between African Americans and persons of European descent. This finding demonstrates the potential effect of population stratification on studies of this type and supports the growing use of parental and familial samples for controls in association studies. Further study of this polymorphism is warranted as it may be involved in other disease processes for which there are known ethnic-specific susceptibilities. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:79-83, 2000. Copyright 2000 Wiley-Liss, Inc.

Childhood socioeconomic status and serotonin transporter gene polymorphism enhance cardiovascular reactivity to mental stress.

PubMed

Williams, Redford B; Marchuk, Douglas A; Siegler, Ilene C; Barefoot, John C; Helms, Michael J; Brummett, Beverly H; Surwit, Richard S; Lane, James D; Kuhn, Cynthia M; Gadde, Kishore M; Ashley-Koch, Allison; Svenson, Ingrid K; Schanberg, Saul M

2008-01-01

To test the hypothesis that low socioeconomic status (SES) and the 5HTTLPR L allele are associated with increased cardiovascular reactivity (CVR) to stress in a larger sample and that SES and 5HTTLPR genotypes interact to enhance CVR to stress. CVR to mental stress has been proposed as one mechanism linking stress to the pathogenesis of cardiovascular disease. The more transcriptionally efficient long (L) allele of a polymorphism of the serotonin transporter gene promoter (5HTTLPR) has been found associated with increased risk of myocardial infarction. We found the long allele associated with larger CVR to mental stress in a preliminary study of 54 normal volunteers. Subjects included 165 normal community volunteers stratified for race, gender, and SES, who underwent mental stress testing. Childhood SES as indexed by Father's Education Level was associated with larger systolic blood pressure (SBP) (p < .05) and diastolic blood pressure (DBP) (p = .01) responses to mental stress. The L allele was associated with larger SBP (p = .04), DBP (p < .0001), and heart rate (p = .04) responses to mental stress compared with the short (S) allele. Subjects with the SS genotype and high Father's Education exhibited smaller SBP (5.2 mm Hg) and DBP (2.9 mm Hg) responses than subjects with LL genotype and low Father's Education (SBP = 13.3 mm Hg, p = .002; DBP = 9.7 mm Hg, p < .0001). Both the 5HTTLPR long allele and low SES, particularly during childhood, are associated with increased CVR to mental stress, which could account, at least in part, for the increased cardiovascular disease risk associated with these characteristics. If confirmed in further research, these characteristics could be used to identify persons who might benefit from preventive interventions.

Investigating Direct Links between Depression, Emotional Control, and Physical Punishment with Adolescent Drive for Thinness and Bulimic Behaviors, Including Possible Moderation by the Serotonin Transporter 5-HTTLPR Polymorphism.

PubMed

Rozenblat, Vanja; Ryan, Joanne; Wertheim, Eleanor H; King, Ross; Olsson, Craig A; Krug, Isabel

2017-01-01

Objectives: To examine the relationship between psychological and social factors (depression, emotional control, sexual abuse, and parental physical punishment) and adolescent drive for Thinness and Bulimic behaviors in a large community sample, and to investigate possible genetic moderation. Method: Data were drawn from the Australian Temperament Project (ATP), a population-based cohort study that has followed a representative sample of 2443 participants from infancy to adulthood across 16 waves since 1983. A subsample of 650 participants (50.2% female) of Caucasian descent who provided DNA were genotyped for a serotonin transporter promoter polymorphism ( 5-HTTLPR ). Adolescent disordered eating attitudes and behaviors were assessed using the Bulimia and Drive for Thinness scales of the Eating Disorder Inventory-2 (15-16 years). Depression and emotional control were examined at the same age using the Short Mood and Feelings Questionnaire, and an ATP-devised measure of emotional control. History of sexual abuse and physical punishment were assessed retrospectively (23-24 years) in a subsample of 467 of those providing DNA. Results: EDI-2 scores were associated with depression, emotional control, and retrospectively reported parental physical punishment. Although there was statistically significant moderation of the relationship between parental physical punishment and bulimic behaviors by 5-HTTLPR ( p = 0.0048), genotypes in this subsample were not in Hardy-Weinberg Equilibrium. No other G×E interactions were significant. Conclusion: Findings from this study affirm the central importance of psychosocial processes in disordered eating patterns in adolescence. Evidence of moderation by 5-HTTLPR was not conclusive; however, genetic moderation observed in a subsample not in Hardy-Weinberg Equilibrium warrants further investigation.

Investigating Direct Links between Depression, Emotional Control, and Physical Punishment with Adolescent Drive for Thinness and Bulimic Behaviors, Including Possible Moderation by the Serotonin Transporter 5-HTTLPR Polymorphism

PubMed Central

Rozenblat, Vanja; Ryan, Joanne; Wertheim, Eleanor H.; King, Ross; Olsson, Craig A.; Krug, Isabel

2017-01-01

Objectives: To examine the relationship between psychological and social factors (depression, emotional control, sexual abuse, and parental physical punishment) and adolescent drive for Thinness and Bulimic behaviors in a large community sample, and to investigate possible genetic moderation. Method: Data were drawn from the Australian Temperament Project (ATP), a population-based cohort study that has followed a representative sample of 2443 participants from infancy to adulthood across 16 waves since 1983. A subsample of 650 participants (50.2% female) of Caucasian descent who provided DNA were genotyped for a serotonin transporter promoter polymorphism (5-HTTLPR). Adolescent disordered eating attitudes and behaviors were assessed using the Bulimia and Drive for Thinness scales of the Eating Disorder Inventory-2 (15–16 years). Depression and emotional control were examined at the same age using the Short Mood and Feelings Questionnaire, and an ATP-devised measure of emotional control. History of sexual abuse and physical punishment were assessed retrospectively (23–24 years) in a subsample of 467 of those providing DNA. Results: EDI-2 scores were associated with depression, emotional control, and retrospectively reported parental physical punishment. Although there was statistically significant moderation of the relationship between parental physical punishment and bulimic behaviors by 5-HTTLPR (p = 0.0048), genotypes in this subsample were not in Hardy–Weinberg Equilibrium. No other G×E interactions were significant. Conclusion: Findings from this study affirm the central importance of psychosocial processes in disordered eating patterns in adolescence. Evidence of moderation by 5-HTTLPR was not conclusive; however, genetic moderation observed in a subsample not in Hardy–Weinberg Equilibrium warrants further investigation. PMID:28848475

"Diminished" association between the serotonin transporter linked polymorphism (5HTTLPR) and body mass index in a large psychiatric sample.

PubMed

Shinozaki, Gen; Kumar, Yingying; Rosen, Brooke H; Rundell, James R; Mrazek, David A; Kung, Simon

2013-10-01

The role of the promoter polymorphism (5HTTLPR) of the serotonin transporter gene (SLC6A4) in psychiatric illnesses has been studied extensively. Serotonergic function also regulates many central nervous system, including appetite and feeding behaviors. The 5HTTLPR short allele was found to be associated with increased body mass index and obesity risk among the general population. No data is available to support generalizability of such association among psychiatric population. We examined the relationship between BMI and the 5HTTLPR genotype in a large sample of 1831 psychiatric patients at Mayo Clinic, Rochester, Minnesota, using a retrospective chart review. Average BMI among groups with the short/short (28.29 ± 7.27 kg/m(2)), the short/long (28.07 ± 6.45 kg/m(2)) and the long/long (28.15 ± 7.51 kg/m(2)) genotypes of 5HTTLPR were not statistically different. This negative association persisted even with the sub-analysis of the Caucasians. However, we observed an increased rate of obesity among our psychiatric patient sample compared to the general population of Minnesota (36.6% versus 27.6%, p=0.0001 for males, 30.3% versus 24.4%, p=0.0001 for females). Also, sub-analysis showed female inpatients to have a significantly higher average BMI than outpatients (28.64 ± 8.08 kg/m(2) versus 27.13 ± 6.92 kg/m(2), p=0.026). This confirmed a significant association between mental health disorder and BMI. Retrospective study design with limited control for potential confounders. In this large sample of psychiatric patients we found no significant association between 5HTTLPR genotype and BMI, which is different from the case with general population reported in the literature. Published by Elsevier B.V.

Serotonin transporter bi- and triallelic genotypes and their relationship with anxiety and academic performance: a preliminary study.

PubMed

Calapoğlu, Mustafa; Sahin-Calapoğlu, Nilufer; Karaçöp, Ataman; Soyöz, Mustafa; Elyıldırım, Umit Y; Avşaroğlu, Selahattin

2011-01-01

Considerable evidence suggests that variation of the serotonin-transporter-linked promoter region (5- HTTLPR) is associated with anxiety-related traits. Academic outcomes are also more closely related to trait anxiety. This preliminary study aimed to explore the association between academic performance and levels of anxiety with respect to the bi- and triallelic classification of 5-HTTLPR polymorphism of the 5-HTT gene in teacher candidates. In our study, Spielberger's State-Trait Anxiety Inventory, the Selection Examination for Professional Posts in Public Organizations (KPSS) and 5-HTTLPR genotypes were used to investigate a group of 94 healthy teacher candidates. Higher anxiety scores were significantly associated with the S'S' genotype. There was no direct, statistically significant association between academic performance and genotypic groups regarding bi- and triallelic classification. However, the students who have L'L' or LL genotypes had the lowest levels of trait anxiety and the poorest academic performance. Additionally, there was a significant positive correlation between academic performance and anxiety levels. These findings support the idea that S and L(G) alleles are associated with anxiety-related traits, and that the S'S' genotype may be a good indicator for anxiety-related traits in a sample from the Turkish population. A specific degree of anxiety is considered to be a motivation for learning and high academic performance. However, 5-HTTLPR polymorphism of the 5-HTT gene may be one of the genetic factors affecting academic performance in connection with anxiety levels. Implications for incorporating anxiety management training in the educational process in terms of both environmental and individual factors will have a very important role in improving effective strategies for student personality services, as well as for development and planning. © 2010 S. Karger AG, Basel.

Serotonin Transporter Gene, Depressive Symptoms and Interleukin-6

PubMed Central

Su, Shaoyong; Zhao, Jinying; Bremner, J. Douglas; Miller, Andrew H.; Tang, Weining; Bouzyk, Mark; Snieder, Harold; Novik, Olga; Afzal, Nadeem; Goldberg, Jack; Vaccarino, Viola

2009-01-01

Background We explored the relationship of genetic variants of the serotonin transporter gene SLC6A4, a key regulator of the serotonergic neurotransmission, with both depressive symptoms and plasma Interleukin-6 (IL-6) levels. Methods and Results We genotyped 20 polymorphisms in 360 male twins (mean age: 54) from the Vietnam Era Twin Registry. Current depressive symptoms were measured with the Beck Depression Inventory-II (BDI-II). IL-6 was assessed using a commercially available ELISA kit. Genotype associations were analyzed using generalized estimating equations. To study how SLC6A4 genetic vulnerability influences the relationship between depressive symptoms and IL-6, bivariate models were constructed using structural equation modeling. Of the 20 polymorphisms examined, the effective number of independent tests was 6 and the threshold of significance after Bonferroni correction was 0.008. There were 6 SNPs significantly associated with BDI (P≤0.008), including rs8071667, rs2020936, rs25528, rs6354, rs11080122 and rs8076005, and 1 SNP borderline associated (rs12150214, P=0.017). Of these 7 SNPs, 3 were also significantly associated with IL-6 (P<0.008), including rs25528, rs6354 and rs8076005, and the other 4 were borderline associated (P=0.009~0.025). The subjects with one copy of the minor allele of these 7 SNPs had higher BDI scores and IL-6 levels. Further bivariate modeling revealed that approximately 10% of the correlation between BDI and IL-6 could be explained by the SLC6A4 gene. Conclusions Genetic vulnerability involving the SLC6A4 gene is significantly associated with both increased depressive symptoms and elevated IL-6 plasma levels. Common pathophysiological processes may link depression and inflammation, and implicate the serotonin pathway in neural-immune interactions. PMID:20031642

The effect of polymorphism at the serotonin transporter gene on decision-making, memory and executive function in ecstasy users and controls

PubMed Central

Roiser, Jonathan P.; Rogers, Robert D.; Cook, Lynnette J.; Sahakian, Barbara J.

2008-01-01

Rationale 3, 4-Methylenedioxymethamphetamine (MDMA or “ecstasy”) is a popular drug of abuse known to result in depletions of the serotonin (5-HT) system. A number of studies have reported that ecstasy users differ from controls on a variety of measures of cognitive function. However, the literature is not consistent and many negative findings were also reported. One reason for such inconsistency might be interindividual variance in vulnerability to the deleterious effects of ecstasy due to a number of factors, both genetic and environmental. Objectives To investigate the hypothesis that carriers of the s allele at the 5-HT transporter gene-linked polymorphic region (5-HTTLPR), which was associated with reduced serotonergic neurotransmission relative to the l allele, would be most vulnerable to the effects of ecstasy on cognitive function. Methods We assessed memory, decision-making, and executive function in ecstasy users and controls, stratifying by genotype at the 5-HTTLPR. Results We observed that the 5-HTTLPR genotype groups differed on a number of measures in both the ecstasy users and the controls. While performing a risky decision-making task, ss and ls controls attended to differences in the probability of winning chosen gambles to a greater extent than the ll controls. However, this difference was dramatically attenuated in the ss ecstasy users. Furthermore, independent of ecstasy use, volunteers of the ss genotype outperformed the ll genotype on a visual planning task. Conclusions The results are consistent with the hypothesis that cognitive impairment in ecstasy users may depend on genetic variation at the 5-HTTLPR. PMID:16941121

Paclitaxel sensitivity in relation to ABCB1 expression, efflux and single nucleotide polymorphisms in ovarian cancer.

PubMed

Gao, Bo; Russell, Amanda; Beesley, Jonathan; Chen, Xiao Qing; Healey, Sue; Henderson, Michelle; Wong, Mark; Emmanuel, Catherine; Galletta, Laura; Johnatty, Sharon E; Bowtell, David; Haber, Michelle; Norris, Murray; Harnett, Paul; Chenevix-Trench, Georgia; Balleine, Rosemary L; deFazio, Anna

2014-05-09

ABCB1 (adenosine triphosphate-binding cassette transporter B1) mediates cellular elimination of many chemotherapeutic agents including paclitaxel, which is commonly used to treat ovarian cancer. A significant association between common single nucleotide polymorphisms (SNPs) in ABCB1 and progression-free survival has been reported in patients with ovarian cancer. Variable paclitaxel clearance due to genotype specific differences in ABCB1 activity in cancer cells and/or normal tissues may underlie the association. Using cell-based models, we evaluated the correlations between ABCB1 expression, polymorphisms, transporter activity and paclitaxel sensitivity in ovarian cancer (n = 10) and lymphoblastoid (n = 19) cell lines. Close associations between ABCB1 expression, transporter function and paclitaxel sensitivity were found in lymphoblastoid cell lines, although we could not demonstrate an association with common SNPs. In ovarian cancer cell lines, ABCB1 expression was low and the association between expression and function was lost. These results suggest that ABCB1 related survival difference in ovarian cancer patients is more likely to be due to differential whole body paclitaxel clearance mediated by normal cells rather than a direct effect on cancer cells.

Candidate-gene approach in posttraumatic stress disorder after urban violence: association analysis of the genes encoding serotonin transporter, dopamine transporter, and BDNF.

PubMed

Valente, Nina Leão Marques; Vallada, Homero; Cordeiro, Quirino; Miguita, Karen; Bressan, Rodrigo Affonseca; Andreoli, Sergio Baxter; Mari, Jair Jesus; Mello, Marcelo Feijó

2011-05-01

Posttraumatic stress disorder (PTSD) is a prevalent, disabling anxiety disorder marked by behavioral and physiologic alterations which commonly follows a chronic course. Exposure to a traumatic event constitutes a necessary, but not sufficient, factor. There is evidence from twin studies supporting a significant genetic predisposition to PTSD. However, the precise genetic loci still remain unclear. The objective of the present study was to identify, in a case-control study, whether the brain-derived neurotrophic factor (BDNF) val66met polymorphism (rs6265), the dopamine transporter (DAT1) three prime untranslated region (3'UTR) variable number of tandem repeats (VNTR), and the serotonin transporter (5-HTTPRL) short/long variants are associated with the development of PTSD in a group of victims of urban violence. All polymorphisms were genotyped in 65 PTSD patients as well as in 34 victims of violence without PTSD and in a community control group (n = 335). We did not find a statistical significant difference between the BDNF val66met and 5-HTTPRL polymorphism and the traumatic phenotype. However, a statistical association was found between DAT1 3'UTR VNTR nine repeats and PTSD (OR = 1.82; 95% CI, 1.20-2.76). This preliminary result confirms previous reports supporting a susceptibility role for allele 9 and PTSD.

Serotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder.

PubMed

Betancur, C; Corbex, M; Spielewoy, C; Philippe, A; Laplanche, J L; Launay, J M; Gillberg, C; Mouren-Siméoni, M C; Hamon, M; Giros, B; Nosten-Bertrand, M; Leboyer, M

2002-01-01

Previous studies have provided conflicting evidence regarding the association of the serotonin transporter (5-HTT) gene with autism. Two polymorphisms have been identified in the human 5-HTT gene, a VNTR in intron 2 and a functional deletion/insertion in the promoter region (5-HTTLPR) with short and long variants. Positive associations of the 5-HTTLPR polymorphism with autism have been reported by two family-based studies, but one found preferential transmission of the short allele and the other of the long allele. Two subsequent studies failed to find evidence of transmission disequilibrium at the 5-HTTLPR locus. These conflicting results could be due to heterogeneity of clinical samples with regard to serotonin (5-HT) blood levels, which have been found to be elevated in some autistic subjects. Thus, we examined the association of the 5-HTTLPR and VNTR polymorphisms of the 5-HTT gene with autism, and we investigated the relationship between 5-HTT variants and whole-blood 5-HT. The transmission/disequilibrium test (TDT) revealed no linkage disequilibrium at either loci in a sample of 96 families comprising 43 trios and 53 sib pairs. Furthermore, no significant relationship between 5-HT blood levels and 5-HTT gene polymorphisms was found. Our results suggest that the 5-HTT gene is unlikely to play a major role as a susceptibility factor in autism.

Serotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder

PubMed Central

Betancur, Catalina; Corbex, Marylis; Spielewoy, Cécile; Philippe, Anne; Laplanche, Jean-Louis; Launay, Jean-Marie; Gillberg, Christopher; Mouren-Simeoni, Marie-Christine; Hamon, Michel; Giros, Bruno; Nosten-Bertrand, Marika; Leboyer, Marion

2002-01-01

Previous studies have provided conflicting evidence regarding the association of the serotonin transporter (5-HTT) gene with autism. Two polymorphisms have been identified in the human 5-HTT gene, a VNTR in intron 21 and a functional deletion/insertion in the promoter region (5-HTTLPR) with short and long variants.2 Positive associations of the 5-HTTLPR polymorphism with autism have been reported by two family-based studies, but one found preferential transmission of the short allele3 and the other of the long allele.4 Two subsequent studies failed to find evidence of transmission disequilibrium at the 5-HTTLPR locus.5,6 These conflicting results could be due to heterogeneity of clinical samples with regard to serotonin (5-HT) blood levels, which have been found to be elevated in some autistic subjects.7–9 Thus, we examined the association of the 5-HTTLPR and VNTR polymorphisms of the 5-HTT gene with autism, and we investigated the relationship between 5-HTT variants and whole-blood 5-HT. The transmission/disequilibrium test (TDT) revealed no linkage disequilibrium at either loci in a sample of 96 families comprising 43 trios and 53 sib pairs. Furthermore, no significant relationship between 5-HT blood levels and 5-HTT gene polymorphisms was found. Our results suggest that the 5-HTT gene is unlikely to play a major role as a susceptibility factor in autism. PMID:11803447

Further exploration of the conformational space of α-synuclein fibrils: solid-state NMR assignment of a high-pH polymorph.

PubMed

Verasdonck, Joeri; Bousset, Luc; Gath, Julia; Melki, Ronald; Böckmann, Anja; Meier, Beat H

2016-04-01

Polymorphism is a common and important phenomenon for protein fibrils which has been linked to the appearance of strains in prion and other neurodegenerative diseases. Parkinson disease is a frequently occurring neurodegenerative pathology, tightly associated with the formation of Lewy bodies. These deposits mainly consist of α-synuclein in fibrillar, β-sheet-rich form. α-synuclein is known to form numerous different polymorphs, which show distinct structural features. Here, we describe the chemical shift assignments, and derive the secondary structure, of a polymorph that was fibrillized at higher-than-physiological pH conditions. The fibrillar core contains residues 40-95, with both the C- and N-terminus not showing any ordered, rigid parts. The chemical shifts are similar to those recorded previously for an assigned polymorph that was fibrillized at neutral pH.

Association of HaeIII single nucleotide polymorphisms in the SLC2A1 gene with risk of diabetic nephropathy; evidence from Kurdish patients with type 2 diabetes mellitus.

PubMed

Amini, Sabrieh; Javanmardi, Mitra; Mokarizadeh, Aram; Maroofi, Farzad; Jalali, Chiya; Azadi, Namam-Ali; Mohammadi, Hamid; Abdi, Mohammad

2016-06-01

Given the growing rate of patients with type 2 diabetes mellitus, uncovering the effects of gene polymorphism on diabetes pathogenesis has attracted a lot of attention. Because glucose transporter 1 is involved in glucose uptake, the polymorphism of this gene may be an important risk factor in type 2 diabetes mellitus or in the progression of diabetes complications such as diabetic nephropathy. As far as the authors are concerned, this study is the first one aiming at evaluating the probable effects of solute carrier family 2 facilitated glucose transporter member 1 (SLC2A1) HaeIII polymorphism on clinical and laboratory outcomes of Kurdish patients with type 2 diabetes mellitus. This study was conducted involving 126 diabetic nephropathy patients and 150 diabetic patients without renal involvement. Serum levels of Cystatin C, fasting blood glucose, creatinine and urinary albumin; levels of glycated hemoglobin and estimated glomerular filtration rate were measured. Moreover, the Hae III polymorphism of SLC2A1 gene was determined by PCR-restriction fragment length polymorphism (RFLP). The rate of CC genotype was higher (37%) in patients with diabetic nephropathy compared with controls. There were a significant correlation between the CC genotype and risk of diabetic nephropathy. There were significant correlations between genotypes, serum Cystatin C and estimated glomerular filtration rate in patients with diabetic nephropathy. The results demonstrated the high frequency of C allele of SLC2A1 HaeIII in Kurdish patients with diabetic nephropathy. It was also found that this polymorphism is a significant risk factor for diabetic nephropathy. The effect of this polymorphism on clinical and laboratory characteristics of diabetic nephropathy patients was significant. © The Author 2015. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Polymorphisms of delta-aminolevulinic acid dehydratase (ALAD) and peptide transporter 2 (PEPT2) genes in children with low-level lead exposure

PubMed Central

Sobin, Christina; Gutierrez, Marisela; Alterio, Heather

2009-01-01

Low-level lead exposure during early childhood has long been associated with altered neurocognitive development and diminished cognitive functions. Over nine thousand U.S. industrial facilities annually emit significant amounts of lead, creating exposure risk particularly for minority children. The mechanisms by which low-level lead exerts neurotoxic effects are poorly understood. Once absorbed, the only intervention is source removal, thus primary prevention is key. Genetic biomarkers could provide an efficient means of identifying children at greatest risk. Common functional variants of genes that alter lead's neurotoxic potential have been identified and include delta-aminolevulinic acid dehydratase (ALAD2) and peptide transporter 2 (PEPT2*2). These polymorphisms have not been examined previously in Hispanic minority samples, or with regard to lowest level lead exposure. In 116 children of Mexican-American/Hispanic descent residing in zip codes previously designated as “high risk” for lead exposure (mean age = 8.1, S.D. = 1.9), blood lead level was measured at three time points over a 3-month period and averaged. DNA extraction was completed using buccal swab samples. The frequencies of the ALAD2 and PEPT2*2 polymorphisms observed in this sample closely approximated those previously reported for Anglo, European and Asian samples. As compared to children heterozygous for the PEPT2*2 polymorphism, and without the PEPT2*2 polymorphism, the geometric mean blood lead level of children homozygous for the PEPT2*2 polymorphism was significantly higher. In contrast to past studies, mean blood lead level of children heterozygous and homozygous for the ALAD2 polymorphism in this sample did not differ from that of children without the ALAD2 polymorphism. Higher blood lead burden in children with the PEPT2*2 mutation may suggest that this common genetic variant is a biomarker of increased vulnerability to the neurotoxic effects of lowest level lead exposure. PMID:19723536

Polymorphism in the intron 20 of porcine O-linked N-acetylglucosamine transferase

USDA-ARS?s Scientific Manuscript database

Objective: O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) catalyzes the addition of O-GlcNAc and GlcNAcylation has extensive crosstalk with phosphorylation to regulate signaling and transcription. Pig OGT is located near the region of chromosome X that affects follicle stimulating hormone...

Controlling the crystal polymorph by exploiting the time dependence of nucleation rates.

PubMed

Little, Laurie J; King, Alice A K; Sear, Richard P; Keddie, Joseph L

2017-10-14

Most substances can crystallise into two or more different crystal lattices called polymorphs. Despite this, there are no systems in which we can quantitatively predict the probability of one competing polymorph forming instead of the other. We address this problem using large scale (hundreds of events) studies of the competing nucleation of the alpha and gamma polymorphs of glycine. In situ Raman spectroscopy is used to identify the polymorph of each crystal. We find that the nucleation kinetics of the two polymorphs is very different. Nucleation of the alpha polymorph starts off slowly but accelerates, while nucleation of the gamma polymorph starts off fast but then slows. We exploit this difference to increase the purity with which we obtain the gamma polymorph by a factor of ten. The statistics of the nucleation of crystals is analogous to that of human mortality, and using a result from medical statistics, we show that conventional nucleation data can say nothing about what, if any, are the correlations between competing nucleation processes. Thus we can show that with data of our form it is impossible to disentangle the competing nucleation processes. We also find that the growth rate and the shape of a crystal depend on it when nucleated. This is new evidence that nucleation and growth are linked.

CCR2-64I polymorphism is not associated with altered CCR5 expression or coreceptor function.

PubMed

Mariani, R; Wong, S; Mulder, L C; Wilkinson, D A; Reinhart, A L; LaRosa, G; Nibbs, R; O'Brien, T R; Michael, N L; Connor, R I; Macdonald, M; Busch, M; Koup, R A; Landau, N R

1999-03-01

A polymorphism in the gene encoding CCR2 is associated with a delay in progression to AIDS in human immunodeficiency virus (HIV)-infected individuals. The polymorphism, CCR2-64I, changes valine 64 of CCR2 to isoleucine. However, it is not clear whether the effect on AIDS progression results from the amino acid change or whether the polymorphism marks a genetically linked, yet unidentified mutation that mediates the effect. Because the gene encoding CCR5, the major coreceptor for HIV type 1 primary isolates, lies 15 kb 3' to CCR2, linked mutations in the CCR5 promoter or other regulatory sequences could explain the association of CCR2-64I with slowed AIDS pathogenesis. Here, we show that CCR2-64I is efficiently expressed on the cell surface but does not have dominant negative activity on CCR5 coreceptor function. A panel of peripheral blood mononuclear cells (PBMC) from uninfected donors representing the various CCR5/CCR2 genotypes was assembled. Activated primary CD4(+) T cells of CCR2 64I/64I donors expressed cell surface CCR5 at levels comparable to those of CCR2 +/+ donors. A slight reduction in CCR5 expression was noted, although this was not statistically significant. CCR5 and CCR2 mRNA levels were nearly identical for each of the donor PBMC, regardless of genotype. Cell surface CCR5 and CCR2 levels were more variable than mRNA transcript levels, suggesting that an alternative mechanism may influence CCR5 cell surface levels. CCR2-64I is linked to the CCR5 promoter polymorphisms 208G, 303A, 627C, and 676A; however, in transfected promoter reporter constructs, these did not affect transcriptional activity. Taken together, these findings suggest that CCR2-64I does not act by influencing CCR5 transcription or mRNA levels.

A genetic study of various enzyme polymorphisms in Pleurodeles waltlii (Urodele Amphibian). II. Peptidases: demonstration of sex linkage.

PubMed

Ferrier, V; Gasser, F; Jaylet, A; Cayrol, C

1983-06-01

The existence of four peptidases was demonstrated by starch gel electrophoresis in Pleurodeles waltlii: PEP-1, PEP-2, PEP-3, and PEP-4. Peptidases-3 and -4 are monomorphic, and peptidases-1 and -2 are polymorphic. The heredity of the polymorphisms was studied using individuals arising from crosses or of gynogenetic origin. Peptidase-1 is dimeric; its polymorphism depends on a pair of codominant alleles, Pep-1A and Pep-1B, which are situated on the Z and W sex chromosomes, respectively, in close proximity to, or even within, the sex differential segment. As the differential segment is very close to the centromere, the PEP-1 locus therefore also appears to be closely linked to it. Expression of the PEP-1 locus was shown to be independent of the sex hormone environment. This locus is the first case reported in amphibians of an enzyme marker linked to the genetic sex. It allows the sex of PLeurodeles to be determined before they reach sexual maturity. Peptidase-2 is monomeric. Its polymorphism depends on a pair of codominant alleles on an autosomal PEP-2 locus. The high proportion of heterozygous animals in the gynogenetic offspring of females heterozygous for the PEP-2 locus indicates segregation which is independent of the centromere. Analysis of the offspring of doubly heterozygous females (i.e., for two of the loci--LDH-B, G6PDH, PEP-1, and PEP-2) shows that the four loci are independent.

Epidermal growth factor receptor expression in gastric tumors and its relationship with the germline polymorphisms - 216 G>T, -191 C>A, (CA) n IVS1, and R521K.

PubMed

Torres-Jasso, J H; Bustos-Carpinteyro, A R; Garcia-Gonzalez, J R; Peregrina-Sandoval, J; Cruz-Ramos, J A; Santiago-Luna, E; Sanchez-Lopez, J Y

2016-01-01

Gastric cancer (GC) is the third worldwide leading cause of cancer-related death affecting both sexes. The aberrant expression of epidermal growth factor receptor (EGFR) gene has been detected in many human epithelial malignancies and linked to advanced disease, more aggressive phenotype, and poor prognosis. To analyze the relation that the expression of EGFR in gastric tumors holds with pathological characteristics and with the germline polymorphisms -216 G>T, -191 C>A, (CA) n IVS1, and R521K. We studied 22 biopsies from gastric tumors obtained by endoscopy. EGFR expression was determined by relative quantification real-time polymerase chain reaction with the glyceraldehyde-3-phosphate dehydrogenase reference gene (as for messenger RNA [mRNA]) and by immunohistochemistry (IHC) (as for protein). EGFR germline polymorphisms were analyzed by sequencing, GeneScan, and restriction fragment length polymorphisms. EGFR mRNA expression was increased (>2-fold) in 13.6% of GC cases, decreased (<0.5-fold) in 68.2%, and normal in 18.2%; overexpression was related to well-differentiated gastric tumors, whereas underexpression was linked to moderate or poorly differentiated gastric tumors (P < 0.001). EGFR protein expression was high (IHC 2+ and 3+) in 29.4% of gastric tumors and was normal or low (score 0 to 1+) in 70.6% cases. EGFR expression, in both mRNA and protein, was not related to any EGFR polymorphism (P > 0.05). Most gastric tumors showed low EGFR expression (mRNA and protein), whereas EGFR overexpression was related to well-differentiated gastric tumors. Furthermore, germinal polymorphisms -216, -191, (CA) n IVS1, and R521K were not related to EGFR expression (mRNA or protein).

Vitamin E transport gene variants and prostate cancer

USDA-ARS?s Scientific Manuscript database

In the February 15, 2009 issue of Cancer Research, Wright et al. investigated whether polymorphisms in two vitamin E transport genes are associated with elevated prostate cancer risk resulting from altered plasma vitamin E concentrations. However, the circulating vitamin E level is influenced by man...

Mechanistic insights into the link between visfatin gene C-1535T polymorphism and coronary artery disease: an in vitro study.

PubMed

Wang, Yong-Sheng; Gao, Wei; Li, Hong-Fen; Wang, Ze-Mu; Zhu, Jun; Zhao, Huan; Yan, Jian-Jun; Jia, En-Zhi; Yang, Zhi-Jian; Wang, Lian-Sheng

2012-04-01

Visfatin, a pro-inflammatory cytokine predominantly released from leucocytes, is correlated with coronary artery disease (CAD). We have previously reported that the -1535C>T polymorphism (rs1330082), which located on the promoter region of visfatin, was associated with decreased risk of CAD. Here, we investigated the underlying mechanism by which this polymorphism affects the genetic susceptibility to CAD. The difference of the promoter activities between -1535T variant and -1535C allele was tested by luciferase reporter gene assay. The difference of transcription factor binding activities between T and C allele was evaluated by electrophoretic mobility shift assay. In reporter gene assay, we showed that the T variant had a significantly reduced transcriptional activity compared with the C allele. The T-variant significantly attenuated the promoter binding affinity to nuclear transcription factors and this effect became much obvious after treatment with TNF-α. Moreover, competition experiment revealed that the retarded complex formed by T-1535- or C-1535-probe binding to nuclear extracts was nearly completely inhibited by unlabeled activator protein-1 (AP-1) specific probe, indicating that AP-1 might be the target nuclear effector. Taken together, our data provided potential mechanistic link between the visfatin -1535C>T polymorphism and reduced CAD risk.

One-dimensional self-confinement promotes polymorph selection in large-area organic semiconductor thin films.

PubMed

Giri, Gaurav; Li, Ruipeng; Smilgies, Detlef-M; Li, Er Qiang; Diao, Ying; Lenn, Kristina M; Chiu, Melanie; Lin, Debora W; Allen, Ranulfo; Reinspach, Julia; Mannsfeld, Stefan C B; Thoroddsen, Sigurdur T; Clancy, Paulette; Bao, Zhenan; Amassian, Aram

2014-04-16

A crystal's structure has significant impact on its resulting biological, physical, optical and electronic properties. In organic electronics, 6,13(bis-triisopropylsilylethynyl)pentacene (TIPS-pentacene), a small-molecule organic semiconductor, adopts metastable polymorphs possessing significantly faster charge transport than the equilibrium crystal when deposited using the solution-shearing method. Here, we use a combination of high-speed polarized optical microscopy, in situ microbeam grazing incidence wide-angle X-ray-scattering and molecular simulations to understand the mechanism behind formation of metastable TIPS-pentacene polymorphs. We observe that thin-film crystallization occurs first at the air-solution interface, and nanoscale vertical spatial confinement of the solution results in formation of metastable polymorphs, a one-dimensional and large-area analogy to crystallization of polymorphs in nanoporous matrices. We demonstrate that metastable polymorphism can be tuned with unprecedented control and produced over large areas by either varying physical confinement conditions or by tuning energetic conditions during crystallization through use of solvent molecules of various sizes.

Polymorphisms in the serotonin transporter and monoamine oxidase A genes and their relationship to personality traits measured by the Temperament and Character Inventory and NEO Five-Factor Inventory in healthy volunteers.

PubMed

Samochowiec, Jerzy; Syrek, Szymon; Michał, Parus; Ryzewska-Wódecka, Aneta; Samochowiec, Agnieszka; Horodnicki, Jan; Zakrzewska, Marzena; Kucharska-Mazur, Jolanta

2004-01-01

The associations between 5-HTT-linked polymorphic region (5-HTT-LPR), monoamine oxidase A (MAOA)-LPR and the dimensions of temperament evaluated using the Temperament and Character Inventory (TCI) and NEO Five-Factor Inventory (NEO-FFI) were studied. One hundred healthy volunteers (without psychiatric disorders) were recruited to represent a cross-section of the population of Szczecin (Poland) in terms of sex, age and education. No associations between 5-HTT-LPR and the TCI harm avoidance dimension and between 5-HTT-LPR and the NEO-FFI neuroticism dimension were found. Males carrying the 3-VNTR MAOA gene variant (209 bp) had significantly lower values on the NEO-FFI openness dimension (p = 0.039) and obtained higher scores on the subdimension 3 of the TCI reward dependence (RD3), i.e. attachment vs. detachment (p = 0.005). Individuals carrying the 'short' variant of 5-HTT-LPR had lower values on the reward dependence dimension and the RD4 subdimension (dependence vs. independence) than individuals not carrying the 'short' variant (p = 0.039 and p = 0.011, respectively). Females carrying the 'short' variant had lower values on NS1 (exploratory excitability vs. stoic rigidity) and RD4 (dependence vs. independence) than those not carrying the variant (p = 0.042 and 0.043, respectively). The obtained level of significance with respect to the observed associations between 5-HTT-LPR and the reward dependence scales and subscales and between 5-HTT-LPR and the NS1 subscale are too weak for further interpretation. Our results do not confirm the hypothesis that there is a simple correlation between single gene polymorphisms and a personality trait measured by the TCI and NEO-FFI scales.

Serotonin Transporter Gene-Linked Polymorphic Region (5-HTTLPR) Influences Decision Making under Ambiguity and Risk in a Large Chinese Sample

PubMed Central

He, Qinghua; Xue, Gui; Chen, Chuansheng; Lu, Zhonglin; Dong, Qi; Lei, Xuemei; Ding, Ni; Li, Jin; Li, He; Chen, Chunhui; Li, Jun; Moyzis, Robert K.; Bechara, Antoine

2010-01-01

Risky decision-making is a complex process that involves weighing the probabilities of alternative options that can be desirable, undesirable, or neutral. Individuals vary greatly in how they make decisions either under ambiguity and/or under risk. Such individual differences may have genetic bases. Based on previous studies on the genetic basis of decision making, two decision making tasks [i.e., Iowa Gambling Task (IGT) and Loss Aversion Task (LAT)] were used to test the effect of 5-HTTLPR polymorphism on decision making under ambiguity and under risk in a large Han Chinese sample (572 college students, 312 females). Basic intelligence and memory tests were also included to control for the influence of basic cognitive abilities on decision making. We found that 5-HTTLPR polymorphism significantly influenced performance in both IGT and LAT. After controlling for intellectual and memory abilities, subjects homozygous for s allele had lower IGT scores than l carriers in the first 40 trials of the IGT task. They also exhibited higher loss aversion than l carriers in the LAT task. Moreover, the effects of 5-HTTLPR were stronger for males than for females. These results extend the literature on the important role of emotion in decision under ambiguity and risk, and provide additional lights on how decision-making is influenced by culture as well as sex differences. Combining our results with existing literature, we propose that these effects might be mediated by a neural circuitry that comprises the amygdala, ventromedial prefrontal cortex, and insular cortex. Understanding the genetic factors affecting decision in healthy subjects may allow us better identify at-risk individuals, and target better the development of new potential treatments for specific disorders such as schizophrenia, addiction, and depression. PMID:20659488

Preschoolers’ Genetic, Physiological, and Behavioral Sensitivity Factors Moderate Links Between Parenting Stress and Child Internalizing, Externalizing, and Sleep Problems

PubMed Central

Davis, Molly; Thomassin, Kristel; Bilms, Joanie; Suveg, Cynthia; Shaffer, Anne; Beach, Steven R. H.

2017-01-01

This study examined three potential moderators of the relations between maternal parenting stress and preschoolers’ adjustment problems: a genetic polymorphism - the short allele of the serotonin transporter (5-HTTLPR, ss/sl allele) gene, a physiological indicator - children’s baseline respiratory sinus arrhythmia (RSA), and a behavioral indicator - mothers’ reports of children’s negative emotionality. A total of 108 mothers (Mage = 30.68 years, SDage = 6.06) reported on their parenting stress as well as their preschoolers’ (Mage = 3.50 years, SDage = .51, 61% boys) negative emotionality and internalizing, externalizing, and sleep problems. Results indicated that the genetic sensitivity variable functioned according to a differential susceptibility model; however, the results involving physiological and behavioral sensitivity factors were most consistent with a diathesis-stress framework. Implications for prevention and intervention efforts to counter the effects of parenting stress are discussed. PMID:28295263

Mapping of the X-linked cataract (Xcat) mutation, the gene implicated in the Nance Horan syndrome, on the mouse X chromosome.

PubMed

Stambolian, D; Favor, J; Silvers, W; Avner, P; Chapman, V; Zhou, E

1994-07-15

The Xcat mutation in the mouse, an X-linked inherited disorder, is characterized by the congenital onset of cataracts. The cataracts have morphologies similar to those of cataracts found in the human Nance Horan (X-linked cataract dental) syndrome, suggesting that Xcat is an animal model for Nance Horan. The Xcat mutation provides an opportunity to investigate, at the molecular level, the pathogenesis of cataract. As a first step to cloning the Xcat gene, we report the localization of the Xcat mutation with respect to known molecular markers on the mouse X chromosome. Back-cross progeny carrying the Xcat mutation were obtained from an interspecific cross. Genomic DNA from each mouse was subjected to Southern and PCR analysis to identify restriction fragment length polymorphisms and simple sequence length polymorphisms, respectively. Our results refine the location of Xcat to a 2-cM region, eliminate several genes from consideration as the Xcat mutation, identify molecular probes tightly linked with Xcat, and suggest candidate genes responsible for the Xcat phenotype.

Characterization of demographic expansions from pairwise comparisons of linked microsatellite haplotypes.

PubMed

Navascués, Miguel; Hardy, Olivier J; Burgarella, Concetta

2009-03-01

This work extends the methods of demographic inference based on the distribution of pairwise genetic differences between individuals (mismatch distribution) to the case of linked microsatellite data. Population genetics theory describes the distribution of mutations among a sample of genes under different demographic scenarios. However, the actual number of mutations can rarely be deduced from DNA polymorphisms. The inclusion of mutation models in theoretical predictions can improve the performance of statistical methods. We have developed a maximum-pseudolikelihood estimator for the parameters that characterize a demographic expansion for a series of linked loci evolving under a stepwise mutation model. Those loci would correspond to DNA polymorphisms of linked microsatellites (such as those found on the Y chromosome or the chloroplast genome). The proposed method was evaluated with simulated data sets and with a data set of chloroplast microsatellites that showed signal for demographic expansion in a previous study. The results show that inclusion of a mutational model in the analysis improves the estimates of the age of expansion in the case of older expansions.

Evidence of lactate dehydrogenase-B allozyme effects in the teleost, Fundulus heteroclitus.

PubMed

DiMichele, L; Paynter, K T; Powers, D A

1991-08-23

The evolutionary significance of protein polymorphisms has long been debated. Exponents of the balanced theory advocate that selection operates to maintain polymorphisms, whereas the neoclassical school argues that most genetic variation is neutral. Some studies have suggested that protein polymorphisms are not neutral, but their significance has been questioned because one cannot eliminate the possibility that linked loci were responsible for the observed differences. Evidence is presented that an enzymatic phenotype can affect carbon flow through a metabolic pathway. Glucose flux differences between lactate dehydrogenase-B phenotypes of Fundulus heteroclitus were reversed by substituting the Ldh-B gene product of one homozygous genotype with that of another.

Structural patterns of the human ABCC4/MRP4 exporter in lipid bilayers rationalize clinically observed polymorphisms.

PubMed

Chantemargue, B; Di Meo, F; Berka, K; Picard, N; Arnion, H; Essig, M; Marquet, P; Otyepka, M; Trouillas, P

2018-03-10

The ABCC4/MRP4 exporter has a clinical impact on membrane transport of a broad range of xenobiotics. It is expressed at key locations for drug disposition or effects such as in the liver, the kidney and blood cells. Several polymorphisms and mutations (e.g., p.Gly187Trp) leading to MRP4 dysfunction are associated with an increased risk of toxicity of some drugs. So far, no human MRP4 structure has been elucidated, precluding rationalization of these dysfunctions at a molecular level. We constructed an atomistic model of the wild type (WT) MRP4 and the p.Gly187Trp mutant embedded in different lipid bilayers and relaxed them for hundreds of nanoseconds by molecular dynamics simulations. The WT MRP4 molecular structure confirmed and ameliorated the general knowledge about the transmembrane helices and the two nucleotide binding domains. Moreover, our model elucidated positions of three generally unresolved domains: L 1 (linker between the two halves of the exporter); L 0 (N-terminal domain); and the zipper helices (between the two NBDs). Each domain was thoroughly described in view of its function. The p.Gly187Trp mutation induced a huge structural impact on MRP4, mainly affecting NBD 1 structure and flexibility. The structure of transporter enabled rationalization of known dysfunctions associated with polymorphism of MRP4. This model is available to the pharmacology community to decipher the impact of any other clinically observed polymorphism and mutation on drug transport, giving rise to in silico predictive pharmacogenetics. Copyright © 2018 Elsevier Ltd. All rights reserved.

The role of ITPA and ribavirin transporter genes polymorphisms in prediction of ribavirin-induced anaemia in chronic hepatitis C Egyptian patients.

PubMed

El Desoky, Ehab S; Abdelhafez, Alaa T; Cusato, Jessica; Kamel, Sherif I; Hussein, Abeer Mr; De Nicolo, Amedeo; Di Perri, Giovanni; D'Avolio, Antonio

2017-09-01

Few data are available concerning the roles of polymorphisms of inosine triphosphatase (ITPA) gene and ribavirin (RBV) transporter genes in the prediction of RBV-induced anaemia among Egyptians with chronic hepatitis C (CHC). Genotyping of three ITPA gene variants and two variants of RBV transporter genes has been performed in 123 patients under pegylated interferon-α/ribavirin treatment. The baseline haemoglobin and ITPA rs1127354 CA/AA have been found as predictors of anaemia at 4, 8 and 12 weeks of RBV therapy. In addition, ITPA rs7270101 AC/CC and age predicted anaemia after 12 weeks of therapy. In conclusion, the ITPA variant rs1127354C>A significantly predict RBV-induced anaemia during the first 3 months of treatment and it is recommended to be assessed before RBV administration. © 2017 John Wiley & Sons Australia, Ltd.

Association of adiponectin gene -11377C>G polymorphism with adiponectin levels and the metabolic syndrome in Thais.

PubMed

Suriyaprom, Kanjana; Phonrat, Benjaluck; Tungtrongchitr, Rungsunn

2014-01-01

The metabolic syndrome is related to increased risk of developing cardiovascular disease and type 2 diabetes. Adiponectin is an adipocyte-secreted protein with insulin-sensitizing and anti-atherogenic properties. The aims of this study were to evaluate adiponectin levels and biochemical parameters in metabolic-syndrome subjects and healthy controls. The study also sought to identify links between two polymorphisms, -11377C>G (rs266729) and +45T>G (rs2241766) of the adiponectin gene, in relation to adiponectin levels and the metabolic syndrome. Three hundres and thirty-two Thai volunteers: 164 metabolic-syndrome subjects and 168 healthy control subjects were investigated. The adiponectin and HDL-C levels of the metabolic-syndrome group were significantly lower than the control group (p<0.001). Decreased concentration of adiponectin was associated with -11377C>G polymorphism (p<0.001); this polymorphism was significantly more frequent in the metabolic syndrome group than in the control group (p<0.001). However, +45T>G polymorphism of the adiponectin gene was found not to be related to adiponectin level or metabolic syndrome. Therefore, -11377C>G polymorphism was related to the metabolic syndrome susceptibility, and this polymorphism impacted on circulating adiponectin concentrations among Thais.

The interplay of genetic and environmental factors in shaping well-being across the lifespan: Evidence from the serotonin transporter gene.

PubMed

Gärtner, Matti; Grimm, Simone; Aust, Sabine; Fan, Yan; von Scheve, Christian; Bajbouj, Malek

2017-07-07

Converging evidence suggests that well-being plays an important role in promoting and maintaining mental health across the life span. It has been shown that well-being has a considerable heritable component, but little is known about the specific genes involved. In this study, we investigated a healthy sample (N = 298) that was genotyped for the serotonin transporter-linked polymorphic region (5-HTTLPR). We hypothesized that 5-HTTLPR gene variation would influence well-being, and additionally investigated interaction effects with age and the environmental influence of early life stress (ELS). Using multiple regression, our results showed a significant three-way interaction between genotype, ELS, and age. Exploration of this interaction showed that young subjects had decreased levels of well-being if they were exposed to ELS and homozygous for the short variant of 5-HTTLPR. This relationship was reversed in old age: subjects that were exposed to ELS and carried the long variant of 5-HTTLPR had decreased levels of well-being. Our results indicate that genetic and environmental factors have joint effects on well-being that are susceptible to profound changes across the life span.

Variations in the serotonin-transporter gene are associated with attention bias patterns to positive and negative emotion faces.

PubMed

Pérez-Edgar, Koraly; Bar-Haim, Yair; McDermott, Jennifer Martin; Gorodetsky, Elena; Hodgkinson, Colin A; Goldman, David; Ernst, Monique; Pine, Daniel S; Fox, Nathan A

2010-03-01

Both attention biases to threat and a serotonin-transporter gene polymorphism (5-HTTLPR) have been linked to heightened neural activation to threat and the emergence of anxiety. The short allele of 5-HTTLPR may act via its effect on neurotransmitter availability, while attention biases shape broad patterns of cognitive processing. We examined individual differences in attention bias to emotion faces as a function of 5-HTTLPR genotype. Adolescents (N=117) were classified for presumed SLC6A4 expression based on 5-HTTLPR-low (SS, SL(G), or L(G)L(G)), intermediate (SL(A) or L(A)L(G)), or high (L(A)L(A)). Participants completed the dot-probe task, measuring attention biases toward or away from angry and happy faces. Biases for angry faces increased with the genotype-predicted neurotransmission levels (low>intermediate>high). The reverse pattern was evident for happy faces. The data indicate a linear relation between 5-HTTLPR allelic status and attention biases to emotion, demonstrating a genetic mechanism for biased attention using ecologically valid stimuli that target socioemotional adaptation. Copyright 2009 Elsevier B.V. All rights reserved.

Pharmacogenetics of neurological and psychiatric diseases at older age: has the time come?

PubMed

Lozupone, Madia; Panza, Francesco; Stella, Eleonora; La Montagna, Maddalena; Bisceglia, Paola; Miscio, Giuseppe; Galizia, Ilaria; Daniele, Antonio; di Mauro, Lazzaro; Bellomo, Antonello; Logroscino, Giancarlo; Greco, Antonio; Seripa, Davide

2017-03-01

In recent years, a number of pharmacological approaches for treating neuropsychiatric conditions at older age have proven to be inadequate. The resulting increased prevalence of therapeutic failures (TF) and a worsening of clinical symptoms often linked to adverse reactions (ADRs), are perhaps among the major causes of the increasing rate of hospitalizations and institutionalizations observed in these patients. Areas covered: This review underlines the importance of pharmacogenetic data to fingerprint the pharmacological treatment of neuropsychiatric late-life conditions throughout the analysis of metabolizing enzymes and transporters of psychotropic drugs, mainly those of the cytochrome P450 (CYP) family. Pharmacodynamic response measures as treatment effects mediated through targets (i.e., receptors in the brain) may also contribute to this image. Expert opinion: CYP genetics is the basis of a continuum on which environmental and physiological factors act, modeling the phenotype observed in clinical practice with advancing age. Furthermore, other specific polymorphic genes influence drug response through differential effects of their functional genetic variants. The known genotypes associated with an altered metabolizer status and drug transporters may help clinical decision-making to avoid concomitant treatments, reduce therapeutic attempts and increase drug safety in neuropsychiatric conditions in older age, after controlling for other clinical variables.

A genetic polymorphism in the sex-linked ATP5A1 gene is associated with individual fitness in Ovenbirds (Seiurus aurocapilla)

Treesearch

Judith D. Toms; Lori S. Eggert; Wayne J. Arendt; John Faaborg

2012-01-01

While testing genetic sexing techniques in Ovenbirds (Seiurus aurocapilla),we found a genetic polymorphism in the ATP5A1 gene in 38% of individuals. The Z ' allele included changes in both intronic and exonic portions of the sequenced region, but there was no evidence that this changed the resulting ATP synthase product. Males that had one or more copies of...

A pilot genetic study of the continuum between compulsivity and impulsivity in females: the serotonin transporter promoter polymorphism.

PubMed

Baca-García, Enrique; Salgado, Beatríz Rodríguez; Segal, Helen Dolengevich; Lorenzo, Concepción Vaquero; Acosta, Mercedes Navio; Romero, Manuel Arrojo; Hernández, Montserrat Díaz; Saiz-Ruiz, Jeronimo; Fernandez Piqueras, Jose; de Leon, Jose

2005-06-01

According to some authors the obsessive-compulsive (OC) spectrum includes on one extreme, the Obsessive-Compulsive Disorder (OCD) and on the other extreme the most impulsive behaviors. This is a controversial idea and other authors define the OC spectrum in different ways. The serotonin transporter (5-HTT) gene is one of the main genes that control serotonergic function. A polymorphism in the promoter area of this gene classifies subjects with low expression as S individuals (s/s or s/l) and subjects with high expression as L individuals (l/l). This polymorphism was studied in female OCD patients (n = 24), non-impulsive controls (n = 112) and impulsive suicidal patients (n = 118) to support the OC spectrum hypothesis from a genetic perspective. A linear association exists among the serotonin transporter promoter functional genotypes (S versus L individuals) (chi2 linear by linear association = 8.9; df = 1; p = 0.003). The frequency of S individuals (s/l or s/s) was lowest in OCD (54%, 13/24); intermediate in non-impulsive controls (71%, 80/112) and highest in impulsive suicide attempters (82%, 96/117). More importantly, future studies need to consider that genetics may be related to behavioral dimensions (compulsivity to impulsivity) instead of to specific psychiatric disorders defined in clinical terms.

Influence of Cremophor EL and genetic polymorphisms on the pharmacokinetics of paclitaxel and its metabolites using a mechanism-based model.

PubMed

Fransson, Martin N; Gréen, Henrik; Litton, Jan-Eric; Friberg, Lena E

2011-02-01

The formulation vehicle Cremophor EL has previously been shown to affect paclitaxel kinetics, but it is not known whether it also affects the kinetics of paclitaxel metabolites. This information may be important for understanding paclitaxel metabolism in vivo and in the investigation of the role of genetic polymorphisms in the metabolizing enzymes CYP2C8 and CYP3A4/CYP3A5 and the ABCB1 transporter. In this study we used the population pharmacokinetic approach to explore the influence of predicted Cremophor EL concentrations on paclitaxel (Taxol) metabolites. In addition, correlations between genetic polymorphisms and enzyme activity with clearance of paclitaxel, its two primary metabolites, 6α-hydroxypaclitaxel and p-3'-hydroxypaclitaxel, and its secondary metabolite, 6α-p-3'-dihydroxypaclitaxel were investigated. Model building was based on 1156 samples from a study with 33 women undergoing paclitaxel treatment for gynecological cancer. Total concentrations of paclitaxel were fitted to a model described previously. One-compartment models characterized unbound metabolite concentrations. Total concentrations of 6α-hydroxypaclitaxel and p-3'-hydroxypaclitaxel were strongly dependent on predicted Cremophor EL concentrations, but this association was not found for 6α-p-3'-dihydroxypaclitaxel. Clearance of 6α-hydroxypaclitaxel (fraction metabolized) was significantly correlated (p < 0.05) to the ABCB1 allele G2677T/A. Individuals carrying the polymorphisms G/A (n = 3) or G/G (n = 5) showed a 30% increase, whereas individuals with polymorphism T/T (n = 8) showed a 27% decrease relative to those with the polymorphism G/T (n = 17). The correlation of G2677T/A with 6α-hydroxypaclitaxel has not been described previously but supports other findings of the ABCB1 transporter playing a part in paclitaxel metabolism.

Influence Of Carboxymethyl Cellulose For The Transport Of Titanium Dioxide Nanoparticles In Clean Silica And Mineral-Coated Sands

EPA Science Inventory

The transport properties of titanium dioxide (anatase polymorph) nanoparticles encapsulated by carboxymethyl cellulose (CMC) were evaluated as a function of changes in the solute chemical properties in clean quartz, amorphous aluminum and iron hydroxide-coated sands. While prist...

Clinical relevance of the interleukin 10 promoter polymorphisms in Chinese Han patients with major trauma: genetic association studies.

PubMed

Zeng, Ling; Gu, Wei; Chen, Kehong; Jiang, Dongpo; Zhang, Lianyang; Du, Dingyuan; Hu, Ping; Liu, Qing; Huang, Suna; Jiang, Jianxin

2009-01-01

An excessive inflammatory response is thought to account for the pathogenesis of sepsis and multiple organ dysfunction syndrome (MODS) after severe trauma. The interleukin-10 (IL-10) is a potent anti-inflammatory cytokine. The objectives of this prospective study were to investigate the distribution of IL-10 promoter polymorphisms in a cohort of 308 Chinese Han patients with major trauma, and to identify associations of IL-10 promoter polymorphisms with IL-10 production and incidence of sepsis and MODS. A total of 308 patients with major trauma were included in this study. The genotypes of polymorphisms -1082, -819 and -592 were determined by polymerase chain reaction-restriction fragment length polymorphism. The IL-10 levels in the supernatants were determined with enzyme-linked immunoabsorbent assay. The -1082A and -592A alleles were significantly associated with lower lipopolysaccharide-induced IL-10 production in an allele-dose dependent fashion. There was no significant difference for the -819 polymorphism. Except for the -1082 polymorphism, the -819 and -592 polymorphisms were not significantly associated with sepsis morbidity rate and MOD scores. Our results further confirm the functionality of the IL-10 promoter single nucleotide polymorphisms in relation to IL-10 production. They also suggest that individual difference in IL-10 production in trauma patients might be at least in part related to genetic variations in the IL-10 promoter region.

Linked PNPLA3 polymorphisms confer susceptibility to nonalcoholic steatohepatitis and decreased viral load in chronic hepatitis B.

PubMed

Pan, Qin; Zhang, Rui-Nan; Wang, Yu-Qin; Zheng, Rui-Dan; Mi, Yu-Qiang; Liu, Wen-Bin; Shen, Feng; Chen, Guang-Yu; Lu, Jia-Fa; Zhu, Chan-Yan; Zhang, Shu-Yi; Chen, Yi-Ming; Sun, Wan-Lu; Fan, Jian-Gao

2015-07-28

To investigate the association of PNPLA3 polymorphisms with concurrent chronic hepatitis B (CHB) and nonalcoholic fatty liver disease (NAFLD). A cohort of Han patients with biopsy-proven CHB, with or without NAFLD (CHB group, n = 51; CHB + NAFLD group, n = 57), and normal controls (normal group, n = 47) were recruited from Northern (Tianjin), Central (Shanghai), and Southern (Zhangzhou) China. Their PNPLA3 polymorphisms were genotyped by gene sequencing. The association between PNPLA3 polymorphisms and susceptibility to NAFLD, and clinical characteristics of NAFLD were evaluated on the basis of physical indices, liver function tests, glycolipid metabolism, and histopathologic scoring. The association of PNPLA3 polymorphisms and hepatitis B virus (HBV) load was determined by the serum level of HBV DNA. After adjusting for age, sex, and body mass index, we found that four linked single nucleotide polymorphisms (SNPs) of PNPLA3, including the rs738409 G allele (CHB + NAFLD group vs CHB group: odds ratio [OR] = 2.77, 95% confidence interval [CI]: 1.18-6.54; P = 0.02), rs3747206 T allele (CHB + NAFLD group vs CHB group: OR = 2.77, 95%CI: 1.18-6.54; P = 0.02), rs4823173 A allele (CHB + NAFLD group vs CHB group: OR = 2.73, 95%CI: 1.16-6.44; P = 0.02), and rs2072906 G allele (CHB + NAFLD group vs CHB group: OR = 3.05, 95%CI: 1.28-7.26; P = 0.01), conferred high risk to NAFLD in CHB patients. In patients with both CHB and NAFLD, these genotypes of PNPLA3 polymorphisms were associated with increased susceptibility to nonalcoholic steatohepatitis (NASH) (NAFLD activity score ≥ 3; P = 0.01-0.03) and liver fibrosis (> 1 Metavir grading; P = 0.01-0.04). As compared to those with C/C and C/G at rs738409, C/C and C/T at rs3747206, G/G and G/A at rs4823173, and A/A and A/G at rs2072906, patients in the CHB + NAFLD group with G/G at rs738409, T/T at rs3747206, A/A at rs4823173, and G/G at rs2072906 showed significantly lower serum levels of HBV DNA (P < 0.01-0.05). Four linked SNPs of PNPLA3 (rs738409, rs3747206, rs4823173, and rs2072906) are correlated with susceptibility to NAFLD, NASH, liver fibrosis, and HBV dynamics in CHB patients.

Linked PNPLA3 polymorphisms confer susceptibility to nonalcoholic steatohepatitis and decreased viral load in chronic hepatitis B

PubMed Central

Pan, Qin; Zhang, Rui-Nan; Wang, Yu-Qin; Zheng, Rui-Dan; Mi, Yu-Qiang; Liu, Wen-Bin; Shen, Feng; Chen, Guang-Yu; Lu, Jia-Fa; Zhu, Chan-Yan; Zhang, Shu-Yi; Chen, Yi-Ming; Sun, Wan-Lu; Fan, Jian-Gao

2015-01-01

AIM: To investigate the association of PNPLA3 polymorphisms with concurrent chronic hepatitis B (CHB) and nonalcoholic fatty liver disease (NAFLD). METHODS: A cohort of Han patients with biopsy-proven CHB, with or without NAFLD (CHB group, n = 51; CHB + NAFLD group, n = 57), and normal controls (normal group, n = 47) were recruited from Northern (Tianjin), Central (Shanghai), and Southern (Zhangzhou) China. Their PNPLA3 polymorphisms were genotyped by gene sequencing. The association between PNPLA3 polymorphisms and susceptibility to NAFLD, and clinical characteristics of NAFLD were evaluated on the basis of physical indices, liver function tests, glycolipid metabolism, and histopathologic scoring. The association of PNPLA3 polymorphisms and hepatitis B virus (HBV) load was determined by the serum level of HBV DNA. RESULTS: After adjusting for age, sex, and body mass index, we found that four linked single nucleotide polymorphisms (SNPs) of PNPLA3, including the rs738409 G allele (CHB + NAFLD group vs CHB group: odds ratio [OR] = 2.77, 95% confidence interval [CI]: 1.18-6.54; P = 0.02), rs3747206 T allele (CHB + NAFLD group vs CHB group: OR = 2.77, 95%CI: 1.18-6.54; P = 0.02), rs4823173 A allele (CHB + NAFLD group vs CHB group: OR = 2.73, 95%CI: 1.16-6.44; P = 0.02), and rs2072906 G allele (CHB + NAFLD group vs CHB group: OR = 3.05, 95%CI: 1.28-7.26; P = 0.01), conferred high risk to NAFLD in CHB patients. In patients with both CHB and NAFLD, these genotypes of PNPLA3 polymorphisms were associated with increased susceptibility to nonalcoholic steatohepatitis (NASH) (NAFLD activity score ≥ 3; P = 0.01-0.03) and liver fibrosis (> 1 Metavir grading; P = 0.01-0.04). As compared to those with C/C and C/G at rs738409, C/C and C/T at rs3747206, G/G and G/A at rs4823173, and A/A and A/G at rs2072906, patients in the CHB + NAFLD group with G/G at rs738409, T/T at rs3747206, A/A at rs4823173, and G/G at rs2072906 showed significantly lower serum levels of HBV DNA (P < 0.01-0.05). CONCLUSION: Four linked SNPs of PNPLA3 (rs738409, rs3747206, rs4823173, and rs2072906) are correlated with susceptibility to NAFLD, NASH, liver fibrosis, and HBV dynamics in CHB patients. PMID:26229402

[Polymorphisms of the multiple drug resistance gene (MDR1) in Mapuche, Mestizo and Maori populations in Chile].

PubMed

Wielandt, Ana María; Vollrath, Valeska; Chianale, José

2004-09-01

There are significant differences in drug responses among different ethnic groups. The multidrug transporter P-gp, encoded by the MDR1 gene, plays a key role in determining drug bioavailability, and an association between a polymorphism in exon 26 (C3435T) and lower P-gp expression has been found. The co-segregation of this polymorphism with the polymorphism in exon 12 (C1236T) and in exon 21 (G2677T/A) determines several MDR1 haplotypes in humans. To characterize the polymorphisms of exons 26, 21 and 12 of the MDR1 gene in different Chilean populations. Using a polymerase chain reaction and restriction fragment length polymorphism technique, we studied the allelic frequencies and the distribution of MDR1 haplotypes in 3 Chilean populations: Mestizo (n=104), Mapuche (n=96, living in the National Reservation of the Huapi Island, Ranico Lake) and Maori (n=52, living in Eastern Island). The frequency of the normal MDR1*1 haplotype, without mutations, was lower in Mapuches than in Mestizos or Maoris (p<0.005) but similar to that reported in Asian population (p=0.739), probably due to the Asian origin of the Amerindian populations. In addition, the MDR1*l haplotype fequency hin Mestizos was similar to the frequency reported in Caucasians (p=0.49), in agreement with the origin of our population, with a strong influence of Caucasian genes from the Spanish conquerors. The MDR1*2 haplotype distribution, with the three polymoyphisms and probably lower multidrug transporter expression, was similar in the three Chilean populations studied (p>0.0.5), but lower than the frequencies reported in Caucasians or Asians (p<0.05). We found significant differences in the frequencies of genetic polymorphisms of the MDR1 gene in Chilean populations, related to the ethnic origins of our ancestors.

A possible association between panic disorder and a polymorphism in the preproghrelingene.

PubMed

Hansson, Caroline; Annerbrink, Kristina; Nilsson, Staffan; Bah, Jessica; Olsson, Marie; Allgulander, Christer; Andersch, Sven; Sjödin, Ingemar; Eriksson, Elias; Dickson, Suzanne L

2013-03-30

The aim of the study was to investigate whether polymorphisms in the preproghrelin gene are associated with anxiety disorders, such as panic disorder, in humans. Panic disorder is a severe anxiety disorder, characterized by sudden attacks of intense fear or anxiety in combination with somatic symptoms. The preproghrelin gene codes for two gut-derived circulating peptides that have been linked to anxiety-like behaviour in rodents: ghrelin (an orexigenic, pro-obesity hormone) and obestatin. In the present study, we genotyped three missense mutations in the preproghrelin gene in 215 patients suffering from panic disorder and in 451 controls. The A allele of the rs4684677 polymorphism was significantly associated with panic disorder, while there were no significant associations with the two other polymorphisms studied. We conclude that the rs4684677 (Gln90Leu) polymorphism in the preproghrelin gene may be associated with increased risk of panic disorder. It will be important to confirm these findings in additional panic disorder patient groups. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Supergenes and their role in evolution.

PubMed

Thompson, M J; Jiggins, C D

2014-07-01

Adaptation is commonly a multidimensional problem, with changes in multiple traits required to match a complex environment. This is epitomized by balanced polymorphisms in which multiple phenotypes co-exist and are maintained in a population by a balance of selective forces. Consideration of such polymorphisms led to the concept of the supergene, where alternative phenotypes in a balanced polymorphism segregate as if controlled by a single genetic locus, resulting from tight genetic linkage between multiple functional loci. Recently, the molecular basis for several supergenes has been resolved. Thus, major chromosomal inversions have been shown to be associated with polymorphisms in butterflies, ants and birds, offering a mechanism for localised reduction in recombination. In several examples of plant self-incompatibility, the functional role of multiple elements within the supergene architecture has been demonstrated, conclusively showing that balanced polymorphism can be maintained at multiple coadapted and tightly linked elements. Despite recent criticism, we argue that the supergene concept remains relevant and is more testable than ever with modern molecular methods.

Structural organization and mutational analysis of the human uncoupling protein-2 (hUCP2) gene.

PubMed

Tu, N; Chen, H; Winnikes, U; Reinert, I; Marmann, G; Pirke, K M; Lentes, K U

1999-01-01

Uncoupling proteins (UCPs) are mitochondrial membrane transporters which are involved in dissipating the proton electrochemical gradient thereby releasing stored energy as heat. This implies a major role of UCPs in energy metabolism and thermogenesis which when deregulated are key risk factors for the development of obesity and other eating disorders. From the three different human UCPs identified so far by gene cloning both UCP2 and UCP3 were mapped in close proximity (75-150 kb) to regions of human chromosome 11 (11q13) that have been linked to obesity and hyperinsulinaemia. At the amino acid level hUCP2 has about 55% identity to hUCP1 while hUCP3 is 71% identical to hUCP2. In this study we have deduced the genomic structure of the human UCP2 gene by PCR and direct sequence analysis. The hUCP2 gene spans over 8.7 kb distributed on 8 exons. The localization of the exon/intron boundaries within the coding region matches precisely that of the hUCP1 gene and is almost conserved in the recently discovered hUCP3 gene as well. The high degree of homology at the nucleotide level and the conservation of the exon /intron boundaries among the three UCP genes suggests that they may have evolved from a common ancestor or are the result from gene duplication events. Mutational analysis of the hUCP2 gene in a cohort of 172 children (aged 7 - 13) of Caucasian origin revealed a polymorphism in exon 4 (C to T transition at position 164 of the cDNA resulting in the substitution of an alanine by a valine at codon 55) and an insertion polymorphism in exon 8. The insertion polymorphism consists of a 45 bp repeat located 150 bp downstream of the stop codon in the 3'-UTR. The allele frequencies were 0.63 and 0.37 for the alanine and valine encoded alleles, respectively, and 0.71 versus 0.29 for the insertion polymorphism. The allele frequencies of both polymorphisms were not significantly elevated in a subgroup of 25 children characterized by low Resting Metabolic Rates (RMR). So far a direct correlation of the observed genotype with (RMR) and Body Mass Index (BMI) was not evident. Expression studies of the wild type and mutant forms of UCP2 should clarify the functional consequences these polymorphisms may have on energy metabolism and body weight regulation.

Epitaxial stabilization and phase instability of VO2 polymorphs

NASA Astrophysics Data System (ADS)

Lee, Shinbuhm; Ivanov, Ilia N.; Keum, Jong K.; Lee, Ho Nyung

2016-01-01

The VO2 polymorphs, i.e., VO2(A), VO2(B), VO2(M1) and VO2(R), have a wide spectrum of functionalities useful for many potential applications in information and energy technologies. However, synthesis of phase pure materials, especially in thin film forms, has been a challenging task due to the fact that the VO2 polymorphs are closely related to each other in a thermodynamic framework. Here, we report epitaxial stabilization of the VO2 polymorphs to synthesize high quality single crystalline thin films and study the phase stability of these metastable materials. We selectively deposit all the phases on various perovskite substrates with different crystallographic orientations. By investigating the phase instability, phonon modes and transport behaviours, not only do we find distinctively contrasting physical properties of the VO2 polymorphs, but that the polymorphs can be on the verge of phase transitions when heated as low as ~400 °C. Our successful epitaxy of both VO2(A) and VO2(B) phases, which are rarely studied due to the lack of phase pure materials, will open the door to the fundamental studies of VO2 polymorphs for potential applications in advanced electronic and energy devices.

Epitaxial stabilization and phase instability of VO2 polymorphs.

PubMed

Lee, Shinbuhm; Ivanov, Ilia N; Keum, Jong K; Lee, Ho Nyung

2016-01-20

The VO2 polymorphs, i.e., VO2(A), VO2(B), VO2(M1) and VO2(R), have a wide spectrum of functionalities useful for many potential applications in information and energy technologies. However, synthesis of phase pure materials, especially in thin film forms, has been a challenging task due to the fact that the VO2 polymorphs are closely related to each other in a thermodynamic framework. Here, we report epitaxial stabilization of the VO2 polymorphs to synthesize high quality single crystalline thin films and study the phase stability of these metastable materials. We selectively deposit all the phases on various perovskite substrates with different crystallographic orientations. By investigating the phase instability, phonon modes and transport behaviours, not only do we find distinctively contrasting physical properties of the VO2 polymorphs, but that the polymorphs can be on the verge of phase transitions when heated as low as ~400 °C. Our successful epitaxy of both VO2(A) and VO2(B) phases, which are rarely studied due to the lack of phase pure materials, will open the door to the fundamental studies of VO2 polymorphs for potential applications in advanced electronic and energy devices.

Epitaxial stabilization and phase instability of VO2 polymorphs

PubMed Central

Lee, Shinbuhm; Ivanov, Ilia N.; Keum, Jong K.; Lee, Ho Nyung

2016-01-01

The VO2 polymorphs, i.e., VO2(A), VO2(B), VO2(M1) and VO2(R), have a wide spectrum of functionalities useful for many potential applications in information and energy technologies. However, synthesis of phase pure materials, especially in thin film forms, has been a challenging task due to the fact that the VO2 polymorphs are closely related to each other in a thermodynamic framework. Here, we report epitaxial stabilization of the VO2 polymorphs to synthesize high quality single crystalline thin films and study the phase stability of these metastable materials. We selectively deposit all the phases on various perovskite substrates with different crystallographic orientations. By investigating the phase instability, phonon modes and transport behaviours, not only do we find distinctively contrasting physical properties of the VO2 polymorphs, but that the polymorphs can be on the verge of phase transitions when heated as low as ~400 °C. Our successful epitaxy of both VO2(A) and VO2(B) phases, which are rarely studied due to the lack of phase pure materials, will open the door to the fundamental studies of VO2 polymorphs for potential applications in advanced electronic and energy devices. PMID:26787259

The interaction of reward genes with environmental factors in contribution to alcoholism in mexican americans.

PubMed

Du, Yanlei; Wan, Yu-Jui Yvonne

2009-12-01

Alcoholism is a polygenic disorder resulting from reward deficiency; polymorphisms in reward genes including serotonin transporter (5-HTT)-linked polymorphic region (5-HTTLPR), A118G in opioid receptor mu1 (OPRM1), and -141C Insertion/Deletion (Ins/Del) in dopamine receptor D2 (DRD2) as well as environmental factors (education and marital status) might affect the risk of alcoholism. Objective of the current study was to examine the main and interacting effect of these 3 polymorphisms and 2 environmental factors in contribution to alcoholism in Mexican Americans. Genotyping of 5-HTTLPR, OPRM1 A118G, and DRD2-141C Ins/Del was performed in 365 alcoholics and 338 nonalcoholic controls of Mexican Americans who were gender- and age-matched. Alcoholics were stratified according to tertiles of MAXDRINKS, which denotes the largest number of drinks consumed in one 24-hour period. Data analysis was done in the entire data set and in each alcoholic stratum. Multinomial logistic regression was conducted to explore the main effect of 3 polymorphisms and 2 environmental factors (education and marital status); classification tree, generalized multifactor dimensionality reduction (GMDR) analysis, and polymorphism interaction analysis version 2.0 (PIA 2) program were used to study factor interaction. Main effect of education, OPRM1, and DRD2 was detected in alcoholic stratum of moderate and/or largest MAXDRINKS with education < or =12 years, OPRM1 118 A/A, and DRD2 -141C Ins/Ins being risk factors. Classification tree analysis, GMDR analysis, and PIA 2 program all supported education*OPRM1 interaction in alcoholics of largest MAXDRINKS with education < or =12 years coupled with OPRM1 A/A being a high risk factor; dendrogram showed synergistic interaction between these 2 factors; dosage-effect response was also observed for education*OPRM1 interaction. No definite effect of marital status and 5-HTTLPR in pathogenesis of alcoholism was observed. Our results suggest main effect of education background, OPRM1 A118G, and DRD2 -141C Ins/Del as well as education*OPRM1 interaction in contribution to moderate and/or severe alcoholism in Mexican Americans. Functional relevance of these findings still needs to be explored.

Behavioral and Pharmacogenetics of Aggressive Behavior

PubMed Central

Takahashi, Aki; Quadros, Isabel M.; de Almeida, Rosa M. M.; Miczek, Klaus A.

2013-01-01

Serotonin (5-HT) has long been considered as a key transmitter in the neurocircuitry controlling aggression. Impaired regulation of each subtype of 5-HT receptor, 5-HT transporter, synthetic and metabolic enzymes has been linked particularly to impulsive aggression. The current summary focuses mostly on recent findings from pharmacological and genetic studies. The pharmacological treatments and genetic manipulations or polymorphisms of a specific target (e.g., 5-HT1A receptor) can often result in inconsistent results on aggression, due to “phasic” effects of pharmacological agents vs “trait”-like effects of genetic manipulations. Also, the local administration of a drug using the intracranial microinjection technique has shown that activation of specific subtypes of 5-HT receptors (5-HT1A and 5-HT1B) in mesocorticolimbic areas can reduce species-typical and other aggressive behaviors, but the same receptors in the medial prefrontal cortex or septal area promote escalated forms of aggression. Thus, there are receptor populations in specific brain regions that preferentially modulate specific types of aggression. Genetic studies have shown important gene × environment interactions; it is likely that the polymorphisms in the genes of 5-HT transporters (e.g., MAO A) or rate-limiting synthetic and metabolic enzymes of 5-HT determine the vulnerability to adverse environmental factors that escalate aggression. We also discuss the interaction between the 5-HT system and other systems. Modulation of 5-HT neurons in the dorsal raphe nucleus by GABA, glutamate, and CRF profoundly regulate aggressive behaviors. Also, interactions of the 5-HT system with other neuropeptides (arginine vasopressin, oxytocin, neuropeptide Y, opioid) have emerged as important neurobiological determinants of aggression. Studies of aggression in genetically modified mice identified several molecules that affect the 5-HT system directly (e.g., Tph2, 5-HT1B, 5-HT transporter, Pet1, MAOA) or indirectly (e.g. BDNF, nNOS, αCaMKII, Neuropeptide Y). The future agenda delineates specific receptor subpopulations for GABA, glutamate and neuropeptides as they modulate the canonical aminergic neurotransmitters in brainstem, limbic and cortical regions with the ultimate outcome of attenuating or escalating aggressive behavior. PMID:22297576

Enterovirus Exposure Uniquely Discriminates Type 1 Diabetes Patients with a Homozygous from a Heterozygous Melanoma Differentiation-Associated Protein 5/Interferon Induced with Helicase C Domain 1 A946T Genotype.

PubMed

Schulte, Barbara M; Gielen, Paul R; Kers-Rebel, Esther D; Prosser, Amy C; Lind, Katharina; Flodström-Tullberg, Malin; Tack, Cees J; Elving, Lammy D; Adema, Gosse J

2016-09-01

In children at risk for type 1 diabetes, innate immune activity is detected before seroconversion. Enterovirus infections have been linked to diabetes development, and a polymorphism (A946T) in the innate immune sensor recognizing enterovirus RNA, interferon-induced with helicase C domain 1/melanoma differentiation-associated protein 5, predisposes to disease. We hypothesized that the strength of innate antienteroviral responses is affected in autoimmune type 1 diabetes patients and linked to the A946T polymorphism. We compared induction of interferon-stimulated genes (ISGs) in peripheral blood mononuclear cells (PBMCs) and dendritic cells (DCs) in healthy individuals and diabetes patients upon stimulation with enterovirus, enterovirus-antibody complexes, or ligands mimicking infection in relation to the A946T polymorphism. Overall, PBMCs of diabetes patients and healthy donors showed comparable ISG induction upon stimulation. No differences were observed in DCs. Interestingly, the data imply that the magnitude of responses to enterovirus and enterovirus-antibody complexes in PBMCs is critically influenced by the A946T polymorphism and elevated in heterozygotes compared to TT homozygous individuals in autoimmune diabetes patients, but not healthy controls. These data imply an intrinsic difference in the responses to enterovirus and enterovirus-antibody complexes in diabetes patients carrying a TT risk genotype compared to heterozygotes that may influence control of enterovirus clearance.

The effect of a promoter polymorphism on the transcription of nitric oxide synthase 1 and its relevance to Parkinson's disease.

PubMed

Rife, Terrie; Rasoul, Bareza; Pullen, Nicholas; Mitchell, David; Grathwol, Kristen; Kurth, Janice

2009-08-01

Transcriptional changes of the enzyme nitric oxide synthase I (NOS1) are believed to play a role in the development of many diseases. The gene for NOS1 has 12 alternative first exons (1A-1L). The 1F exon is one of the most highly utilized first exons in the brain and has a polymorphism ((TG)(m)TA(TG)(n)) located in its promoter region. The polymorphism's length has been suggested to affect NOS1 transcription and play a role in Parkinson's disease (PD); however, the actual influence of the polymorphism on NOS1 transcription has not been studied. To better characterize the links of the polymorphism with PD, a genotyping study was done comparing polymorphism length among 170 PD patients and 150 age-matched controls. The pattern of changes between the two group's allele frequencies shows statistical significance (P = 0.0359). The smallest polymorphism sizes are more predominant among PD patients than controls. To study the effects of this polymorphism on NOS1 gene transcription, reporter gene constructs were made by cloning the NOS1 1F promoter with polymorphism lengths of either 42, 54, or 62 bp in front of the luciferase gene and transfecting them into HeLa or Sk-N-MC cells. NOS1-directed reporter gene constructs with the 62-bp polymorphism increased transcription of luciferase 2.2-fold in HeLa and 1.8-fold in Sk-N-MC cells compared with reporter gene constructs with the 42-bp polymorphism. These data suggest that if smaller polymorphism size contributes to the higher NOS1 levels in PD patients, an as yet unknown transcriptional mechanism is required. Copyright 2009 Wiley-Liss, Inc.

Genomic polymorphism, recombination, and linkage disequilibrium in human major histocompatibility complex-encoded antigen-processing genes.

PubMed Central

van Endert, P M; Lopez, M T; Patel, S D; Monaco, J J; McDevitt, H O

1992-01-01

Recently, two subunits of a large cytosolic protease and two putative peptide transporter proteins were found to be encoded by genes within the class II region of the major histocompatibility complex (MHC). These genes have been suggested to be involved in the processing of antigenic proteins for presentation by MHC class I molecules. Because of the high degree of polymorphism in MHC genes, and previous evidence for both functional and polypeptide sequence polymorphism in the proteins encoded by the antigen-processing genes, we tested DNA from 27 consanguineous human cell lines for genomic polymorphism by restriction fragment length polymorphism (RFLP) analysis. These studies demonstrate a strong linkage disequilibrium between TAP1 and LMP2 RFLPs. Moreover, RFLPs, as well as a polymorphic stop codon in the telomeric TAP2 gene, appear to be in linkage disequilibrium with HLA-DR alleles and RFLPs in the HLA-DO gene. A high rate of recombination, however, seems to occur in the center of the complex, between the TAP1 and TAP2 genes. Images PMID:1360671

γ-Herringbone Polymorph of 6,13-Bis(trimethylsilylethynyl)pentacene: A Potential Material for Enhanced Hole Mobility.

PubMed

Bhat, Vinayak; Gopan, Gopika; Nair, Nanditha G; Hariharan, Mahesh

2018-04-06

The introduction of the trialkylsilylethynyl group to the acene core is known to predominantly transform the herringbone structure of pentacene to a slip-stacked packing. However, herein, the occurrence of an unforeseen polymorph of 6,13-bis(trimethylsilylethynyl)pentacene (TMS-pentacene), with an atypical γ-herringbone packing arrangement, is reported. Intermolecular noncovalent interactions in the γ-herringbone polymorph are determined from Hirshfeld surface and quantum theory of atoms-in-molecules (QTAIM) analyses. Furthermore, a comparative truncated symmetry-adapted perturbation theory (SAPT(0)) energy decomposition analysis discloses the role of exchange repulsions that govern molecular packing in the γ-herringbone polymorph. Moreover, the computationally predicted electronic coupling and anisotropic mobility reveal the possibility of enhanced hole transport (μ h =3.7 cm 2  V -1  s -1 ) in the γ-herringbone polymorph, in contrast to the reported polymorph with a hole mobility of μ h =0.1 cm 2  V -1  s -1 . © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Haemophilia A: carrier detection and prenatal diagnosis by linkage analysis using DNA polymorphism.

PubMed Central

Tuddenham, E G; Goldman, E; McGraw, A; Kernoff, P B

1987-01-01

Restriction fragment length polymorphisms (RFLPs) within or close to the factor VIII locus are very useful for genetic linkage analysis. Such RFLPs allow a mutant allele to be tracked in a family, segregating haemophilia A even when, as is usually the case, the precise mutation causing failure to synthesise factor VIII is unknown. To date two markers tightly linked to the factor VIII locus have been described, one of which is highly polymorphic and therefore informative in most kindreds. A significant crossover rate, however, does not make diagnosis absolute. Three intragenic RFLPs have been defined, which, taken together, are informative in about 70% of women, providing virtually deterministic genetic diagnosis. PMID:2889753

Modification of menopausal hormone therapy-associated colorectal cancer risk by polymorphisms in sex steroid signaling, metabolism and transport related genes.

PubMed

Rudolph, Anja; Sainz, Juan; Hein, Rebecca; Hoffmeister, Michael; Frank, Bernd; Försti, Asta; Brenner, Hermann; Hemminki, Kari; Chang-Claude, Jenny

2011-06-01

The mechanisms underlying the association of menopausal hormone therapy (MHT) with reduced colorectal cancer (CRC) risk are unknown and the identification of genetic modifiers may yield further insight. We explored the effect modification of MHT-associated CRC risk in postmenopausal women by 47 polymorphisms with known or putative functional relevance in 16 candidate genes related to hormone metabolism (COMT, CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2C19, CYP3A4, CYP17A1, GSTP, and HSD17B1), transport (ABCB1), and signaling (ESR1, ESR2, SHBG, PGR, and NR1I2). A total of 685 CRC patients and 684 healthy controls from a German population-based case-control study (DACHS) were genotyped. Multiplicative statistical interaction between polymorphisms and ever MHT use as well as duration of use was assessed using multivariate logistic regression. CRC risk associated with ever MHT use as well as with duration was significantly modified by rs1202168 in the transporter gene ABCB1 (P interaction=0.04). The MHT-associated risk reduction was not significant in homozygous non-carriers (odds ratio (OR) ever use=0.84, 95% confidence interval (CI) 0.53-1.34; OR per 5 year duration=0.94, 95% CI 0.83-1.08), while homozygous carriers of the minor T allele had a 57% lower risk with ever use of MHT (95% CI 0.21-0.88) and a 22% lower risk per 5 years of MHT use (95% CI 0.62-0.97). Significant effect modification was also observed for the ESR1_rs910416 polymorphism (P interaction=0.03 for ever use and 0.07 for duration of use), whereby the decreased risk was attenuated in homozygous carriers of the minor C allele (OR ever use=0.87, 95% CI 0.48-1.60, OR per 5 year duration=0.99, 95% CI 0.83-1.18). Results of this exploratory study provide first evidence that polymorphisms in genes related to estrogen transport and signaling may modify MHT-associated CRC risk but warrant replication in an independent population.

High-resolution genetic mapping of allelic variants associated with cell wall chemistry in Populus

DOE PAGES

Muchero, Wellington; Guo, Jianjun; Difazio, Stephen P.; ...

2015-01-23

We report the identification of six genetic loci and the allelic-variants associated with Populus cell wall phenotypes determined independently using pyrolysis Molecular Beam Mass Spectrometry (pyMBMS), saccharification assay and wet chemistry in two partially overlapping populations of P. trichocarpa genotypes sampled from multiple environments in the Pacific Northwest of North America. All 6 variants co-located with a quantitative trait locus (QTL) hotspot on chromosome XIV for lignin content, syringyl to guaiacyl (S/G) ratio, 5- and 6- carbon sugars identified in an interspecific P. trichocarpa x P. deltoides pseudo-backcross mapping pedigree. Genomic intervals containing an amino acid transporter, a MYB transcriptionmore » factor, an angustifolia CtBP transcription factor, a copper transport protein ATOX1-related, a Ca 2+ transporting ATPase and a protein kinase were identified within 5 QTL regions. Each interval contained single nucleotide polymorphisms (SNPs) that were significantly associated to cell-wall phenotypes, with associations exceeding the chromosome-wise Bonferroni-adjusted p-values in at least one environment. cDNA sequencing for allelic variants of 3 of the 6 genes identified polymorphisms leading to premature stop codons in the MYB transcription factor and protein kinase. On the other hand, variants of the Angustifolia CtBP transcription factor exhibited a polyglutamine (PolyQ) length polymorphism. Results from transient protoplast assays suggested that each of the polymorphisms conferred allelic differences in activation of cellulose, hemicelluloses and lignin pathway marker genes, with truncated and short PolyQ alleles exhibiting significantly reduced marker gene activation. Genes identified in this study represent novel targets for reducing cell wall recalcitrance for lignocellulosic biofuels production using plant biomass.« less

Selected ABCB1, ABCB4 and ABCC2 polymorphisms do not enhance the risk of drug-induced hepatotoxicity in a Spanish cohort.

PubMed

Ulzurrun, Eugenia; Stephens, Camilla; Ruiz-Cabello, Francisco; Robles-Diaz, Mercedes; Saenz-López, Pablo; Hallal, Hacibe; Soriano, German; Roman, Eva; Fernandez, M Carmen; Lucena, M Isabel; Andrade, Raúl J

2014-01-01

Flawed ABC transporter functions may contribute to increased risk of drug-induced liver injury (DILI). We aimed to analyse the influence of genetic variations in ABC transporters on the risk of DILI development and clinical presentations in a large Spanish DILI cohort. A total of ten polymorphisms in ABCB1 (1236T>C, 2677G>T,A, 3435T>C), ABCB4 (1954A>G) and ABCC2 (-1774G>del, -1549A>G, -24C>T, 1249G>A, 3972C>T and 4544G>A) were genotyped using Taqman 5' allelic discrimination assays or sequencing in 141 Spanish DILI patients and 161 controls. The influence of specific genotypes, alleles and haplotypes on the risk of DILI development and clinical presentations was analysed. None of the individual polymorphisms or haplotypes was found to be associated with DILI development. Carriers homozygous for the ABCC2 -1774del allele were however only found in DILI patients. Hence, this genotype could potentially be associated with increased risk, though its low frequency in our Spanish cohort prevented a final conclusion. Furthermore, carriers homozygous for the ABCC2 -1774G/-1549A/-24T/1249G/3972T/4544G haplotype were found to have a higher propensity for total bilirubin elevations when developing DILI. Our findings do not support a role for the analysed polymorphisms in the ABCB1, ABCB4 and ABCC2 transporter genes in DILI development in Spanish patients. The ABCC2 -1774deldel genotype was however restricted to DILI cases and could potentially contribute to enhanced DILI susceptibility.

Selected ABCB1, ABCB4 and ABCC2 Polymorphisms Do Not Enhance the Risk of Drug-Induced Hepatotoxicity in a Spanish Cohort

PubMed Central

Ulzurrun, Eugenia; Stephens, Camilla; Ruiz-Cabello, Francisco; Robles-Diaz, Mercedes; Saenz-López, Pablo; Hallal, Hacibe; Soriano, German; Roman, Eva; Fernandez, M. Carmen; Lucena, M. Isabel; Andrade, Raúl J.

2014-01-01

Background and Aims Flawed ABC transporter functions may contribute to increased risk of drug-induced liver injury (DILI). We aimed to analyse the influence of genetic variations in ABC transporters on the risk of DILI development and clinical presentations in a large Spanish DILI cohort. Methods A total of ten polymorphisms in ABCB1 (1236T>C, 2677G>T,A, 3435T>C), ABCB4 (1954A>G) and ABCC2 (−1774G>del, −1549A>G, −24C>T, 1249G>A, 3972C>T and 4544G>A) were genotyped using Taqman 5′ allelic discrimination assays or sequencing in 141 Spanish DILI patients and 161 controls. The influence of specific genotypes, alleles and haplotypes on the risk of DILI development and clinical presentations was analysed. Results None of the individual polymorphisms or haplotypes was found to be associated with DILI development. Carriers homozygous for the ABCC2 −1774del allele were however only found in DILI patients. Hence, this genotype could potentially be associated with increased risk, though its low frequency in our Spanish cohort prevented a final conclusion. Furthermore, carriers homozygous for the ABCC2 −1774G/−1549A/−24T/1249G/3972T/4544G haplotype were found to have a higher propensity for total bilirubin elevations when developing DILI. Conclusions Our findings do not support a role for the analysed polymorphisms in the ABCB1, ABCB4 and ABCC2 transporter genes in DILI development in Spanish patients. The ABCC2 −1774deldel genotype was however restricted to DILI cases and could potentially contribute to enhanced DILI susceptibility. PMID:24732756

Serotonin transporter polymorphism (5-HTTLPR) and citalopram effectiveness and side effects in children with depression and/or anxiety disorders.

PubMed

Kronenberg, Sefi; Apter, Alan; Brent, David; Schirman, Shella; Melhem, Nadine; Pick, Nimrod; Gothelf, Doron; Carmel, Miri; Frisch, Amos; Weizman, Abraham

2007-12-01

The aim of this study was to examine the association between polymorphism in the serotonin transporter gene and citalopram effectiveness and side effects in children and adolescents with major depressive disorder (MDD) and/or anxiety disorders. Outpatients, aged 7- 18 years with a Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR) MDD and/or anxiety disorder were treated in an 8-week open trial with 20-40 mg/day of citalopram. Subjects were genotyped with respect to short (s) versus long (l) forms of the 5-HTTLPR polymorphism of the serotonin transporter, and the relationship between genotype and outcome and side effects was assessed. Subjects with 5-HTTLPR ss genotype showed a less vigorous response with regard to depressive symptoms measured by the Children's Depression Rating Scale-Revised (CDRS-R) scores over time compared to subjects with sl/ll genotypes (beta = 0.67, z = 2.02, p = 0.04). In addition, the 5-HTTLPR ss group exhibited lower rates of agitation compared to those with sl/ll genotype (6.3% vs. 32.8%, p = 0.05). Also, subjects with 5-HTTLPR ss genotype had consistently higher scores of suicidality at each week compared to the sl/ll group (beta = 0.76, z = 2.04, p = 0.04) as measured by item number 13 of the CDRS-R. The 5-HTTLPR ss genotype was associated with a poorer clinical response with regard to depressive symptoms as well with fewer reports of agitation. The 5-HTTLPR polymorphism may be a genetic marker of response to citalopram in children and adolescents with depression and/or anxiety.

Prolonged neutropenia after irinotecan-based chemotherapy in a child with polymorphisms of UGT1A1 and SLCO1B1.

PubMed

Sakaguchi, S; Garcia-Bournissen, F; Kim, R; Schwarz, U I; Nathan, P C; Ito, S

2009-12-01

Genetic polymorphisms of uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1), and SLCO1B1 coding organic anion-transporter polypeptide 1B1, are independent risk factors known to increase irinotecan toxicity in adults. Although combined occurrence of polymorphisms in these 2 genes is likely to influence susceptibility to irinotecan toxicity, data are scarce, especially in children. We report an 11-year-old female with severe and prolonged neutropenia after irinotecan-based chemotherapy. The patient's genotyping revealed polymorphisms in both UGT1A1 and SLCO1B1. To our knowledge, this is the first case report of combined genotyping of both UGT1A1 and SLCO1B1 in a child with severe irinotecan toxicity.

Crystallization of D-mannitol in binary mixtures with NaCl: phase diagram and polymorphism.

PubMed

Telang, Chitra; Suryanarayanan, Raj; Yu, Lian

2003-12-01

To study the crystallization, polymorphism, and phase behavior of D-mannitol in binary mixtures with NaCl to better understand their interactions in frozen aqueous solutions. Differential scanning calorimetry, hot-stage microscopy, Raman microscopy, and variable-temperature X-ray diffractometry were used to characterize D-mannitol-NaCl mixtures. NaCl and D-mannitol exhibited significant melt miscibility (up to 7.5% w/w or 0.20 mole fraction of NaCl) and a eutectic phase diagram (eutectic composition 7.5% w/w NaCl; eutectic temperature 150 degrees C for the alpha and beta polymorphs of D-mannitol and 139 degrees C for the delta). The presence of NaCl did not prevent mannitol from crystallizing but, depending on sample size, affected the polymorph crystallized: below 10 mg, delta was obtained; above 100 mg, alpha was obtained. Pure mannitol crystallized under the same conditions first as the delta polymorph and then as the a polymorph, with the latter nucleating on the former. KCl showed similar eutectic points and melt miscibility with D-mannitol as NaCl. LiCl yielded lower eutectic melting points, inhibited the crystallization of D-mannitol during cooling, and enabled the observation of its glass transition. Despite their structural dissimilarity, significant melt miscibility exists between D-mannitol and NaCl. Their phase diagram has been determined and features polymorph-dependent eutectic points. NaCl influences the polymorphic behavior of mannitol, and the effect is linked to the crystallization of mannitol in two polymorphic stages.

Tuning polymorphism and orientation in organic semiconductor thin films via post-deposition processing.

PubMed

Hiszpanski, Anna M; Baur, Robin M; Kim, Bumjung; Tremblay, Noah J; Nuckolls, Colin; Woll, Arthur R; Loo, Yueh-Lin

2014-11-05

Though both the crystal structure and molecular orientation of organic semiconductors are known to impact charge transport in thin-film devices, separately accessing different polymorphs and varying the out-of-plane molecular orientation is challenging, typically requiring stringent control over film deposition conditions, film thickness, and substrate chemistry. Here we demonstrate independent tuning of the crystalline polymorph and molecular orientation in thin films of contorted hexabenzocoronene, c-HBC, during post-deposition processing without the need to adjust deposition conditions. Three polymorphs are observed, two of which have not been previously reported. Using our ability to independently tune the crystal structure and out-of-plane molecular orientation in thin films of c-HBC, we have decoupled and evaluated the effects that molecular packing and orientation have on device performance in thin-film transistors (TFTs). In the case of TFTs comprising c-HBC, polymorphism and molecular orientation are equally important; independently changing either one affects the field-effect mobility by an order of magnitude.

Polymorphisms in Plasmodium falciparum Chloroquine Resistance Transporter and Multidrug Resistance 1 Genes: Parasite Risk Factors that Affect Treatment Outcomes for P. falciparum Malaria after Artemether-Lumefantrine and Artesunate-Amodiaquine

PubMed Central

Venkatesan, Meera; Gadalla, Nahla B.; Stepniewska, Kasia; Dahal, Prabin; Nsanzabana, Christian; Moriera, Clarissa; Price, Ric N.; Mårtensson, Andreas; Rosenthal, Philip J.; Dorsey, Grant; Sutherland, Colin J.; Guérin, Philippe; Davis, Timothy M. E.; Ménard, Didier; Adam, Ishag; Ademowo, George; Arze, Cesar; Baliraine, Frederick N.; Berens-Riha, Nicole; Björkman, Anders; Borrmann, Steffen; Checchi, Francesco; Desai, Meghna; Dhorda, Mehul; Djimdé, Abdoulaye A.; El-Sayed, Badria B.; Eshetu, Teferi; Eyase, Frederick; Falade, Catherine; Faucher, Jean-François; Fröberg, Gabrielle; Grivoyannis, Anastasia; Hamour, Sally; Houzé, Sandrine; Johnson, Jacob; Kamugisha, Erasmus; Kariuki, Simon; Kiechel, Jean-René; Kironde, Fred; Kofoed, Poul-Erik; LeBras, Jacques; Malmberg, Maja; Mwai, Leah; Ngasala, Billy; Nosten, Francois; Nsobya, Samuel L.; Nzila, Alexis; Oguike, Mary; Otienoburu, Sabina Dahlström; Ogutu, Bernhards; Ouédraogo, Jean-Bosco; Piola, Patrice; Rombo, Lars; Schramm, Birgit; Somé, A. Fabrice; Thwing, Julie; Ursing, Johan; Wong, Rina P. M.; Zeynudin, Ahmed; Zongo, Issaka; Plowe, Christopher V.; Sibley, Carol Hopkins

2014-01-01

Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 – 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36–17.97, P < 0.001) were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine. PMID:25048375

Interaction between serotonin transporter and serotonin receptor 1 B genes polymorphisms may be associated with antisocial alcoholism.

PubMed

Wang, Tzu-Yun; Lee, Sheng-Yu; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chen, Shih-Heng; Chu, Chun-Hsien; Huang, San-Yuan; Tzeng, Nian-Sheng; Wang, Chen-Lin; Lee, I Hui; Yeh, Tzung Lieh; Yang, Yen Kuang; Lu, Ru-Band

2012-07-11

Several studies have hypothesized that genes regulating the components of the serotonin system, including serotonin transporter (5-HTTLPR) and serotonin 1 B receptor (5-HT1B), may be associated with alcoholism, but their results are contradictory because of alcoholism's heterogeneity. Therefore, we examined whether the 5-HTTLPR gene and 5-HT1B gene G861C polymorphism are susceptibility factors for a specific subtype of alcoholism, antisocial alcoholism in Han Chinese in Taiwan. We recruited 273 Han Chinese male inmates with antisocial personality disorder (ASPD) [antisocial alcoholism (AS-ALC) group (n=120) and antisocial non-alcoholism (AS-N-ALC) group (n=153)] and 191 healthy male controls from the community. Genotyping was done using PCR-RFLP. There were no significant differences in the genotypic frequency of the 5-HT1B G861C polymorphism between the 3 groups. Although AS-ALC group members more frequently carried the 5-HTTLPR S/S, S/LG, and LG/LG genotypes than controls, the difference became non-significant after controlling for the covarying effects of age. However, the 5-HTTLPR S/S, S/LG, and LG/LG genotypes may have interacted with the 5-HT1B G861C C/C polymorphism and increased the risk of becoming antisocial alcoholism. Our study suggests that neither the 5-HTTLPR gene nor the 5-HT1B G861C polymorphism alone is a risk factor for antisocial alcoholism in Taiwan's Han Chinese population, but that the interaction between both genes may increase susceptibility to antisocial alcoholism.

Extrapolating from local ecological processes to genus-wide patterns in colour polymorphism in South African Protea

PubMed Central

Carlson, Jane E.; Holsinger, Kent E.

2015-01-01

Polymorphic traits are central to many fundamental discoveries in evolution, yet why they are found in some species and not others remains poorly understood. We use the African genus Protea—within which more than 40% of species have co-occurring pink and white floral colour morphs—to ask whether convergent evolution and ecological similarity could explain the genus-wide pattern of polymorphism. First, we identified environmental correlates of pink morph frequency across 28 populations of four species. Second, we determined whether the same correlates could predict species-level polymorphism and monomorphism across 31 species. We found that pink morph frequency increased with elevation in Protea repens and three section Exsertae species, increased eastward in P. repens, and increased with seed predation intensity in section Exsertae. For cross-species comparisons, populations of monomorphic pink species occurred at higher elevations than populations of monomorphic white species, and 18 polymorphic species spanned broader elevational gradients than 13 monomorphic species. These results suggest that divergent selection along elevational clines has repeatedly favoured polymorphism, and that more uniform selection in altitudinally restricted species may promote colour monomorphism. Our findings are, to our knowledge, the first to link selection acting within species to the presence and absence of colour polymorphism at broader phylogenetic scales. PMID:25876847

Milan hypertensive rat as a model for studying cation transport abnormality in genetic hypertension

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ferrari, P.; Barber, B.R.; Torielli, L.

1987-11-01

Environmental factors, genetic polymorphisms, and different experimental designs have been the main impediments to evaluating a genetic association between cell membrane cation transport abnormalities and human essential or genetic hypertension. We review the results obtained in the Milan hypertensive strain of rats (MHS) and in its appropriate control normotensive strain (MNS) to illustrate our approach to defining the role of cation transport abnormality in a type of genetic hypertension. Before the development of a difference in blood pressure between the two strains, the comparison of kidney and erythrocyte functions showed that MHS had an increased glomerular filtration rate and urinarymore » output, and lower plasma renin and urine osmolality. Kidney cross-transplantation between the strains showed that hypertension is transplanted with the kidney. Proximal tubular cell volume and sodium content were lower in MHS while sodium transport across the brush border membrane vesicles of MHS was faster. Erythrocytes in MHS were smaller and had lower sodium concentration, and Na+-K+ cotransport and passive permeability were faster. The differences in volume, sodium content, and Na+-K+ cotransport between erythrocytes of the two strains persisted after transplantation of bone marrow to irradiated F1 (MHS X MNS) hybrids. Moreover, in normal segregating F2 hybrid populations there was a positive correlation between blood pressure and Na+-K+ cotransport. These results suggest a genetic and functional link in MHS between cell membrane cation transport abnormalities and hypertension. Thus, erythrocyte cell membrane may be used for approaching the problem of defining the genetically determined molecular mechanism underlying the development of a type of essential hypertension. 35 references.« less

The Serotonin Transporter and Early Life Stress: Translational Perspectives

PubMed Central

Houwing, Danielle J.; Buwalda, Bauke; van der Zee, Eddy A.; de Boer, Sietse F.; Olivier, Jocelien D. A.

2017-01-01

The interaction between the serotonin transporter (SERT) linked polymorphic region (5-HTTLPR) and adverse early life stressing (ELS) events is associated with enhanced stress susceptibility and risk to develop mental disorders like major depression, anxiety, and aggressiveness. In particular, human short allele carriers are at increased risk. This 5-HTTLPR polymorphism is absent in the rodent SERT gene, but heterozygous SERT knockout rodents (SERT+/−) show several similarities to the human S-allele carrier, therefore creating an animal model of the human situation. Many rodent studies investigated ELS interactions in SERT knockout rodents combined with ELS. However, underlying neuromolecular mechanisms of the (mal)adaptive responses to adversity displayed by SERT rodents remain to be elucidated. Here, we provide a comprehensive review including studies describing mechanisms underlying SERT variation × ELS interactions in rodents. Alterations at the level of translation and transcription but also epigenetic alterations considerably contribute to underlying mechanisms of SERT variation × ELS interactions. In particular, SERT+/− rodents exposed to adverse early rearing environment may be of high translational and predictive value to the more stress sensitive human short-allele carrier, considering the similarity in neurochemical alterations. Therefore, SERT+/− rodents are highly relevant in research that aims to unravel the complex psychopathology of mental disorders. So far, most studies fail to show solid evidence for increased vulnerability to develop affective-like behavior after ELS in SERT+/− rodents. Several reasons may underlie these failures, e.g., (1) stressors used might not be optimal or severe enough to induce maladaptations, (2) effects in females are not sufficiently studied, and (3) few studies include both behavioral manifestations and molecular correlates of ELS-induced effects in SERT+/− rodents. Of course, one should not exclude the (although unlikely) possibility of SERT+/− rodents not being sensitive to ELS. In conclusion, future studies addressing ELS-induced effects in the SERT+/− rodents should extensively study both long-term behavioral and (epi)genetic aspects in both sexes. Finally, further research is warranted using more severe stressors in animal models. From there on, we should be able to draw solid conclusions whether the SERT+/− exposed to ELS is a suitable translational animal model for studying 5-HTTLPR polymorphism and stress interactions. PMID:28491024

Association of a serotonin transporter gene (SLC6A4) 5-HTTLPR polymorphism with body mass index categories but not type 2 diabetes mellitus in Mexicans

PubMed Central

Peralta-Leal, Valeria; Leal-Ugarte, Evelia; Meza-Espinoza, Juan P.; Dávalos-Rodríguez, Ingrid P.; Bocanegra-Alonso, Anabel; Acosta-González, Rosa I.; Gonzales, Enrique; Nair, Saraswathy; Durán-González, Jorge

2012-01-01

The serotonergic system has been hypothesized to contribute to the biological susceptibility to type 2 diabetes mellitus (T2DM) and body-mass index (BMI) categories. We investigate a possible association of 5-HTTLPR polymorphism (L and S alleles) in the promoter region of the serotonin transporter gene (SLC6A4) with the development of T2DM and/or higher BMI by analyzing a sample of 138 individuals diagnosed with T2DM and 172 unrelated controls from the Mexican general population. In the total sample genotypes were distributed according to Hardy-Weinberg equilibrium, and S allele frequency was 0.58. There was no statistical association between 5-HTTLPR polymorphism and the development of T2DM in this Mexican population sample (p = 0.12). Nevertheless, logistic regression analysis of the L allele and increased BMI disclosed an association, after adjusting for age, sex and T2DM (p = 0.02, OR 1.74, 95% CI: 1.079–2.808). PMID:23055796

Association of a serotonin transporter gene (SLC6A4) 5-HTTLPR polymorphism with body mass index categories but not type 2 diabetes mellitus in Mexicans.

PubMed

Peralta-Leal, Valeria; Leal-Ugarte, Evelia; Meza-Espinoza, Juan P; Dávalos-Rodríguez, Ingrid P; Bocanegra-Alonso, Anabel; Acosta-González, Rosa I; Gonzales, Enrique; Nair, Saraswathy; Durán-González, Jorge

2012-07-01

The serotonergic system has been hypothesized to contribute to the biological susceptibility to type 2 diabetes mellitus (T2DM) and body-mass index (BMI) categories. We investigate a possible association of 5-HTTLPR polymorphism (L and S alleles) in the promoter region of the serotonin transporter gene (SLC6A4) with the development of T2DM and/or higher BMI by analyzing a sample of 138 individuals diagnosed with T2DM and 172 unrelated controls from the Mexican general population. In the total sample genotypes were distributed according to Hardy-Weinberg equilibrium, and S allele frequency was 0.58. There was no statistical association between 5-HTTLPR polymorphism and the development of T2DM in this Mexican population sample (p = 0.12). Nevertheless, logistic regression analysis of the L allele and increased BMI disclosed an association, after adjusting for age, sex and T2DM (p = 0.02, OR 1.74, 95% CI: 1.079-2.808).

PON1 promoter polymorphisms contribute to PCOS susceptibility and phenotypic outcomes in Indian women.

PubMed

Dadachanji, Roshan; Shaikh, Nuzhat; Patil, Anushree; Shah, Nalini; Mukherjee, Srabani

2018-06-30

Polycystic ovary syndrome is a common endocrinopathy characterized by anovulatory infertility, hyperandrogenism, insulin resistance and oxidative stress, which predisposes affected women to reproductive and cardiometabolic complications in later life. We have investigated the association of PON1 promoter polymorphisms with PCOS susceptibility, PON1 activity and its related traits in Indian women. The genotypic and allelic frequency distribution of only -907G/C polymorphism in PON1 promoter showed significant difference between non-hyperandrogenic control and PCOS women, and was significantly associated with reduced susceptibility to PCOS, considering the recessive model. PON1 lactonase and arylesterase activities were also significantly decreased in women with PCOS compared to controls. Further, PON1 promoter polymorphisms were linked to altered insulin and testosterone levels in hyperandrogenic and non-hyperandrogenic women with PCOS. This study highlights PON1 as an important candidate gene influencing genetic pathophysiology of PCOS. Copyright © 2018 Elsevier B.V. All rights reserved.

1-Nitro-4-(4-nitro-phen-oxy)benzene: a second monoclinic polymorph.

PubMed

Naz, Mehwish; Akhter, Zareen; McKee, Vickie; Nadeem, Arif

2013-11-06

In the title compound, C12H8N2O5, the aromatic rings are inclined to one another by 56.14 (7)°. The nitro groups are inclined by to the benzene rings to which they are attached by 3.86 (17) and 9.65 (15)°. In the crystal, mol-ecules are linked by C-H⋯O hydrogen bonds, forming a three-dimensional structure. The title compound is a new monoclinic polymorph, crystallizing in space group P21/c. The first polymorph crystallized in space group C2/c and the mol-ecule possesses twofold rotation symmetry. Two low-temperature structures of this polymorph (150 K and 100 K, respectively) have been reported [Meciarova et al. (2004). Private Communication (refcode IXOGAD). CCDC, Cambridge, England, and Dey & Desiraju (2005). Chem. Commun. pp. 2486-2488].

The candidate histocompatibility locus of a Basal chordate encodes two highly polymorphic proteins.

PubMed

Nydam, Marie L; Netuschil, Nikolai; Sanders, Erin; Langenbacher, Adam; Lewis, Daniel D; Taketa, Daryl A; Marimuthu, Arumugapradeep; Gracey, Andrew Y; De Tomaso, Anthony W

2013-01-01

The basal chordate Botryllus schlosseri undergoes a natural transplantation reaction governed by a single, highly polymorphic locus called the fuhc. Our initial characterization of this locus suggested it encoded a single gene alternatively spliced into two transcripts: a 555 amino acid-secreted form containing the first half of the gene, and a full-length, 1008 amino acid transmembrane form, with polymorphisms throughout the ectodomain determining outcome. We have now found that the locus encodes two highly polymorphic genes which are separated by a 227 bp intergenic region: first, the secreted form as previously described, and a second gene encoding a 531 amino acid membrane-bound gene containing three extracellular immunoglobulin domains. While northern blotting revealed only these two mRNAs, both PCR and mRNA-seq detect a single capped and polyadenylated transcript that encodes processed forms of both genes linked by the intergenic region, as well as other transcripts in which exons of the two genes are spliced together. These results might suggest that the two genes are expressed as an operon, during which both genes are co-transcribed and then trans-spliced into two separate messages. This type of transcriptional regulation has been described in tunicates previously; however, the membrane-bound gene does not encode a typical Splice Leader (SL) sequence at the 5' terminus that usually accompanies trans-splicing. Thus, the presence of stable transcripts encoding both genes may suggest a novel mechanism of regulation, or conversely may be rare but stable transcripts in which the two mRNAs are linked due to a small amount of read-through by RNA polymerase. Both genes are highly polymorphic and co-expressed on tissues involved in histocompatibility. In addition, polymorphisms on both genes correlate with outcome, although we have found a case in which it appears that the secreted form may be major allorecognition determinant.

COMT val158met and 5-HTTLPR Genetic Polymorphisms Moderate Executive Control in Cannabis Users

PubMed Central

Verdejo-García, Antonio; Beatriz Fagundo, Ana; Cuenca, Aida; Rodriguez, Joan; Cuyás, Elisabet; Langohr, Klaus; de Sola Llopis, Susana; Civit, Ester; Farré, Magí; Peña-Casanova, Jordi; de la Torre, Rafael

2013-01-01

The adverse effects of cannabis use on executive functions are still controversial, fostering the need for novel biomarkers able to unveil individual differences in the cognitive impact of cannabis consumption. Two common genetic polymorphisms have been linked to the neuroadaptive impact of Δ9-tetrahydrocannabinol (THC) exposure and to executive functions in animals: the catechol-O-methyltransferase (COMT) gene val158met polymorphism and the SLC6A4 gene 5-HTTLPR polymorphism. We aimed to test if these polymorphisms moderate the harmful effects of cannabis use on executive function in young cannabis users. We recruited 144 participants: 86 cannabis users and 58 non-drug user controls. Both groups were genotyped and matched for genetic makeup, sex, age, education, and IQ. We used a computerized neuropsychological battery to assess different aspects of executive functions: sustained attention (CANTAB Rapid Visual Information Processing Test, RVIP), working memory (N-back), monitoring/shifting (CANTAB ID/ED set shifting), planning (CANTAB Stockings of Cambridge, SOC), and decision-making (Iowa Gambling Task, IGT). We used general linear model-based analyses to test performance differences between cannabis users and controls as a function of genotypes. We found that: (i) daily cannabis use is not associated with executive function deficits; and (ii) COMT val158met and 5-HTTLPR polymorphisms moderate the link between cannabis use and executive performance. Cannabis users carrying the COMT val/val genotype exhibited lower accuracy of sustained attention, associated with a more strict response bias, than val/val non-users. Cannabis users carrying the COMT val allele also committed more monitoring/shifting errors than cannabis users carrying the met/met genotype. Finally, cannabis users carrying the 5-HTTLPR s/s genotype had worse IGT performance than s/s non-users. COMT and SLC6A4 genes moderate the impact of cannabis use on executive functions. PMID:23449176

Transforming Growth Factor-β1 T869C Gene Polymorphism Is Associated with Acquired Sick Sinus Syndrome via Linking a Higher Serum Protein Level

PubMed Central

Chen, Jan-Yow; Liu, Jiung-Hsiun; Wu, Hong-Dar Isaac; Lin, Kuo-Hung; Chang, Kuan-Cheng; Liou, Ying-Ming

2016-01-01

Background Familial sick sinus syndrome is associated with gene mutations and dysfunction of ion channels. In contrast, degenerative fibrosis of the sinus node tissue plays an important role in the pathogenesis of acquired sick sinus syndrome. There is a close relationship between transforming growth factor-β1 mediated cardiac fibrosis and acquired arrhythmia. It is of interest to examine whether transforming growth factor-β1 is involved in the pathogenesis of acquired sick sinus syndrome. Methods Overall, 110 patients with acquired SSS and 137 age/gender-matched controls were screened for transforming growth factor-β1 and cardiac sodium channel gene polymorphisms using gene sequencing or restriction fragment length polymorphism methods. An enzyme-linked immunosorbent assay was used to determine the serum level of transforming growth factor-β1. Results Two transforming growth factor-β1 gene polymorphisms (C-509T and T+869C) and one cardiac sodium channel gene polymorphism (H588R) have been identified. The C-dominant CC/CT genotype frequency of T869C was significantly higher in acquired sick sinus syndrome patients than in controls (OR 2.09, 95% CI 1.16–3.75, P = 0.01). Consistently, the level of serum transforming growth factor-β1 was also significantly greater in acquired sick sinus syndrome group than in controls (5.3±3.4 ng/ml vs. 3.7±2.4 ng/ml, P = 0.01). In addition, the CC/CT genotypes showed a higher transforming growth factor-β1 serum level than the TT genotype (4.25 ± 2.50 ng/ml vs. 2.71± 1.76 ng/ml, P = 0.028) in controls. Conclusion Transforming growth factor-β1 T869C polymorphism, correlated with high serum transforming growth factor-β1 levels, is associated with susceptibility to acquired sick sinus syndrome. PMID:27380173

Patterns of gene variation in central and marginal populations of Drosophila robusta.

PubMed

Prakash, S

1973-10-01

The central and marginal populations of D. robusta differ greatly in the level of inversion polymorphism; the marginal populations are monomorphic or nearly so and the central populations are highly polymorphic. This paper presents the frequencies of alleles at forty gene loci in various populations of D. robusta, studied by electrophoresis of proteins and enzymes. Population samples were obtained from eight widely separated populations of D. robusta which included the central, the extreme marginal and the intervening populations between the center and the margins. We find that the proportion of polymorphic loci and average heterozygosity per individual is slightly higher in the marginal populations than the central populations. In D. robusta on an average, 39% of the loci are polymorphic and the average proportion of loci heterozygous per individual is 11%. A breakdown of loci in three categories, viz, hydrolytic enzymes and some other enzymes, larval proteins and glycolytic and Kreb's cycle enzymes, shows that in all populations the level of polymorphism is highest in the hydrolytic enzymes, intermediate in larval proteins and least in the glycolytic and Kreb's cycle enzymes. On the average, the proportion of loci heterozygous per individual for three groups of loci is: hydrolytic enzymes and others (.164), larval proteins (.115) and glycolytic and Kreb's cycle enzymes (.037). We also observe that in all populations the level of polymorphism on the X chromosome is far less than the expected 38%; in salivary gland cells the euchromatic length of the X chromosome is 38% of the entire genome. Lower levels of polymorphism for the X chromosome loci are explained due to low probability of balanced polymorphisms for the X-linked loci since the conditions for establishment of balanced polymorphism for X-linked loci are more restrictive than for the autosomal loci.-The polymorphic loci can be grouped according to pattern of allele frequencies in different populations as follows: (1) The allele frequencies are similar in all populations at the XDH, Pep-1 and Hex-1 loci. (2) The alleles at the Est-1, Est-2, Amy loci and the AP-4(1.0) and the LAP-1(.90) alleles show north south clinal change in frequency. (3) There is north south and east west differentiation at the Pt-5, Pt-8 and Pt-9 loci and the allele AP-4(.81). (4) Polymorphism at loci such as Fum, B.Ox, Hex-8, Pep-2 and Pep-3 are restricted to only one or two of the populations. (5) Allele frequencies at the MDH and ODH loci fluctuate between populations. (6) Allele frequencies at many polymorphic loci such as Est-1, Est-2, LAP-1, AP-4, Pt-5, Pt-8, Pt-9, Pt-16, MDH, Fum change clinally within a gene arrangement. The pattern of gene variation in D. robusta is very complex and cannot be easily explained due to migration of neutral alleles between once-isolated populations or to semi-isolation of neutral alleles. The observations of the pattern of allele variation in different populations, high levels of polymorphism in the marginal populations which have small population size and low levels of polymorphism of the X chromosome loci all support the argument in favor of balancing selection as the main mechanism for the maintenance of these polymorphisms. Environmental factors must play a role in the maintenance of a great deal of these polymorphisms, since we observe clinal allele frequency changes even within a given inversion type.

Patterns of Gene Variation in Central and Marginal Populations of DROSOPHILA ROBUSTA

PubMed Central

Prakash, Satya

1973-01-01

The central and marginal populations of D. robusta differ greatly in the level of inversion polymorphism; the marginal populations are monomorphic or nearly so and the central populations are highly polymorphic. This paper presents the frequencies of alleles at forty gene loci in various populations of D. robusta, studied by electrophoresis of proteins and enzymes. Population samples were obtained from eight widely separated populations of D. robusta which included the central, the extreme marginal and the intervening populations between the center and the margins. We find that the proportion of polymorphic loci and average heterozygosity per individual is slightly higher in the marginal populations than the central populations. In D. robusta on an average, 39% of the loci are polymorphic and the average proportion of loci heterozygous per individual is 11%. A breakdown of loci in three categories, viz, hydrolytic enzymes and some other enzymes, larval proteins and glycolytic and Kreb's cycle enzymes, shows that in all populations the level of polymorphism is highest in the hydrolytic enzymes, intermediate in larval proteins and least in the glycolytic and Kreb's cycle enzymes. On the average, the proportion of loci heterozygous per individual for three groups of loci is: hydrolytic enzymes and others (.164), larval proteins (.115) and glycolytic and Kreb's cycle enzymes (.037). We also observe that in all populations the level of polymorphism on the X chromosome is far less than the expected 38%; in salivary gland cells the euchromatic length of the X chromosome is 38% of the entire genome. Lower levels of polymorphism for the X chromosome loci are explained due to low probability of balanced polymorphisms for the X-linked loci since the conditions for establishment of balanced polymorphism for X-linked loci are more restrictive than for the autosomal loci.—The polymorphic loci can be grouped according to pattern of allele frequencies in different populations as follows: (1) The allele frequencies are similar in all populations at the XDH, Pep-1 and Hex-1 loci. (2) The alleles at the Est-1, Est-2, Amy loci and the AP-41.0 and the LAP-1.90 alleles show north south clinal change in frequency. (3) There is north south and east west differentiation at the Pt-5, Pt-8 and Pt-9 loci and the allele AP-4.81. (4) Polymorphism at loci such as Fum, B.Ox, Hex-8, Pep-2 and Pep-3 are restricted to only one or two of the populations. (5) Allele frequencies at the MDH and ODH loci fluctuate between populations. (6) Allele frequencies at many polymorphic loci such as Est-1, Est-2, LAP-1, AP-4, Pt-5, Pt-8, Pt-9, Pt-16, MDH, Fum change clinally within a gene arrangement. The pattern of gene variation in D. robusta is very complex and cannot be easily explained due to migration of neutral alleles between once-isolated populations or to semi-isolation of neutral alleles. The observations of the pattern of allele variation in different populations, high levels of polymorphism in the marginal populations which have small population size and low levels of polymorphism of the X chromosome loci all support the argument in favor of balancing selection as the main mechanism for the maintenance of these polymorphisms. Environmental factors must play a role in the maintenance of a great deal of these polymorphisms, since we observe clinal allele frequency changes even within a given inversion type. PMID:4203580

Polymorphisms of the oxytocin receptor gene and overeating: the intermediary role of endophenotypic risk factors

PubMed Central

Davis, C; Patte, K; Zai, C; Kennedy, J L

2017-01-01

Background/Objectives: Oxytocin (OXT) is an evolutionarily ancient neuropeptide with strong links to affiliative and prosocial behaviors, and the management of stress. Increases in OXT also tend to decrease food intake, especially of sweet carbohydrates. The social correlates of low OXT levels mesh with the social deficits and stress proneness identified in interpersonal models of overeating, as well as the increased appetite for highly palatable foods typically seen in chronic overeaters. The objectives of this study were to investigate links between polymorphisms of the oxytocin receptor (OXTR) gene and overeating, and to examine OXTR links with relevant endophenotypes of overeating related to reward and stress sensitivity, and to food preferences. Subject/Methods: The sample comprised 460 adults between the ages of 25 and 50 years recruited from the community, and representing a broad range of body weights. Overeating, reward and punishment sensitivity, and food preferences, were quantified as composite variables using well-validated questionnaires. In addition, seven single-nucleotide polymorphisms (rs237878, rs237885, rs2268493, rs2268494, rs2254298, rs53576, rs2268498) of the OXTR gene were genotyped. Results: Analyses identified a four-marker haplotype that was significantly related to food preferences. Individual genotype analyses also found that at least one of the markers was related to each of the phenotypic variables. In addition, an empirically derived structural equation model linking genetic and phenotype variables produced a good fit to the data. Conclusions: The results of this preliminary study have demonstrated that OXTR variation is associated with overeating, and with endophenotypic traits such as sweet and fatty food preferences, and reward and punishment sensitivity. In general, the genetic findings also favor the view that overeating may be associated with relatively low basal OXT levels. PMID:28530679

The impact of GPX1 on the association of groundwater selenium and depression: a project FRONTIER study

PubMed Central

2013-01-01

Background Prior animal model and human-based studies have linked selenium concentrations to decreased risk for depression; however, this work has not focused on household groundwater levels or specific depressive symptoms. The current study evaluated the link between groundwater selenium levels and depression. We also sought to determine if a functional polymorphism in the glutathione peroxidase 1 (GPX1) gene impacted this link. Methods We used a cross-sectional design to analyze data from 585 participants (183 men and 402 women) from Project FRONTIER, a study of rural health in West Texas. Residential selenium concentrations were estimated using Geospatial Information System (GIS) analyses. Linear regression models were created using Geriatric Depression Scale (GDS-30) total and subfactor scores as outcome variables and selenium concentrations as predictor variables. Analyses were re-run after stratification of the sample on GPX1 Pro198Leu genotype (rs1050454). Results Selenium levels were significantly and negatively related to all GDS and subfactor scores accounting for up to 17% of the variance beyond covariates. Selenium was most strongly protective against depression among homozygous carriers of the C allele at the Pro198Leu polymorphism of the GPX1 gene. Analyses also point towards a gene-environmental interaction between selenium exposure and GPX1 polymorphism. Conclusion Our results support the link between groundwater selenium levels and decreased depression symptoms. These findings also highlight the need to consider the genetics of the glutathione peroxidase system when examining this relationship, as variation in the GPX1 gene is related to depression risk and significantly influences the protective impact of selenium, which is indicative of a gene-environment interaction. PMID:23289525

Polymorphisms of the oxytocin receptor gene and overeating: the intermediary role of endophenotypic risk factors.

PubMed

Davis, C; Patte, K; Zai, C; Kennedy, J L

2017-05-22

Oxytocin (OXT) is an evolutionarily ancient neuropeptide with strong links to affiliative and prosocial behaviors, and the management of stress. Increases in OXT also tend to decrease food intake, especially of sweet carbohydrates. The social correlates of low OXT levels mesh with the social deficits and stress proneness identified in interpersonal models of overeating, as well as the increased appetite for highly palatable foods typically seen in chronic overeaters. The objectives of this study were to investigate links between polymorphisms of the oxytocin receptor (OXTR) gene and overeating, and to examine OXTR links with relevant endophenotypes of overeating related to reward and stress sensitivity, and to food preferences. The sample comprised 460 adults between the ages of 25 and 50 years recruited from the community, and representing a broad range of body weights. Overeating, reward and punishment sensitivity, and food preferences, were quantified as composite variables using well-validated questionnaires. In addition, seven single-nucleotide polymorphisms (rs237878, rs237885, rs2268493, rs2268494, rs2254298, rs53576, rs2268498) of the OXTR gene were genotyped. Analyses identified a four-marker haplotype that was significantly related to food preferences. Individual genotype analyses also found that at least one of the markers was related to each of the phenotypic variables. In addition, an empirically derived structural equation model linking genetic and phenotype variables produced a good fit to the data. The results of this preliminary study have demonstrated that OXTR variation is associated with overeating, and with endophenotypic traits such as sweet and fatty food preferences, and reward and punishment sensitivity. In general, the genetic findings also favor the view that overeating may be associated with relatively low basal OXT levels.

Contrasting patterns of X/Y polymorphism distinguish Carica papaya from other sex chromosome systems.

PubMed

Weingartner, Laura A; Moore, Richard C

2012-12-01

The sex chromosomes of the tropical crop papaya (Carica papaya) are evolutionarily young and consequently allow for the examination of evolutionary mechanisms that drive early sex chromosome divergence. We conducted a molecular population genetic analysis of four X/Y gene pairs from a collection of 45 wild papaya accessions. These population genetic analyses reveal striking differences in the patterns of polymorphism between the X and Y chromosomes that distinguish them from other sex chromosome systems. In most sex chromosome systems, the Y chromosome displays significantly reduced polymorphism levels, whereas the X chromosome maintains a level of polymorphism that is comparable to autosomal loci. However, the four papaya sex-linked loci that we examined display diversity patterns that are opposite this trend: the papaya X alleles exhibit significantly reduced polymorphism levels, whereas the papaya Y alleles maintain greater than expected levels of diversity. Our analyses suggest that selective sweeps in the regions of the X have contributed to this pattern while also revealing geographically restricted haplogroups on the Y. We discuss the possible role sexual selection and/or genomic conflict have played in shaping the contrasting patterns of polymorphism found for the papaya X and Y chromosomes.

The dopamine transporter gene may not contribute to susceptibility and the specific personality traits of amphetamine dependence.

PubMed

Tzeng, Nian-Sheng; Lu, Ru-Band; Yeh, Hui-Wen; Yeh, Yi-Wei; Huang, Chang-Chih; Yen, Che-Hung; Kuo, Shin-Chang; Chen, Chun-Yen; Chang, Hsin-An; Ho, Pei-Shen; Cheng, Serena; Shih, Mei-Chen; Huang, San-Yuan

2015-04-01

A substantial amount of evidence suggests that dysfunction of the dopamine transporter may be involved in the pathophysiology of amphetamine dependence (AD). The aim of this study was to examine whether the dopamine transporter gene (DAT1, SLC6A3) is associated with development of AD and whether this gene influences personality traits in patients with AD. Eighteen polymorphisms of the DAT1 gene were analyzed in a case-control study that included 909 Han Chinese men (568 patients with AD and 341 control subjects). The patients fulfilled the DSM-IV-TR criteria for AD. The Tridimensional Personality Questionnaire (TPQ) was used to assess personality traits and to examine the association between these traits and DAT1 gene variants. A weak association was found between the rs27072 polymorphism and development of AD, but these borderline associations were unconfirmed by logistic regression and haplotype analysis. Although harm avoidance and novelty seeking scores were significantly higher in patients than in controls, DAT1 polymorphisms did not influence these scores. This study suggests that high harm avoidance and novelty seeking personality traits may be a risk factor for the development of AD. However, the DAT1 gene may not contribute to AD susceptibility and specific personality traits observed in AD among Han Chinese men. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Genetic variations in toll-like receptor 4 in Mexican-Mestizo patients with intra-abdominal infection and/or pneumonia.

PubMed

Rodriguez-Osorio, Carlos A; Lima, Guadalupe; Herrera-Caceres, Jaime O; Villegas-Torres, Beatriz E; Zuñiga, Joaquin; Ponce-de-Leon, Sergio; Llorente, Luis; Sifuentes-Osornio, Jose

2013-06-01

Sepsis is a leading cause of death around the world, and 73-83% of all sepsis cases requiring attention in intensive care units are linked to intra-abdominal infection (IAI) or pneumonia. The activation of innate immunity is central to the manifestation of sepsis, and toll-like receptor (TLR) 4 plays an important role in this activation process. The 299G and 399I alleles of TLR4 have been linked with an increased risk of Gram-negative bacteria (GNB) infections and septic shock in some populations. This case-control study evaluated the prevalence of D299G/T399I polymorphisms in Mexican patients with IAI and/or pneumonia and in healthy controls. Genotyping revealed that 1 in 44 patients (2.3%; CI 95%: 0.05-12.0%) and 4 in 126 controls (3.2%; CI 95%: 0.9-7.9%) were heterozygous for both the D299G and T399l polymorphisms (OR: 0.71, CI 95%: 0.01-7.44, p = NS), confirming the co-segregation of these alleles in this population. Furthermore, the patients with a GNB infection and severe sepsis were not carriers of the risk alleles. In summary, this report shows that the frequency of the D299G and T399I polymorphisms in Mexican-Mestizos is lower than anticipated in comparison with other ethnic groups, emphasizing the variable distribution of TLR4 polymorphisms among different populations. Consequently, this study was not able to detect associations between TLR4 polymorphisms and sepsis in this population. Copyright © 2013 Elsevier B.V. All rights reserved.

Concept mapping One-Carbon Metabolism to model future ontologies for nutrient-gene-phenotype interactions.

PubMed

Joslin, A C; Green, R; German, J B; Lange, M C

2014-09-01

Advances in the development of bioinformatic tools continue to improve investigators' ability to interrogate, organize, and derive knowledge from large amounts of heterogeneous information. These tools often require advanced technical skills not possessed by life scientists. User-friendly, low-barrier-to-entry methods of visualizing nutrigenomics information are yet to be developed. We utilized concept mapping software from the Institute for Human and Machine Cognition to create a conceptual model of diet and health-related data that provides a foundation for future nutrigenomics ontologies describing published nutrient-gene/polymorphism-phenotype data. In this model, maps containing phenotype, nutrient, gene product, and genetic polymorphism interactions are visualized as triples of two concepts linked together by a linking phrase. These triples, or "knowledge propositions," contextualize aggregated data and information into easy-to-read knowledge maps. Maps of these triples enable visualization of genes spanning the One-Carbon Metabolism (OCM) pathway, their sequence variants, and multiple literature-mined associations including concepts relevant to nutrition, phenotypes, and health. The concept map development process documents the incongruity of information derived from pathway databases versus literature resources. This conceptual model highlights the importance of incorporating information about genes in upstream pathways that provide substrates, as well as downstream pathways that utilize products of the pathway under investigation, in this case OCM. Other genes and their polymorphisms, such as TCN2 and FUT2, although not directly involved in OCM, potentially alter OCM pathway functionality. These upstream gene products regulate substrates such as B12. Constellations of polymorphisms affecting the functionality of genes along OCM, together with substrate and cofactor availability, may impact resultant phenotypes. These conceptual maps provide a foundational framework for development of nutrient-gene/polymorphism-phenotype ontologies and systems visualization.

Biomarkers of Risk for Post-Traumatic Stress Disorder (PTSD)

DTIC Science & Technology

2011-04-01

transporter (DAT), catechol-o- methyltransferase ( COMT Val66Met), brain-derived neurotrophic factor (BDNF), and polymorphisms in the gene for neuropeptide Y...study which has a larger number of participants and explores these effects more systematically), only one gene, again the COMT Val/Met polymorphism...relatively high or low exposure to combat on the Hoge scale (median split), there was an effect of COMT (B=4.8, p<.01), an effect of combat exposure

The 5-HTTLPR Polymorphism in the Serotonin Transporter Gene Moderates the Association between Emotional Behavior and Changes in Marital Satisfaction over Time

PubMed Central

Haase, Claudia M.; Saslow, Laura R.; Bloch, Lian; Saturn, Sarina R.; Casey, James J.; Seider, Benjamin H.; Lane, Jessica; Coppola, Giovanni; Levenson, Robert W.

2014-01-01

Why do some individuals become dissatisfied with their marriages when levels of negative emotion are high and levels of positive emotions are low, whereas others remain unaffected? Using data from a 13-year longitudinal study of middle-aged and older adults in long-term marriages, we examined whether the 5-HTTLPR polymorphism in the serotonin transporter gene moderates the association between negative and positive emotional behavior (objectively measured during marital conflict) and changes in marital satisfaction over time. For individuals with two short alleles of 5-HTTLPR, higher negative and lower positive emotional behavior at Time 1 predicted declines in marital satisfaction over time (even after controlling for depression and other covariates). For individuals with one or two long alleles, emotional behavior did not predict changes in marital satisfaction. We also found evidence for a crossover interaction (individuals with two short alleles of 5-HTTLPR and low levels of negative or high levels of positive emotion had the highest levels of marital satisfaction). These findings provide the first evidence of a specific genetic polymorphism that moderates the association between emotional behavior and changes in marital satisfaction over time and are consistent with increasing evidence that the short allele of this polymorphism serves as a susceptibility factor that amplifies sensitivity to both negative and positive emotional influences. PMID:24098925

Serotonin Transporter (5-HTTLPR) Genotype, Childhood Abuse, and Suicide Attempts in Adult Psychiatric Inpatients

ERIC Educational Resources Information Center

Gibb, Brandon E.; McGeary, John E.; Beevers, Christopher G.; Miller, Ivan W.

2006-01-01

There is growing evidence that a functional polymorphism in the serotonin transporter gene (5-HTTLPR) moderates the impact of negative life events (e.g., childhood abuse) on the development of depression. However, it is unclear whether the gene x environment interaction predicts suicide attempts specifically. In addition, previous studies have not…

Interaction of Dopamine Transporter Gene and Observed Parenting Behaviors on Attention-Deficit/Hyperactivity Disorder: A Structural Equation Modeling Approach

ERIC Educational Resources Information Center

Li, James J.; Lee, Steve S.

2013-01-01

Emerging evidence suggests that some individuals may be simultaneously more responsive to the effects from environmental adversity "and" enrichment (i.e., differential susceptibility). Given that parenting behavior and a variable number tandem repeat polymorphism in the 3'untranslated region of the dopamine transporter (DAT1) gene are…

Polymorphic butterfly reveals the missing link in ecological speciation.

PubMed

Chamberlain, Nicola L; Hill, Ryan I; Kapan, Durrell D; Gilbert, Lawrence E; Kronforst, Marcus R

2009-11-06

Ecological speciation occurs when ecologically based, divergent selection causes the evolution of reproductive isolation. There are many empirical examples of this process; however, there exists a poorly characterized stage during which the traits that distinguish species ecologically and reproductively segregate in a single population. By using a combination of genetic mapping, mate-choice experiments, field observations, and population genetics, we studied a butterfly population with a mimetic wing color polymorphism and found that the butterflies exhibited partial, color-based, assortative mate preference. These traits represent the divergent, ecologically based signal and preference components of sexual isolation that usually distinguish incipient and sibling species. The association between behavior and recognition trait in a single population may enhance the probability of speciation and provides an example of the missing link between an interbreeding population and isolated species.

Brief Report: Glutamate Transporter Gene (SLC1A1) Single Nucleotide Polymorphism (rs301430) and Repetitive Behaviors and Anxiety in Children with Autism Spectrum Disorder

PubMed Central

Gadow, Kenneth D.; Roohi, Jasmin; DeVincent, Carla J.; Kirsch, Sarah; Hatchwell, Eli

2015-01-01

Investigated association of single nucleotide polymorphism (SNP) rs301430 in glutamate transporter gene (SLC1A1) with severity of repetitive behaviors (obsessive–compulsive behaviors, tics) and anxiety in children with autism spectrum disorder (ASD). Mothers and/or teachers completed a validated DSM-IV-referenced rating scale for 67 children with autism spectrum disorder. Although analyses were not significant for repetitive behaviors, youths homozygous for the high expressing C allele had more severe anxiety than carriers of the T allele. Allelic variation in SLC1A1 may be a biomarker for or modifier of anxiety symptom severity in children with ASD, but study findings are best conceptualized as tentative pending replication with larger independent samples. PMID:20155310

Glutamate transporter gene (SLC1A1) single nucleotide polymorphism (rs301430) and repetitive behaviors and anxiety in children with autism spectrum disorder.

PubMed

Gadow, Kenneth D; Roohi, Jasmin; DeVincent, Carla J; Kirsch, Sarah; Hatchwell, Eli

2010-09-01

Investigated association of single nucleotide polymorphism (SNP) rs301430 in glutamate transporter gene (SLC1A1) with severity of repetitive behaviors (obsessive-compulsive behaviors, tics) and anxiety in children with autism spectrum disorder (ASD). Mothers and/or teachers completed a validated DSM-IV-referenced rating scale for 67 children with autism spectrum disorder. Although analyses were not significant for repetitive behaviors, youths homozygous for the high expressing C allele had more severe anxiety than carriers of the T allele. Allelic variation in SLC1A1 may be a biomarker for or modifier of anxiety symptom severity in children with ASD, but study findings are best conceptualized as tentative pending replication with larger independent samples.

Epitaxial stabilization and phase instability of VO 2 polymorphs

DOE PAGES

Lee, Shinbuhm; Ivanov, Ilia N.; Keum, Jong K.; ...

2016-01-20

The VO 2 polymorphs, i.e., VO 2(A), VO 2(B), VO 2(M1) and VO 2(R), have a wide spectrum of functionalities useful for many potential applications in information and energy technologies. However, synthesis of phase pure materials, especially in thin film forms, has been a challenging task due to the fact that the VO 2 polymorphs are closely related to each other in a thermodynamic framework. Here, we report epitaxial stabilization of the VO 2 polymorphs to synthesize high quality single crystalline thin films and study the phase stability of these metastable materials. We selectively deposit all the phases on variousmore » perovskite substrates with different crystallographic orientations. By investigating the phase instability, phonon modes and transport behaviours, not only do we find distinctively contrasting physical properties of the VO 2 polymorphs, but that the polymorphs can be on the verge of phase transitions when heated as low as ~400 °C. In conclusion, our successful epitaxy of both VO 2(A) and VO 2(B) phases, which are rarely studied due to the lack of phase pure materials, will open the door to the fundamental studies of VO 2 polymorphs for potential applications in advanced electronic and energy devices.« less

The evaluation of the photocatalytic activity of magnetic and non-magnetic polymorphs of Fe2O3 in natural sunlight exposure: A comparison of photocatalytic activity

NASA Astrophysics Data System (ADS)

Aslam, M.; Qamar, M. Tariq; Rehman, Ateeq Ur; Soomro, M. Tahir; Ali, Shahid; Ismail, I. M. I.; Hameed, A.

2018-09-01

The non-magnetic and magnetic polymorphs of iron oxide (Fe2O3) namely: α-Fe2O3 (hematite) and γ-Fe2O3 (maghemite) respectively, were synthesized by a facile surfactant aided hydrogel route. The synthesized polymorphs were characterized by diffuse reflectance, photoluminescence and raman spectroscopy for optical properties whereas the morphological, structural, chemical and electronic state evaluation were performed by FESEM, HRTEM, XRD, and XPS. The charge transport and the stability of the materials were examined electrochemically. The photocatalytic activity of the synthesized polymorphs was evaluated for the degradation of 2-chlorophenol and 2-nitrophenol in the exposure of the visible region and complete spectrum natural sunlight. Both the polymorphs exhibited a significantly high activity for the degradation of the phenolic substrate in the exposure of the complete spectrum of sunlight, however, the activity in the visible region of the sunlight was relatively lower. A substantial increase in the activity in the visible region was noticed when the polymorphs were exposed to complete spectrum sunlight prior to the photocatalytic experiments. The comparison of the exposed and unexposed samples revealed the induction of defects that served as traps for the excited electrons and increased activity of the polymorphs.

Identification of sequence-related amplified polymorphism markers linked to the red leaf trait in ornamental kale (Brassica oleracea L. var. acephala).

PubMed

Wang, Y S; Liu, Z Y; Li, Y F; Zhang, Y; Yang, X F; Feng, H

2013-04-02

Artistic diversiform leaf color is an important agronomic trait that affects the market value of ornamental kale. In the present study, genetic analysis showed that a single-dominant gene, Re (red leaf), determines the red leaf trait in ornamental kale. An F2 population consisting of 500 individuals from the cross of a red leaf double-haploid line 'D05' with a white leaf double-haploid line 'D10' was analyzed for the red leaf trait. By combining bulked segregant analysis and sequence-related amplified polymorphism technology, we identified 3 markers linked to the Re/re locus. A genetic map of the Re locus was constructed using these sequence-related amplified polymorphism markers. Two of the markers, Me8Em4 and Me8Em17, were located on one side of Re/re at distances of 2.2 and 6.4 cM, whereas the other marker, Me9Em11, was located on the other side of Re/re at a distance of 3.7 cM. These markers could be helpful for the subsequent cloning of the red trait gene and marker-assisted selection in ornamental kale breeding programs.

Natural Selection and Recombination Rate Variation Shape Nucleotide Polymorphism Across the Genomes of Three Related Populus Species

PubMed Central

Wang, Jing; Street, Nathaniel R.; Scofield, Douglas G.; Ingvarsson, Pär K.

2016-01-01

A central aim of evolutionary genomics is to identify the relative roles that various evolutionary forces have played in generating and shaping genetic variation within and among species. Here we use whole-genome resequencing data to characterize and compare genome-wide patterns of nucleotide polymorphism, site frequency spectrum, and population-scaled recombination rates in three species of Populus: Populus tremula, P. tremuloides, and P. trichocarpa. We find that P. tremuloides has the highest level of genome-wide variation, skewed allele frequencies, and population-scaled recombination rates, whereas P. trichocarpa harbors the lowest. Our findings highlight multiple lines of evidence suggesting that natural selection, due to both purifying and positive selection, has widely shaped patterns of nucleotide polymorphism at linked neutral sites in all three species. Differences in effective population sizes and rates of recombination largely explain the disparate magnitudes and signatures of linked selection that we observe among species. The present work provides the first phylogenetic comparative study on a genome-wide scale in forest trees. This information will also improve our ability to understand how various evolutionary forces have interacted to influence genome evolution among related species. PMID:26721855

Natural Selection and Recombination Rate Variation Shape Nucleotide Polymorphism Across the Genomes of Three Related Populus Species.

PubMed

Wang, Jing; Street, Nathaniel R; Scofield, Douglas G; Ingvarsson, Pär K

2016-03-01

A central aim of evolutionary genomics is to identify the relative roles that various evolutionary forces have played in generating and shaping genetic variation within and among species. Here we use whole-genome resequencing data to characterize and compare genome-wide patterns of nucleotide polymorphism, site frequency spectrum, and population-scaled recombination rates in three species of Populus: Populus tremula, P. tremuloides, and P. trichocarpa. We find that P. tremuloides has the highest level of genome-wide variation, skewed allele frequencies, and population-scaled recombination rates, whereas P. trichocarpa harbors the lowest. Our findings highlight multiple lines of evidence suggesting that natural selection, due to both purifying and positive selection, has widely shaped patterns of nucleotide polymorphism at linked neutral sites in all three species. Differences in effective population sizes and rates of recombination largely explain the disparate magnitudes and signatures of linked selection that we observe among species. The present work provides the first phylogenetic comparative study on a genome-wide scale in forest trees. This information will also improve our ability to understand how various evolutionary forces have interacted to influence genome evolution among related species. Copyright © 2016 by the Genetics Society of America.

Three-dimensional distribution of polymorphs and magnesium in a calcified underwater attachment system by diffraction tomography

PubMed Central

Leemreize, Hanna; Almer, Jonathan D.; Stock, Stuart R.; Birkedal, Henrik

2013-01-01

Biological materials display complicated three-dimensional hierarchical structures. Determining these structures is essential in understanding the link between material design and properties. Herein, we show how diffraction tomography can be used to determine the relative placement of the calcium carbonate polymorphs calcite and aragonite in the highly mineralized holdfast system of the bivalve Anomia simplex. In addition to high fidelity and non-destructive mapping of polymorphs, we use detailed analysis of X-ray diffraction peak positions in reconstructed powder diffraction data to determine the local degree of Mg substitution in the calcite phase. These data show how diffraction tomography can provide detailed multi-length scale information on complex materials in general and of biomineralized tissues in particular. PMID:23804437

Exploring the role of ionic liquids to tune the polymorphic outcome of organic compounds.

PubMed

Zeng, Qingying; Mukherjee, Arijit; Müller, Peter; Rogers, Robin D; Myerson, Allan S

2018-02-14

While molecular solvents are commonly used in the screening of polymorphs, the choices are often restricted. Ionic liquids (ILs) - also referred as designer solvents - have immense possibility in this regard because of their wide flexibility of tunability. More importantly, the interactions among the IL components are completely unique compared to those present in the molecular solvents. In this context, we have chosen tetrolic acid (TA) and isonicotinamide (INA), which showed solution-structure link in molecular solvents in the past, as probes to investigate the role of imidazolium based ionic liquids in the polymorphism of these two systems and whether the different solute-solvent interactions in ILs affect the polymorphic outcome. It is observed that the selected imidazolium-based ILs, with varying anion basicity have influenced the crystallization outcome by the interaction between ILs and model compounds. Later, we have utilized the concept of double salt ionic liquids (DSIL) for INA, a penta-morphic system, to investigate the variation in the polymorphic outcome. This approach helped to obtain the forms that were otherwise inaccessible in ILs.

Human C-reactive protein gene polymorphism and metabolic syndrome are associated with premature coronary artery disease.

PubMed

Abd El-Aziz, Tarek A; Mohamed, Rasha H

2013-12-15

The aim of this study was to investigate the association between C-reactive protein (CRP) gene polymorphism and metabolic syndrome (MetS) with premature coronary artery disease (PCAD). 116 patients with PCAD (58 with MetS and 58 without MetS) and 119 controls were included in the study. CRP gene +1059 G>C polymorphism was analyzed by polymerase chain reaction. Serum hs-CRP was measured using high-sensitivity enzyme-linked immunosorbent assay. Carriers of C allele of the CRP +1059 G>C polymorphism had 3.37 fold increased risk to develop MetS in patients with PCAD. In addition CRP gene and hs-CRP levels were independent risk factors for PCAD and MetS. The present study provides new evidence that the presence of CRP +1059 G>C polymorphism and hs-CRP levels are independent determinants of PCAD and MetS in Egyptians. The results of our study suggest a synergistic effect of CRP C allele with classical risk factors such as hypertension, obesity, dyslipidemia and MetS. © 2013 Elsevier B.V. All rights reserved.

Analysis of some polymorphic markers of the CFTR gene in cystic fibrosis patients and healthy donors from the Moscow region

DOE Office of Scientific and Technical Information (OSTI.GOV)

Amosenko, F.A.; Sazonova, M.A.; Kapranov, N.I.

1995-04-01

Allelic frequencies of three polymorphic markers in the CFTR gene were estimated on chromosomes derived from cystic fibrosis (CF) patients and healthy donors from Moscow and the Moscow region. These polymorphic markers are tetranucleotide tandem repeats GATT in intron 6B, M470V in exon 10, and T854T in exon 14 (fragment A). Frequencies at allele 1 of the M470V marker, along with allele 2 of GATT and T854T, are two times higher for CF patients without {Delta}F508 mutation than for healthy donors, and there is linkage disequilibrium of these alleles of the polymorphic markers analyzed with the CF gene. Allele 1more » of M470V and T854T markers, as well as allele 2 of the GATT marker (six repeats), are absolutely linked to mutation F508 of the CFTR gene. Using the polymorphic markers studied, family analysis of CF was carried out in two families. 10 refs., 1 fig., 1 tab.« less

The DRD4 exon 3 VNTR polymorphism and addiction-related phenotypes: a review

PubMed Central

McGeary, John

2009-01-01

In addition to the large literatures on associations of the DRD4 VNTR polymorphism with ADHD and personality traits, there is an emerging literature linking this variant to addiction and addiction-related phenotypes. When only diagnosis-based studies are considered, an inconsistent picture emerges raising doubts as to the relevance of this polymorphism to addiction. However the use of multiple levels of analysis in examining the importance of this polymorphism has raised the possibility of an urge-related “intermediate phenotype” that puts one at risk for developing addiction but may not be found in all persons with an addiction diagnosis. From cellular assays through neuroimaging and behavioral phenotypes, these studies highlight the power of the “intermediate phenotype” approach and suggest a possible explanation of the mixed findings when diagnosis is used as the phenotype. Strengths and weaknesses of alternative DRD4 VNTR genotype grouping strategies are discussed. In sum, converging evidence across multiple methodologies supports the possibility of a robust relationship between the DRD4 exon 3 VNTR polymorphism and urge for addictive substances. PMID:19336242

Serotonin-transporter-linked polymorphic region (5-HTTLPR) genotype and stressful life events interact to predict preschool onset depression: A replication and developmental extension

PubMed Central

Bogdan, Ryan; Agrawal, Arpana; Gaffrey, Michael S; Tillman, Rebecca; Luby, Joan L

2013-01-01

Background Scientific enthusiasm about gene x environment interactions, spurred by the 5-HTTLPR (serotonin transporter polymorphic-region) x SLEs (stressful life events) interaction predicting depression, have recently been tempered by sober realizations of small effects and meta-analyses reaching opposing conclusions. These mixed findings highlight the need for further research. Converging evidence suggests that the effects of 5-HTTLPR genotype may be neurodevelopmental in origin but we are not aware of empirical studies that have investigated whether the 5-HTTLPR genotype x SLE interaction predicts preschool-onset depression (PO-MDD), the earliest validated form of depression. Methods Children (n = 234) aged 3–5 were recruited for a longitudinal study designed to examine PO-MDD. In a comprehensive baseline assessment, the child’s primary caregivers completed questionnaires and were interviewed about their child’s behaviors, psychiatric symptoms, and exposure to SLEs. Results A 5-HTTLPR x SLEs interaction emerged, such that children homozygous for the short allele were more susceptible to depression in the context of elevated SLE than long allele carriers. In contrast, at low SLE exposure, short allele homozygotes had fewer depressive symptoms. The data were best fit by a plasticity model with a substantial reduction in fit by diathesis-stress models. Conclusions Extending studies in adult and adolescent populations, these data suggest that 5-HTTLPR genotype may provide plasticity to environmental influence, for better or worse. Specifically, children homozygous for the short allele were more susceptible to the depressogenic effects of SLEs but benefitted, in the form of reduced depressive symptoms, in the context of relatively benign environmental conditions (i.e., relatively low SLE exposure). These data highlight the importance of examining gene x environment interactions across development, environment, and outcome but should be interpreted cautiously given the small sample size. PMID:24117502

Breast cancer resistance protein (ABCG2) and drug disposition: intestinal expression, polymorphisms and sulfasalazine as an in vivo probe

PubMed Central

Urquhart, Bradley L.; Ware, Joseph A.; Tirona, Rommel G.; Ho, Richard H.; Leake, Brenda F.; Schwarz, Ute I.; Zaher, Hani; Palandra, Joe; Gregor, Jamie C.; Dresser, George K.; Kim, Richard B.

2014-01-01

Breast cancer resistance protein (BCRP) is an efflux transporter expressed in tissues that act as barriers to drug entry. Given that single nucleotide polymorphisms (SNPs) in the ABCG2 gene encoding BCRP are common, the possibility exists that these genetic variants may be a determinant of interindividual variability in drug response. The objective of this study is to confirm the human BCRP-mediated transport of sulfasalazine in vitro, evaluate interindividual variation in BCRP expression in human intestine and to determine the role of ABCG2 SNPs to drug disposition in healthy patients using sulfasalazine as a novel in vivo probe. To evaluate these objectives, pinch biopsies were obtained from 18 patients undergoing esophagogastro–duodenoscopy or colonoscopy for determination of BCRP expression in relation to genotype. Wild-type and variant BCRP were expressed in a heterologous expression system to evaluate the effect of SNPs on cell-surface trafficking. A total of 17 healthy individuals participated in a clinical investigation to determine the effect of BCRP SNPs on sulfasalazine pharmacokinetics. In vitro, the cell surface protein expression of the common BCRP 421 C>A variant was reduced in comparison with the wild-type control. Intestinal biopsy samples revealed that BCRP protein and mRNA expression did not significantly differ between patients with 34GG/421CC versus patients with 34GG/421CA genotypes. Remarkably, in subjects with 34GG/421CA genotype, sulfasalazine area under the concentration-time curve was 2.4-fold greater compared with 34GG/421CC subjects (P<0.05). This study links commonly occurring SNPs in BCRP with significantly increased oral sulfasalazine plasma exposure in humans. Accordingly, sulfasalazine may prove to have utility as in vivo probe for assessing the clinical impact of BCRP for the disposition and efficacy of drugs. PMID:18408567

Genetic Variation Linked to Lung Cancer Survival in White Smokers | Center for Cancer Research

Cancer.gov

CCR investigators have discovered evidence that links lung cancer survival with genetic variations (called single nucleotide polymorphisms) in the MBL2 gene, a key player in innate immunity. The variations in the gene, which codes for a protein called the mannose-binding lectin, occur in its promoter region, where the RNA polymerase molecule binds to start transcription, and

Molecular Signatures of Chronic Pain Subtypes

DTIC Science & Technology

2013-01-01

on August 4, 2011. Our project coordinator was in touch with Ms. Lesnow on December 21. We were asked to provide a breakdown of costs for the...49]. A few candidate gene polymorphisms have been linked to pain susceptibility, including catechol-O-methyltranferase ( COMT ). This gene modulates...nociceptive and inflammatory pain and has been linked to temporomandibular joint pain syndromes [50]. Even studies of COMT , however, have demonstrated

Markers linked to vegetative incompatibility (vic) genes and a region of high heterogeneity and reduced recombination near the mating type locus (MAT) in Cryphonectria parasitica

Treesearch

Thomas L. Kubisiak; Michael g. Milgroom

2006-01-01

To find markers linked to vegetative incompatibility (vic) genes in the chestnut blight fungus, Cryphonectria parasitica, we constructed a preliminary linkage map. In general, this map is characterized by low levels of polymorphism, as evident from the more than 24 linkage groups observed, compared to seven expected from electrophoretic karyotyping....

Similar Efficacies of Selection Shape Mitochondrial and Nuclear Genes in Both Drosophila melanogaster and Homo sapiens.

PubMed

Cooper, Brandon S; Burrus, Chad R; Ji, Chao; Hahn, Matthew W; Montooth, Kristi L

2015-08-21

Deleterious mutations contribute to polymorphism even when selection effectively prevents their fixation. The efficacy of selection in removing deleterious mitochondrial mutations from populations depends on the effective population size (Ne) of the mitochondrial DNA and the degree to which a lack of recombination magnifies the effects of linked selection. Using complete mitochondrial genomes from Drosophila melanogaster and nuclear data available from the same samples, we reexamine the hypothesis that nonrecombining animal mitochondrial DNA harbor an excess of deleterious polymorphisms relative to the nuclear genome. We find no evidence of recombination in the mitochondrial genome, and the much-reduced level of mitochondrial synonymous polymorphism relative to nuclear genes is consistent with a reduction in Ne. Nevertheless, we find that the neutrality index, a measure of the excess of nonsynonymous polymorphism relative to the neutral expectation, is only weakly significantly different between mitochondrial and nuclear loci. This difference is likely the result of the larger proportion of beneficial mutations in X-linked relative to autosomal loci, and we find little to no difference between mitochondrial and autosomal neutrality indices. Reanalysis of published data from Homo sapiens reveals a similar lack of a difference between the two genomes, although previous studies have suggested a strong difference in both species. Thus, despite a smaller Ne, mitochondrial loci of both flies and humans appear to experience similar efficacies of purifying selection as do loci in the recombining nuclear genome. Copyright © 2015 Cooper et al.

Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis.

PubMed

Wagschal, Alexandre; Najafi-Shoushtari, S Hani; Wang, Lifeng; Goedeke, Leigh; Sinha, Sumita; deLemos, Andrew S; Black, Josh C; Ramírez, Cristina M; Li, Yingxia; Tewhey, Ryan; Hatoum, Ida; Shah, Naisha; Lu, Yong; Kristo, Fjoralba; Psychogios, Nikolaos; Vrbanac, Vladimir; Lu, Yi-Chien; Hla, Timothy; de Cabo, Rafael; Tsang, John S; Schadt, Eric; Sabeti, Pardis C; Kathiresan, Sekar; Cohen, David E; Whetstine, Johnathan; Chung, Raymond T; Fernández-Hernando, Carlos; Kaplan, Lee M; Bernards, Andre; Gerszten, Robert E; Näär, Anders M

2015-11-01

Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, miR-148a, miR-130b, and miR-301b) control the expression of key proteins involved in cholesterol-lipoprotein trafficking, such as the low-density lipoprotein (LDL) receptor (LDLR) and the ATP-binding cassette A1 (ABCA1) cholesterol transporter. Consistent with human liver expression data and genetic links to abnormal blood lipid levels, overexpression and antisense targeting of miR-128-1 or miR-148a in high-fat diet-fed C57BL/6J and Apoe-null mice resulted in altered hepatic expression of proteins involved in lipid trafficking and metabolism, and in modulated levels of circulating lipoprotein-cholesterol and triglycerides. Taken together, these findings support the notion that altered expression of miRNAs may contribute to abnormal blood lipid levels, predisposing individuals to human cardiometabolic disorders.

[The value of 5-HTT gene polymorphism for the assessment and prediction of male adolescence violence].

PubMed

Yu, Yue; Liu, Xiang; Yang, Zhen-xing; Qiu, Chang-jian; Ma, Xiao-hong

2012-08-01

To establish an adolescent violence crime prediction model, and to assess the value of serotonin transporter (5-HTT) gene polymorphism for the assessment and prediction of violent crime. Investigative tools were used to analyze the difference in personality dimensions, social support, coping styles, aggressiveness, impulsivity, and family condition scale between 223 adolescents with violence behavior and 148 adolescents without violence behavior. The distribution of 5-HTT gene polymorphisms (5-HTTLPR and 5-HTTVNTR) was compared between the two groups. The role of 5-HTT gene polymorphism on adolescent personality, impulsion and aggression scale also was also analyzed. Stepwise logistic regression was used to establish a predictive model for adolescent violent crime. Significant difference was found between the violence group and the control group on multiple dimensions of psychology and environment scales. However, no statistical difference was found with regard to the 5-HTT genotypes and alleles between adolescents with violent behaviors and normal controls. The rate of prediction accuracy was not significantly improved when 5-HTT gene polymorphism was taken into the model. The violent crime of adolescents was closely related with social and environmental factors. No association was found between 5-HTT polymorphisms and adolescent violence criminal behavior.

Unsupportive social interactions and affective states: examining associations of two oxytocin-related polymorphisms.

PubMed

McInnis, Opal A; McQuaid, Robyn J; Matheson, Kimberly; Anisman, Hymie

2017-01-01

Two single-nucleotide polymorphisms (SNPs) on oxytocin-related genes, specifically the oxytocin receptor (OXTR) rs53576 and the CD38 rs3796863 variants, have been associated with alterations in prosocial behaviors. A cross-sectional study was conducted among undergraduate students (N = 476) to examine associations between the OXTR and CD38 polymorphisms and unsupportive social interactions and mood states. Results revealed no association between perceived levels of unsupportive social interactions and the OXTR polymorphism. However, A carriers of the CD38 polymorphism, a variant previously associated with elevated oxytocin, reported greater perceived peer unsupportive interactions compared to CC carriers. As expected, perceived unsupportive interactions from peers was associated with greater negative affect, which was moderated by the CD38 polymorphism. Specifically, this relation was stronger among CC carriers of the CD38 polymorphism (a variant thought to be linked to lower oxytocin). When examining whether the OXTR polymorphism moderated the relation between unsupportive social interactions from peers and negative affect there was a trend toward significance, however, this did not withstand multiple testing corrections. These findings are consistent with the perspective that a variant on an oxytocin polymorphism that may be tied to lower oxytocin is related to poor mood outcomes in association with negative social interactions. At the same time, having a genetic constitution presumed to be associated with higher oxytocin was related to increased perceptions of unsupportive social interactions. These seemingly paradoxical findings could be related to previous reports in which variants associated with prosocial behaviors were also tied to relatively more effective coping styles to deal with challenges.

Association of the osteopontin rs1126616 polymorphism and a higher serum osteopontin level with lupus nephritis

PubMed Central

SALIMI, SAEEDEH; NOORA, MEHRANGIZ; NABIZADEH, SIMA; REZAEI, MAHNAZ; SHAHRAKI, HOSSAIN; MILAD, MOHAMMADOO-KHORASSANI; NAGHAVI, ANOOSH; FARAJIAN-MASHHADI, FARZANEH; ZAKERI, ZAHRA; SANDOUGHI, MAHNAZ

2016-01-01

Osteopontin (OPN) is a chemokine-like glycoprotein that has a prominent role in regulating inflammation and immunity. OPN polymorphisms and elevated OPN levels are associated with systemic lupus erythematosus (SLE) in several populations. The aim of present study was to evaluate the association between the OPN rs1126616 polymorphism and OPN level with SLE susceptibility. A total of 163 SLE patients and 180 age-, gender- and ethnically matched controls were genotyped for the rs1126616 polymorphism by the polymerase chain reaction-restriction fragment length polymorphism method. Serum OPN levels were assayed by the enzyme-linked immunosorbent assay. There was no association between the OPN rs1126616 C/T polymorphism and SLE. The frequency of the OPN rs1126616 CT genotype was significantly higher in SLE patients with nephritis compared to SLE patients without nephritis and controls. Additionally, the frequency of TT genotypes was higher in SLE patients with nephritis compared to controls. The serum OPN levels were significantly higher in SLE patients compared to controls (50.6±22 vs. 35.6±15.8 ng/ml, P<0.001). Increased serum OPN levels were observed in SLE patients with lupus nephritis and joint symptoms. There was no correlation between OPN levels and the OPN rs1126616 polymorphism. The present data suggest that the CT and TT genotypes of the OPN rs1126616 polymorphism could be a risk factor for lupus nephritis. The OPN level is associated with SLE and certain SLE manifestations. However, there was no association between the OPN rs1126616 C/T polymorphism and SLE susceptibility. PMID:26998275

Epistatic interaction between FCRL3 and NFκB1 genes in Spanish patients with rheumatoid arthritis

PubMed Central

Martínez, A; Sánchez, E; Valdivia, A; Orozco, G; López‐Nevot, M A; Pascual‐Salcedo, D; Balsa, A; Fernández‐Gutiérrez, B; de la Concha, E G; García‐Sánchez, A; Koeleman, B P C; Urcelay, E; Martín, J

2006-01-01

Background A Japanese study has described a strong association between rheumatoid arthritis and several polymorphisms located in the Fc receptor‐like 3 (FCRL3) gene, a member of a family of genes related to Fc receptors located on chromosome 1q21–23. Objectives To evaluate the association between rheumatoid arthritis and FCLR3 polymorphisms in a large cohort of Caucasian patients with rheumatoid arthritis and healthy controls of Spanish origin. Owing to the described functional link between the FCRL3 polymorphisms and the transcription factor nuclear factor κB (NFκB), a functional polymorphism located in the NFκB1 gene was included. Methods 734 patients with rheumatoid arthritis from Madrid and Granada, Spain, were included in the study, along with 736 healthy controls. Polymorphisms in the FCRL3 gene were studied by TaqMan technology. The −94ins/delATTG NFκB1 promoter polymorphism was analysed by fragment analysis after polymerase chain reaction with labelled primers. Genotypes were compared using 3×2 contingency tables and χ2 values. Results No overall differences were found in any of the FCRL3 polymorphisms and in the NFκB1 promoter polymorphism when patients were compared with controls. However, when stratified according to NFκB1 genotypes, a susceptibility effect of FCRL3 polymorphisms was observed in patients who were heterozygotes for NFκB1 (pc = 0.003). Conclusions The FCRL3 polymorphisms associated with rheumatoid arthritis in a Japanese population are not associated per se with rheumatoid arthritis in a Spanish population. A genetic interaction was found between NFκB1 and FCRL3 in Spanish patients with rheumatoid arthritis. These findings may provide a general rationale for divergent genetic association results in different populations. PMID:16476711

Polymorphisms of IL-17 and ICAM-1 and their expression in Guillain-Barré syndrome.

PubMed

Kharwar, N K; Prasad, K N; Singh, K; Paliwal, V K; Modi, D R

2017-08-01

Guillain-Barré syndrome (GBS) is an acute inflammatory, autoimmune disorder of peripheral nervous system. Interleukin-17 (IL-17) and intercellular adhesion molecule-1 (ICAM-1) polymorphisms with higher expression levels have already been studied in many inflammatory and autoimmune diseases. However, the possible role of IL-17 and ICAM-1 polymorphisms in GBS remains unknown. Therefore, the current study investigated IL-17 (His161Arg and Glu126Gly) and ICAM-1 (Gly241Arg) polymorphisms. In this study, total 80 GBS patients and 75 normal healthy controls were included. IL-17 (His161Arg and Glu126Gly) and ICAM-1 (Gly241Arg) polymorphisms were performed using polymerase chain reaction -restriction fragment length polymorphism analysis. Further, the expression of ICAM-1 and IL-17 was determined by reverse-transcriptase PCR and enzyme-linked immunosorbent assay. IL-17 (Glu126Gly) mutant and ICAM-1 (Gly241Arg) heterozygous genotypes were strongly associated with increased risk of GBS (p < 0.016; OR = 3.706, 95% CI = 1.28-10.67; p < 0.001; OR = 4.148, 95% CI = 2.119-8.119, respectively). IL-17 and ICAM-1 genes showed significantly higher expression in GBS when compared with healthy controls. IL-17 and ICAM-1 polymorphisms showed significant association with GBS and their enhanced expressions have possible role in GBS development. IL-17 and ICAM-1 polymorphisms could be genetic markers to GBS susceptibility.

The clinical application of single-sperm-based SNP haplotyping for PGD of osteogenesis imperfecta.

PubMed

Chen, Linjun; Diao, Zhenyu; Xu, Zhipeng; Zhou, Jianjun; Yan, Guijun; Sun, Haixiang

2018-05-15

Osteogenesis imperfecta (OI) is a genetically heterogeneous disorder, presenting either autosomal dominant, autosomal recessive or X-linked inheritance patterns. The majority of OI cases are autosomal dominant and are caused by heterozygous mutations in either the COL1A1 or COL1A2 gene. In these dominant disorders, allele dropout (ADO) can lead to misdiagnosis in preimplantation genetic diagnosis (PGD). Polymorphic markers linked to the mutated genes have been used to establish haplotypes for identifying ADO and ensuring the accuracy of PGD. However, the haplotype of male patients cannot be determined without data from affected relatives. Here, we developed a method for single-sperm-based single-nucleotide polymorphism (SNP) haplotyping via next-generation sequencing (NGS) for the PGD of OI. After NGS, 10 informative polymorphic SNP markers located upstream and downstream of the COL1A1 gene and its pathogenic mutation site were linked to individual alleles in a single sperm from an affected male. After haplotyping, a normal blastocyst was transferred to the uterus for a subsequent frozen embryo transfer cycle. The accuracy of PGD was confirmed by amniocentesis at 19 weeks of gestation. A healthy infant weighing 4,250 g was born via vaginal delivery at the 40th week of gestation. Single-sperm-based SNP haplotyping can be applied for PGD of any monogenic disorders or de novo mutations in males in whom the haplotype of paternal mutations cannot be determined due to a lack of affected relatives. ADO: allele dropout; DI: dentinogenesis imperfect; ESHRE: European Society of Human Reproduction and Embryology; FET: frozen embryo transfer; gDNA: genomic DNA; ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilization; MDA: multiple displacement amplification; NGS: next-generation sequencing; OI: osteogenesis imperfect; PBS: phosphate buffer saline; PCR: polymerase chain reaction; PGD: preimplantation genetic diagnosis; SNP: single-nucleotide polymorphism; STR: short tandem repeat; TE: trophectoderm; WGA: whole-genome amplification.

Low genetic variation in the MHC class II DRB gene and MHC-linked microsatellites in endangered island populations of the leopard cat (Prionailurus bengalensis) in Japan.

PubMed

Saka, Toshinori; Nishita, Yoshinori; Masuda, Ryuichi

2018-02-01

Isolated populations of the leopard cat (Prionailurus bengalensis) on Tsushima and Iriomote islands in Japan are classified as subspecies P. b. euptilurus and P. b. iriomotensis, respectively. Because both populations have decreased to roughly 100, an understanding of their genetic diversity is essential for conservation. We genotyped MHC class II DRB exon 2 and MHC-linked microsatellite loci to evaluate the diversity of MHC genes in the Tsushima and Iriomote cat populations. We detected ten and four DRB alleles in these populations, respectively. A phylogenetic analysis showed DRB alleles from both populations to be closely related to those in other felid DRB lineages, indicating trans-species polymorphism. The MHC-linked microsatellites were more polymorphic in the Tsushima than in the Iriomote population. The MHC diversity of both leopard cat populations is much lower than in the domestic cat populations on these islands, probably due to inbreeding associated with founder effects, geographical isolation, or genetic drift. Our results predict low resistance of the two endangered populations to new pathogens introduced to the islands.

Evidence for Hitchhiking of Deleterious Mutations within the Human Genome

PubMed Central

Chun, Sung; Fay, Justin C.

2011-01-01

Deleterious mutations present a significant obstacle to adaptive evolution. Deleterious mutations can inhibit the spread of linked adaptive mutations through a population; conversely, adaptive substitutions can increase the frequency of linked deleterious mutations and even result in their fixation. To assess the impact of adaptive mutations on linked deleterious mutations, we examined the distribution of deleterious and neutral amino acid polymorphism in the human genome. Within genomic regions that show evidence of recent hitchhiking, we find fewer neutral but a similar number of deleterious SNPs compared to other genomic regions. The higher ratio of deleterious to neutral SNPs is consistent with simulated hitchhiking events and implies that positive selection eliminates some deleterious alleles and increases the frequency of others. The distribution of disease-associated alleles is also altered in hitchhiking regions. Disease alleles within hitchhiking regions have been associated with auto-immune disorders, metabolic diseases, cancers, and mental disorders. Our results suggest that positive selection has had a significant impact on deleterious polymorphism and may be partly responsible for the high frequency of certain human disease alleles. PMID:21901107

Relationship between Job Stress and 5-HT2A Receptor Polymorphisms on Self-Reported Sleep Quality in Physicians in Urumqi (Xinjiang, China): A Cross-Sectional Study

PubMed Central

Ge, Hua; Jiang, Yu; Zhang, Chen; Liu, Jiwen

2018-01-01

The serotonin receptor (5-HTR) plays a key role in sleep quality regulation. Job-related stress is an important factor that influences sleep quality. However, few reports on the interaction between 5-HTR2A polymorphisms and job stress, and how they may impact upon sleep quality are available. Therefore this study investigated the effects of job stress, 5-HTR2A polymorphisms, and their interaction on sleep quality, in physicians. Using a two-stage stratified sampling method, 918 participants were initially invited to participate in the study. After screening for study inclusion and exclusion criteria, 504 subjects were eventually included in the study. Job stress and sleep quality were assessed using the Job Stress Survey (JSS) and Pittsburgh Sleep Quality Index (PSQI), respectively. The 5-HTR2A receptor gene polymorphisms T102C and -1438G/A of were determined using polymerase chain reaction-restriction fragment length polymorphism. Job stress was significantly associated with sleep quality. High levels of job stress were linked to a higher risk of poor sleep quality compared to low or moderate levels [odds ratio (OR) = 2.909, 95% confidence interval (CI): 1.697–4.986]. High levels of stress may reduce subjects’ sleep quality, leading to an increase the likelihood of sleep disturbances and subsequent daytime dysfunction. The 5-HTR2A receptor gene polymorphism T102C was not significantly associated with sleep quality in this study, however, the -1438G/A polymorphism was significantly associated with sleep quality. The GG genotype of the -1438G/A polymorphism was linked to poorer sleep quality. When compared with subjects with low job-related stress levels×AG/AA genotype (OR = 2.106, 95% CI: 1.278–3.471), physicians with high job-related stress levels×GG genotype had a higher risk of experiencing poor sleep quality (OR = 13.400, 95% CI: 3.143–57.137). The findings of our study indicate that job stress and 5-HTR2A receptor gene polymorphisms are associated with sleep quality in physicians. Subjects with high job stress level or/and the -1438G/A GG genotype were more likely to report poor sleep quality, and furthermore, their combination effect on sleep quality was higher than their independent effects, so it may be suggested that job-related stress and genes have a cumulative effect on sleep quality; that is, stress can increase the risk of poor sleep quality, but this effect is worse in a group of people with specific gene polymorphisms. PMID:29883419

Relationship between Job Stress and 5-HT2A Receptor Polymorphisms on Self-Reported Sleep Quality in Physicians in Urumqi (Xinjiang, China): A Cross-Sectional Study.

PubMed

Gao, Xiaoyan; Ge, Hua; Jiang, Yu; Lian, Yulong; Zhang, Chen; Liu, Jiwen

2018-05-21

The serotonin receptor (5-HTR) plays a key role in sleep quality regulation. Job-related stress is an important factor that influences sleep quality. However, few reports on the interaction between 5-HTR2A polymorphisms and job stress, and how they may impact upon sleep quality are available. Therefore this study investigated the effects of job stress, 5-HTR2A polymorphisms, and their interaction on sleep quality, in physicians. Using a two-stage stratified sampling method, 918 participants were initially invited to participate in the study. After screening for study inclusion and exclusion criteria, 504 subjects were eventually included in the study. Job stress and sleep quality were assessed using the Job Stress Survey (JSS) and Pittsburgh Sleep Quality Index (PSQI), respectively. The 5-HTR2A receptor gene polymorphisms T102C and -1438G/A of were determined using polymerase chain reaction-restriction fragment length polymorphism. Job stress was significantly associated with sleep quality. High levels of job stress were linked to a higher risk of poor sleep quality compared to low or moderate levels [odds ratio (OR) = 2.909, 95% confidence interval (CI): 1.697⁻4.986]. High levels of stress may reduce subjects’ sleep quality, leading to an increase the likelihood of sleep disturbances and subsequent daytime dysfunction. The 5-HTR2A receptor gene polymorphism T102C was not significantly associated with sleep quality in this study, however, the -1438G/A polymorphism was significantly associated with sleep quality. The GG genotype of the -1438G/A polymorphism was linked to poorer sleep quality. When compared with subjects with low job-related stress levels×AG/AA genotype (OR = 2.106, 95% CI: 1.278⁻3.471), physicians with high job-related stress levels×GG genotype had a higher risk of experiencing poor sleep quality (OR = 13.400, 95% CI: 3.143⁻57.137). The findings of our study indicate that job stress and 5-HTR2A receptor gene polymorphisms are associated with sleep quality in physicians. Subjects with high job stress level or/and the -1438G/A GG genotype were more likely to report poor sleep quality, and furthermore, their combination effect on sleep quality was higher than their independent effects, so it may be suggested that job-related stress and genes have a cumulative effect on sleep quality; that is, stress can increase the risk of poor sleep quality, but this effect is worse in a group of people with specific gene polymorphisms.

Deiodinases, Organic Anion Transporter Polypeptide Polymorphisms, and Thyroid Hormones in Patients with Myocardial Infarction.

PubMed

Brozaitiene, Julija; Skiriute, Daina; Burkauskas, Julius; Podlipskyte, Aurelija; Jankauskiene, Edita; Serretti, Alessandro; Mickuviene, Narseta

2018-04-01

To investigate the association among deiodinases (DIO), organic anion-transporting polypeptide 1C1 (OATP1C1) gene polymorphisms, and thyroid hormones (THs) in patients with acute myocardial infarction (AMI). In summary, 290 patients with AMI were evaluated for sociodemographic and clinical characteristics, coronary artery disease (CAD) risk factors, and comorbidities, as well as circulating thyroid-stimulating hormone and TH (triiodothyronine [T3], thyroxine [T4], free T3, free T4, and reverse T3) levels. Ten single nucleotide polymorphisms for thyroid axis related genes: DIO1 (rs11206244-C/T, rs12095080-A/G, rs2235544-A/C), DIO2 (rs225014-T/C, rs225015-G/A), DIO3 (rs945006-T/G), and OATP1C1 (rs10444412-T/C, rs10770704-C/T, rs1515777-A/G, rs974453-G/A) were genotyped. Marginal associations were observed between the DIO1, DIO2, and OATP1C1 gene polymorphisms and almost all analyzed THs (p's < 0.05). After controlling for potential confounders, the OATP1C1 rs1515777-A/G minor allele homozygous genotype (G/G) was associated with a decrease in circulating free T3 and free T3/free T4. In the AMI cohort, associations between: DIO1 rs12095080 and hypertension; DIO2 rs225015 and diabetes mellitus; and the OATP1C1 rs974453 genotype, and AMI type were established. DIO1 and DIO2 gene polymorphisms are mainly associated with T3, free T4, free T3/free T4, and [natural-log transformed (ln)] reverse T3 levels, while the OATP1C1 minor allele homozygous genotype is associated with free T3 and free T3/free T4 in CAD patients after AMI.

Allelic association of a dopamine transporter gene polymorphism with antisocial behaviour in heroin-dependent patients.

PubMed

Gerra, Gilberto; Garofano, Luciano; Pellegrini, Caterina; Bosari, Silvano; Zaimovic, Amir; Moi, Gabriele; Avanzini, Paola; Talarico, Enrica; Gardini, Federica; Donnini, Claudia

2005-09-01

Polymorphism of a variable number of tandem repeats (VNTR) in the 3' untranslated region of exon 15 of the SLC6A3 gene, coding for the dopamine transporter (DAT), was analysed to test whether length variation contributes to differences in the individual susceptibility to aggressive - criminal behaviour and liability to heroin dependence. The repeat number of the DAT polymorphism was assessed in 125 healthy subjects and 104 heroin-dependent subjects (including 52 addicted individuals with violent behaviour and criminal records). There was no significant difference in the frequencies of genotypes and alleles between heroin-dependent subjects and control subjects. On the contrary, there was a significant difference between offenders and non-offenders, p = 0.004 and p = 0.002, respectively, among heroin-dependent subjects. No association was found between DAT polymorphism and history of suicide. Buss - Durkee Hostility Inventory (BDHI) mean total scores were significantly higher in heroin addicts than in controls (p < 0.001) and in antisocial - violent heroin addicts in comparison with addicted individuals without antisocial behaviour (p < 0.005). The regression analysis of BDHI subscales, performed to provide an estimate of the magnitude of any potential effect on the risk of aggressiveness associated with the variants in DAT VNTR, showed that the presence of the 9 - 9 genotype significantly increases the risk of irritability and direct aggressiveness more than six and 10 times with respect to the 9 - 10 genotype. Our findings suggest that the 9-repeat allele of the DAT polymorphism confers increased susceptibility to antisocial - violent behaviour and aggressiveness, rather than drug dependence per se in heroin-dependent males.

Interaction between Serotonin Transporter and Serotonin Receptor 1 B genes polymorphisms may be associated with antisocial alcoholism

PubMed Central

2012-01-01

Background Several studies have hypothesized that genes regulating the components of the serotonin system, including serotonin transporter (5-HTTLPR) and serotonin 1 B receptor (5-HT1B), may be associated with alcoholism, but their results are contradictory because of alcoholism’s heterogeneity. Therefore, we examined whether the 5-HTTLPR gene and 5-HT1B gene G861C polymorphism are susceptibility factors for a specific subtype of alcoholism, antisocial alcoholism in Han Chinese in Taiwan. Methods We recruited 273 Han Chinese male inmates with antisocial personality disorder (ASPD) [antisocial alcoholism (AS-ALC) group (n = 120) and antisocial non-alcoholism (AS-N-ALC) group (n = 153)] and 191 healthy male controls from the community. Genotyping was done using PCR-RFLP. Results There were no significant differences in the genotypic frequency of the 5-HT1B G861C polymorphism between the 3 groups. Although AS-ALC group members more frequently carried the 5-HTTLPR S/S, S/LG, and LG/LG genotypes than controls, the difference became non-significant after controlling for the covarying effects of age. However, the 5-HTTLPR S/S, S/LG, and LG/LG genotypes may have interacted with the 5-HT1B G861C C/C polymorphism and increased the risk of becoming antisocial alcoholism. Conclusion Our study suggests that neither the 5-HTTLPR gene nor the 5-HT1B G861C polymorphism alone is a risk factor for antisocial alcoholism in Taiwan’s Han Chinese population, but that the interaction between both genes may increase susceptibility to antisocial alcoholism. PMID:22550993

Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy.

PubMed

Liu, Chia-Chen; Liu, Chia-Chan; Kanekiyo, Takahisa; Xu, Huaxi; Bu, Guojun

2013-02-01

Apolipoprotein E (Apo-E) is a major cholesterol carrier that supports lipid transport and injury repair in the brain. APOE polymorphic alleles are the main genetic determinants of Alzheimer disease (AD) risk: individuals carrying the ε4 allele are at increased risk of AD compared with those carrying the more common ε3 allele, whereas the ε2 allele decreases risk. Presence of the APOE ε4 allele is also associated with increased risk of cerebral amyloid angiopathy and age-related cognitive decline during normal ageing. Apo-E-lipoproteins bind to several cell-surface receptors to deliver lipids, and also to hydrophobic amyloid-β (Aβ) peptide, which is thought to initiate toxic events that lead to synaptic dysfunction and neurodegeneration in AD. Apo-E isoforms differentially regulate Aβ aggregation and clearance in the brain, and have distinct functions in regulating brain lipid transport, glucose metabolism, neuronal signalling, neuroinflammation, and mitochondrial function. In this Review, we describe current knowledge on Apo-E in the CNS, with a particular emphasis on the clinical and pathological features associated with carriers of different Apo-E isoforms. We also discuss Aβ-dependent and Aβ-independent mechanisms that link Apo-E4 status with AD risk, and consider how to design effective strategies for AD therapy by targeting Apo-E.

Apolipoprotein E and Alzheimer disease: risk, mechanisms, and therapy

PubMed Central

Liu, Chia-Chen; Kanekiyo, Takahisa; Xu, Huaxi; Bu, Guojun

2013-01-01

Apolipoprotein E (ApoE) is a major cholesterol carrier that supports lipid transport and injury repair in the brain. APOE polymorphic alleles are the main genetic determinants of Alzheimer disease (AD) risk: individuals carrying the ε4 allele are at increased risk of AD compared with those carrying the more common ε3 allele, whereas the ε2 allele decreases risk. Presence of the APOE ε4 allele is also associated with increased risk for cerebral amyloid angiopathy and age-related cognitive decline during normal ageing. ApoE–lipoproteins bind to several cell-surface receptors to deliver lipids and also to hydrophobic amyloid-β (Aβ) peptide, which is thought to initiate toxic events that lead to synaptic dysfunction and neurodegeneration in AD. ApoE isoforms differentially regulate Aβ aggregation and clearance in the brain, and have distinct functions in regulating brain lipid transport, glucose metabolism, neuronal signalling, neuroinflammation, and mitochondrial function. In this Review, we describe current knowledge on ApoE in the CNS, with a particular emphasis on the clinical and pathological features associated with carriers of different ApoE isoforms. We also discuss Aβ-dependent and Aβ-independent mechanisms that link ApoE4 status with AD risk, and consider how to design effective strategies for AD therapy by targeting ApoE. PMID:23296339

49 CFR 238.207 - Link between coupling mechanism and car body.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 49 Transportation 4 2012-10-01 2012-10-01 false Link between coupling mechanism and car body. 238.207 Section 238.207 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL... Requirements for Tier I Passenger Equipment § 238.207 Link between coupling mechanism and car body. All...

49 CFR 238.207 - Link between coupling mechanism and car body.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 49 Transportation 4 2011-10-01 2011-10-01 false Link between coupling mechanism and car body. 238.207 Section 238.207 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL... Requirements for Tier I Passenger Equipment § 238.207 Link between coupling mechanism and car body. All...

49 CFR 238.207 - Link between coupling mechanism and car body.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 49 Transportation 4 2014-10-01 2014-10-01 false Link between coupling mechanism and car body. 238.207 Section 238.207 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL... Requirements for Tier I Passenger Equipment § 238.207 Link between coupling mechanism and car body. All...

49 CFR 238.207 - Link between coupling mechanism and car body.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 49 Transportation 4 2013-10-01 2013-10-01 false Link between coupling mechanism and car body. 238.207 Section 238.207 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL... Requirements for Tier I Passenger Equipment § 238.207 Link between coupling mechanism and car body. All...

49 CFR 238.207 - Link between coupling mechanism and car body.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 4 2010-10-01 2010-10-01 false Link between coupling mechanism and car body. 238.207 Section 238.207 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL... Requirements for Tier I Passenger Equipment § 238.207 Link between coupling mechanism and car body. All...

Extrapolating from local ecological processes to genus-wide patterns in colour polymorphism in South African Protea.

PubMed

Carlson, Jane E; Holsinger, Kent E

2015-05-07

Polymorphic traits are central to many fundamental discoveries in evolution, yet why they are found in some species and not others remains poorly understood. We use the African genus Protea-within which more than 40% of species have co-occurring pink and white floral colour morphs-to ask whether convergent evolution and ecological similarity could explain the genus-wide pattern of polymorphism. First, we identified environmental correlates of pink morph frequency across 28 populations of four species. Second, we determined whether the same correlates could predict species-level polymorphism and monomorphism across 31 species. We found that pink morph frequency increased with elevation in Protea repens and three section Exsertae species, increased eastward in P. repens, and increased with seed predation intensity in section Exsertae. For cross-species comparisons, populations of monomorphic pink species occurred at higher elevations than populations of monomorphic white species, and 18 polymorphic species spanned broader elevational gradients than 13 monomorphic species. These results suggest that divergent selection along elevational clines has repeatedly favoured polymorphism, and that more uniform selection in altitudinally restricted species may promote colour monomorphism. Our findings are, to our knowledge, the first to link selection acting within species to the presence and absence of colour polymorphism at broader phylogenetic scales. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

Inherited Variation in Cytokine, Acute Phase Response, and Calcium Metabolism Genes Affects Susceptibility to Infective Endocarditis

PubMed Central

Rutkovskaya, Natalia V.; Kondyukova, Natalia V.; Odarenko, Yuri N.; Kazachek, Yana V.; Tsepokina, Anna V.; Barbarash, Leonid S.

2017-01-01

Infective endocarditis (IE) is a septic inflammation of the endocardium. Recognition of microbial patterns, cytokine and acute phase responses, hemostasis features, and alterations in plasma lipid and calcium profile all have been reported to affect pathogenesis and clinical course of IE. Having recruited 123 patients with IE and 300 age-, sex-, and ethnicity-matched healthy blood donors, we profiled their genomic DNA for 35 functionally significant polymorphisms within the 22 selected genes involved in the abovementioned pathways, with the further genetic association analysis. We found that the G/A genotype of the rs1143634 polymorphism within the IL1B gene, the G/T genotype of the rs3212227 polymorphism within the IL12B gene, the A/G genotype of the rs1130864 polymorphism within the CRP gene, and the G allele of the rs1801197 polymorphism within the CALCR gene were associated with a decreased risk of IE whereas the T/T genotype of the rs1205 polymorphism within the CRP gene was associated with a higher risk of IE. Furthermore, heterozygous genotypes of the rs1143634 and rs3212227 polymorphisms were associated with the higher plasma levels of IL-1β and IL-12, respectively. Our results indicate that inherited variation in the cytokine, acute phase response, and calcium metabolism pathways may be linked to IE. PMID:28659664

The methylenetetrahydrofolate reductase (MTHFR) 677 C>T polymorphism increases the risk of developing chronic myeloid leukemia-a case-control study.

PubMed

Bănescu, Claudia; Iancu, Mihaela; Trifa, Adrian P; Macarie, Ioan; Dima, Delia; Dobreanu, Minodora

2015-04-01

The methylenetetrahydrofolate reductase (MTHFR) 677 C>T and 1298 A>C polymorphisms are associated with variations in folate levels, a phenomenon linked to the development of various malignancies. The aim of this study was to investigate the influence of the 677 C>T and 1298 A>C polymorphisms in the MTHFR gene on the risk of developing chronic myeloid leukemia (CML). Our study included 151 patients with CML and 305 controls. The MTHFR 677 C>T and 1298 A>C polymorphisms were investigated by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and allele-specific PCR techniques. The CT and TT genotypes of the MTHFR 677 C>T polymorphism were associated with an increased risk of developing CML (odds ratio (OR) = 1.556, 95% confidence interval (CI) = 1.017-2.381, p value = 0.041, and OR = 1.897, 95% CI = 1.046-3.44, p value = 0.035, respectively). No association was observed between the prognostic factors (blasts, basophils, additional chromosomal abnormalities, EUTOS score, Sokal and Hasford risk groups) and the MTHFR 677 C>T and 1298 A>C variant genotypes in CML patients. Our study shows that the MTHFR 677 C>T polymorphism is significantly associated with the risk of CML in Romanian patients.

Testing bidirectional effects between cannabis use and depressive symptoms: moderation by the serotonin transporter gene.

PubMed

Otten, Roy; Engels, Rutger C M E

2013-09-01

Evidence for the assumption that cannabis use is associated with depression and depressive symptoms is inconsistent and mostly weak. It is likely that the mixed results are due to the fact that prior studies ignored the moderating effects of an individual's genetic vulnerability. The present study takes a first step in scrutinizing the relationship between cannabis use and depressive symptoms by taking a developmental molecular-genetic perspective. Specifically, we concentrated on changes in cannabis use and depressive symptoms over time in a simultaneous manner and differences herein for individuals with and without the short allele of the 5-hydroxytryptamine (serotonin) transporter gene-linked polymorphic region (5-HTTLPR) genotype. Data were from 310 adolescents over a period of 4 years. We used a parallel-process growth model, which allows co-development of cannabis use and depressive symptoms throughout adolescence, and the possible role of the 5-HTTLPR genotype in this process. We used data from the younger siblings of these adolescents in an attempt to replicate potential findings. The parallel-process growth model shows that cannabis use increases the risk for an increase in depressive symptoms over time but only in the presence of the short allele of the 5-HTTLPR genotype. This effect remained significant after controlling for covariates. We did not find conclusive support for the idea that depressive symptoms affect cannabis use. These findings were replicated in the sample of the younger siblings. The findings of the present study show first evidence that the links between cannabis use and depressive symptoms are conditional on the individual's genetic makeup. © 2011 The Authors, Addiction Biology © 2011 Society for the Study of Addiction.

Latent Class Analysis of Antisocial Behavior: Interaction of Serotonin Transporter Genotype and Maltreatment

ERIC Educational Resources Information Center

Li, James J.; Lee, Steve S.

2010-01-01

To improve understanding about genetic and environmental influences on antisocial behavior (ASB), we tested the association of the 44-base pair polymorphism of the serotonin transporter gene (5-HTTLPR) and maltreatment using latent class analysis in 2,488 boys and girls from Wave 1 of the National Longitudinal Study of Adolescent Health. In boys,…

Relational Security Moderates the Effect of Serotonin Transporter Gene Polymorphism (5-HTTLPR) on Stress Generation and Depression among Adolescents

ERIC Educational Resources Information Center

Starr, Lisa R.; Hammen, Constance; Brennan, Patricia A.; Najman, Jake M.

2013-01-01

Previous research demonstrates that carriers of the short allele of the serotonin transporter gene (5-HTTLPR) show both greater susceptibility to depression in response to stressful life events and higher rates of generation of stressful events in response to depression. The current study examines relational security (i.e., self-reported beliefs…

Therapygenetics: anterior cingulate cortex-amygdala coupling is associated with 5-HTTLPR and treatment response in panic disorder with agoraphobia.

PubMed

Lueken, Ulrike; Straube, Benjamin; Wittchen, Hans-Ulrich; Konrad, Carsten; Ströhle, Andreas; Wittmann, André; Pfleiderer, Bettina; Arolt, Volker; Kircher, Tilo; Deckert, Jürgen; Reif, Andreas

2015-01-01

Variation in the 5'-flanking promoter region of the serotonin transporter gene SLC6A4, the 5-HTT-linked polymorphic region (5-HTTLPR) has been inconclusively associated with response to cognitive-behavioural therapy (CBT). As genomic functions are stronger related to neural than to behavioural markers, we investigated the association of treatment response, 5-HTTLPR and functional brain connectivity in patients with panic disorder with agoraphobia (PD/AG). Within the national research network PANIC-NET 231 PD/AG patients who provided genetic information underwent a manualized exposure-based CBT. A subset of 41 patients participated in a functional magnetic resonance imaging (fMRI) add-on study prior to treatment applying a differential fear conditioning task. Neither the treatment nor the reduced fMRI sample showed a direct effect of 5-HTTLPR on treatment response as defined by a reduction in the Hamilton Anxiety Scale score ≥50 % from baseline to post assessment. On a neural level, inhibitory anterior cingulate cortex (ACC)-amygdala coupling during fear conditioning that had previously been shown to characterize treatment response in this sample was driven by responders with the L/L genotype. Building upon conclusive evidence from basic and preclinical findings on the association of the 5-HTTLPR polymorphism with emotion regulation and related brain connectivity patterns, present findings translate these to a clinical sample of PD/AG patients and point towards a potential intermediate connectivity phenotype modulating response to exposure-based CBT.

Association of MAOA, 5-HTT, and NET promoter polymorphisms with gene expression and protein activity in human placentas

PubMed Central

Zhang, Huiping; Smith, Graeme N.; Liu, Xudong

2010-01-01

Monoamine oxidase A (MAOA) and the transporters for serotonin (5-HTT) and norepinephrine (NET) may play important roles in regulating maternal monoamine neurotransmitters transferred across the placenta to the fetus. We investigated whether promoter polymorphisms in MAOA (uVNTR), 5-HTT (5-HTTLPR), and NET (NETpPR AAGG4) could influence gene expression and protein activity in human placentas. Normal term human placentas (n = 73) were collected, and placental MAOA, 5-HTT, and NET mRNA levels and protein activity were determined. The mRNA levels or protein activities were compared between different genotype groups. Placentas hemizygous (male fetus) or homozygous (female fetus) for MAOA uVNTR 4-repeat allele had significantly higher MAOA mRNA levels than those hemizygous or homozygous for the 3-repeat allele (P = 0.001). However, no significant difference in MAOA enzyme activity was found for these two groups of genotypes (P = 0.161). Placentas with the 5-HTTLPR short (S)-allele (S/S+S/L) had significantly lower 5-HTT mRNA levels and serotonin uptake rate than those homozygous for the long (L)-allele (L/L) (mRNA: P < 0.001; serotonin transporting activity: P < 0.001). Placentas homozygous for the NET AAGG4 L4 allele had significantly higher NET mRNA levels, as well as dopamine and norepinephrine uptake rates, than those with the S4/L4 genotype (mRNA: P < 0.001; dopamine transporting activity: P = 0.012; norepinephrine transporting activity: P = 0.011). These findings suggest that the three promoter polymorphisms of MAOA, 5-HTT, and NET influence gene expression levels and protein activity of these genes in human placentas, potentially leading to different fetal levels of maternal monoamine neurotransmitters, which may have an impact on fetal neurodevelopment. PMID:20332182

Association of MAOA, 5-HTT, and NET promoter polymorphisms with gene expression and protein activity in human placentas.

PubMed

Zhang, Huiping; Smith, Graeme N; Liu, Xudong; Holden, Jeanette J A

2010-06-01

Monoamine oxidase A (MAOA) and the transporters for serotonin (5-HTT) and norepinephrine (NET) may play important roles in regulating maternal monoamine neurotransmitters transferred across the placenta to the fetus. We investigated whether promoter polymorphisms in MAOA (uVNTR), 5-HTT (5-HTTLPR), and NET (NETpPR AAGG(4)) could influence gene expression and protein activity in human placentas. Normal term human placentas (n = 73) were collected, and placental MAOA, 5-HTT, and NET mRNA levels and protein activity were determined. The mRNA levels or protein activities were compared between different genotype groups. Placentas hemizygous (male fetus) or homozygous (female fetus) for MAOA uVNTR 4-repeat allele had significantly higher MAOA mRNA levels than those hemizygous or homozygous for the 3-repeat allele (P = 0.001). However, no significant difference in MAOA enzyme activity was found for these two groups of genotypes (P = 0.161). Placentas with the 5-HTTLPR short (S)-allele (S/S+S/L) had significantly lower 5-HTT mRNA levels and serotonin uptake rate than those homozygous for the long (L)-allele (L/L) (mRNA: P < 0.001; serotonin transporting activity: P < 0.001). Placentas homozygous for the NET AAGG(4) L(4) allele had significantly higher NET mRNA levels, as well as dopamine and norepinephrine uptake rates, than those with the S(4)/L(4) genotype (mRNA: P < 0.001; dopamine transporting activity: P = 0.012; norepinephrine transporting activity: P = 0.011). These findings suggest that the three promoter polymorphisms of MAOA, 5-HTT, and NET influence gene expression levels and protein activity of these genes in human placentas, potentially leading to different fetal levels of maternal monoamine neurotransmitters, which may have an impact on fetal neurodevelopment.

Therapygenetics: 5-HTTLPR genotype predicts the response to exposure therapy for agoraphobia.

PubMed

Knuts, Inge; Esquivel, Gabriel; Kenis, Gunter; Overbeek, Thea; Leibold, Nicole; Goossens, Lies; Schruers, Koen

2014-08-01

This study was intended to assess the extent to which the low-expression allele of the serotonin transporter gene promoter predicts better response to exposure-based behavior therapy in patients with panic disorder with agoraphobia (PDA). Ninety-nine patients with PDA underwent a 1-week in vivo exposure-based behavior therapy program and provided saliva samples to extract genomic DNA and classify individuals according to four allelic forms (SA, SG, LA, LG) of the 5-HTT-linked polymorphic region (5-HTTLPR). We determined whether the 5-HTTLPR genotype predicted change in avoidance behavior in PDA following treatment. After controlling for pre-treatment avoidance behavior, the 5-HTTLPR low-expression genotypes showed a more favorable response to exposure therapy two weeks following treatment, compared to the other patients. This study suggests a genetic contribution to treatment outcome following behavior therapy and implicates the serotonergic system in response to exposure-based treatments in PDA. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

Preschoolers' genetic, physiological, and behavioral sensitivity factors moderate links between parenting stress and child internalizing, externalizing, and sleep problems.

PubMed

Davis, Molly; Thomassin, Kristel; Bilms, Joanie; Suveg, Cynthia; Shaffer, Anne; Beach, Steven R H

2017-05-01

This study examined three potential moderators of the relations between maternal parenting stress and preschoolers' adjustment problems: a genetic polymorphism-the short allele of the serotonin transporter (5-HTTLPR, ss/sl allele) gene, a physiological indicator-children's baseline respiratory sinus arrhythmia (RSA), and a behavioral indicator-mothers' reports of children's negative emotionality. A total of 108 mothers (M age  = 30.68 years, SD age  = 6.06) reported on their parenting stress as well as their preschoolers' (M age  = 3.50 years, SD age  = 0.51, 61% boys) negative emotionality and internalizing, externalizing, and sleep problems. Results indicated that the genetic sensitivity variable functioned according to a differential susceptibility model; however, the results involving physiological and behavioral sensitivity factors were most consistent with a diathesis-stress framework. Implications for prevention and intervention efforts to counter the effects of parenting stress are discussed. © 2017 Wiley Periodicals, Inc.

Genetic and caregiving-based contributions to infant attachment: unique associations with distress reactivity and attachment security.

PubMed

Raby, K Lee; Cicchetti, Dante; Carlson, Elizabeth A; Cutuli, J J; Englund, Michelle M; Egeland, Byron

2012-09-01

In the longitudinal study reported here, we examined genetic and caregiving-based contributions to individual differences in infant attachment classifications. For 154 mother-infant pairs, we rated mothers' responsiveness to their 6-month-old infants during naturalistic interactions and classified infants' attachment organization at 12 and 18 months using the Strange Situation procedure. These infants were later genotyped with respect to the serotonin-transporter-linked polymorphic region (5-HTTLPR). Maternal responsiveness uniquely predicted infants' attachment security. Infants' 5-HTTLPR variation uniquely predicted their subtype of attachment security at 12 months and their subtype of attachment insecurity at 12 and 18 months. The short allele for 5-HTTLPR was associated with attachment classifications characterized by higher emotional distress. These findings suggest that 5-HTTLPR variation contributes to infants' emotional reactivity and that the degree to which caregivers are responsive influences how effectively infants use their caregivers for emotion regulation. Theoretical implications for the study of genetic and caregiving influences are discussed.

Disentangling the effects of serotonin on risk perception: S-carriers of 5-HTTLPR are primarily concerned with the magnitude of the outcomes, not the uncertainty.

PubMed

Millroth, Philip; Juslin, Peter; Eriksson, Elias; Agren, Thomas

2017-10-01

Serotonin signaling is vital for reward processing, and hence, also for decision-making. The serotonin transporter gene linked polymorphic region (5-HTTLPR) has been connected to decision making, suggesting that short-allele carriers (s) are more risk averse than long-allele homozygotes (ll). However, previous research has not identified if this occurs because s-carriers (i) are more sensitive to the uncertainty of the outcomes or (ii) are more sensitive to the magnitude of the outcomes. This issue was disentangled using a willingness-to-pay task, where the participants evaluated prospects involving certain gains, uncertain gains, and ambiguous gains. The results clearly favored the hypothesis that s-carriers react more to the magnitude of the outcomes. Self-reported measures of everyday risk-taking behavior also favored this hypothesis. We discuss how these results are in line with recent research on the serotonergic impact on reward processing. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Negative self-referential processing is associated with genetic variation in the serotonin transporter-linked polymorphic region (5-HTTLPR): Evidence from two independent studies.

PubMed

Dainer-Best, Justin; Disner, Seth G; McGeary, John E; Hamilton, Bethany J; Beevers, Christopher G

2018-01-01

The current research examined whether carriers of the short 5-HTTLPR allele (in SLC6A4), who have been shown to selectively attend to negative information, exhibit a bias towards negative self-referent processing. The self-referent encoding task (SRET) was used to measure self-referential processing of positive and negative adjectives. Ratcliff's diffusion model isolated and extracted decision-making components from SRET responses and reaction times. Across the initial (N = 183) and replication (N = 137) studies, results indicated that short 5-HTTLPR allele carriers more easily categorized negative adjectives as self-referential (i.e., higher drift rate). Further, drift rate was associated with recall of negative self-referential stimuli. Findings across both studies provide further evidence that genetic variation may contribute to the etiology of negatively biased processing of self-referent information. Large scale studies examining the genetic contributions to negative self-referent processing may be warranted.

Genetic polymorphisms of enzyme proteins and transporters related to methotrexate response and pharmacokinetics in a Japanese population.

PubMed

Hashiguchi, Masayuki; Shimizu, Mikiko; Hakamata, Jun; Tsuru, Tomomi; Tanaka, Takanori; Suzaki, Midori; Miyawaki, Kumika; Chiyoda, Takeshi; Takeuchi, Osamu; Hiratsuka, Jiro; Irie, Shin; Maruyama, Junya; Mochizuki, Mayumi

2016-01-01

Methotrexate (MTX) is currently the anchor drug widely used worldwide in the treatment of rheumatoid arthritis (RA). However, the therapeutic response to MTX has been shown to vary widely among individuals, genders and ethnic groups. The reason for this has been not clarified but it is considered to be partially due to several mechanisms in the cellular pathway of MTX including single-nucleotide polymorphisms (SNPs). The purpose of this study was to investigate the allelic frequencies in different ethnic and/or population groups in the 10 polymorphisms of enzyme proteins and transporters related to the MTX response and pharmacokinetics including MTHFR, TYMS, RFC1, FPGS, GGH, ABCB1, ABCC2 and ABCG2 in unrelated healthy Japanese adults and patients with RA. Ten polymorphisms, methylenetetrahydrofolate reductase (MTHFR) 1298, thymidylate synthase (TYMS) 3'-UTR, reduced folate carrier 1 (RFC1) 80 and-43, folypolyglutamyl synthase (FPGS) 1994, γ-glutamyl hydrolase (GGH) 452 and-401, the ABC transporters (ABCB1 3435, ABCC2 IVS23 + 56, ABCG2 914) of enzyme proteins and transporters related to MTX response and pharmacokinetics in 299 unrelated healthy Japanese adults and 159 Japanese patients with RA were investigated to clarify their contributions to individual variations in response and safety to MTX and establish personalized MTX therapy. SNPs were evaluated using real-time polymerase chain reaction (PCR). Comparison of allelic frequencies in our study with other ethnic/population groups of healthy adults and RA patients showed significant differences in 10 polymorphisms among healthy adults and 7 among RA patients. Allelic frequencies of MTHFR 1298 C, FPGS 1994A and ABCB1 3435 T were lower in Japanese than in Caucasian populations and those of ABCC2 IVS23 + 56 C and ABCG2 914A were higher in Japanese than in Caucasian/European populations in both healthy adults and RA patients. Allelic frequencies of MTHFR 1298 C, GGH-401 T, ABCB1 3435 T, and ABCG2 914A were higher in healthy Japanese adults than in an African population, and those of RFC1 80A, RFC1-43C and ABCC2 IVS23 + 56 C in healthy Japanese adults were lower than in Africans. However, no significant differences were seen in the distribution of allelic frequencies between healthy Japanese adults and RA patients. The variations in allelic frequencies in different ethnic and/or population groups in healthy adults and RA patients may contribute to individual variations in MTX response and toxicity.

Characterization of microsatellite loci from two-spotted octopus Octopus bimaculatus Verrill 1883 from pyrosequencing reads

USGS Publications Warehouse

Domínguez-Contreras, J. F.; Munguía-Vega, A.; Ceballos-Vázquez, B. P.; Arellano-Martínez, M.; Culver, Melanie

2014-01-01

We characterized 22 novel microsatellite loci in the two-spotted octopus Octopus bimaculatus using 454 pyrosequencing reads. All loci were polymorphic and will be used in studies of marine connectivity aimed at increasing sustainability of the resource. The mean number alleles per locus was 13.09 (range 7–19) and observed heterozygosities ranged from 0.50 to 1.00. Four loci pairs were linked and three deviated from Hardy–Weinberg equilibrium. Eighteen and 12 loci were polymorphic in Octopus bimaculoides and Octopus hubbsorum, respectively.

Investigation of polymorphic transitions of piracetam induced during wet granulation.

PubMed

Potter, Catherine B; Kollamaram, Gayathri; Zeglinski, Jacek; Whitaker, Darren A; Croker, Denise M; Walker, Gavin M

2017-10-01

Piracetam was investigated as a model API which is known to exhibit a number of different polymorphic forms. It is freely soluble in water so the possibility exists for polymorphic transformations to occur during wet granulation. Analysis of the polymorphic form present during lab-scale wet granulation, using water as a granulation liquid, was studied with powder X-ray diffraction and Raman spectroscopy as off-line and inline analysis tools respectively. Different excipients with a range of hydrophilicities, aqueous solubilities and molecular weights were investigated to examine their influence on these solution-mediated polymorphic transitions and experimental results were rationalised using molecular modelling. Our results indicated that as an increasing amount of water was added to the as-received piracetam FIII, a greater amount of the API dissolved which recrystallised upon drying to the metastable FII(6.403) via a monohydrate intermediary. Molecular level analysis revealed that the observed preferential transformation of monohydrate to FII is linked with a greater structural similarity between the monohydrate and FII polymorph in comparison to FIII. The application of Raman spectroscopy as a process analytical technology (PAT) tool to monitor the granulation process for the production of the monohydrate intermediate as a precursor to the undesirable metastable form was demonstrated. Copyright © 2017 Elsevier B.V. All rights reserved.

Variation in the serotonin transporter gene modulates selective attention to threat.

PubMed

Osinsky, Roman; Reuter, Martin; Küpper, Yvonne; Schmitz, Anja; Kozyra, Eva; Alexander, Nina; Hennig, Jürgen

2008-08-01

The 5-HTTLPR is an insertion/deletion polymorphism in the promoter region of the serotonin transporter gene. Prior research has revealed associations between the short-allele variant of this polymorphism, enhanced self-reported negative emotionality, and hypersensitivity of fear relevant neural circuits. In a sample of 50 healthy women we examined the role of 5-HTTLPR for cognitive-affective processing of phylogenetical fear-relevant stimuli (spiders) in a dot probe task. In contrast to homozygote long-allele carriers (ll), participants carrying at least 1 short allele (ss and sl) selectively shifted attention toward pictures of spiders, when these were presented for a duration of 2,000 ms. These results argue for an involvement of 5-HTTLPR in cognitive processing of threatening stimuli and thus, underpin its general role for individual differences in negative affect.

Effects of dopamine D2 receptor (DRD2) and transporter (SLC6A3) polymorphisms on smoking cue-induced cigarette craving among African-American smokers.

PubMed

Erblich, J; Lerman, C; Self, D W; Diaz, G A; Bovbjerg, D H

2005-04-01

Cue-induced craving for addictive substances has long been known to contribute to the problem of persistent addiction in humans. Research in animals over the past decade has solidly established the central role of dopamine in cue-induced craving for addictive substances, including nicotine. Analogous studies in humans, however, are lacking, especially among African-American smokers, who have lower quit rates than Caucasian smokers. Based on the animal literature, the study's objective was to test the hypothesis that smokers carrying specific variants in dopamine-related genes previously associated with risk for addictive behaviors would exhibit heightened levels of cigarette craving following laboratory exposure to cues. To this end, cigarette craving was induced in healthy African-American smokers (n=88) through laboratory exposure to smoking cues. Smokers carrying either the DRD2 (D2 dopamine receptor gene) TaqI A1 RFLP or the SLC6A3 (dopamine transporter gene) 9-repeat VNTR polymorphisms had stronger cue-induced cravings than noncarriers (Ps <0.05 and 0.01, respectively). Consistent with the separate biological pathways involved (receptor, transporter), carriers of both polymorphisms had markedly higher craving responses compared to those with neither (P<0.0006), reflecting additive effects. Findings provide support for the role of dopamine in cue-induced craving in humans, and suggest a possible genetic risk factor for persistent smoking behavior in African-American smokers.

Attachment and Temperament Revisited: Infant Distress, Attachment Disorganization, and the Serotonin Transporter Polymorphism.

PubMed

Brumariu, Laura E; Bureau, Jean-François; Nemoda, Zsofia; Sasvari-Szekely, Maria; Lyons-Ruth, Karlen

This study's aim was to evaluate whether infant disorganized attachment and infant proneness to distress exhibited differential relations to infant genetic factors as indexed by the serotonin transporter polymorphism. The role of the short allele of the serotonin transporter polymorphism (5-HTTLPR) in enhancing sensitivity to fearful and negative affect has been well-established (Canli & Lesch, 2007). In the current study, we used this known property of the short allele to provide a test of an important postulate of attachment theory, namely that infant attachment security or disorganization is not a function of the infant's proneness to distress. Participants were 39 parents and infants assessed between 12 and 18 months in the Strange Situation procedure. Genotype categories for the 5-HTTLPR (and rs25531) were created by both the original and the reclassified grouping system; infant proneness to distress was assessed directly in the Strange Situation Procedure. We also assessed maternal behavior at 18 months to evaluate whether any observed genetic effect indicated a passive effect through the mother. Consistent with previous findings, the 5-HTTLPR short allele was significantly related to the infant's wariness and distress, but was not related to attachment security or attachment disorganization. In addition, maternal disrupted interaction with the infant was not related to infant genotype or infant distress. Results support the concept that infant proneness to distress is associated with serotonergic factors while infant attachment security or disorganization is not a function of either 5-HTTLPR or behaviorally rated proneness to distress.

The Fusarium Graminearum Genome Reveals a Link Between Localized Polymorphism and Pathogen Specialization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cuomo, Christina A.; Guldener, Ulrich; Xu, Jin Rong

2007-09-07

We sequenced and annotated the genome of the filamentous fungus Fusarium graminearum, a major pathogen of cultivated cereals. Very few repetitive sequences were detected, and the process of repeat-induced point mutation, in which duplicated sequences are subject to extensive mutation, may partially account for the reduced repeat content and apparent low number of paralogous (ancestrally duplicated) genes. A second strain of F. graminearum contained more than 10,000 single-nucleotide polymorphisms, which were frequently located near telomeres and within other discrete chromosomal segments. Many highly polymorphic regions contained sets of genes implicated in plant-fungus interactions and were unusually divergent, with higher ratesmore » of recombination. These regions of genome innovation may result from selection due to interactions of F. graminearum with its plant hosts.« less

Serotonin transporter gene-linked polymorphic region (5-HTTLPR) influences decision making under ambiguity and risk in a large Chinese sample.

PubMed

He, Qinghua; Xue, Gui; Chen, Chuansheng; Lu, Zhonglin; Dong, Qi; Lei, Xuemei; Ding, Ni; Li, Jin; Li, He; Chen, Chunhui; Li, Jun; Moyzis, Robert K; Bechara, Antoine

2010-11-01

Risky decision making is a complex process that involves weighing the probabilities of alternative options that can be desirable, undesirable, or neutral. Individuals vary greatly in how they make decisions either under ambiguity and/or under risk. Such individual differences may have genetic bases. Based on previous studies on the genetic basis of decision making, two decision making tasks [i.e., the Iowa Gambling Task (IGT) and Loss Aversion Task (LAT)] were used to test the effect of 5-HTTLPR polymorphism on decision making under ambiguity and under risk in a large Han Chinese sample (572 college students, 312 females). Basic intelligence and memory tests were also included to control for the influence of basic cognitive abilities on decision making. We found that 5-HTTLPR polymorphism significantly influenced performance in both IGT and LAT. After controlling for intelligence and memory abilities, subjects homozygous for s allele had lower IGT scores than l carriers in the first 40 trials of the IGT task. They also exhibited higher loss aversion than l carriers in the LAT task. Moreover, the effects of 5-HTTLPR were stronger for males than for females. These results extend the literature on the important role of emotion in decision making under ambiguity and risk, and shed additional lights on how decision making is influenced by culture as well as sex differences. Combining our results with existing literature, we propose that these effects might be mediated by a neural circuitry that comprises the amygdala, ventromedial prefrontal cortex, and insular cortex. Understanding the genetic factors affecting decision making in healthy subjects may allow us to better identify at-risk individuals, and better target the development of new potential treatments for specific disorders such as schizophrenia, addiction, and depression. Copyright © 2010 Elsevier Ltd. All rights reserved.

Single-fiber myosin heavy chain polymorphism during postnatal development: modulation by hypothyroidism

NASA Technical Reports Server (NTRS)

di Maso, N. A.; Caiozzo, V. J.; Baldwin, K. M.

2000-01-01

The primary objective of this study was to follow the developmental time course of myosin heavy chain (MHC) isoform transitions in single fibers of the rodent plantaris muscle. Hypothyroidism was used in conjunction with single-fiber analyses to better describe a possible linkage between the neonatal and fast type IIB MHC isoforms during development. In contrast to the general concept that developmental MHC isoform transitions give rise to muscle fibers that express only a single MHC isoform, the single-fiber analyses revealed a very high degree of MHC polymorphism throughout postnatal development. In the adult state, MHC polymorphism was so pervasive that the rodent plantaris muscles contained approximately 12-15 different pools of fibers (i.e., fiber types). The degree of polymorphism observed at the single-fiber level made it difficult to determine specific developmental schemes analogous to those observed previously for the rodent soleus muscle. However, hypothyroidism was useful in that it confirmed a possible link between the developmental regulation of the neonatal and fast type IIB MHC isoforms.

Effect of ancient population structure on the degree of polymorphism shared between modern human populations and ancient hominins.

PubMed

Eriksson, Anders; Manica, Andrea

2012-08-28

Recent comparisons between anatomically modern humans and ancient genomes of other hominins have raised the tantalizing, and hotly debated, possibility of hybridization. Although several tests of hybridization have been devised, they all rely on the degree to which different modern populations share genetic polymorphisms with the ancient genomes of other hominins. However, spatial population structure is expected to generate genetic patterns similar to those that might be attributed to hybridization. To investigate this problem, we take Neanderthals as a case study, and build a spatially explicit model of the shared history of anatomically modern humans and this hominin. We show that the excess polymorphism shared between Eurasians and Neanderthals is compatible with scenarios in which no hybridization occurred, and is strongly linked to the strength of population structure in ancient populations. Thus, we recommend caution in inferring admixture from geographic patterns of shared polymorphisms, and argue that future attempts to investigate ancient hybridization between humans and other hominins should explicitly account for population structure.

The CAG polymorphism in androgen receptor (AR) gene impacts the moral permissibility of harmful behavior in females.

PubMed

Gong, Pingyuan; Fang, Pengpeng; Yang, Xing; Ru, Wenzhao; Wang, Bei; Gao, Xiaocai; Liu, Jinting

2017-06-01

The moral permissibility of harm is strikingly varied among individuals. In light of the connection between testosterone levels and utilitarian moral judgment, this study examined to what extent a CAG polymorphism in the androgen receptor gene, a genetic polymorphism with the ability to regulate testosterone function, contributes to individual differences in moral judgment. Four hundred and thirty-nine Chinese Han participants completed permissibility ratings of harm in moral dilemmas and moral transgression scenarios. Results showed a significant association between the CAG polymorphism and moral permissibility of harm in females. Females with more copies of the S allele, which is associated with higher availability of testosterone, were more likely to judge harmful utilitarian acts and unintentionally harmful acts as permissible, while these effects were absent in males. The findings provide the first evidence for a link between the androgen receptor gene and moral judgment and highlight the role of androgens in moral foundations. Copyright © 2017 Elsevier Ltd. All rights reserved.

Polymorphism in alkali metal uranyl nitrates: Synthesis and crystal structure of gamma-K(UO2)(NO3)3

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jouffret, Laurent J.; Krivovichev, Sergey V.; Burns, Peter C.

2011-07-20

Single crystals of γ-K(UO₂)(NO₃)₃ were prepared from aqueous solutions by evaporation. The crystal structure [orthorhombic, Pbca (61), a = 9.2559(3) Å, b = 12.1753(3) Å, c = 15.8076(5) Å, V = 1781.41(9) ų, Z = 8] was determined by direct methods and refined to R₁ = 0.0267 on the basis of 3657 unique observed reflections. The structure is composed of isolated anionic uranyl trinitrate units, [(UO₂)(NO₃)₃] –, that are linked through eleven-coordinated K + cations. Both known polymorphs of K(UO₂)(NO₃)₃ (α- and γ-phases) can be considered as based upon sheets of isolated complex [(UO₂)(NO₃)₃] – ions separated by K +more » cations. The existence of polymorphism in the two K[UO₂(NO₃)₃] polymorphs is due to the different packing modes of uranyl trinitrate clusters that adopt the same two-dimensional but different three-dimensional arrangements.« less

A polymorphic DNA marker that represents a conserved expressed sequence in the region of the Huntington disease gene.

PubMed Central

Hayden, M R; Hewitt, J; Wasmuth, J J; Kastelein, J J; Langlois, S; Conneally, M; Haines, J; Smith, B; Hilbert, C; Allard, D

1988-01-01

A polymorphic marker (D4S62) that is genetically closely linked to D4S10 and is in the region of the gene for Huntington disease is described. A four-allele polymorphism is detected when HincII-digested DNA is hybridized with D4S62. D4S62 maps, by Southern blot analysis using somatic-cell hybrids, to 4p16.1 closer to the centromere than does D4S10. The use of the polymorphisms detected by D4S62 increases the informativeness of markers close to the gene for Huntington disease and will be useful for preclinical diagnosis. D4S62 detects transcripts of approximately 6,000 nucleotides in rat, mouse, and monkey liver and brain. This represents the first demonstration of conserved expressed sequences close to the gene for Huntington disease. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 6 PMID:2892395

Evaluation of human epidermal growth factor receptor 2 (HER2) single nucleotide polymorphisms (SNPs) in normal and breast tumor tissues and their link with breast cancer prognostic factors.

PubMed

Furrer, Daniela; Lemieux, Julie; Côté, Marc-André; Provencher, Louise; Laflamme, Christian; Barabé, Frédéric; Jacob, Simon; Michaud, Annick; Diorio, Caroline

2016-12-01

Amplification of the human epidermal growth factor receptor 2 (HER2) gene is associated with worse prognosis and decreased overall survival in breast cancer patients. The HER2 gene contains several polymorphisms; two of the best-characterized HER2 polymorphisms are Ile655Val and Ala1170Pro. The aim of this study was to evaluate the association between these two HER2 polymorphisms in normal breast and breast cancer tissues and known breast cancer prognostic factors in a retrospective cohort study of 73 women with non-metastatic HER2-positive breast cancer. HER2 polymorphisms were assessed in breast cancer tissue and normal breast tissue using TaqMan assay. Ala1170Pro polymorphism in normal breast tissue was associated with age at diagnosis (p = 0.007), tumor size (p = 0.004) and lymphovascular invasion (p = 0.06). Similar significant associations in cancer tissues were observed. No association between the Ile655Val polymorphism and prognostic factors were observed. However, we found significant differences in the distribution of Ile655Val (p = 0.03) and Ala1170Pro (p = 0.01) genotypes between normal breast and breast tumor tissues. This study demonstrates that only the Ala1170Pro polymorphism is associated with prognostic factors in HER2-positive breast cancer patients. Moreover, our results suggest that both HER2 polymorphisms could play a significant role in carcinogenesis in non-metastatic HER2-positive breast cancer women. Copyright © 2016 Elsevier Ltd. All rights reserved.

Gender-related survival differences associated with EGFR polymorphisms in metastatic colon cancer.

PubMed

Press, Oliver A; Zhang, Wu; Gordon, Michael A; Yang, Dongyun; Lurje, Georg; Iqbal, Syma; El-Khoueiry, Anthony; Lenz, Heinz-Josef

2008-04-15

Evidence is accumulating supporting gender-related differences in the development of colonic carcinomas. Sex steroid hormone receptors are expressed in the colon and interact with epidermal growth factor receptor (EGFR), a gene widely expressed in colonic tissue. Increased EGFR expression is linked with poor prognosis in colon cancer. Within the EGFR gene there are two functional polymorphisms of interest: a polymorphism located at codon 497 (HER-1 R497K) and a dinucleotide (CA)(n) repeat polymorphism located within intron 1. These germ-line polymorphisms of EGFR were analyzed in genomic DNA from 318 metastatic colon cancer patients, 177 males and 141 females, collected from 1992 to 2003. Gender-related survival differences were associated with the HER-1 R497K polymorphism (P(interaction) = 0.003). Females with the HER-1 497 Arg/Arg variant had better overall survival (OS) when compared with the Lys/Lys and/or Lys/Arg variants. In males the opposite was true. The EGFR dinucleotide (CA)(n) repeat also trended with a gender-related OS difference (P(interaction) = 0.11). Females with both short <20 (CA)(n) repeat alleles had better OS than those with any long >or=20 (CA)(n) repeats. In males the opposite was true. Combination analysis of the two polymorphisms taken together also revealed the same gender-related survival difference (P(interaction) = 0.002). These associations were observed using multivariable analysis. The two polymorphisms were not in linkage disequilibrium and are independent of one another. This study supports the role of functional EGFR polymorphisms as independent prognostic markers in metastatic colon cancer. As a prognostic factor, these variants had opposite prognostic implications based on gender.

The effect of SLCO1B1 polymorphism on repaglinide pharmacokinetics persists over a wide dose range

PubMed Central

Kalliokoski, Annikka; Neuvonen, Mikko; Neuvonen, Pertti J; Niemi, Mikko

2008-01-01

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTOrganic anion transporting polypeptide 1B1 is an influx transporter expressed on the basolateral membrane of hepatocytes.A common single nucleotide polymorphism, c.521T→C (p.Val174Ala), of the SLCO1B1 gene has been associated with increased plasma repaglinide concentrations in healthy volunteers.Previous studies at low repaglinide doses have suggested that the effect of SLCO1B1 c.521T→C polymorphism on the pharmacokinetics of repaglinide could be dose-dependent. WHAT THIS STUDY ADDSRepaglinide peak plasma concentration and area under the plasma concentration–time curve increased linearly along with repaglinide dose ranging from 0.25 to 2 mg in both the predominant c.521TT and rare c.521CC genotype group.The effect of SLCO1B1 c.521T→C polymorphism on repaglinide pharmacokinetics persists over a wide dose range. AIMS To establish whether the effect of SLCO1B1[encoding organic anion transporting polypeptide 1B1 (OATP1B1)] c.521T→C (p.Val174Ala) polymorphism on the pharmacokinetics of repaglinide is dose-dependent. METHODS Twelve healthy volunteers with the SLCO1B1 c.521TT genotype (controls) and eight with the c.521CC genotype ingested a single 0.25-, 0.5-, 1- or 2-mg dose of repaglinide in a dose-escalation study with a wash-out period of ≥1 week. RESULTS The mean area under the plasma concentration–time curve from time 0 to infinity (AUC0–∞) of 0.25, 0.5, 1 or 2 mg repaglinide was 82% (95% confidence interval 47, 125), 72% (24, 138), 56% (24, 95) or 108% (59, 171) (P ≤ 0.001) larger in participants with the SLCO1B1 c.521CC genotype than in those with the c.521TT genotype, respectively. Repaglinide peak plasma concentration and AUC0–∞ increased linearly along with repaglinide dose in both genotype groups (r > 0.88, P < 0.001). There was a tendency towards lower blood glucose concentrations after repaglinide administration in the participants with the c.521CC genotype than in those with the c.521TT genotype. CONCLUSIONS The effect of SLCO1B1 c.521T→C polymorphism on the pharmacokinetics of repaglinide persists throughout the clinically relevant dose range. PMID:18823304

Interactions between Serotonin Transporter Gene Haplotypes and Quality of Mothers' Parenting Predict the Development of Children's Noncompliance

ERIC Educational Resources Information Center

Sulik, Michael J.; Eisenberg, Nancy; Lemery-Chalfant, Kathryn; Spinrad, Tracy L.; Silva, Kassondra M.; Eggum, Natalie D.; Betkowski, Jennifer A.; Kupfer, Anne; Smith, Cynthia L.; Gaertner, Bridget; Stover, Daryn A.; Verrelli, Brian C.

2012-01-01

The LPR and STin2 polymorphisms of the serotonin transporter gene (SLC6A4) were combined into haplotypes that, together with quality of maternal parenting, were used to predict initial levels and linear change in children's (N = 138) noncompliance and aggression from age 18-54 months. Quality of mothers' parenting behavior was observed when…

Brain Serotonin Receptors and Transporters: Initiation vs. Termination of Escalated Aggression

PubMed Central

Takahashi, Aki; Quadros, Isabel M.; de Almeida, Rosa M. M.; Miczek, Klaus A.

2013-01-01

Rationale Recent findings have shown a complexly regulated 5-HT system as it is linked to different kinds of aggression. Objective We focus on (1) phasic and tonic changes of 5-HT and (2) state and trait of aggression, and emphasize the different receptor subtypes, their role in specific brain regions, feed-back regulation and modulation by other amines, acids and peptides. Results New pharmacological tools differentiate the first three 5-HT receptor families and their modulation by GABA, glutamate and CRF. Activation of 5-HT1A, 5-HT1B and 5-HT2A/2C receptors in mesocorticolimbic areas, reduce species-typical and other aggressive behaviors. In contrast, agonists at 5-HT1A and 5-HT1B receptors in the medial prefrontal cortex or septal area can increase aggressive behavior under specific conditions. Activation of serotonin transporters reduce mainly pathological aggression. Genetic analyses of aggressive individuals have identified several molecules that affect the 5-HT system directly (e.g., Tph2, 5-HT1B, 5-HT transporter, Pet1, MAOA) or indirectly (e.g., Neuropeptide Y, αCaMKII, NOS, BDNF). Dysfunction in genes for MAOA escalates pathological aggression in rodents and humans, particularly in interaction with specific experiences. Conclusions Feedback to autoreceptors of the 5-HT1 family and modulation via heteroreceptors are important in the expression of aggressive behavior. Tonic increase of the 5-HT2 family expression may cause escalated aggression, whereas the phasic increase of 5-HT2 receptors inhibits aggressive behaviors. Polymorphisms in the genes of 5-HT transporters or rate-limiting synthetic and metabolic enzymes of 5-HT modulate aggression, often requiring interaction with the rearing environment. PMID:20938650

Repaglinide-irbesartan drug interaction: effects of SLCO1B1 polymorphism on repaglinide pharmacokinetics and pharmacodynamics in Chinese population.

PubMed

Pei, Qi; Liu, Jun-Yan; Yin, Ji-Ye; Yang, Guo-Ping; Liu, Shi-Kun; Zheng, Yi; Xie, Pan; Guo, Cheng-Xian; Luo, Mi; Zhou, Hong-Hao; Li, Xi; Liu, Zhao-Qian

2018-05-11

On account of the potential inhibition of OATP1B1 (organic anion transporting polypeptide) by angiotensin II receptor blockers (ARBs) and the effects of SLCO1B1 (solute carrier organic anion transporter family member) polymorphism, the aim of current study is to assess the impact of ARBs on the pharmacokinetics (PK) and pharmacodynamics (PD) of repaglinide in Chinese healthy volunteers with different SLCO1B1 genotypes. The in vitro study was conducted on irbesartan, valsartan, olmesartan, and losartan by using HEK293 cells transfected with OATP1B1. Data on drug interactions between repaglinide and irbesartan from 21 healthy Chinese-Han male volunteers were collected and analyzed. IC 50 from in vitro study suggested irbesartan was the most potent inhibitor of OATP1B1 transporter. Clinical data from single dose of repaglinide indicated SLCO1B1 c.521 T>C polymorphism influenced the PK and PD of repaglinide in healthy Chinese-Han male volunteers. In subjects with SLCO1B1 c.521 TT genotype, irbesartan comedication increased the exposure of repaglinide. In details, the peak plasma concentration [C max ] increased 84% (P = 0.003) and the area under the curve of plasma concentration 0-8 h [AUC 0-8 ] increased 34% (P = 0.004), while the minimum blood glucose concentration [C min ] decreased 33.8% (P = 0.005). No significant change was observed in repaglinide exposure in subjects with SLCO1B1 c.521 TC genotype in presence or absence of irbesartan. SLCO1B1 c.521 T>C polymorphism affects the PK of repaglinide in Chinese population. Irbesartan increased repaglinide exposure in subjects with SLCO1B1 c.521 TT genotype, but not SLCO1B1 c.521 TC genotype.

Intelligent Transportation Systems for Commercial Vehicle Operations

DOT National Transportation Integrated Search

1997-10-15

What is TransLink? - Public/private partnership - Multi-modal initiative - Focused on linking elements of transportation system - Laboratory using real world data - Looking toward the next generation of transportation operations and management

DNApod: DNA polymorphism annotation database from next-generation sequence read archives.

PubMed

Mochizuki, Takako; Tanizawa, Yasuhiro; Fujisawa, Takatomo; Ohta, Tazro; Nikoh, Naruo; Shimizu, Tokurou; Toyoda, Atsushi; Fujiyama, Asao; Kurata, Nori; Nagasaki, Hideki; Kaminuma, Eli; Nakamura, Yasukazu

2017-01-01

With the rapid advances in next-generation sequencing (NGS), datasets for DNA polymorphisms among various species and strains have been produced, stored, and distributed. However, reliability varies among these datasets because the experimental and analytical conditions used differ among assays. Furthermore, such datasets have been frequently distributed from the websites of individual sequencing projects. It is desirable to integrate DNA polymorphism data into one database featuring uniform quality control that is distributed from a single platform at a single place. DNA polymorphism annotation database (DNApod; http://tga.nig.ac.jp/dnapod/) is an integrated database that stores genome-wide DNA polymorphism datasets acquired under uniform analytical conditions, and this includes uniformity in the quality of the raw data, the reference genome version, and evaluation algorithms. DNApod genotypic data are re-analyzed whole-genome shotgun datasets extracted from sequence read archives, and DNApod distributes genome-wide DNA polymorphism datasets and known-gene annotations for each DNA polymorphism. This new database was developed for storing genome-wide DNA polymorphism datasets of plants, with crops being the first priority. Here, we describe our analyzed data for 679, 404, and 66 strains of rice, maize, and sorghum, respectively. The analytical methods are available as a DNApod workflow in an NGS annotation system of the DNA Data Bank of Japan and a virtual machine image. Furthermore, DNApod provides tables of links of identifiers between DNApod genotypic data and public phenotypic data. To advance the sharing of organism knowledge, DNApod offers basic and ubiquitous functions for multiple alignment and phylogenetic tree construction by using orthologous gene information.

DNApod: DNA polymorphism annotation database from next-generation sequence read archives

PubMed Central

Mochizuki, Takako; Tanizawa, Yasuhiro; Fujisawa, Takatomo; Ohta, Tazro; Nikoh, Naruo; Shimizu, Tokurou; Toyoda, Atsushi; Fujiyama, Asao; Kurata, Nori; Nagasaki, Hideki; Kaminuma, Eli; Nakamura, Yasukazu

2017-01-01

With the rapid advances in next-generation sequencing (NGS), datasets for DNA polymorphisms among various species and strains have been produced, stored, and distributed. However, reliability varies among these datasets because the experimental and analytical conditions used differ among assays. Furthermore, such datasets have been frequently distributed from the websites of individual sequencing projects. It is desirable to integrate DNA polymorphism data into one database featuring uniform quality control that is distributed from a single platform at a single place. DNA polymorphism annotation database (DNApod; http://tga.nig.ac.jp/dnapod/) is an integrated database that stores genome-wide DNA polymorphism datasets acquired under uniform analytical conditions, and this includes uniformity in the quality of the raw data, the reference genome version, and evaluation algorithms. DNApod genotypic data are re-analyzed whole-genome shotgun datasets extracted from sequence read archives, and DNApod distributes genome-wide DNA polymorphism datasets and known-gene annotations for each DNA polymorphism. This new database was developed for storing genome-wide DNA polymorphism datasets of plants, with crops being the first priority. Here, we describe our analyzed data for 679, 404, and 66 strains of rice, maize, and sorghum, respectively. The analytical methods are available as a DNApod workflow in an NGS annotation system of the DNA Data Bank of Japan and a virtual machine image. Furthermore, DNApod provides tables of links of identifiers between DNApod genotypic data and public phenotypic data. To advance the sharing of organism knowledge, DNApod offers basic and ubiquitous functions for multiple alignment and phylogenetic tree construction by using orthologous gene information. PMID:28234924

Association study of interferon gamma (IFN-γ) +874T/A gene polymorphism in patients with paranoid schizophrenia.

PubMed

Paul-Samojedny, Monika; Owczarek, Aleksander; Suchanek, Renata; Kowalczyk, Malgorzata; Fila-Danilow, Anna; Borkowska, Paulina; Kucia, Krzysztof; Kowalski, Jan

2011-03-01

Schizophrenia is a multifactorial disease with changes affecting the immune system. Dysregulation of the cytokine network in schizophrenia has been well documented. Such changes may occur due to disturbances in cytokine levels that are linked to polymorphisms of cytokine genes. However, research in the role of cytokine gene polymorphisms in schizophrenia has been surprisingly scanty. The aim of this study was to identify, in a case control study, whether polymorphism of IFN-γ gene is a risk factor for the development of paranoid schizophrenia. To the best of our knowledge, this is the first study that examines the association between the IFN-γ gene polymorphism and psychopathological symptoms in patients with paranoid schizophrenia. Polymorphism of IFN-γ (+874T/A, rs 62559044) in schizophrenic patients (n=179), as well as healthy individuals (n=196), both Polish residents, was genotyped using AS-PCR method. Of note, when analyzing the results, we took into consideration the gender of studied individuals. Surprisingly, a single-nucleotide polymorphism in the first intron of the IFN-γ gene was found to be associated with paranoid schizophrenia in males, but not in females. The presence of allele A at position +874 in the IFN-γ gene correlates with 1.66-fold higher risk of paranoid schizophrenia development in males. Differences in the genotypes may have an important role in determining the level of I gene transcription. Because other polymorphisms have been demonstrated to influence IFN-γ transcription, further analysis is necessary to clarify the role of this gene in the pathogenesis of paranoid schizophrenia.

Sudden infant death syndrome (SIDS) and polymorphisms in Monoamine oxidase A gene (MAOA): a revisit.

PubMed

Groß, Maximilian; Bajanowski, Thomas; Vennemann, Mechtild; Poetsch, Micaela

2014-01-01

Literature describes multiple possible links between genetic variations in the neuroadrenergic system and the occurrence of sudden infant death syndrome. The X-chromosomal Monoamine oxidase A (MAOA) is one of the genes with regulatory activity in the noradrenergic and serotonergic neuronal systems and a polymorphism of the promoter which affects the activity of this gene has been proclaimed to contribute significantly to the prevalence of sudden infant death syndrome (SIDS) in three studies from 2009, 2012 and 2013. However, these studies described different significant correlations regarding gender or age of children. Since several studies, suggesting associations between genetic variations and SIDS, were disproved by follow-up analysis, this study was conducted to take a closer look at the MAOA gene and its polymorphisms. The functional MAOA promoter length polymorphism was investigated in 261 SIDS cases and 93 control subjects. Moreover, the allele distribution of 12 coding and non-coding single nucleotide polymorphisms (SNPs) of the MAOA gene was examined in 285 SIDS cases and 93 controls by a minisequencing technique. In contrast to prior studies with fewer individuals, no significant correlations between the occurrence of SIDS and the frequency of allele variants of the promoter polymorphism could be demonstrated, even including the results from the abovementioned previous studies. Regarding the SNPs, three statistically significant associations were observed which had not been described before. This study clearly disproves interactions between MAOA promoter polymorphisms and SIDS, even if variations in single nucleotide polymorphisms of MAOA should be subjected to further analysis to clarify their impact on SIDS.

Macrophage Migration Inhibitory Factor (MIF) Gene Promotor Polymorphism Is Associated with Increased Fibrosis in Biliary Atresia Patients, but Not with Disease Susceptibility.

PubMed

Sadek, Khaled H; Ezzat, Sameera; Abdel-Aziz, Samira A; Alaraby, Hanaa; Mosbeh, Asmaa; Abdel-Rahman, Mohamed H

2017-09-01

Two polymorphisms, rs755622 and rs5844572, in the promoter region of the macrophage migration inhibitory factor (MIF) gene influence the basal and/or induced transcriptional activity and have been linked to several inflammatory and autoimmune diseases. The aim of this study was to investigate the association between these two polymorphisms and disease susceptibility in patients with biliary atresia (BA). Allele frequencies of rs755622 and rs5844572 were assessed in 60 Egyptian infants with a confirmed diagnosis of BA. DNA was extracted from archival material. For the rs755622, samples were tested using Taqman real-time PCR, and for the rs5844572, samples were tested using fluorescence-based genotyping. The allele frequency in the general population was assessed in 141 healthy adults from the same geographical location. No statistical differences were observed in the allele frequencies of either rs755622 or rs5844572 between BA patients and controls. The homozygous and heterozygous short repeats (5/5, or 5/X) of rs5844572 were observed more frequently (16/28, 57.1%) in BA patients with mild to moderate fibrosis compared with those with marked fibrosis (10/32, 31.3%). The difference was statistically significant (P  =  0.032). In conclusion, we observed no association between MIF rs755622 and rs5844572 polymorphisms and susceptibility to BA; however, the rs5844572 could be linked to the rate of progression of the disease and extent of fibrosis. © 2017 John Wiley & Sons Ltd/University College London.

The functional BDNF Val66Met polymorphism affects functions of pre-attentive visual sensory memory processes.

PubMed

Beste, Christian; Schneider, Daniel; Epplen, Jörg T; Arning, Larissa

2011-01-01

The brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is involved in nerve growth and survival. Especially, a single nucleotide polymorphism (SNP) in the BDNF gene, Val66Met, has gained a lot of attention, because of its effect on activity-dependent BDNF secretion and its link to impaired memory processes. We hypothesize that the BDNF Val66Met polymorphism may have modulatory effects on the visual sensory (iconic) memory performance. Two hundred and eleven healthy German students (106 female and 105 male) were included in the data analysis. Since BDNF is also discussed to be involved in the pathogenesis of depression, we additionally tested for possible interactions with depressive mood. The BDNF Val66Met polymorphism significantly influenced iconic-memory performance, with the combined Val/Met-Met/Met genotype group revealing less time stability of information stored in iconic memory than the Val/Val group. Furthermore, this stability was positively correlated with depressive mood exclusively in the Val/Val genotype group. Thus, these results show that the BDNF Val66Met polymorphism has an effect on pre-attentive visual sensory memory processes. Copyright © 2010 Elsevier Ltd. All rights reserved.

Fc receptors for mouse IgG1 on human monocytes: polymorphism and role in antibody-induced T cell proliferation.

PubMed

Tax, W J; Hermes, F F; Willems, R W; Capel, P J; Koene, R A

1984-09-01

In previous studies, it was shown that there is polymorphism in the mitogenic effect of mouse IgG1 monoclonal antibodies against the T3 antigen of human T cells. This polymorphism implies that IgG1 anti-T3 antibodies are not mitogenic for T cells from 30% of healthy individuals. The present results demonstrate that this polymorphism is caused by polymorphism of an Fc receptor for mouse IgG1, present on human monocytes. The Fc receptor for murine IgG1 could be detected by a newly developed rosetting assay on monocytes from all individuals responsive to the mitogenic effect of IgG1 anti-T3 antibodies. This Fc receptor was not detectable on monocytes from those individuals exhibiting no mitogenic responses to IgG1 anti-T3 monoclonal antibodies. Cross-linking of T3 antigens appears to be essential for antibody-induced mitosis of T cells, because mononuclear cells that did not proliferate in response to WT 31 (an IgG1 antibody against T3 antigen) showed a proliferative response to Sepharose beads coated with WT 31. The Fc receptor--if functionally present--may be involved in the cross-linking of T3 antigens through anti-T3 antibodies. Further evidence for the involvement of this Fc receptor in antibody-induced T cell proliferation was provided by inhibition studies. Immune complexes containing IgG1 antibodies were able to inhibit the proliferative response to IgG1 anti-T3 antibodies. This inhibition by immune complexes appears to be mediated through the monocyte Fc receptor for mouse IgG1. These findings are important for the interpretation of previously described inhibitory effects of anti-T cell monoclonal antibodies on T cell proliferation, and show that such inhibitory effects may be monocyte-mediated (via immune complexes) rather than caused by a direct involvement of the respective T cell antigens in T cell mitosis. The Fc receptor for mouse IgG1 plays a role in antibody-induced T cell proliferation. Its polymorphism may have important implications for the therapeutic use of IgG1 monoclonal antibodies.

No Association between Personality and Candidate Gene Polymorphisms in a Wild Bird Population

PubMed Central

Durieux, Gillian; Burke, Terry; Dugdale, Hannah L.

2015-01-01

Consistency of between-individual differences in behaviour or personality is a phenomenon in populations that can have ecological consequences and evolutionary potential. One way that behaviour can evolve is to have a genetic basis. Identifying the molecular genetic basis of personality could therefore provide insight into how and why such variation is maintained, particularly in natural populations. Previously identified candidate genes for personality in birds include the dopamine receptor D4 (DRD4), and serotonin transporter (SERT). Studies of wild bird populations have shown that exploratory and bold behaviours are associated with polymorphisms in both DRD4 and SERT. Here we tested for polymorphisms in DRD4 and SERT in the Seychelles warbler (Acrocephalus sechellensis) population on Cousin Island, Seychelles, and then investigated correlations between personality and polymorphisms in these genes. We found no genetic variation in DRD4, but identified four polymorphisms in SERT that clustered into five haplotypes. There was no correlation between bold or exploratory behaviours and SERT polymorphisms/haplotypes. The null result was not due to lack of power, and indicates that there was no association between these behaviours and variation in the candidate genes tested in this population. These null findings provide important data to facilitate representative future meta-analyses on candidate personality genes. PMID:26473495

Sulfadiazine resistance in Toxoplasma gondii: no involvement of overexpression or polymorphisms in genes of therapeutic targets and ABC transporters

PubMed Central

Doliwa, Christelle; Escotte-Binet, Sandie; Aubert, Dominique; Sauvage, Virginie; Velard, Frédéric; Schmid, Aline; Villena, Isabelle

2013-01-01

Several treatment failures have been reported for the treatment of toxoplasmic encephalitis, chorioretinitis, and congenital toxoplasmosis. Recently we found three Toxoplasma gondii strains naturally resistant to sulfadiazine and we developed in vitro two sulfadiazine resistant strains, RH-RSDZ and ME-49-RSDZ, by gradual pressure. In Plasmodium, common mechanisms of drug resistance involve, among others, mutations and/or amplification within genes encoding the therapeutic targets dhps and dhfr and/or the ABC transporter genes family. To identify genotypic and/or phenotypic markers of resistance in T. gondii, we sequenced and analyzed the expression levels of therapeutic targets dhps and dhfr, three ABC genes, two Pgp, TgABC.B1 and TgABC.B2, and one MRP, TgABC.C1, on sensitive strains compared to sulfadiazine resistant strains. Neither polymorphism nor overexpression was identified. Contrary to Plasmodium, in which mutations and/or overexpression within gene targets and ABC transporters are involved in antimalarial resistance, T. gondii sulfadiazine resistance is not related to these toxoplasmic genes studied. PMID:23707894

Genetic and vascular modifiers of age-sensitive cognitive skills: effects of COMT, BDNF, ApoE, and hypertension.

PubMed

Raz, Naftali; Rodrigue, Karen M; Kennedy, Kristen M; Land, Susan

2009-01-01

Several single nucleotide polymorphisms have been linked to neural and cognitive variation in healthy adults. We examined contribution of three polymorphisms frequently associated with individual differences in cognition (Catechol-O-Methyl-Transferase Val158Met, Brain-Derived-Neurotrophic-Factor Val66Met, and Apolipoprotein E epsilon4) and a vascular risk factor (hypertension) in a sample of 189 volunteers (age 18-82). Genotypes were determined from buccal culture samples, and cognitive performance was assessed in 4 age-sensitive domains?fluid intelligence, executive function (inhibition), associative memory, and processing speed. We found that younger age and COMT Met/Met genotype, associated with low COMT activity and higher prefrontal dopamine content, were independently linked to better performance in most of the tested domains. Homozygotes for Val allele of BDNF polymorphism exhibited better associative memory and faster speed of processing than the Met allele carriers, with greater effect for women and persons with hypertension. Carriers of ApoE epsilon4 allele evidenced steeper age-related increase in costs of Stroop color interference, but showed no negative effects on memory. The findings indicate that age-related cognitive performance is differentially affected by distinct genetic factors and their interactions with vascular health status. (c) 2009 APA, all rights reserved.

Initial evidence that polymorphisms in neurotransmitter-regulating genes contribute to being born small for gestational age

PubMed Central

Morgan, Angharad R.; Thompson, John M.D.; Waldie, Karen E.; Cornforth, Christine M.; Turic, Darko; Sonuga-Barke, Edmund J.S.; Lam, Wen-Jiun; Ferguson, Lynnette R.; Mitchell, Edwin A.

2012-01-01

Being born small for gestational age (SGA) is a putative risk factor for the development of later cognitive and psychiatric health problems. While the inter-uterine environment has been shown to play an important role in predicting birth weight, little is known about the genetic factors that might be important. Here we test the hypothesis that neurotransmitter-regulating genes implicated in psychiatric disorders previously shown to be associated with SGA (such as attention-deficit hyperactivity disorder) are themselves predictive of SGA. DNA was collected from 227 SGA and 319 appropriate for gestational age children taking part in the Auckland Birthweight Collaborative Study. Candidate single nucleotide polymorphisms in genes regulating activity within dopamine, serotonin, glutamate and gamma-aminobutyric acid pathways were genotyped. Multiple regression analysis, controlling for potentially confounding factors, supported nominally significant associations between SGA and single nucleotide polymorphisms in COMT, HTR2A, SLC1A1 and SLC6A1. This is the first evidence that genes implicated in psychiatric disorders previously linked to SGA status themselves predict SGA. This highlights the possibility that the link between SGA and psychiatric disorders such as attention-deficit hyperactivity disorder may in part be genetically determined – that SGA marks pre-existing genetic risk for later problems. PMID:27625810

No evidence for involvement of genetic variants in the X-linked neuroligin genes NLGN3 and NLGN4X in probands with autism spectrum disorder on high functioning level.

PubMed

Wermter, Anne-Kathrin; Kamp-Becker, Inge; Strauch, Konstantin; Schulte-Körne, Gerd; Remschmidt, Helmut

2008-06-05

Several lines of evidence indicate a role of mutations in the two X-linked genes neuroligin 3 (NLGN3) and neuroligin 4 (NLGN4X) in the etiology of autistic spectrum disorders. To analyze whether genetic variants in the NLGN3 and NLGN4X genes occurs in patients with autistic disorders on high functioning level, we performed a mutation screen of both genes using SSCP in 107 probands with Asperger syndrome, high-functioning autism and atypical autism. We identified four polymorphisms (rs2290488, rs7049300, rs3747333, rs3747334) and one novel synonymous variant (A558) in the NLGN4X. The polymorphisms rs7049300, rs3747333, and rs3747334 did not cause any amino acid substitutions in the total of the eight detected carriers. A family-based association study for rs2290488 in 101 trios did not reveal association of this polymorphism with autistic disorders on high functioning level. We conclude that there is no evidence for an involvement of NLGN3 and NLGN4X genetic variants with autism spectrum disorder on high functioning level in our study group. (c) 2008 Wiley-Liss, Inc.

Transposon Variants and Their Effects on Gene Expression in Arabidopsis

PubMed Central

Wang, Xi; Weigel, Detlef; Smith, Lisa M.

2013-01-01

Transposable elements (TEs) make up the majority of many plant genomes. Their transcription and transposition is controlled through siRNAs and epigenetic marks including DNA methylation. To dissect the interplay of siRNA–mediated regulation and TE evolution, and to examine how TE differences affect nearby gene expression, we investigated genome-wide differences in TEs, siRNAs, and gene expression among three Arabidopsis thaliana accessions. Both TE sequence polymorphisms and presence of linked TEs are positively correlated with intraspecific variation in gene expression. The expression of genes within 2 kb of conserved TEs is more stable than that of genes next to variant TEs harboring sequence polymorphisms. Polymorphism levels of TEs and closely linked adjacent genes are positively correlated as well. We also investigated the distribution of 24-nt-long siRNAs, which mediate TE repression. TEs targeted by uniquely mapping siRNAs are on average farther from coding genes, apparently because they more strongly suppress expression of adjacent genes. Furthermore, siRNAs, and especially uniquely mapping siRNAs, are enriched in TE regions missing in other accessions. Thus, targeting by uniquely mapping siRNAs appears to promote sequence deletions in TEs. Overall, our work indicates that siRNA–targeting of TEs may influence removal of sequences from the genome and hence evolution of gene expression in plants. PMID:23408902

Refined genetic mapping of X-linked Charcot-Marie-Tooth neuropathy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fain, P.R.; Barker, D.F.; Chance, P.F.

1994-02-01

Genetic linkage studies were conducted in four multigenerational families with X-linked Charcot-Marie-Tooth disease (CMTX), using 12 highly polymorphic short-tandem-repeat markers for the pericentromeric region of the X Chromosome. Pairwise linkage analysis with individual markers confirmed tight linkage of CMTX to the pericentromeric region in each family. Multipoint analyses strongly support the order DXS337-CMTX-DXS441-(DXS56, PGK1). 38 refs., 2 figs., 1 tab.

APOA5 -1131T>C and APOC3 -455T>C polymorphisms are associated with an increased risk of coronary heart disease.

PubMed

Sun, Y; Zhou, R B; Chen, D M

2015-12-28

The aim of this study was to investigate correlations between apolipoprotein A-V (APOA5) -1131T>C and apolipoprotein C-III (APOC3) -455T>C polymorphisms and coronary heart disease (CHD). PubMed, Ovid, Cochrane Library, Embase, China National Knowledge Infrastructure, and Wanfang databases were searched using combinations of keywords relating to these polymorphisms and CHD. Studies retrieved from database searches were screened using our stringent inclusion and exclusion criteria, and Comprehensive Meta-Analysis Version 2.0 software was used for statistical analyses. In total, 115 studies were initially retrieved and after further selection, 11 were included in the meta-analysis. These 11 articles comprised 4840 patients with CHD in the case group and 4913 healthy participants in the control group. Meta-analysis revealed that APOA5 -1131T>C and APOC3 -455T>C polymorphisms increased CHD risk. In addition, subgroup analysis by ethnicity showed that while the -1131T>C polymorphism elevated the risk of CHD in the Caucasian population under both allelic and dominant models, this increased risk was observed only under a dominant model in the Asian population. The results of our meta-analysis point to a strong link between both APOA5 -1131T>C and APOC3 -455T>C polymorphisms and an increased risk of CHD. Thus, these polymorphisms constitute important predictive indicators of CHD susceptibility.

[The effect of the serotonin transporter 5-HTTLPR polymorphism on the recognition of facial emotions in schizophrenia].

PubMed

Alfimova, M V; Golimbet, V E; Korovaitseva, G I; Lezheiko, T V; Abramova, L I; Aksenova, E V; Bolgov, M I

2014-01-01

The 5-HTTLPR SLC6A4 and catechol-o-methyltransferase (COMT) Val158Met polymorphisms are reported to be associated with processing of facial expressions in general population. Impaired recognition of facial expressions that is characteristic of schizophrenia negatively impacts on the social adaptation of the patients. To search for molecular mechanisms of this deficit, we studied main and epistatic effects of 5-HTTLPR and Val158Met polymorphisms on the facial emotion recognition in patients with schizophrenia (n=299) and healthy controls (n=232). The 5-HTTLPR polymorphism was associated with the emotion recognition in patients. The ll-homozygotes recognized facial emotions significantly better compared to those with an s-allele (F=8.00; p=0.005). Although the recognition of facial emotions was correlated with negative symptoms, verbal learning and trait anxiety, these variables did not significantly modified the association. In both groups, no effect of the COMT on the recognition of facial emotions was found.

DFT-Assisted Polymorph Identification from Lattice Raman Fingerprinting

PubMed Central

2017-01-01

A combined experimental and theoretical approach, consisting of lattice phonon Raman spectroscopy and density functional theory (DFT) calculations, is proposed as a tool for lattice dynamics characterization and polymorph phase identification. To illustrate the reliability of the method, the lattice phonon Raman spectra of two polymorphs of the molecule 2,7-dioctyloxy[1]benzothieno[3,2-b]benzothiophene are investigated. We show that DFT calculations of the lattice vibrations based on the known crystal structures, including many-body dispersion van der Waals (MBD-vdW) corrections, predict experimental data within an accuracy of ≪5 cm–1 (≪0.6 meV). Due to the high accuracy of the simulations, they can be used to unambiguously identify different polymorphs and to characterize the nature of the lattice vibrations and their relationship to the structural properties. More generally, this work implies that DFT-MBD-vdW is a promising method to describe also other physical properties that depend on lattice dynamics like charge transport. PMID:28731723

C1473G polymorphism in mouse tph2 gene is linked to tryptophan hydroxylase-2 activity in the brain, intermale aggression, and depressive-like behavior in the forced swim test.

PubMed

Osipova, Daria V; Kulikov, Alexander V; Popova, Nina K

2009-04-01

Tryptophan hydroxylase-2 (TPH2) is the rate-limiting enzyme of brain serotonin synthesis. The C1473G polymorphism in the mouse tryptophan hydroxylase-2 gene affects the enzyme's activity. In the present study, we investigated the linkage between the C1473G polymorphism, enzyme activity in the brain, and behavior in the forced swim, intermale aggression, and open field tests using mice of the C57BL/6 (C/C) and CC57BR/Mv (G/G) strains and the B6-1473C (C/C) and B6-1473G (G/G) lines created by three successive backcrossings on C57BL/6. Mice of the CC57BR/Mv strain had decreased brain enzyme activity, aggression intensity, and immobility in the forced swim test, but increased locomotor activity and time spent in the central part of the open field arena compared with animals of the C57BL/6 strain. Mice of the B6-1473G line homozygous for the 1473G allele had lower TPH2 activity in the brain, aggression intensity, and immobility time in the forced swim test compared with animals of the B6-1473C line homozygous for the 1473C allele. No differences were found between the B6-1473G and B6-1473C mice in locomotor activity and time spent in the central part of the arena in the open field test. Thus, the C1473G polymorphism is involved in the determination of TPH2 activity and is linked to aggression intensity and forced-swim immobility in mice. At the same time, the polymorphism does not affect locomotion and anxiety-related behavior in the open field test. The B6-1473C and B6-1473G mice represent a valuable experimental model for investigating molecular mechanisms of serotonin-related behavior.

APOC3 rs2070666 Is Associated with the Hepatic Steatosis Independently of PNPLA3 rs738409 in Chinese Han Patients with Nonalcoholic Fatty Liver Diseases.

PubMed

Zhang, Rui-Nan; Zheng, Rui-Dan; Mi, Yu-Qiang; Zhou, Da; Shen, Feng; Chen, Guang-Yu; Zhu, Chan-Yan; Pan, Qin; Fan, Jian-Gao

2016-08-01

The association between nonalcoholic fatty liver disease (NAFLD) and apolipoprotein C3 gene (APOC3) promoter region single-nucleotide polymorphisms (SNPs) rs2854117 and rs2854116 is controversial. The aim of this study was to investigate the relationship between other polymorphisms of APOC3 and NAFLD in Chinese. Fifty-nine liver biopsy-proven NAFLD patients and 72 healthy control subjects were recruited to a cohort representing Chinese Han population. The polymorphisms in the exons and flanking regions of APOC3 and patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 polymorphisms were genotyped. Among the five SNPs (rs4225, rs4520, rs5128, rs2070666, and rs2070667) in APOC3, only rs2070666 (c.179 + 62 T/A) was significantly different in genotype and allele frequency (both p < 0.01) between groups of NAFLD and control. After adjusting for sex, age, serum triglycerides, total cholesterol, body mass index, and the PNPLA3 rs738409 polymorphism, the APOC3 rs2070666 A allele was an independent risk factor for NAFLD with an odds ratio (OR) of 3.683 and 95 % confidence interval (CI) of 1.037-13.084. The APOC3 rs2070666 A allele was linked to the fourth quartile of the controlled attenuation parameter values (OR 2.769, 95 % CI 1.002-7.651) in 131 subjects, and also linked to the significant histological steatosis (OR 4.986, 95 % CI 1.020-24.371), but neither to liver stiffness measurement values nor to hepatic histological activity and fibrosis in NAFLD patients. The APOC3 rs2070666 A allele is a risk factor for NAFLD independent of obesity, dyslipidemia, and PNPLA3 rs738409, and it might contribute to increased liver fat content in Chinese Han population.

Pharmacogenomics and histone deacetylase inhibitors

PubMed Central

Goey, Andrew KL; Sissung, Tristan M; Peer, Cody J; Figg, William D

2016-01-01

The histone deacetylase inhibitor valproic acid (VPA) has been used for many decades in neurology and psychiatry. The more recent introduction of the histone deacetylase inhibitors (HDIs) belinostat, romidepsin and vorinostat for treatment of hematological malignancies indicates the increasing popularity of these agents. Belinostat, romidepsin and vorinostat are metabolized or transported by polymorphic enzymes or drug transporters. Thus, genotype-directed dosing could improve pharmacotherapy by reducing the risk of toxicities or preventing suboptimal treatment. This review provides an overview of clinical studies on the effects of polymorphisms on the pharmacokinetics, efficacy or toxicities of HDIs including belinostat, romidepsin, vorinostat, panobinostat, VPA and a number of novel compounds currently being tested in Phase I and II trials. Although pharmacogenomic studies for HDIs are scarce, available data indicate that therapy with belinostat (UGT1A1), romidepsin (ABCB1), vorinostat (UGT2B17) or VPA (UGT1A6) could be optimized by upfront genotyping. PMID:27767376

Mutations in SLC2A2 Gene Reveal hGLUT2 Function in Pancreatic β Cell Development*

PubMed Central

Michau, Aurélien; Guillemain, Ghislaine; Grosfeld, Alexandra; Vuillaumier-Barrot, Sandrine; Grand, Teddy; Keck, Mathilde; L'Hoste, Sébastien; Chateau, Danielle; Serradas, Patricia; Teulon, Jacques; De Lonlay, Pascale; Scharfmann, Raphaël; Brot-Laroche, Edith; Leturque, Armelle; Le Gall, Maude

2013-01-01

The structure-function relationships of sugar transporter-receptor hGLUT2 coded by SLC2A2 and their impact on insulin secretion and β cell differentiation were investigated through the detailed characterization of a panel of mutations along the protein. We studied naturally occurring SLC2A2 variants or mutants: two single-nucleotide polymorphisms and four proposed inactivating mutations associated to Fanconi-Bickel syndrome. We also engineered mutations based on sequence alignment and conserved amino acids in selected domains. The single-nucleotide polymorphisms P68L and T110I did not impact on sugar transport as assayed in Xenopus oocytes. All the Fanconi-Bickel syndrome-associated mutations invalidated glucose transport by hGLUT2 either through absence of protein at the plasma membrane (G20D and S242R) or through loss of transport capacity despite membrane targeting (P417L and W444R), pointing out crucial amino acids for hGLUT2 transport function. In contrast, engineered mutants were located at the plasma membrane and able to transport sugar, albeit with modified kinetic parameters. Notably, these mutations resulted in gain of function. G20S and L368P mutations increased insulin secretion in the absence of glucose. In addition, these mutants increased insulin-positive cell differentiation when expressed in cultured rat embryonic pancreas. F295Y mutation induced β cell differentiation even in the absence of glucose, suggesting that mutated GLUT2, as a sugar receptor, triggers a signaling pathway independently of glucose transport and metabolism. Our results describe the first gain of function mutations for hGLUT2, revealing the importance of its receptor versus transporter function in pancreatic β cell development and insulin secretion. PMID:23986439

Genome-wide association study of serum coenzyme Q10 levels identifies susceptibility loci linked to neuronal diseases.

PubMed

Degenhardt, Frauke; Niklowitz, Petra; Szymczak, Silke; Jacobs, Gunnar; Lieb, Wolfgang; Menke, Thomas; Laudes, Matthias; Esko, Tõnu; Weidinger, Stephan; Franke, Andre; Döring, Frank; Onur, Simone

2016-07-01

Coenzyme Q 10 (CoQ 10 ) is a lipophilic redox molecule that is present in membranes of almost all cells in human tissues. CoQ 10 is, amongst other functions, essential for the respiratory transport chain and is a modulator of inflammatory processes and gene expression. Rare monogenetic CoQ 10 deficiencies show noticeable symptoms in tissues (e.g. kidney) and cell types (e.g. neurons) with a high energy demand. To identify common genetic variants influencing serum CoQ 10 levels, we performed a fixed effects meta-analysis in two independent cross-sectional Northern German cohorts comprising 1300 individuals in total. We identified two genome-wide significant susceptibility loci. The best associated single nucleotide polymorphism (SNP) was rs9952641 (P value = 1.31 × 10 - 8 , β = 0.063, CI 0.95 [0.041, 0.085]) within the COLEC12 gene on chromosome 18. The SNP rs933585 within the NRXN-1 gene on chromosome 2 also showed genome wide significance (P value = 3.64 × 10 - 8 , β = -0.034, CI 0.95 [-0.046, -0.022]). Both genes have been previously linked to neuronal diseases like Alzheimer's disease, autism and schizophrenia. Among our 'top-10' associated variants, four additional loci with known neuronal connections showed suggestive associations with CoQ 10 levels. In summary, this study demonstrates that serum CoQ 10 levels are associated with common genetic loci that are linked to neuronal diseases. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Single-nucleotide polymorphism-gene intermixed networking reveals co-linkers connected to multiple gene expression phenotypes

PubMed Central

Gong, Bin-Sheng; Zhang, Qing-Pu; Zhang, Guang-Mei; Zhang, Shao-Jun; Zhang, Wei; Lv, Hong-Chao; Zhang, Fan; Lv, Sa-Li; Li, Chuan-Xing; Rao, Shao-Qi; Li, Xia

2007-01-01

Gene expression profiles and single-nucleotide polymorphism (SNP) profiles are modern data for genetic analysis. It is possible to use the two types of information to analyze the relationships among genes by some genetical genomics approaches. In this study, gene expression profiles were used as expression traits. And relationships among the genes, which were co-linked to a common SNP(s), were identified by integrating the two types of information. Further research on the co-expressions among the co-linked genes was carried out after the gene-SNP relationships were established using the Haseman-Elston sib-pair regression. The results showed that the co-expressions among the co-linked genes were significantly higher if the number of connections between the genes and a SNP(s) was more than six. Then, the genes were interconnected via one or more SNP co-linkers to construct a gene-SNP intermixed network. The genes sharing more SNPs tended to have a stronger correlation. Finally, a gene-gene network was constructed with their intensities of relationships (the number of SNP co-linkers shared) as the weights for the edges. PMID:18466544

The role of androgens and polymorphisms in the androgen receptor in the epidemiology of breast cancer

PubMed Central

Lillie, Elizabeth O; Bernstein, Leslie; Ursin, Giske

2003-01-01

Testosterone binds to the androgen receptor in target tissue to mediate its effects. Variations in testosterone levels and androgen receptor activity may play a role in the etiology of breast cancer. Here, we review the epidemiologic evidence linking endogenous testosterone to breast cancer risk. Paradoxically, results from observational studies that have examined polymorphisms in the androgen receptor suggest that the low-activity androgen receptor increases breast cancer risk. We review the quality of this evidence and conclude with a discussion of how the androgen receptor and testosterone results coincide. PMID:12793900

Ala397Asp mutation of myosin VIIA gene segregating in a Spanish family with type-Ib Usher syndrome.

PubMed

Espinós, C; Millán, J M; Sánchez, F; Beneyto, M; Nájera, C

1998-06-01

In the current study, 12 Spanish families affected by type-I Usher syndrome, that was previously linked to chromosome 11q, were screened for the presence of mutations in the N-terminal coding portion of the motor domain of the myosin VIIA gene by single-strand conformation polymorphism analysis of the first 14 exons. A mutation (Ala397Asp) segregating with the disease was identified, and several polymorphisms were also detected. It is presumed that the other USHIB mutations in these families could be located in the unscreened regions of the gene.

[Polymorphism g.37190613 G>A of the ELMO1 gene in the Mexican population: potential marker for clinical-surgical pathology].

PubMed

Topete-González, Luz Rosalba; Ramirez-Garcia, Sergio Alberto; Charles-Niño, Claudia; Villa-Ruano, Nemesio; Mosso-González, Clemente; Dávalos-Rodríguez, Nory Omayra

2014-01-01

ELMO1 is a gene located at locus 7p14.2-14.1 that codifies a regulatory protein involved in fibrogenesis, cell migration, phagocytosis and apoptosis. This gene presents a single nucleotide polymorphism, which appears to be linked with the development of diabetic nephropathy. Currently, there are no studies in regard to the presence of such polymorphism in the Mexican population. Therefore, the aim of this work was to estimate the frequency rate of alleles and genotypes of polymorphism rs1345365 from ELMO1 in Mexican mestizos who inhabit the west and the southeast regions of Mexico in order to generate reliable data for further association studies. There were 322 individuals who were screened for the identification of polymorphism rs1345365 using genomic DNA from leucocytes as a template for PCR-PASA reactions. Amplicons were separated in 7% PAGE and visualized after staining with silver nitrate. The reference allele (A) was the most frequent in both western and southeastern populations of Mexico. In addition, a different genotype distribution was found with respect to other populations. The results of this study indicate that both populations are in Hardy-Weinberg equilibrium. This study also reveals a low frequency rate of the ancestral genotype for the polymorphism rs1345365 in mestizos from the western and southeastern regions of Mexico.

Association of 5-HT2A receptor gene polymorphisms with gastrointestinal disorders in Egyptian children with autistic disorder.

PubMed

Abdelrahman, Hadeel M; Sherief, Laila M; Alghobashy, Ashgan A; Abdel Salam, Sanaa M; Hashim, Haitham M; Abdel Fattah, Nelly R; Mohamed, Randa H

2014-11-12

Gastrointestinal disturbances (GID) are frequently reported in children with autism spectrum disorders (ASD). Recently, mounting evidence suggests that there may be a genetic link for autism with gastrointestinal disturbances. We aimed to investigate whether there were any association between the -1438A/G, 102T/C and His452Tyr polymorphisms of the serotonin 2A receptor gene (5-HT2A) in Egyptian children with ASD and GID. Eighty children with autistic disorder and 100 healthy control children were examined. -1438A/G, 102T/C and His452Tyr polymorphisms of 5-HT2A were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Significant increase of the G allele and the GG genotype of the -1438A/G polymorphism was observed in children with autism than control, but there were no significant differences in the frequencies either of the 102T/C genotype or His452Tyr genotype between the two groups. There was a significant increase of homozygote A allele of the -1438A/G and CC genotype of the 102T/C polymorphism in ASD children with GID. This study supports the possible involvement of the 5-HT2A receptor in the development of ASD and associated GID. Copyright © 2014 Elsevier Ltd. All rights reserved.

A case-control study of apoA5 -1131T-->C polymorphism that examines the role of triglyceride levels in diabetic nephropathy.

PubMed

Baum, Larry; Ng, Maggie C Y; So, Wing-Yee; Poon, Emily; Wang, Ying; Lam, Vincent K L; Tomlinson, Brian; Chan, Juliana C N

2007-01-01

Patients with diabetic nephropathy (DN) have increased plasma fasting triglyceride (TG) levels, and most prospective studies report that elevated TG precedes DN. TG-rich lipoprotein particles might promote progression of DN. To test the hypothesis that elevated TG levels contribute to the development of DN, one may examine whether a polymorphism strongly associated with TG levels affects DN risk. The apolipoprotein A5 (apoA5) -1131T-->C polymorphism has a large effect on the TG level, and all three genotypes are relatively common in East Asians. Therefore, we sought to examine the association of this polymorphism with DN. We genotyped the apoA5 -1131T-->C polymorphism in a case-control study involving 367 Chinese Type 2 diabetes patients with DN and 382 without DN, as well as 198 subjects without diabetes. Mean fasting TG levels were higher in CC than in TT carriers by 41%, 54%, and 62% in each of the three subject groups, respectively. However, the genotype distributions did not differ between patients with and without nephropathy (P=.69). Therefore, these results weigh against the hypothesis that high fasting TG per se causes DN. The strong association between TG level and DN may be due to a factor that is usually closely linked to TG level but that is not affected by the apoA5 polymorphism.

Association of Interleukin-17 polymorphism (-197G/A) in chronic and localized aggressive periodontitis.

PubMed

Chaudhari, Harshal Liladhar; Warad, Shivaraj; Ashok, Nipun; Baroudi, Kusai; Tarakji, Bassel

2016-01-01

Interleukin 17(IL-17) is a pro-inflammatory cytokine produced mainly by Th17 cells. The present study was undertaken to investigate a possible association between IL-17 A genetic polymorphism at (-197A/G) and susceptibility to chronic and localized aggressive periodontitis (LAgP) in an Indian population. The study was carried out on 105 subjects, which included 35 LAgP patients, 35 chronic periodontitis patients and 35 healthy controls. Blood samples were drawn from the subjects and analyzed for IL-17 genetic polymorphism at (-197A/G), by using the polymerase chain reaction-restriction fragment length polymorphism method. A statistically significant difference was seen in the genotype distribution among chronic periodontitis patients, LAgP patients and healthy subjects. There was a significant difference in the distribution of alleles among chronic periodontitis patients, LAgP patients and healthy subjects. The odds ratio for A allele versus G allele was 5.1 between chronic periodontitis patients and healthy controls, and 5.1 between LAgp patients and healthy controls. Our study concluded that IL-17 A gene polymorphism at (-197A/G) is linked to chronic periodontitis and LAgP in Indian population. The presence of allele A in the IL-17 gene polymorphism (-197A/G) can be considered a risk factor for chronic periodontitis and LAgP.

Preproghrelin Leu72Met polymorphism in Chinese subjects with coronary artery disease and controls.

PubMed

Tang, Na-Ping; Wang, Lian-Sheng; Yang, Li; Gu, Hai-Juan; Zhu, Huai-Jun; Zhou, Bo; Sun, Qing-Min; Cong, Ri-Hong; Wang, Bin

2008-01-01

Ghrelin, a novel endogenous ligand for the growth hormone secretagogue receptor, is considered to exert a protective effect against atherosclerosis. The Leu72Met (+408C>A) polymorphic variant of the preproghrelin, the gene for the ghrelin precursor, has been linked to obesity, diabetes and metabolic syndrome. However, it is unclear whether this polymorphism is associated with coronary artery disease (CAD). We conducted a case-control study with 317 CAD patients and 323 controls to investigate the potential association of the Leu72Met polymorphism with the occurrence of CAD and CAD-related phenotypes in Chinese population. No significant difference in the Leu72Met genotype frequency was observed between CAD patients and controls (P=NS). The Leu72Met polymorphism was not associated with hypertension, diabetes, dyslipidemia, the number of diseased vessels, plasma total cholesterol, triglyceride, high density lipoprotein cholesterol, low density lipoprotein cholesterol or fasting glucose levels in CAD patients. However, among CAD patients, those with variant genotypes (Leu72Met and Met72Met) had lower BMI (24.4+/-0.3 kg/m(2)) than Leu72Leu carriers (25.4+/-0.2 kg/m(2), adjusted P=0.033). Our data indicate that the preproghrelin Leu72Met polymorphism is not associated with CAD in Chinese population. However, the Leu72Met variant is associated with BMI among CAD patients.

Safety Information, Transportation & Public Facilities, State of Alaska

Science.gov Websites

Department of Transportation & Public Facilities/ Safety Information Search DOT&PF State of Alaska DOT&PF> Safety Information DOT&PF Safety Information link to 511 511.alaska.gov - Traveler Information link to AHSO Alaska Highway Safety Office link to HSIP Highway Safety Improvement Program link to

[Study on association of FABP2 gene Ala54Thr polymorphism with risk of obesity, body fat mass and physical activity].

PubMed

Nasibulina, É S; Borisova, A V; Akhmetov, I I

2013-01-01

Obesity is a multifactorial disease which depends on the interaction between genome and environment. Fatty acid-binding protein 2 (FABP2) regulates lipid transport, intestinal absorption and metabolism. The aim of the study was to investigate the interrelation between the FABP2 gene Ala54Thr polymorphism, body mass index and body fat mass and to study distribution of genotypes and alleles frequencies of FABP2 gene in athletes and individuals who are not involved in sports. 315 athletes of different sport disciplines and levels and 612 controls (predominantly students) participated in the study. Genotyping for the FABP2 gene Ala54Thr polymorphism was performed by PCR. Body composition was analyzed by bioimpedance method. The study did not confirm the association of FABP2 gene Ala54Thr polymorphism with the risk of obesity and body fat mass. However, the frequency of the Thr54 allele was significantly higher in elite stayers (50.0%, p = 0.025) and combat athletes (46.2%, p = 0.013) in comparison with controls (32.2%). Thus, FABP2 gene Ala54Thr polymorphism is associated with the predisposition to endurance athletic performance.

CYP3A5 and ABCB1 polymorphisms influence tacrolimus concentrations in peripheral blood mononuclear cells after renal transplantation.

PubMed

Capron, Arnaud; Mourad, Michel; De Meyer, Martine; De Pauw, Luc; Eddour, Djamila Chaib; Latinne, Dominique; Elens, Laure; Haufroid, Vincent; Wallemacq, Pierre

2010-05-01

This prospective study investigated the effect of genetic polymorphisms in a biotransformation enzyme (CYP3A5) and a transporter protein (ABCB1) on tacrolimus (Tac) whole blood concentrations in renal transplantation, and more specifically on peripheral blood mononuclear cell (PBMC) drug concentrations, after renal transplantation. A total of 96 renal transplant recipients were genotyped for the exon 11 (1199G>A), 21 (3435C>T) and 26 (2677G>T/A) polymorphisms in the ABCB1 gene and for the intron 3 polymorphism in the CYP3A5 gene. Tac blood and PBMC concentrations were determined at day 7 after transplantation and at steady state, and then compared with recipient genotypes. The ABCB1 1199G>A, 3435C>T and 2677G>T/A SNPs, appeared to reduce the activity of P-glycoprotein towards Tac, increasing Tac PBMC concentrations. The impact of ABCB1 genetic polymorphisms on Tac blood concentrations was negligible. As increased Tac intracellular concentrations might in turn enhance immunosuppressive status and prevention or rejection, ABCB1 recipient genotyping might be useful to better individualize the Tac immunosuppressive therapy in renal transplantation.

Making connections : intermodal links in the public transportation system

DOT National Transportation Integrated Search

2007-09-01

Since at least 1991, federal transportation policy has sought to encourage intermodal connections the links that allow passengers to switch from one mode of public transportation to another. The intermodal terminal is a key building block for dev...

Serotonin transporter promoter polymorphism and monoamine oxidase type A VNTR allelic variants together influence alcohol binge drinking risk in young women.

PubMed

Herman, Aryeh I; Kaiss, Kristi M; Ma, Rui; Philbeck, John W; Hasan, Asfar; Dasti, Humza; DePetrillo, Paolo B

2005-02-05

The short allelic variant of the serotonin transporter protein promoter polymorphism (5HTTLPR) appears to influence binge drinking in college students. Both monoamine oxidase type A (MAOA) and the serotonin transporter protein are involved in the processing of serotonin, and allelic variants are both associated with differences in the efficiency of expression. We hypothesized that a significant gene x gene interaction would further stratify the risk of binge drinking in this population. Participants were college students (n = 412) who completed the College Alcohol Study, used to measure binge drinking behaviors. Genomic DNA was extracted from saliva for PCR based genotyping. The risk function for binge drinking was modeled using logistic regression, with final model fit P < 0.0005. This model was valid only for Caucasian females (n = 223), but the power to detect sex and ethnic effects was small. Young Caucasian women carrying higher expression MAOA VNTR alleles homozygous for the short allelic variant of the 5HTTLPR demonstrated the highest rate of binge drinking by self-report, odds ratio (genotype odds: population odds) and 95% confidence intervals, 3.11 (1.14-18.10). Individuals carrying higher expression MAOA VNTR alleles carrying at least one long 5HTTLPR allelic variant had the lowest risk of binge drinking 0.46 (0.28-0.71). These results support the hypothesis that binge drinking behavior in young adulthood may be influenced by neurobiological differences in serotonergic function conferred by functional polymorphisms in genes involved in serotonin processing. (c) 2004 Wiley-Liss, Inc.

Narrow Groove and Restricted Anchors of MHC Class I Molecule BF2*0401 Plus Peptide Transporter Restriction can Explain Disease Susceptibility of B4 Chickens

PubMed Central

Zhang, Jianhua; Chen, Yong; Qi, Jianxun; Gao, Feng; Liu, Yanjie; Liu, Jun; Zhou, Xuyu; Kaufman, Jim; Xia, Chun; Gao, George F.

2016-01-01

The major histocompatibility complex (MHC) has genetic associations with many diseases, often due to differences in presentation of antigenic peptides by polymorphic MHC molecules to T lymphocytes of the immune system. In chickens, only a single classical class I molecule in each MHC haplotype is expressed well due to co-evolution with the polymorphic transporters associated with antigen presentation (TAPs), which means that resistance and susceptibility to infectious pathogens are particularly easy to observe. Previously, structures of chicken MHC class I molecule BF2*2101 from B21 haplotype showed an unusually large peptide-binding groove that accommodates a broad spectrum of peptides to present as epitopes to cytotoxic T lymphocytes (CTL), explaining the MHC-determined resistance of B21 chickens to Marek's disease. Here, we report the crystal structure of BF2*0401 from the B4 (also known as B13) haplotype, showing a highly positively-charged surface hitherto unobserved in other MHC molecules, as well as a remarkably narrow groove due to the allele-specific residues with bulky side chains. Together, these properties limit the number of epitope peptides that can bind this class I molecule. However, peptide-binding assays show that in vitro BF2*0401 can bind a wider variety of peptides than are found on the surface of B4 cells. Thus, a combination of the specificities of the polymorphic TAP transporter and the MHC results in a very limited set of BF2*0401 peptides with negatively charged anchors to be presented to T lymphocytes. PMID:23041567

Role of the monocarboxylate transporter MCT1 in the uptake of lactate during active recovery.

PubMed

Cupeiro, Rocío; Pérez-Prieto, Raúl; Amigo, Teresa; Gortázar, Pilar; Redondo, Carlos; González-Lamuño, Domingo

2016-05-01

We assessed the role of monocarboxylate transporter 1 (MCT1) on lactate clearance during an active recovery after high-intensity exercise, by comparing genetic groups based on the T1470A (rs1049434) MCT1 polymorphism, whose influence on lactate transport has been proven. Sixteen young male elite field hockey players participated in this study. All of them completed two 400 m maximal run tests performed on different days, followed by 40 min of active or passive recovery. Lactate samples were measured immediately after the tests, and at min 10, 20, 30 and 40 of the recoveries. Blood lactate decreases were calculated for each 10-min period. Participants were distributed into three groups according to the T1470A polymorphism (TT, TA and AA). TT group had a lower blood lactate decrease than AA group during the 10-20 min period of the active recovery (p = 0.018). This period had the highest blood lactate for the whole sample, significantly differing from the other periods (p ≤ 0.003). During the passive recovery, lactate declines were constant except for the 0-10-min period (p ≤ 0.003), suggesting that liver uptake is similar in all the genetic groups, and that the difference seen during the active recovery is mainly due to muscle lactate uptake. These differences according to the polymorphic variant T1470A suggest that MCT1 affects the plasma lactate decrease during a crucial period of active recovery, where the maximal lactate amount is cleared (i.e. 10-20 min period).

Attachment and Temperament Revisited: Infant Distress, Attachment Disorganization, and the Serotonin Transporter Polymorphism

PubMed Central

Brumariu, Laura E.; Bureau, Jean-François; Nemoda, Zsofia; Sasvari-Szekely, Maria; Lyons-Ruth, Karlen

2015-01-01

Objective This study's aim was to evaluate whether infant disorganized attachment and infant proneness to distress exhibited differential relations to infant genetic factors as indexed by the serotonin transporter polymorphism. Background The role of the short allele of the serotonin transporter polymorphism (5-HTTLPR) in enhancing sensitivity to fearful and negative affect has been well-established (Canli & Lesch, 2007). In the current study, we used this known property of the short allele to provide a test of an important postulate of attachment theory, namely that infant attachment security or disorganization is not a function of the infant's proneness to distress. Methods Participants were 39 parents and infants assessed between 12 and 18 months in the Strange Situation procedure. Genotype categories for the 5-HTTLPR (and rs25531) were created by both the original and the reclassified grouping system; infant proneness to distress was assessed directly in the Strange Situation Procedure. We also assessed maternal behavior at 18 months to evaluate whether any observed genetic effect indicated a passive effect through the mother. Results Consistent with previous findings, the 5-HTTLPR short allele was significantly related to the infant's wariness and distress, but was not related to attachment security or attachment disorganization. In addition, maternal disrupted interaction with the infant was not related to infant genotype or infant distress. Conclusion Results support the concept that infant proneness to distress is associated with serotonergic factors while infant attachment security or disorganization is not a function of either 5-HTTLPR or behaviorally rated proneness to distress. PMID:26912941

Prognostic role of the CDNK1B V109G polymorphism in multiple endocrine neoplasia type 1

PubMed Central

Circelli, Luisa; Ramundo, Valeria; Marotta, Vincenzo; Sciammarella, Concetta; Marciello, Francesca; Del Prete, Michela; Sabatino, Lina; Pasquali, Daniela; Izzo, Francesco; Scala, Stefania; Colao, Annamaria; Faggiano, Antongiulio; Colantuoni, Vittorio

2015-01-01

CDKN1B encodes the cyclin-dependent kinase inhibitor p27/Kip1. CDKN1B mutations and polymorphisms are involved in tumorigenesis; specifically, the V109G single nucleotide polymorphism has been linked to different tumours with controversial results. Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant syndrome, characterized by the development of different types of neuroendocrine tumours and increased incidence of other malignancies. A clear genotype–phenotype correlation in MEN1 has not been established yet. In this study, we assessed whether the CDKN1B V109G polymorphism was associated with the development of aggressive tumours in 55 consecutive patients affected by MEN1. The polymorphism was investigated by PCR amplification of germline DNA followed by direct sequencing. Baseline and follow-up data of tumour types and their severity were collected and associated with the genetic data. MEN1-related aggressive and other malignant tumours of any origin were detected in 16.1% of wild-type and 33.3% of polymorphism allele-bearing patients (P = NS). The time interval between birth and the first aggressive tumour was significantly shorter in patients with the CDKN1B V109G polymorphism (median 46 years) than in those without (median not reached; P = 0.03). Similarly, shorter was the time interval between MEN1 diagnosis and age of the first aggressive tumour (P = 0.02). Overall survival could not be estimated as 96% patients were still alive at the time of the study. In conclusion, CDKN1B V109G polymorphism seems to play a role in the development of aggressive tumours in MEN1. PMID:25824098

Association between polymorphisms in prostanoid receptor genes and aspirin-intolerant asthma.

PubMed

Kim, Sang-Heon; Kim, Yoon-Keun; Park, Heung-Woo; Jee, Young-Koo; Kim, Sang-Hoon; Bahn, Joon-Woo; Chang, Yoon-Seok; Kim, Seung-Hyun; Ye, Young-Min; Shin, Eun-Soon; Lee, Jong-Eun; Park, Hae-Sim; Min, Kyung-Up

2007-04-01

Genetic predisposition is linked to the pathogenesis of aspirin-intolerant asthma. Most candidate gene approaches have focused on leukotriene-related pathways, whereas there have been relatively few studies evaluating the effects of polymorphisms in prostanoid receptor genes on the development of aspirin-intolerant asthma. Therefore, we investigated the potential association between prostanoid receptor gene polymorphisms and the aspirin-intolerant asthma phenotype. We screened for genetic variations in the prostanoid receptor genes PTGER1, PTGER2, PTGER3, PTGER4, PTGDR, PTGIR, PTGFR, and TBXA2R using direct sequencing, and selected 32 tagging single nucleotide polymorphisms among the 77 polymorphisms with frequencies >0.02 based on linkage disequilibrium for genotyping. We compared the genotype distributions and allele frequencies of three participant groups (108 patients with aspirin-intolerant asthma, 93 patients with aspirin-tolerant asthma, and 140 normal controls). Through association analyses studies of the 32 single nucleotide polymorphisms, the following single nucleotide polymorphisms were found to have significant associations with the aspirin-intolerant asthma phenotype: -616C>G (P=0.038) and -166G>A (P=0.023) in PTGER2; -1709T>A (P=0.043) in PTGER3; -1254A>G (P=0.018) in PTGER4; 1915T>C (P=0.015) in PTGIR; and -4684C>T (P=0.027), and 795T>C (P=0.032) in TBXA2R. In the haplotype analysis of each gene, the frequency of PTGIR ht3[G-G-C-C], which includes 1915T>C, differed significantly between the aspirin-intolerant asthma patients and aspirin-tolerant asthma patients (P=0.015). These findings suggest that genetic polymorphisms in PTGER2, PTGER3, PTGER4, PTGIR, and TBXA2R play important roles in the pathogenesis of aspirin-intolerant asthma.

Obsessive-compulsive disorder and the promoter region polymorphism (5-HTTLPR) in the serotonin transporter gene (SLC6A4): a negative association study in the Afrikaner population.

PubMed

Kinnear, Craig J.; Niehaus, Dana J. H.; Moolman-Smook, Johanna C.; du Toit, Pieter L.; van Kradenberg, Jeanine; Weyers, Jakobus B.; Potgieter, Annemarie; Marais, Vanessa; Emsley, Robin A.; Knowles, James A.; Corfield, Valerie A.; Brink, Paul A.; Stein, Dan J.

2000-12-01

A polymorphism (5-HTTLPR) in the promoter region of the serotonin transporter gene (SLC6A4) has been reported to have functional significance and to be associated with obsessive-compulsive disorder (OCD). However, other studies have generated confounding results. A study was undertaken to re-evaluate this association in subjects drawn from the relatively genetically homogeneous Afrikaner population of South Africa. Fifty-four OCD patients of Afrikaner descent and 82 ethnically matched control individuals were phenotyped and genotyped. No significant association was found between the distribution of the 5-HTTLPR genotypes at the SLC6A4 locus and OCD. A similar result (p = 0.108) was generated when a meta-analysis of the 5-HTTLPR polymorphism, combining the current study with a previously reported Caucasian group, was performed; the meta-study comprised 129 OCD patients and 479 control individuals. However, both studies lacked power. Therefore, evidence that variation in SLC6A4 plays a significant role in the development of OCD in the population groups studied is inconclusive. Future association studies in Caucasian populations may extend the power of such meta-analyses and assist in delineating the role of SLC6A4 in OCD.

Impulsivity and the 5-HTTLPR Polymorphism in a Non-Clinical Sample

PubMed Central

Lage, Guilherme M.; Malloy-Diniz, Leandro F.; Matos, Lorena O.; Bastos, Marisa A. R.; Abrantes, Suzana S. C.; Corrêa, Humberto

2011-01-01

Background Impulsivity has been associated with serotonergic system functions. However, few researchers have investigated the relationship between a polymorphism in the promoter of the serotonin transporter gene (5-HTTLPR) and the different components of impulsivity in a non-clinical population. The aim of this study was to investigate the relationship between a polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) and the different components of impulsivity in a non-clinical population. Methodology/Principal Findings We administered two neuropsychological tests, the Continuous Performance Task and the Iowa Gambling Task, to 127 healthy participants to measure their levels of motor, attentional and non-planning impulsivity. Then, these participants were grouped by genotype and gender, and their scores on impulsivity measures were compared. There were no significant differences between group scores on attentional, motor and non-planning impulsivity. Conclusions/Significance Our results suggest that 5-HTTLPR genotype is not significantly associated with subsets of impulsive behavior in a non-clinical sample when measured by neuropsychological tests. These findings are discussed in terms of the sensitivity of neuropsychological tests to detect impulsivity in a non-clinical population and the role of gender and race in the relationship between the 5-HTTLPR and impulsivity. PMID:21386887

Linguistic Grammar Learning and DRD2-TAQ-IA Polymorphism

PubMed Central

Wong, Patrick C. M.; Ettlinger, Marc; Zheng, Jing

2013-01-01

As research into the neurobiology of language has focused primarily on the systems level, fewer studies have examined the link between molecular genetics and normal variations in language functions. Because the ability to learn a language varies in adults and our genetic codes also vary, research linking the two provides a unique window into the molecular neurobiology of language. We consider a candidate association between the dopamine receptor D2 gene (DRD2) and linguistic grammar learning. DRD2-TAQ-IA polymorphism (rs1800497) is associated with dopamine receptor D2 distribution and dopamine impact in the human striatum, such that A1 allele carriers show reduction in D2 receptor binding relative to carriers who are homozygous for the A2 allele. The individual differences in grammatical rule learning that are particularly prevalent in adulthood are also associated with striatal function and its role in domain-general procedural memory. Therefore, we reasoned that procedurally-based grammar learning could be associated with DRD2-TAQ-IA polymorphism. Here, English-speaking adults learned artificial concatenative and analogical grammars, which have been respectively associated with procedural and declarative memory. Language learning capabilities were tested while learners’ neural hemodynamic responses were simultaneously measured by fMRI. Behavioral learning and brain activation data were subsequently compared with the learners’ DRD2 (rs1800497) genotype. Learners who were homozygous for the A2 allele were better at concatenative (but not analogical) grammar learning and had higher striatal responses relative to those who have at least one A1 allele. These results provide preliminary evidence for the neurogenetic basis of normal variations in linguistic grammar learning and its link to domain-general functions. PMID:23741438

Genetic variability in ABCB1, occupational pesticide exposure, and Parkinson's disease.

PubMed

Narayan, Shilpa; Sinsheimer, Janet S; Paul, Kimberly C; Liew, Zeyan; Cockburn, Myles; Bronstein, Jeff M; Ritz, Beate

2015-11-01

Studies suggested that variants in the ABCB1 gene encoding P-glycoprotein, a xenobiotic transporter, may increase susceptibility to pesticide exposures linked to Parkinson's Disease (PD) risk. To investigate the joint impact of two ABCB1 polymorphisms and pesticide exposures on PD risk. In a population-based case control study, we genotyped ABCB1 gene variants at rs1045642 (c.3435C/T) and rs2032582 (c.2677G/T/A) and assessed occupational exposures to organochlorine (OC) and organophosphorus (OP) pesticides based on self-reported occupational use and record-based ambient workplace exposures for 282 PD cases and 514 controls of European ancestry. We identified active ingredients in self-reported occupational use pesticides from a California database and estimated ambient workplace exposures between 1974 and 1999 employing a geographic information system together with records for state pesticide and land use. With unconditional logistic regression, we estimated marginal and joint contributions for occupational pesticide exposures and ABCB1 variants in PD. For occupationally exposed carriers of homozygous ABCB1 variant genotypes, we estimated odds ratios of 1.89 [95% confidence interval (CI): (0.87, 4.07)] to 3.71 [95% CI: (1.96, 7.02)], with the highest odds ratios estimated for occupationally exposed carriers of homozygous ABCB1 variant genotypes at both SNPs; but we found no multiplicative scale interactions. This study lends support to a previous report that commonly used pesticides, specifically OCs and OPs, and variant ABCB1 genotypes at two polymorphic sites jointly increase risk of PD. Copyright © 2015 Elsevier Inc. All rights reserved.

The role of methylenetetrahydrofolate reductase in acute lymphoblastic leukemia in a Brazilian mixed population.

PubMed

Zanrosso, Crisiane Wais; Hatagima, Ana; Emerenciano, Mariana; Ramos, Flávio; Figueiredo, Alexandre; Félix, Têmis Maria; Segal, Sandra L; Giugliani, Roberto; Guigliani, Roberto; Muniz, Maria Tereza Cartaxo; Pombo-de-Oliveira, Maria S

2006-04-01

The polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene are associated with leukemogenesis. In order to investigate the influence of two polymorphisms in the MTHFR gene, 677C>T and 1298A>C, on the risk of acute lymphoblastic leukemia (ALL) we performed a case-control study in children from different Brazilians' regions. Genotyping of 176 ALL and 199 unselected healthy subjects was performed using PCR-RFLP assay. There was no association between the 677C>T or 1298A>C and risk of ALL in total case-control sample. However, 677T allele was linked to a decrease risk of ALL [odds ratio (OR), 0.43; 95% confidence interval (CI), 0.22-0.86], whereas the 1298A>C polymorphism presents an elevated risk factor [OR, 2.01; 95% CI, 1.01-3.99] in non-White children. Our investigation provides interesting data concerning the opposite effect of A1298C polymorphisms, particularly in the light of relatively scarce data regarding the MTHFR role in leukemia susceptibility in different populations.

Polymorphism in Alkali Metal Uranyl Nitrates: Synthesis and Crystal Structure of γ-K(UO2)(NO3)3

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jouffret, Laurent J.; Krivovichev, Sergey V.; Burns, Peter C.

2011-07-20

Single crystals of γ-K(UO2)(NO3)3 were prepared from aqueous solutions by evaporation. The crystal structure [orthorhombic, Pbca (61), a = 9.2559(3) Å, b = 12.1753(3) Å, c = 15.8076(5) Å, V = 1781.41(9) Å3, Z = 8] was determined by direct methods and refined to R1 = 0.0267 on the basis of 3657 unique observed reflections. The structure is composed of isolated anionic uranyl trinitrate units, [(UO2)(NO3)3]–, that are linked through eleven-coordinated K+ cations. Both known polymorphs of K(UO2)(NO3)3 (α- and γ-phases) can be considered as based upon sheets of isolated complex [(UO2)(NO3)3]– ions separated by K+ cations. The existence ofmore » polymorphism in the two K[UO2(NO3)3] polymorphs is due to the different packing modes of uranyl trinitrate clusters that adopt the same two-dimensional but different three-dimensional arrangements.« less

Smoking and polymorphisms of fucosyltransferase gene Le affect success of H. pylori eradication with lansoprazole, amoxicillin, and clarithromycin.

PubMed Central

Matsuo, K.; Hamajima, N.; Ikehara, Y.; Suzuki, T.; Nakamura, T.; Matsuura, A.; Tajima, K.; Tominaga, S.

2003-01-01

Identification of factors influencing success of Helicobacter pylori (HP) eradication is important for clinical practice. We have prospectively conducted an HP eradication study in the Aichi Cancer Center with a total of 142 patients available for analysis. The overall success rate was 61.3% (95% confidence interval 52.7-69.3%). Smoking during the medication for eradication significantly decreased the success rate (42.9%), whereas smoking cessation during the treatment was associated with a similar rate as for non-smokers (66.7%). We also examined links between an eradication outcome and polymorphisms of Le, Se, IL1A, IL1B, IL1RN and MPO genes, but with one exception none showed any association. The non-functional le allele of Le polymorphisms, leading to decreased expression of Le(b) antigen to which HP attaches with adhesin, showed a beneficial effect for success. Although further clarification is necessary, our study indicated that smoking cessation and Le gene polymorphisms may affect the success rate of HP eradication. PMID:12729191

Polymorphisms in the presumptive promoter region of the SLC2A9 gene are associated with gout in a Chinese male population.

PubMed

Li, Changgui; Chu, Nan; Wang, Binbin; Wang, Jing; Luan, Jian; Han, Lin; Meng, Dongmei; Wang, Yunlong; Suo, Peisu; Cheng, Longfei; Ma, Xu; Miao, Zhimin; Liu, Shiguo

2012-01-01

Glucose transporter 9 (GLUT9) is a high-capacity/low-affinity urate transporter. To date, several recent genome-wide association studies (GWAS) and follow-up studies have identified genetic variants of SLC2A9 associated with urate concentrations and susceptibility to gout. We therefore investigated associations between gout and polymorphisms and haplotypes in the presumptive promoter region of GLUT9 in Chinese males. The approximately 2000 bp presumptive promoter region upstream of the start site of exon 1 of GLUT9 was sequenced and subjected to genetic analysis. A genotype-phenotype correlation was performed and polymorphisms-induced changes in transcription factor binding sites were predicted. Of 21 SNPs identified in GLUT9, five had not been previously reported. Two of the SNPs (rs13124007 and rs6850166) were associated with susceptibility to gout (p = 0.009 and p = 0.042, respectively). The C allele of rs13124007 appeared to be the risk allele for predisposition to gout (p = 0.006, OR 1.709 [95% CI 1.162-2.514]). For rs6850166, an increased risk of gout was associated with the A allele (p = 0.029, OR 1.645 [95% CI 1.050-2.577]). After Bonferroni correction, there was statistically difference in rs13124007 allele frequencies between gout cases and controls (P = 0.042). Haplotype analyses showed that haplotype GG was a protective haplotype (p = 0.0053) and haplotype CA was associated with increased risk of gout (p = 0.0326). Genotype-phenotype analysis among gout patients revealed an association of rs13124007 with serum triglycerides levels (P = 0.001). The C to G substitution in polymorphism rs13124007 resulted in a loss of a binding site for transcription factor interferon regulatory factor 1 (IRF-1). Polymorphisms rs13124007 and rs6850166 are associated with susceptibility to gout in Chinese males.

Functional Genomics of Attention-Deficit/ Hyperactivity Disorder (ADHD) Risk Alleles on Dopamine Transporter Binding in ADHD and Healthy Control Subjects

PubMed Central

Spencer, Thomas J.; Biederman, Joseph; Faraone, Stephen V.; Madras, Bertha K.; Bonab, Ali A.; Dougherty, Darin D.; Batchelder, Holly; Clarke, Allison; Fischman, Alan J.

2013-01-01

Background The main aim of this study was to examine the relationship between dopamine transporter (DAT) binding in the striatum in individuals with and without attention-deficit/hyperactivity disorder (ADHD), attending to the 3′-untranslated region of the gene (3′-UTR) and intron8 variable number of tandem repeats (VNTR) polymorphisms of the DAT (SLC6A3) gene. Methods Subjects consisted of 68 psychotropic (including stimulant)-naïve and smoking-naïve volunteers between 18 and 55 years of age (ADHD n = 34; control subjects n = 34). Striatal DAT binding was measured with positron emission tomography with 11C altropane. Genotyping of the two DAT (SLC6A3) 3′-UTR and intron8 VNTRs used standard protocols. Results The gene frequencies of each of the gene polymorphisms assessed did not differ between the ADHD and control groups. The ADHD status (t = 2.99; p < .004) and 3′-UTR of SLC6A3 9 repeat carrier status (t = 2.74; p < .008) were independently and additively associated with increased DAT binding in the caudate. The ADHD status was associated with increased striatal (caudate) DAT binding regardless of 3′-UTR genotype, and 3′-UTR genotype was associated with increased striatal (caudate) DAT binding regardless of ADHD status. In contrast, there were no significant associations between polymorphisms of DAT intron8 or the 3′-UTR-intron8 haplotype with DAT binding. Conclusions The 3′-UTR but not intron8 VNTR genotypes were associated with increased DAT binding in both ADHD patients and healthy control subjects. Both ADHD status and the 3′-UTR polymorphism status had an additive effect on DAT binding. Our findings suggest that an ADHD risk polymorphism (3′-UTR) of SLC6A3 has functional consequences on central nervous system DAT binding in humans. PMID:23273726

Abcb1a but not Abcg2 played a predominant role in limiting the brain distribution of Huperzine A in mice.

PubMed

Li, Jiajun; Yue, Mei; Zhou, Dandan; Wang, Meiyu; Zhang, Hongjian

2017-09-01

Huperzine A has been used for improving symptoms of Alzheimer's disease. Its cholinergic side effect is thought to be an exaggerated pharmacological outcome linked to its high brain or CNS concentrations. Although Huperzine A is brain penetrable, its interaction with efflux transporters (ABCB1 and ABCG2) has not been fully investigated. The aim of the present study was to characterize roles of ABCB1 and ABCG2 in the transmembrane transport of Huperzine A and identify a rate limiting step in its brain distribution. Data obtained from stably transfected MDCK II cells showed that Huperzine A is a substrate of ABCB1 but not ABCG2. ABCB1 inhibitors significantly inhibited ABCB1 mediated efflux of Huperzine A. In Abcb1a -/- mice, the brain to plasma concentration ratio of Huperzine A was significantly increased as compared to the wild type mice, while there were no obvious differences between the wild type and Abcg2 -/- mice. Taken together, the present study demonstrated that ABCB1 but not ABCG2 played a predominant role in the efflux of Huperzine A across BBB. The current finding is clinically relevant as changes in ABCB1 activity in the presence of ABCB1 inhibitors or genetic polymorphism may affect efficacy and safety of Huperzine A. Copyright © 2017 Elsevier Ltd. All rights reserved.

Loss aversion and 5HTT gene variants in adolescent anxiety.

PubMed

Ernst, Monique; Plate, Rista C; Carlisi, Christina O; Gorodetsky, Elena; Goldman, David; Pine, Daniel S

2014-04-01

Loss aversion, a well-documented behavioral phenomenon, characterizes decisions under risk in adult populations. As such, loss aversion may provide a reliable measure of risky behavior. Surprisingly, little is known about loss aversion in adolescents, a group who manifests risk-taking behavior, or in anxiety disorders, which are associated with risk-avoidance. Finally, loss aversion is expected to be modulated by genotype, particularly the serotonin transporter (SERT) gene variant, based on its role in anxiety and impulsivity. This genetic modulation may also differ between anxious and healthy adolescents, given their distinct propensities for risk taking. The present work examines the modulation of loss aversion, an index of risk-taking, and reaction-time to decision, an index of impulsivity, by the serotonin-transporter-gene-linked polymorphisms (5HTTLPR) in healthy and clinically anxious adolescents. Findings show that loss aversion (1) does manifest in adolescents, (2) does not differ between healthy and clinically anxious participants, and (3), when stratified by SERT genotype, identifies a subset of anxious adolescents who are high SERT-expressers, and show excessively low loss-aversion and high impulsivity. This last finding may serve as preliminary evidence for 5HTTLPR as a risk factor for the development of comorbid disorders associated with risk-taking and impulsivity in clinically anxious adolescents. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Serotonin Transporter Genotype (5HTTLPR) Moderates the Longitudinal Impact of Atypical Attachment on Externalizing Behavior.

PubMed

Humphreys, Kathryn L; Zeanah, Charles H; Nelson, Charles A; Fox, Nathan A; Drury, Stacy S

2015-01-01

To test whether genotype of the serotonin transporter-linked polymorphic region (5HTTLPR) and atypical attachment interact to predict externalizing psychopathology prospectively in a sample of children with a history of early institutional care. Caregiver report of externalizing behavior at 54 months was examined in 105 children initially reared in institutional care and enrolled in the Bucharest Early Intervention Project, a randomized controlled trial of high quality foster care. 5HTTLPR genotype, attachment status at 42 months of age (typical [secure, avoidant, or ambivalent] or atypical [disorganized-controlling, insecure-other]), and their interaction were examined as predictors of externalizing behavior at age 54 months. 5HTTLPR genotype and atypical attachment at age 42 months interacted to predict externalizing behavior at age 54 months. Specifically, children with the s/s genotype with an atypical attachment had the highest externalizing scores. However, s/s children with a typical attachment demonstrated the lowest externalizing scores, even after controlling for intervention group status. There was no association between attachment status and externalizing behavior among children carrying at least 1 copy of the l allele. These findings indicate that genetic variation in the serotonergic system moderates the association between atypical attachment status and externalizing in young children. Our findings suggest that children, as a result of genetic variability in the serotonergic system, demonstrate differential sensitivity to the attachment relationship.

Serotonin Transporter Genotype (5HTTLPR) Moderates the Longitudinal Impact of Atypical Attachment on Externalizing Behavior

PubMed Central

Humphreys, Kathryn L.; Zeanah, Charles H.; Nelson, Charles A.; Fox, Nathan A.; Drury, Stacy S.

2015-01-01

Objective To test whether genotype of the serotonin transporter-linked polymorphic region (5HTTLPR) and atypical attachment interact to predict externalizing psychopathology prospectively in a sample of children with a history of early institutional care. Methods Caregiver report of externalizing behavior at 54 months was examined in 105 children initially reared in institutional care and enrolled in the Bucharest Early Intervention Project, a randomized controlled trial of high quality foster care. 5HTTLPR genotype, attachment status at 42 months of age (typical [secure, avoidant, or ambivalent] or atypical [disorganized-controlling, insecure-other]), as well as their interaction, were examined as predictors of externalizing behavior at age 54 months. Results 5HTTLPR genotype and atypical attachment at age 42 months interacted to predict externalizing behavior at age 54 months. Specifically, children with the s/s genotype with an atypical attachment had the highest externalizing scores. However, s/s children with a typical attachment demonstrated the lowest externalizing scores, even after controlling for intervention group status. There was no association between attachment status and externalizing behavior among children carrying at least one copy of the l allele. Discussion These findings indicate that genetic variation in the serotonergic system moderates the association between atypical attachment status and externalizing in young children. Our findings suggest that children, as a result of genetic variability in the serotonergic system, demonstrate differential sensitivity to the attachment relationship. PMID:25933228

The Impact of Serotonin Transporter (5-HTTLPR) Genotype on the Development of Resting-State Functional Connectivity in Children and Adolescents: A Preliminary Report

PubMed Central

Wiggins, Jillian Lee; Bedoyan, Jirair K.; Peltier, Scott J.; Ashinoff, Samantha; Carrasco, Melisa; Weng, Shih-Jen; Welsh, Robert C.; Martin, Donna M.; Monk, Christopher S.

2011-01-01

A fundamental component of brain development is the formation of large-scale networks across the cortex. One such network, the default network, undergoes a protracted development, displaying weak connectivity in childhood that strengthens in adolescence and becomes most robust in adulthood. Little is known about the genetic contributions to default network connectivity in adulthood or during development. Alterations in connectivity between posterior and frontal portions of the default network have been associated with several psychological disorders, including anxiety, autism spectrum disorders, schizophrenia, depression, and attention-deficit/hyperactivity disorder. These disorders have also been linked to variants of the serotonin transporter linked polymorphic region (5-HTTLPR). The LA allele of 5-HTTLPR results in higher serotonin transporter expression than the S allele or the rarer LG allele. 5-HTTLPR may influence default network connectivity, as the superior medial frontal region has been shown to be sensitive to changes in serotonin. Also, serotonin as a growth factor early in development may alter large-scale networks such as the default network. The present study examined the influence of 5-HTTLPR variants on connectivity between the posterior and frontal structures and its development in a cross-sectional study of 39 healthy children and adolescents. We found that children and adolescents homozygous for the S allele (S/S, n = 10) showed weaker connectivity in the superior medial frontal cortex compared to those homozygous for the LA allele (LA/LA, n = 13) or heterozygotes (S/LA, S/LG, n = 16). Moreover, there was an age-by-genotype interaction, such that those with LA/LA genotype had the steepest age-related increase in connectivity between the posterior hub and superior medial frontal cortex, followed by heterozygotes. In contrast, individuals with the S/S genotype had the least age-related increase in connectivity strength. This preliminary report expands our understanding of the genetic influences on the development of large-scale brain connectivity and lays down the foundation for future research and replication of the results with a larger sample. PMID:22032950

Recurrent selection on the Winters sex-ratio genes in Drosophila simulans.

PubMed

Kingan, Sarah B; Garrigan, Daniel; Hartl, Daniel L

2010-01-01

Selfish genes, such as meiotic drive elements, propagate themselves through a population without increasing the fitness of host organisms. X-linked (or Y-linked) meiotic drive elements reduce the transmission of the Y (X) chromosome and skew progeny and population sex ratios, leading to intense conflict among genomic compartments. Drosophila simulans is unusual in having a least three distinct systems of X chromosome meiotic drive. Here, we characterize naturally occurring genetic variation at the Winters sex-ratio driver (Distorter on the X or Dox), its progenitor gene (Mother of Dox or MDox), and its suppressor gene (Not Much Yang or Nmy), which have been previously mapped and characterized. We survey three North American populations as well as 13 globally distributed strains and present molecular polymorphism data at the three loci. We find that all three genes show signatures of selection in North America, judging from levels of polymorphism and skews in the site-frequency spectrum. These signatures likely result from the biased transmission of the driver and selection on the suppressor for the maintenance of equal sex ratios. Coalescent modeling indicates that the timing of selection is more recent than the age of the alleles, suggesting that the driver and suppressor are coevolving under an evolutionary "arms race." None of the Winters sex-ratio genes are fixed in D. simulans, and at all loci we find ancestral alleles, which lack the gene insertions and exhibit high levels of nucleotide polymorphism compared to the derived alleles. In addition, we find several "null" alleles that have mutations on the derived Dox background, which result in loss of drive function. We discuss the possible causes of the maintenance of presence-absence polymorphism in the Winters sex-ratio genes.

Oxytocin and Opioid Receptor Gene Polymorphisms Associated with Greeting Behavior in Dogs.

PubMed

Kubinyi, Enikő; Bence, Melinda; Koller, Dora; Wan, Michele; Pergel, Eniko; Ronai, Zsolt; Sasvari-Szekely, Maria; Miklósi, Ádám

2017-01-01

Meeting humans is an everyday experience for most companion dogs, and their behavior in these situations and its genetic background is of major interest. Previous research in our laboratory reported that in German shepherd dogs the lack of G allele, and in Border collies the lack of A allele, of the oxytocin receptor gene (OXTR) 19208A/G single nucleotide polymorphism (SNP) was linked to increased friendliness, which suggests that although broad traits are affected by genetic variability, the specific links between alleles and behavioral variables might be breed-specific. In the current study, we found that Siberian huskies with the A allele approached a friendly unfamiliar woman less frequently in a greeting test, which indicates that certain polymorphisms are related to human directed behavior, but that the relationship patterns between polymorphisms and behavioral phenotypes differ between populations. This finding was further supported by our next investigation. According to primate studies, endogenous opioid peptide (e.g., endorphins) receptor genes have also been implicated in social relationships. Therefore, we examined the rs21912990 of the OPRM1 gene. Firstly, we found that the allele frequencies of Siberian huskies and gray wolves were similar, but differed from that of Border collies and German shepherd dogs, which might reflect their genetic relationship. Secondly, we detected significant associations between the OPRM1 SNP and greeting behavior among German shepherd dogs and a trend in Border collies, but we could not detect an association in Siberian huskies. Although our results with OXTR and OPRM1 gene variants should be regarded as preliminary due to the relatively low sample size, they suggest that (1) OXTR and OPRM1 gene variants in dogs affect human-directed social behavior and (2) their effects differ between breeds.

Oxytocin and Opioid Receptor Gene Polymorphisms Associated with Greeting Behavior in Dogs

PubMed Central

Kubinyi, Enikő; Bence, Melinda; Koller, Dora; Wan, Michele; Pergel, Eniko; Ronai, Zsolt; Sasvari-Szekely, Maria; Miklósi, Ádám

2017-01-01

Meeting humans is an everyday experience for most companion dogs, and their behavior in these situations and its genetic background is of major interest. Previous research in our laboratory reported that in German shepherd dogs the lack of G allele, and in Border collies the lack of A allele, of the oxytocin receptor gene (OXTR) 19208A/G single nucleotide polymorphism (SNP) was linked to increased friendliness, which suggests that although broad traits are affected by genetic variability, the specific links between alleles and behavioral variables might be breed-specific. In the current study, we found that Siberian huskies with the A allele approached a friendly unfamiliar woman less frequently in a greeting test, which indicates that certain polymorphisms are related to human directed behavior, but that the relationship patterns between polymorphisms and behavioral phenotypes differ between populations. This finding was further supported by our next investigation. According to primate studies, endogenous opioid peptide (e.g., endorphins) receptor genes have also been implicated in social relationships. Therefore, we examined the rs21912990 of the OPRM1 gene. Firstly, we found that the allele frequencies of Siberian huskies and gray wolves were similar, but differed from that of Border collies and German shepherd dogs, which might reflect their genetic relationship. Secondly, we detected significant associations between the OPRM1 SNP and greeting behavior among German shepherd dogs and a trend in Border collies, but we could not detect an association in Siberian huskies. Although our results with OXTR and OPRM1 gene variants should be regarded as preliminary due to the relatively low sample size, they suggest that (1) OXTR and OPRM1 gene variants in dogs affect human-directed social behavior and (2) their effects differ between breeds. PMID:28936190

Association of the plasminogen activator inhibitor-1 (PAI-1) Gene -675 4G/5G and -844 A/G promoter polymorphism with risk of keloid in a Chinese Han population.

PubMed

Wang, Yongjie; Long, Jianhong; Wang, Xiaoyan; Sun, Yang

2014-10-28

A keloid is pathological scar caused by aberrant response to skin injuries, characterized by excessive accumulation of histological extracellular matrix, and occurs in genetically susceptible individuals. Plasminogen activator inhibitor-1 (PAI-1) has been implicated in the pathogenesis of keloid. We investigated the association between PAI-1 polymorphisms and plasma PAI-1 level with keloid risk. A total of 242 Chinese keloid patients and 207 controls were enrolled in this study. Polymerase chain reaction-restriction technique was used to determine PAI-1 promoter polymorphism (-675 4G/5G and -844 A/G) distribution. Plasma PAI-1 levels were detected using enzyme-linked immunosorbent assay (ELISA). There was a statistically significant difference in the distribution of PAI-1 -675 4G/5G polymorphism between keloid patients and healthy controls. 4G/4G carriers were more likely to develop keloid. In contrast, the -844 A/G polymorphism distribution did not vary significantly between keloid patients and controls. The keloid patients group had a significantly higher plasma PAI-1 level than the control group. In the -675 4G/4G carrier population, the plasma PAI-1 levels were significant higher in keloid patients compared with controls. Our study provides evidence that PAI-1 promoter polymorphism -675 4G/5G and plasma PAI-1 level are associated with keloid risk. PAI-1 -675 4G/5G polymorphism may be an important hereditary factor responsible for keloid development in the Chinese Han population.

ABCB1 polymorphism as prognostic factor in breast cancer patients treated with docetaxel and doxorubicin neoadjuvant chemotherapy

PubMed Central

Kim, Hee-Jun; Im, Seock-Ah; Keam, Bhumsuk; Ham, Hye Seon; Lee, Kyung Hun; Kim, Tae Yong; Kim, Yu Jung; Oh, Do-Youn; Kim, Jee Hyun; Han, Wonshik; Jang, In-Jin; Kim, Tae-You; Park, In Ae; Noh, Dong Young

2015-01-01

Expression of the adenosine triphosphate-binding cassette B1 (ABCB1) transporter and P-glycoprotein are associated with resistance to anticancer drugs. The purpose of this study was to investigate the role of single nucleotide polymorphism in the ABCB1 and CYP3A genes in breast cancer patients who were treated with neoadjuvant chemotherapy. Stage II/III breast cancer patients were treated with three cycles of neoadjuvant, after which the patients received curative surgery and adjuvant chemotherapy. The polymorphisms of ABCB1 and CYP3A were genotyped. The correlation of polymorphism of ABCB1, CYP3A, and clinical outcomes was analyzed. Among the 216 patients, ABCB1 3435TT genotype had a longer overall survival (OS). than CC/CT. Multivariate analyses demonstrated that good PS, invasive ductal carcinoma, non-triple negative phenotype and initial operable stage were significantly associated with a lower death risk. ABCB1 3435TT genotype had a higher AUC than CC/CT for docetaxel. These higher AUCs in the C3435TT was associated with increased toxicities of neutropenia and diarrhea. This study showed that the genetic polymorphism of ABCB1 C3435T might be associated with a longer OS. Our results also suggest that the prediction of docetaxel toxicity might be possible for C3435T polymorphism. This study results provides valuable information on individualized therapy according to genotypes. PMID:25410489

Structural rearrangements at the translocation pore of the human glutamate transporter, EAAT1.

PubMed

Leighton, Barbara H; Seal, Rebecca P; Watts, Spencer D; Skyba, Mary O; Amara, Susan G

2006-10-06

Structure-function studies of mammalian and bacterial excitatory amino acid transporters (EAATs), as well as the crystal structure of a related archaeal glutamate transporter, support a model in which TM7, TM8, and the re-entrant loops HP1 and HP2 participate in forming a substrate translocation pathway within each subunit of a trimer. However, the transport mechanism, including precise binding sites for substrates and co-transported ions and changes in the tertiary structure underlying transport, is still not known. In this study, we used chemical cross-linking of introduced cysteine pairs in a cysteine-less version of EAAT1 to examine the dynamics of key domains associated with the translocation pore. Here we show that cysteine substitution at Ala-395, Ala-367, and Ala-440 results in functional single and double cysteine transporters and that in the absence of glutamate or dl-threo-beta-benzyloxyaspartate (dl-TBOA), A395C in the highly conserved TM7 can be cross-linked to A367C in HP1 and to A440C in HP2. The formation of these disulfide bonds is reversible and occurs intra-molecularly. Interestingly, cross-linking A395C to A367C appears to abolish transport, whereas cross-linking A395C to A440C lowers the affinities for glutamate and dl-TBOA but does not change the maximal transport rate. Additionally, glutamate and dl-TBOA binding prevent cross-linking in both double cysteine transporters, whereas sodium binding facilitates cross-linking in the A395C/A367C transporter. These data provide evidence that within each subunit of EAAT1, Ala-395 in TM7 resides close to a residue at the tip of each re-entrant loop (HP1 and HP2) and that these residues are repositioned relative to one another at different steps in the transport cycle. Such behavior likely reflects rearrangements in the tertiary structure of the translocation pore during transport and thus provides constraints for modeling the structural dynamics associated with transport.

Entomophaga maimaiga panzootic in northeastern gypsy moth populations

Treesearch

Ann E. Hajek; Joseph S. Elkinton

1991-01-01

The fungal pathogen causing extensive mortality in gypsy moth larval populations during the 1989 field season has been identified as Entomophaga maimaiga. Identification was based on morphology and in vitro culture requirements, as well as results from allozyme and restriction fragment linked polymorphism analyses. E....

Clonality in myeloproliferative disorders: Analysis by means of polymerase chain reaction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gilliland, D.G.; Blanchard, K.L.; Levy, J.

1991-08-01

The myeloproliferative syndromes are acquired disorders of hematopoiesis that provide insights into the transition from somatic cell mutation to neoplasia. The clonal origin of specific blood cells can be assessed in patients with X chromosome-linked polymorphisms, taking advantage of random inactivation of the X chromosome. The authors have adapted the PCR for determination of clonality on as few as 100 cells, including individual colonies grown in culture. Amplifying a polymorphic portion of the X chromosome-linked phosphoglycerate kinase (PGK) gene after selective digestion of the active X chromosome with a methylation-sensitive restriction enzyme gave results fully concordant with standard Southern blottingmore » of DNA samples form normal (polyclonal) polymorphonuclear cells (PMN) as well as clonal PMN from patients with myelodysplastic syndrome and polycythemia vera (PCV). They have used this technique to demonstrate heterogeneity of lineage involvement in patients with PCV. The same clinical phenotype may arise from clonal proliferation of different hematopoietic progenitors.« less

Investigation of Outbreaks of Salmonella enterica Serovar Typhimurium and Its Monophasic Variants Using Whole-Genome Sequencing, Denmark

PubMed Central

Gymoese, Pernille; Sørensen, Gitte; Litrup, Eva; Olsen, John Elmerdal; Nielsen, Eva Møller

2017-01-01

Whole-genome sequencing is rapidly replacing current molecular typing methods for surveillance purposes. Our study evaluates core-genome single-nucleotide polymorphism analysis for outbreak detection and linking of sources of Salmonella enterica serovar Typhimurium and its monophasic variants during a 7-month surveillance period in Denmark. We reanalyzed and defined 8 previously characterized outbreaks from the phylogenetic relatedness of the isolates, epidemiologic data, and food traceback investigations. All outbreaks were identified, and we were able to exclude unrelated and include additional related human cases. We were furthermore able to link possible food and veterinary sources to the outbreaks. Isolates clustered according to sequence types (STs) 19, 34, and 36. Our study shows that core-genome single-nucleotide polymorphism analysis is suitable for surveillance and outbreak investigation for Salmonella Typhimurium (ST19 and ST36), but whole genome–wide analysis may be required for the tight genetic clone of monophasic variants (ST34). PMID:28930002

[Genetic polymorphism of Tulipa gesneriana L. evaluated on the basis of the ISSR marking data].

PubMed

Kashin, A S; Kritskaya, T A; Schanzer, I A

2016-10-01

Using the method of ISSR analysis, the genetic diversity of 18 natural populations of Tulipa gesneriana L. from the north of the Lower Volga region was examined. The ten ISSR primers used in the study provided identification of 102 PCR fragments, of which 50 were polymorphic (49.0%). According to the proportion of polymorphic markers, two population groups were distinguished: (1) the populations in which the proportion of polymorphic markers ranged from 0.35 to 0.41; (2) the populations in which the proportion of polymorphic markers ranged from 0.64 to 0.85. UPGMA clustering analysis provided subdivision of the sample into two large clusters. The unrooted tree constructed using the Neighbor Joining algorithm had similar topology. The first cluster included slightly variable populations and the second cluster included highly variable populations. The AMOVA analysis showed statistically significant differences (F CT = 0.430; p = 0.000) between the two groups. Local populations are considerably genetically differentiated from each other (F ST = 0.632) and have almost no links via modern gene flow, as evidenced by the results of the Mantel test (r =–0.118; p = 0.819). It is suggested that the degree of genetic similarities and differences between the populations depends on the time and the species dispersal patterns on these territories.

Meta-Analysis of the Relation Between IL10 Promoter Polymorphisms and Autoimmune Liver Disease Risk.

PubMed

Qian, Bao-Xin; Ye, Qing; Zhao, Xin-Yu; Han, Tao; Wang, Feng-Mei; Yang, Jie

2018-05-01

Single nucleotide polymorphisms of the IL10 gene have been linked to the occurrence of autoimmune liver disease. We performed a meta-analysis to assess the association between three IL10 promoter polymorphisms (rs1800896, rs1800871, and rs1800872) and the risk of autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. In total, 1420 articles were initially identified through database retrieval. After screening, seven eligible articles were ultimately included in the meta-analysis. A fixed-effect model was used for all Mantel-Haenszel statistics due to the absence of large between-study heterogeneity (all I 2 < 50%, p > 0.1). No association between any of the studied polymorphisms and risk of autoimmune liver disease was detected in the allele, homozygote, heterozygote, dominant, recessive, or carrier genetic models (p association > 0.05). Potential publication bias was excluded using Begg's and Egger's tests. Similar negative results were observed in subgroup analyses and in an analysis of the three haplotypes of rs1800896/rs1800871/rs1800872 (G/C/C, A/C/C, and A/T/A). Our meta-analysis strongly suggests that the IL10 rs1800896, rs1800871, and rs1800872 polymorphisms are not associated with the risk of autoimmune liver disease.

Meta-Prediction of the Effect of Methylenetetrahydrofolate Reductase Polymorphisms and Air Pollution on Alzheimer's Disease Risk.

PubMed

Wu, Suh-Mian; Chen, Zhao-Feng; Young, Lufei; Shiao, S Pamela K

2017-01-11

Background : Alzheimer's disease (AD) is a significant public health issue. AD has been linked with methylenetetrahydrofolate reductase ( MTHFR ) C677T polymorphism, but the findings have been inconsistent. The purpose of this meta-predictive analysis is to examine the associations between MTHFR polymorphisms and epigenetic factors, including air pollution, with AD risk using big data analytics approaches. Methods and Results : Forty-three studies (44 groups) were identified by searching various databases. MTHFR C677T TT and CT genotypes had significant associations with AD risk in all racial populations (RR = 1.13, p = 0.0047; and RR = 1.12, p < 0.0001 respectively). Meta-predictive analysis showed significant increases of percentages of MTHFR C677T polymorphism with increased air pollution levels in both AD case group and control group ( p = 0.0021-0.0457); with higher percentages of TT and CT genotypes in the AD case group than that in the control group with increased air pollution levels. Conclusions : The impact of MTHFR C677T polymorphism on susceptibility to AD was modified by level of air pollution. Future studies are needed to further examine the effects of gene-environment interactions including air pollution on AD risk for world populations.

Association between polymorphisms of the insulin-degrading enzyme gene and late-onset Alzheimer disease.

PubMed

Wang, Shitao; He, Feiyan; Wang, Ying

2015-06-01

The insulin-degrading enzyme (IDE) gene is a strong positional and biological candidate for late-onset Alzheimer disease (LOAD) susceptibility, with recent studies independently demonstrating an association between IDE gene variants and LOAD. However, previous data have been controversial. To investigate the relationship between IDE gene polymorphisms and LOAD risk, a case-control association study of 406 Han Chinese participants in Xinjiang, China, was undertaken. The LOAD and control groups consisted of 202 and 204 participants, respectively. The single-nucleotide polymorphisms rs1887922 and rs1999764 of the IDE gene were linked to LOAD incidence. The presence of the CT+CC genotype of rs1999764 had a protective effect compared to the TT genotype (adjusted P=.0001; odds ratio [OR]=0.226; 95% confidence interval [CI]=0.116-0.441), while the CT+CC genotype of rs1887922 was associated with increased LOAD risk (adjusted P=.0001; OR=3.640; 95% CI=1.889-7.016). Moreover, the effects of rs1887922 and rs1999764 were associated with LOAD risk independent of the apolipoprotein E ∊4 polymorphism and were more significant in men and women, respectively. These results demonstrate that the polymorphisms rs1887922 and rs1999764 of the IDE gene are associated with LOAD susceptibility in the Xinjiang Han population. © The Author(s) 2014.

Meta-Prediction of the Effect of Methylenetetrahydrofolate Reductase Polymorphisms and Air Pollution on Alzheimer’s Disease Risk

PubMed Central

Wu, Suh-Mian; Chen, Zhao-Feng; Young, Lufei; Shiao, S. Pamela K.

2017-01-01

Background: Alzheimer’s disease (AD) is a significant public health issue. AD has been linked with methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, but the findings have been inconsistent. The purpose of this meta-predictive analysis is to examine the associations between MTHFR polymorphisms and epigenetic factors, including air pollution, with AD risk using big data analytics approaches. Methods and Results: Forty-three studies (44 groups) were identified by searching various databases. MTHFR C677T TT and CT genotypes had significant associations with AD risk in all racial populations (RR = 1.13, p = 0.0047; and RR = 1.12, p < 0.0001 respectively). Meta-predictive analysis showed significant increases of percentages of MTHFR C677T polymorphism with increased air pollution levels in both AD case group and control group (p = 0.0021–0.0457); with higher percentages of TT and CT genotypes in the AD case group than that in the control group with increased air pollution levels. Conclusions: The impact of MTHFR C677T polymorphism on susceptibility to AD was modified by level of air pollution. Future studies are needed to further examine the effects of gene-environment interactions including air pollution on AD risk for world populations. PMID:28085050

Sex, Drugs, and Rock ‘N’ Roll: Hypothesizing Common Mesolimbic Activation as a Function of Reward Gene Polymorphisms

PubMed Central

Blum, Kenneth; Werner, Tonia; Carnes, Stefanie; Carnes, Patrick; Bowirrat, Abdalla; Giordano, John; Marlene-Oscar-Berman; Gold, Mark

2014-01-01

The nucleus accumbens, a site within the ventral striatum, plays a prominent role in mediating the reinforcing effects of drugs of abuse, food, sex, and other addictions. Indeed, it is generally believed that this structure mandates motivated behaviors such as eating, drinking, and sexual activity, which are elicited by natural rewards and other strong incentive stimuli. This article focuses on sex addiction, but we hypothesize that there is a common underlying mechanism of action for the powerful effects that all addictions have on human motivation. That is, biological drives may have common molecular genetic antecedents, which if impaired, lead to aberrant behaviors. Based on abundant scientific support, we further hypothesize that dopaminergic genes, and possibly other candidate neurotransmitter-related gene polymorphisms, affect both hedonic and anhedonic behavioral outcomes. Genotyping studies already have linked gene polymorphic associations with alcohol and drug addictions and obesity, and we anticipate that future genotyping studies of sex addicts will provide evidence for polymorphic associations with specific clustering of sexual typologies based on clinical instrument assessments. We recommend that scientists and clinicians embark on research coupling the use of neuroimaging tools with dopaminergic agonistic agents to target specific gene polymorphisms systematically for normalizing hyper- or hypo-sexual behaviors. PMID:22641964

Exploring the role of ionic liquids to tune the polymorphic outcome of organic compounds† †Electronic supplementary information (ESI) available: CCDC 1577981. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7sc04353h

PubMed Central

Zeng, Qingying; Mukherjee, Arijit; Müller, Peter; Rogers, Robin D.

2017-01-01

While molecular solvents are commonly used in the screening of polymorphs, the choices are often restricted. Ionic liquids (ILs) – also referred as designer solvents – have immense possibility in this regard because of their wide flexibility of tunability. More importantly, the interactions among the IL components are completely unique compared to those present in the molecular solvents. In this context, we have chosen tetrolic acid (TA) and isonicotinamide (INA), which showed solution-structure link in molecular solvents in the past, as probes to investigate the role of imidazolium based ionic liquids in the polymorphism of these two systems and whether the different solute–solvent interactions in ILs affect the polymorphic outcome. It is observed that the selected imidazolium-based ILs, with varying anion basicity have influenced the crystallization outcome by the interaction between ILs and model compounds. Later, we have utilized the concept of double salt ionic liquids (DSIL) for INA, a penta-morphic system, to investigate the variation in the polymorphic outcome. This approach helped to obtain the forms that were otherwise inaccessible in ILs. PMID:29675194

Inferences on the evolutionary history of the Drosophila americana polymorphic X/4 fusion from patterns of polymorphism at the X-linked paralytic and elav genes.

PubMed Central

Vieira, Cristina P; Coelho, Paula A; Vieira, Jorge

2003-01-01

In Drosophila there is limited evidence on the nature of evolutionary forces affecting chromosomal arrangements other than inversions. The study of the X/4 fusion polymorphism of Drosophila americana is thus of interest. Polymorphism patterns at the paralytic (para) gene, located at the base of the X chromosome, suggest that there is suppressed crossing over in this region between fusion and nonfusion chromosomes but not within fusion and nonfusion chromosomes. These data are thus compatible with previous claims that within fusion chromosomes the amino acid clines found at fused1 (also located at the base of the X chromosome) are likely maintained by local selection. The para data set also suggests a young age of the X/4 fusion. Polymorphism data on para and elav (located at the middle region of the X chromosome) suggest that there is no population structure other than that caused by the X/4 fusion itself. These findings are therefore compatible with previous claims that selection maintains the strong association observed between the methionine/threonine variants at fused1 and the status of the X chromosome as fused or unfused to the fourth chromosome. PMID:12930752

Association between Q192R paraoxonase 1 polymorphism and serumadipocyte-fatty acid binding protein (FABP4) levels in Mexican women.

PubMed

Ochoa-Martínez, Ángeles C; Ruíz-Vera, Tania; Orta-García, Sandra T; Domínguez-Cortinas, Gabriela; Jiménez-Avalos, Jorge A; Pérez-Maldonado, Iván N

2017-06-01

This study aimed to evaluate the genetic effects of PON1 Q192R polymorphism on serum FABP4 levels in Mexican women. PON1 Q192R polymorphism was genotyped using a TaqMan allelic discrimination assay and serum FABP4 concentration was measured using an enzyme-linked immunosorbent assay. The distribution of genotype frequencies in the assessed women (PON1 Q192R polymorphism) was QQ = 20%, QR = 48% and RR = 32%. Significantly higher serum FABP4 levels were found in women with genotype QR/RR (20.6 ± 2.20 ng/mL), when compared with the levels found in the QQ group (12.8 ± 1.70 ng/mL) (p = .004). After, the odds ratio (OR) was calculated by binomial logistic regression analysis and a significantly higher OR was found in the QR/RR group when compared with the QQ group (OR = 3.45; 95% CI = 1.80-16.50; p < .05). The results support an association between 192R-allele of the PON1 polymorphism (Q192R) and increased serum FABP4 levels (suggested as an early biomarker of CVDs risk) in assessed Mexican women.

Group benefit associated with polymorphic trichromacy in a Malagasy primate (Propithecus verreauxi)

PubMed Central

Veilleux, Carrie C.; Scarry, Clara J.; Di Fiore, Anthony; Kirk, E. Christopher; Bolnick, Deborah A.; Lewis, Rebecca J.

2016-01-01

In some primate lineages, polymorphisms in the X-linked M/LWS opsin gene have produced intraspecific variation in color vision. In these species, heterozygous females exhibit trichromacy, while males and homozygous females exhibit dichromacy. The evolutionary persistence of these polymorphisms suggests that balancing selection maintains color vision variation, possibly through a ‘trichromat advantage’ in detecting yellow/orange/red foods against foliage. We identified genetic evidence of polymorphic trichromacy in a population of Verreaux’s sifaka (Propithecus verreauxi) at Kirindy Mitea National Park in Madagascar, and explored effects of color vision on reproductive success and feeding behavior using nine years of morphological, demographic, and feeding data. We found that trichromats and dichromats residing in social groups with trichromats exhibit higher body mass indices than individuals in dichromat-only groups. Additionally, individuals in a trichromat social group devoted significantly more time to fruit feeding and had longer fruit feeding bouts than individuals in dichromat-only groups. We hypothesize that, due to small, cohesive sifaka social groups, a trichromat advantage in detecting productive fruit patches during the energetically stressful dry season also benefits dichromats in a trichromat’s group. Our results offer the first support for the ‘mutual benefit of association’ hypothesis regarding the maintenance of polymorphic trichromacy in primates. PMID:27910919

Polymorphism of the renalase gene in gestational diabetes mellitus.

PubMed

Fatima, Syeda Sadia; Jamil, Zehra; Alam, Faiza; Malik, Hajira Zafar; Madhani, Sarosh Irfan; Ahmad, Muhammad Saad; Shabbir, Tayyab; Rehmani, Muhammed Noman; Rabbani, Amna

2017-01-01

Renalase is considered as a novel candidate gene for type 2 diabetes. In this study, we aimed to investigate the relationship of serum renalase and two single nucleotide polymorphisms with gestational diabetes mellitus. One hundred and ninety-eight normotensive pregnant females (n = 99 gestational diabetes mellitus; n = 99 euglycemic pregnant controls) were classified according to the International Association of the Diabetes and Pregnancy Study criteria. Fasting and 2-h post glucose load blood levels and anthropometric assessment was performed. Serum renalase was measured using enzyme-linked immunosorbent assay, whereas DNA samples were genotyped for renalase single nucleotide polymorphisms rs2576178 and rs10887800 using Polymerase chain reaction-Restriction fragment length polymorphism method. In an age-matched case control study, no difference was observed in the serum levels of renalase (p > 0.05). The variant rs10887800 showed an association with gestational diabetes mellitus and remained significant after multiple adjustments (p < 0.05), whereas rs2576178 showed weak association (p = 0.030) that was lost after multiple adjustments (p = 0.09). We inferred a modest association of the rs10887800 polymorphism with gestational diabetes. Although gestational diabetes mellitus is self-reversible, yet presence of this minor G allele might predispose to metabolic syndrome phenotypes in near the future.

First Analysis of the Association Between CYP3A4/5, ABCB1 Genetic Polymorphisms and Oxcarbazepine Metabolism and Transport in Chinese Epileptic Patients with Oxcarbazepine Monotherapy and Bitherapy.

PubMed

Wang, Ping; Yin, Tao; Ma, Hong-ying; Liu, Dan-Qi; Sheng, Yangh-ao; Zhou, Bo-Ting

2015-01-01

Oxcarbazepine (OXC) is widely used in anti-epileptic treatment. Cytochrome P450 3A4 (CYP3A4), cytochrome P450 3A5(CYP3A5), and ATP-binding cassette sub-family B member 1 (ABCB1) are potential genes involved in OXC metabolisms and transport in vivo. This study aims to examine the genetic effects of CYP3A4, CYP3A5, and ABCB1 on OXC metabolism and transport in Chinese epileptic patients using OXC as monotherapy and bitherapy with lamotrigine (LTG), levetiracetam (LEV), or valproic acid (VPA). Sixty-six Chinese epileptic patients were recruited from Xiangya Hospital Central South University, of whom 40 patients were receiving OXC monotherapy, 11 patients were placed in the OXC bitherapy group combined with one enzyme-inducing anti-epileptic drugs (LTG or LEV), and 15 patients were placed in the OXC bitherapy group combined with VPA. Oxcarbazepine and its main metabolite 10-hydrocarbazepine (MHD) plasma concentrations were measured using high performance liquid chromatography (HPLC)-UV method. In addition, eight single nucleotide polymorphisms (SNPs) in CYP3A4, CYP3A5, ABCB1 gene were genotyped by polymerase chain reaction-improved multiple ligase detection reaction (PCR-iMLDR). In the OXC+VPA group, ABCB1 rs2032582 and rs2032582-rs10234411-rs1045642 TAG haplotype were associated with MHD and MHD+OXC plasma concentration before permutation test. In OXC monotherapy and OXC+ LTG/LEV groups, no significant association between genetic polymorphisms in CYP3A4/5, ABCB1 gene and OXC plasma concentration parameters were observed. CYP3A4/5 and ABCB1 genetic variants might not take part in the metabolism and transport of MHD and OXC among epileptic patients using OXC monotherapy and bitherapy in combination with LEV, LTG or VPA.

Polymorphisms in ABC Transporter Genes and Concentrations of Mercury in Newborns – Evidence from Two Mediterranean Birth Cohorts

PubMed Central

Llop, Sabrina; Engström, Karin; Ballester, Ferran; Franforte, Elisa; Alhamdow, Ayman; Pisa, Federica; Tratnik, Janja Snoj; Mazej, Datja; Murcia, Mario; Rebagliato, Marisa; Bustamante, Mariona; Sunyer, Jordi; Sofianou-Katsoulis, Αikaterini; Prasouli, Alexia; Antonopoulou, Eleni; Antoniadou, Ioanna; Nakou, Sheena; Barbone, Fabio; Horvat, Milena; Broberg, Karin

2014-01-01

Background The genetic background may influence methylmercury (MeHg) metabolism and neurotoxicity. ATP binding cassette (ABC) transporters actively transport various xenobiotics across biological membranes. Objective To investigate the role of ABC polymorphisms as modifiers of prenatal exposure to MeHg. Methods The study population consisted of participants (n = 1651) in two birth cohorts, one in Italy and Greece (PHIME) and the other in Spain (INMA). Women were recruited during pregnancy in Italy and Spain, and during the perinatal period in Greece. Total mercury concentrations were measured in cord blood samples by atomic absorption spectrometry. Maternal fish intake during pregnancy was determined from questionnaires. Polymorphisms (n = 5) in the ABC genes ABCA1, ABCB1, ABCC1 and ABCC2 were analysed in both cohorts. Results ABCB1 rs2032582, ABCC1 rs11075290, and ABCC2 rs2273697 modified the associations between maternal fish intake and cord blood mercury concentrations. The overall interaction coefficient between rs2032582 and log2-transformed fish intake was negative for carriers of GT (β = −0.29, 95%CI −0.47, −0.12) and TT (β = −0.49, 95%CI −0.71, −0.26) versus GG, meaning that for a doubling in fish intake of the mothers, children with the rs2032582 GG genotype accumulated 35% more mercury than children with TT. For rs11075290, the interaction coefficient was negative for carriers of TC (β = −0.12, 95%CI −0.33, 0.09), and TT (β = −0.28, 95%CI −0.51, −0.06) versus CC. For rs2273697, the interaction coefficient was positive when combining GA+AA (β = 0.16, 95%CI 0.01, 0.32) versus GG. Conclusion The ABC transporters appear to play a role in accumulation of MeHg during early development. PMID:24831289

Isolation of a complementary DNA clone for the human complement protein C2 and its use in the identification of a restriction fragment length polymorphism.

PubMed Central

Woods, D E; Edge, M D; Colten, H R

1984-01-01

Complementary DNA (cDNA) clones corresponding to the major histocompatibility (MHC) class III antigen, complement protein C2, have been isolated from human liver cDNA libraries with the use of a complex mixture of synthetic oligonucleotides (17 mer) that contains 576 different oligonucleotide sequences. The C2 cDNA were used to identify a DNA restriction enzyme fragment length polymorphism that provides a genetic marker within the MHC that was not detectable at the protein level. An extensive search for genomic polymorphisms using a cDNA clone for another MHC class III gene, factor B, failed to reveal any DNA variants. The genomic variants detected with the C2 cDNA probe provide an additional genetic marker for analysis of MHC-linked diseases. Images PMID:6086718

Potential genetic polymorphisms predicting polycystic ovary syndrome.

PubMed

Chen, Yao; Fang, Shu-Ying

2018-05-01

Polycystic ovary syndrome (PCOS) is a heterogenous endocrine disorder with typical symptoms of oligomenorrhoea, hyperandrogenism, hirsutism, obesity, insulin resistance and increased risk of type 2 diabetes mellitus. Extensive evidence indicates that PCOS is a genetic disease and numerous biochemical pathways have been linked with its pathogenesis. A number of genes from these pathways have been investigated, which include those involved with steroid hormone biosynthesis and metabolism, action of gonadotropin and gonadal hormones, folliculogenesis, obesity and energy regulation, insulin secretion and action and many others. In this review, we summarize the historical and recent findings in genetic polymorphisms of PCOS from the relevant publications and outline some genetic polymorphisms that are potentially associated with the risk of PCOS. This information could uncover candidate genes associating with PCOS, which will be valuable for the development of novel diagnostic and treatment platforms for PCOS patients. © 2018 The authors.

Pharmacogenomics of the human ABC transporter ABCG2: from functional evaluation to drug molecular design

NASA Astrophysics Data System (ADS)

Ishikawa, Toshihisa; Tamura, Ai; Saito, Hikaru; Wakabayashi, Kanako; Nakagawa, Hiroshi

2005-10-01

In the post-genome-sequencing era, emerging genomic technologies are shifting the paradigm for drug discovery and development. Nevertheless, drug discovery and development still remain high-risk and high-stakes ventures with long and costly timelines. Indeed, the attrition of drug candidates in preclinical and development stages is a major problem in drug design. For at least 30% of the candidates, this attrition is due to poor pharmacokinetics and toxicity. Thus, pharmaceutical companies have begun to seriously re-evaluate their current strategies of drug discovery and development. In that light, we propose that a transport mechanism-based design might help to create new, pharmacokinetically advantageous drugs, and as such should be considered an important component of drug design strategy. Performing enzyme- and/or cell-based drug transporter, interaction tests may greatly facilitate drug development and allow the prediction of drug-drug interactions. We recently developed methods for high-speed functional screening and quantitative structure-activity relationship analysis to study the substrate specificity of ABC transporters and to evaluate the effect of genetic polymorphisms on their function. These methods would provide a practical tool to screen synthetic and natural compounds, and these data can be applied to the molecular design of new drugs. In this review article, we present an overview on the genetic polymorphisms of human ABC transporter ABCG2 and new camptothecin analogues that can circumvent AGCG2-associated multidrug resistance of cancer.

Transfer of repaglinide in the dually perfused human placenta and the role of organic anion transporting polypeptides (OATPs).

PubMed

Tertti, Kristiina; Petsalo, Aleksanteri; Niemi, Mikko; Ekblad, Ulla; Tolonen, Ari; Rönnemaa, Tapani; Turpeinen, Miia; Heikkinen, Tuija; Laine, Kari

2011-10-09

Our aim was to investigate the placental transfer of repaglinide by ex vivo placental perfusion experiment. In addition, the involvement of the active organic anion transporters (OATP1B1, OATP1B3 and OATP2B1) was studied by assessing the single nucleotide polymorphisms (SNPs) in genes (SLCO1B1, SLCO1B3 and SLCO2B1) encoding OATPs. Fifteen placentas were obtained after delivery and a 2-h non-recirculating perfusion of a single placental cotyledon was performed to study maternal-to-fetal and fetal-to-maternal transport of repaglinide by using antipyrine as a reference of passive-diffusion transfer compound. Genotyping was performed for all placentas. Maternal-to-fetal transfer of repaglinide and antipyrine were 1.5% and 13.2%, respectively, and fetal-to-maternal transfers were 6.7% and 40.3%, respectively. Fetal-to-maternal transfer of repaglinide was statistically significantly higher than maternal-to-fetal transfer (P<0.0001). The number of placentas was not sufficient for proper statistical analysis, but the fetal-to-maternal transfer seemed to be affected by the SLCO1B3 polymorphism. The placental transfer of repaglinide from mother to fetus was low. Since a higher transfer rate of repaglinide was observed in fetal-to-maternal than maternal-to-fetal direction, active transport by OATP-transporters may be an important factor in fetal exposure to repaglinide. Copyright © 2011 Elsevier B.V. All rights reserved.

Association Between 5-HTTLPR Polymorphism and Tics after Treatment with Methylphenidate in Korean Children with Attention-Deficit/Hyperactivity Disorder.

PubMed

Park, Seo Yeon; Kim, Eun Joo; Cheon, Keun-Ah

2015-10-01

The purpose of this study is to examine the relationship between 5-HTTLPR polymorphism (44-bp insertion/deletion polymorphism of serotonin transporter gene) and methylphenidate (MPH) treatment response, as well as the association between the adverse events of MPH treatment and 5-HTTLPR polymorphism in children with attention-deficit/hyperactivity disorder (ADHD). A total of 114 children with ADHD (mean age 9.08 ± 1.94 years) were recruited from the child psychiatric clinic in a hospital in South Korea. We have extracted the genomic DNA of the subjects from their blood lymphocytes and analyzed 5-HTTLPR polymorphism of the SLC6A4 gene. All children were treated with MPH for 8 weeks, with clinicians monitoring both the improvement of ADHD symptoms and the side effects. We compared the response to MPH treatment and adverse events among those with the genotype of 5-HRRLPR polymorphism. There was no significant association between the 5-HTTLPR genotype and the response to MPH treatment in children with ADHD. Subjects with the S/L+L/L genotype tended to have tics and nail biting (respectively, p < 0.001, p = 0.017). The results of this study do not support the association between the 5-HTTLPR polymorphism and treatment response with MPH in ADHD. However, our findings suggest the association between 5-HTTLPR polymorphism and the occurrence of tics and nail-biting as an adverse event of methylphenidate. This may aid in our understanding of the genetic contribution and genetic susceptibility of a particular allele in those ADHD patients with tics or nail biting.

Association Between 5-HTTLPR Polymorphism and Tics after Treatment with Methylphenidate in Korean Children with Attention-Deficit/Hyperactivity Disorder

PubMed Central

Park, Seo Yeon; Kim, Eun Joo

2015-01-01

Abstract Objectives: The purpose of this study is to examine the relationship between 5-HTTLPR polymorphism (44-bp insertion/deletion polymorphism of serotonin transporter gene) and methylphenidate (MPH) treatment response, as well as the association between the adverse events of MPH treatment and 5-HTTLPR polymorphism in children with attention-deficit/hyperactivity disorder (ADHD). Methods: A total of 114 children with ADHD (mean age 9.08 ± 1.94 years) were recruited from the child psychiatric clinic in a hospital in South Korea. We have extracted the genomic DNA of the subjects from their blood lymphocytes and analyzed 5-HTTLPR polymorphism of the SLC6A4 gene. All children were treated with MPH for 8 weeks, with clinicians monitoring both the improvement of ADHD symptoms and the side effects. We compared the response to MPH treatment and adverse events among those with the genotype of 5-HRRLPR polymorphism. Results: There was no significant association between the 5-HTTLPR genotype and the response to MPH treatment in children with ADHD. Subjects with the S/L+L/L genotype tended to have tics and nail biting (respectively, p < 0.001, p = 0.017). Conclusions: The results of this study do not support the association between the 5-HTTLPR polymorphism and treatment response with MPH in ADHD. However, our findings suggest the association between 5-HTTLPR polymorphism and the occurrence of tics and nail-biting as an adverse event of methylphenidate. This may aid in our understanding of the genetic contribution and genetic susceptibility of a particular allele in those ADHD patients with tics or nail biting. PMID:26402385

Polymorphisms in stearoyl coa desaturase and sterol regulatory element binding protein interact with N-3 polyunsaturated fatty acid intake to modify associations with anthropometric variables and metabolic phenotypes in Yup'ik people.

PubMed

Lemas, Dominick J; Klimentidis, Yann C; Aslibekyan, Stella; Wiener, Howard W; O'Brien, Diane M; Hopkins, Scarlett E; Stanhope, Kimber L; Havel, Peter J; Allison, David B; Fernandez, Jose R; Tiwari, Hemant K; Boyer, Bert B

2016-12-01

n-3 polyunsaturated fatty acid (n-3 PUFA) intake is associated with protection from obesity; however, the mechanisms of protection remain poorly characterized. The stearoyl CoA desaturase (SCD), insulin-sensitive glucose transporter (SLC2A4), and sterol regulatory element binding protein (SREBF1) genes are transcriptionally regulated by n-3 PUFA intake and harbor polymorphisms associated with obesity. The present study investigated how consumption of n-3 PUFA modifies associations between SCD, SLC2A4, and SREBF1 polymorphisms and anthropometric variables and metabolic phenotypes. Anthropometric variables and metabolic phenotypes were measured in a cross-sectional sample of Yup'ik individuals (n = 1135) and 33 polymorphisms were tested for main effects and interactions using linear models that account for familial correlations. n-3 PUFA intake was estimated using red blood cell nitrogen stable isotope ratios. SCD polymorphisms were associated with ApoA1 concentration and n-3 PUFA interactions with SCD polymorphisms were associated with reduced fasting cholesterol levels and waist-to-hip ratio. SLC2A4 polymorphisms were associated with hip circumference, high-density lipoprotein and ApoA1 concentrations. SREBF1 polymorphisms were associated with low-density lipoprotein and HOMA-IR and n-3 PUFA interactions were associated with reduced fasting insulin and HOMA-IR levels. The results suggest that an individual's genotype may interact with dietary n-3 PUFAs in ways that are associated with protection from obesity-related diseases in Yup'ik people. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Polymorphisms in stearoyl CoA desaturase and sterol regulatory element binding protein interact with N-3 polyunsaturated fatty acid intake to modify associations with anthropometric variables and metabolic phenotypes in Yup'ik people

PubMed Central

Lemas, Dominick J.; Klimentidis, Yann C.; Aslibekyan, Stella; Wiener, Howard W.; O’Brien, Diane M.; Hopkins, Scarlett E.; Stanhope, Kimber L.; Havel, Peter J.; Allison, David B.; Fernandez, Jose R.; Tiwari, Hemant K.; Boyer, Bert B.

2016-01-01

Scope n-3 polyunsaturated fatty acid (n-3 PUFA) intake is associated with protection from obesity, however, the mechanisms of protection remain poorly characterized. The stearoyl CoA desaturase (SCD), insulin sensitive glucose transporter (SLC2A4), and sterol regulatory element binding protein (SREBF1) genes are transcriptionally regulated by n-3 PUFA intake and harbor polymorphisms associated with obesity. The present study investigated how consumption of n-3 PUFA modifies associations between SCD, SLC2A4, and SREBF1 polymorphisms and anthropometric variables and metabolic phenotypes. Materials and Methods Anthropometric variables and metabolic phenotypes were measured in a cross-sectional sample of Yup’ik individuals (n=1135) and thirty-three polymorphisms were tested for main effects and interactions using linear models that account for familial correlations. n-3 PUFA intake was estimated using red blood cell nitrogen stable isotope ratios. SCD polymorphisms were associated with ApoA1 concentration and n-3 PUFA interactions with SCD polymorphisms were associated with reduced fasting cholesterol levels and waist-to-hip ratio. SLC2A4 polymorphisms were associated with hip circumference, high-density lipoprotein and ApoA1 concentrations. SREBF1 polymorphisms were associated with low-density lipoprotein and HOMA-IR and n-3 PUFA interactions were associated with reduced fasting insulin and HOMA-IR levels. Conclusion These results suggest that an individual’s genotype may interact with dietary n-3 PUFAs in ways that are associated with protection from obesity-related diseases in Yup’ik people. PMID:27467133

Screening of IR50 x Rathu Heenati F7 RILs and identification of SSR markers linked to brown planthopper (Nilaparvata lugens Stål) resistance in rice (Oryza sativa L.).

PubMed

Kumari, Sanju; M Sheba, Jennifer; Marappan, Maheshwaran; Ponnuswamy, Shanmugasunderam; Seetharaman, Suresh; Pothi, Nagarajan; Subbarayalu, Mohankumar; Muthurajan, Raveendran; Natesan, Senthil

2010-09-01

Brown planthopper (Nilaparvata lugens Stål) is one of the major insect pests of rice. A Sri Lankan indica rice cultivar Rathu Heenati was found to be resistant to all biotypes of the brown planthopper. In the present study, a total of 268 F(7) RILs of IR50 and Rathu Heenati were phenotyped for their level of resistance against BPH by the standard seedbox screening test (SSST) in the greenhouse. A total of 53 SSR primers mapped on the chromosome 3 were used to screen the polymorphism between the parents IR50 and Rathu Heenati, out of which eleven were found to be polymorphic between IR50 and Rathu Heenati. The eleven primers that have shown polymorphism between the IR50 and Rathu Heenati parents were genotyped in a set of five resistant RILs and five susceptible RILs along with the parents for co-segregation analysis. Among the eleven primers, two primers namely RM3180 (18.22 Mb) and RM2453 (20.19 Mb) showed complete co-segregation with resistance. The identification of SSR markers linked with BPH resistant could be used for the maker assisted selection (MAS) program in rice breeding and to map the resistant genes on rice chromosomes for further gene cloning.

Plasminogen Activator Inhibitor-2 Polymorphism Associates with Recurrent Coronary Event Risk in Patients with High HDL and C-Reactive Protein Levels

PubMed Central

Corsetti, James P.; Salzman, Peter; Ryan, Dan; Moss, Arthur J.; Zareba, Wojciech; Sparks, Charles E.

2013-01-01

The objective of this work was to investigate whether fibrinolysis plays a role in establishing recurrent coronary event risk in a previously identified group of postinfarction patients. This group of patients was defined as having concurrently high levels of high-density lipoprotein cholesterol (HDL-C) and C-reactive protein (CRP) and was previously demonstrated to be at high-risk for recurrent coronary events. Potential risk associations of a genetic polymorphism of plasminogen activator inhibitor-2 (PAI-2) were probed as well as potential modulatory effects on such risk of a polymorphism of low-density lipoprotein receptor related protein (LRP-1), a scavenger receptor known to be involved in fibrinolysis in the context of cellular internalization of plasminogen activator/plansminogen activator inhibitor complexes. To this end, Cox multivariable modeling was performed as a function of genetic polymorphisms of PAI-2 (SERPINB, rs6095) and LRP-1 (LRP1, rs1800156) as well as a set of clinical parameters, blood biomarkers, and genetic polymorphisms previously demonstrated to be significantly and independently associated with risk in the study population including cholesteryl ester transfer protein (CETP, rs708272), p22phox (CYBA, rs4673), and thrombospondin-4 (THBS4, rs1866389). Risk association was demonstrated for the reference allele of the PAI-2 polymorphism (hazard ratio 0.41 per allele, 95% CI 0.20-0.84, p=0.014) along with continued significant risk associations for the p22phox and thrombospondin-4 polymorphisms. Additionally, further analysis revealed interaction of the LRP-1 and PAI-2 polymorphisms in generating differential risk that was illustrated using Kaplan-Meier survival analysis. We conclude from the study that fibrinolysis likely plays a role in establishing recurrent coronary risk in postinfarction patients with concurrently high levels of HDL-C and CRP as manifested by differential effects on risk by polymorphisms of several genes linked to key actions involved in the fibrinolytic process. PMID:23874812

A novel, non-functional, COL1A1 polymorphism is not associated with lumbar disk disease in young male Greek subjects unlike that of the Sp1 site

PubMed Central

Bei, Thalia; Tilkeridis, Constantinos; Garantziotis, Stavros; Boikos, Sosipatros A.; Kazakos, Konstantinos; Simopoulos, Constantinos; Stratakis, Constantine A.

2011-01-01

OBJECTIVE We recently reported the association of the Sp1 site polymorphism of the COL1A1 gene with lumbar disk disease (LDD). In the present study we searched for a different polymorphism of the COL1A1 gene (which is usually not in linkage disequilibrium with the Sp1 site) in subjects with LDD. DESIGN Blood was collected from 24 Greek army recruits, aged 29±7.6 years, with LDD, and 66 healthy men, aged 26±4.38 years, matched for body mass index (BMI) and age, with normal BMD and with no history of trauma or fractures, who served as controls. DNA was extracted and the COL1A1 gene was sequenced. Of the control subjects, 12 were army recruits and 54 were selected from the general population. RESULTS The four base-pair insertion polymorphism in the COL1A1 gene analyzed by polymerase chain reaction amplification of DNA produces two different fragments (alleles A1 and A2): 14 patients (58.3%) were homozygous for A2A2, versus 35 controls (53%), while 3 patients (12.5%) were A1A1, and 8 of the control subjects (12%) had this genotype. There were no statistically significant differences in the presence of the two alleles of this polymorphism between patients with LDD and control subjects. CONCLUSIONS A four base-pair insertion polymorphism of the COL1A1 gene is not associated with the presence of LDD in young males, unlike the Sp1 site polymorphism of the same gene. These data reinforce the association between LDD and the functional polymorphisms of the Sp1 site by showing that other polymorphic sites of the of the COL1A1 gene in the same population of patients are not linked to the disease. PMID:18694864

The permeability P-glycoprotein: a focus on enantioselectivity and brain distribution.

PubMed

Choong, Eva; Dobrinas, Maria; Carrupt, Pierre-Alain; Eap, Chin B

2010-08-01

The permeability glycoprotein (P-gp) is an important protein transporter involved in the disposition of many drugs with different chemical structures, but few studies have examined a possible stereoselectivity in its activity. P-gp can have a major impact on the distribution of drugs in selected organs, including the brain. Polymorphisms of the ABCB1 gene, which encodes for P-gp, can influence the kinetics of several drugs. A search including publications from 1990 up to 2009 was performed on P-gp stereoselectivity and on the impact of ABCB1 polymorphisms on enantiomer brain distribution. Despite stereoselectivity not being expected because of the large variability of chemical structures of P-gp substrates, structure-activity relationships suggest different P-gp-binding sites for enantiomers. Enantioselectivity in the activity of P-gp has been demonstrated by in vitro studies and in animal models (preferential transport of one enantiomer or different inhibitory potencies towards P-gp activity between enantiomers). There is also in vivo evidence of an enantioselective drug transport at the human blood-brain barrier. The significant enantioselective activity of P-gp might be clinically relevant and must be taken into account in future studies.

Association of a Functional Polymorphism in the Serotonin Transporter Gene With Abnormal Emotional Processing in Ecstasy Users

PubMed Central

Roiser, Jonathan P.; Cook, Lynnette J.; Cooper, Jason D.; Rubinsztein, David C.; Sahakian, Barbara J.

2009-01-01

Objective The long-term effects of the use of 3,4-methylenedioxymethamphetamine (MDMA, or Ecstasy) in humans are controversial and unclear. The authors’ goal was to assess the contribution of a functional polymorphism in the gene encoding serotonin transporter to changes in emotional processing following chronic Ecstasy use. Method They investigated Beck Depression Inventory scores and performance on the Affective Go/No-Go test, a computerized neuropsychological test sensitive to emotional processing, in Ecstasy users and comparison subjects, stratifying the results by serotonin transporter genotype. Results Ecstasy use was associated with higher Beck Depression Inventory score and abnormalities in the Affective Go/No-Go test in individuals with the ss and ls genotype but not those with the ll genotype. Conclusions Ecstasy users carrying the s allele, but not comparison subjects carrying the s allele, showed abnormal emotional processing. On the basis of a comparison with acute tryptophan depletion, the authors hypothesize that chronic Ecstasy use may cause long-term changes to the serotonin system, and that Ecstasy users carrying the s allele may be at particular risk for emotional dysfunction. PMID:15741482

Association Between p21 Ser31Arg Polymorphism and Gastrointestinal Tract Tumor Risk: A Meta-analysis.

PubMed

Dong, Ying; Wang, Xiaohua; Ye, Xiaofeng; Wang, Guanhua; Li, Yan; Wang, Ningju; Yang, Yinxue; Chen, Zhiqiang; Yang, Wenjun

2015-10-01

Human p21 gene is characterized by a polymorphism at codon 31 leading to a Serine-to- Arginine (S/R), two different alleles of p21 Ser31Arg (rs 1801270) polymorphism have been shown to differ significantly in their transcriptional efficiency. More and more investigations are now being carried out to examine a possible link between the p21 Ser31Arg polymorphism and cancer. However, the results were inconclusive. Therefore, we carried out a systematic review and meta-analysis to examine whether this polymorphism is associated with gastrointestinal tract tumor in Asian. Seven studies (n = 2690), comprising 967 cases and 1723 controls in Asian population, were included in our study. The meta-analysis showed significant association between Ser-allele or Ser/Ser genotype and the susceptibility to gastrointestinal tract tumor in overall studies (Ser-allele vs. Arg-allele: OR = 1.17, 95% CI: 1.04-1.31; Ser/Ser vs. Arg/Arg: OR = 1.38, 95% CI: 1.09-1.75; Ser/Ser vs. Arg/Ser: OR = 1.27, 95% CI: 1.05-1.53; Ser/Ser vs. Arg/Ser + Arg/Arg: OR = 1.29, 95% CI: 1.07-1.54). Despite the limitations, the results of the present meta-analysis suggested that, in the p21 Ser31Arg polymorphism, Ser-allele and Ser/Ser genotype might be risk factors for gastrointestinal tract tumor in Asian populations. © The Author(s) 2014.

A link between osteomyelitis and IL1RN and IL1B polymorphisms-a study in patients from Northeast Brazil.

PubMed

Alves De Souza, Clinio; Queiroz Alves De Souza, Argos; Queiroz Alves De Souza, Maria do Socorro; Dias Leite, José Alberto; Silva De Morais, Maíra; Barem Rabenhorst, Sílvia Helena

2017-10-01

Background and purpose - Treatment failure of osteomyelitis can result from genetic susceptibility, highlighting polymorphisms of the interleukin-1 (IL-1) family members, central mediators of innate immunity and inflammation. Polymorphisms are DNA sequence variations that are common in the population (1% or more) and represent multiple forms of a single gene. We investigated the association of IL1RNVNTR (rs2234663) and IL1B-511C > T (rs16944) polymorphisms with osteomyelitis development in patients operated on because of bone trauma. Patients and methods - 153 patients who fulfilled the inclusion criteria were enrolled from a referral public hospital for trauma. All the patients were followed up daily until hospital discharge and, after this, on an outpatient basis. Patients were treated with prophylactic antimicrobials and surgery according to traumatology service protocol. The IL1RNVNTR and the IL1B-511C > T polymorphisms were determined by PCR and PCR-RFLP, respectively. Results - The IL1RN*2/*2 genotype was associated (OR: 7; p < 0.001) with a higher risk of osteomyelitis and was also significantly associated with Staphylococcus aureus infection. The haplotypes (combination of different markers) *2-C and *2-T were also associated with osteomyelitis development. Interpretation - IL1B-511C > T and IL1RNVNTR polymorphisms were associated with osteomyelitis development, which may have implications for patients with bone traumas. These data may be relevant for new therapeutic strategies for this disease.

Modification of the association between early adversity and obsessive-compulsive disorder by polymorphisms in the MAOA, MAOB and COMT genes.

PubMed

McGregor, N W; Hemmings, S M J; Erdman, L; Calmarza-Font, I; Stein, D J; Lochner, C

2016-12-30

The monoamine oxidases (MAOA/B) and catechol-O-methyltransferase (COMT) enzymes break down regulatory components within serotonin and dopamine pathways, and polymorphisms within these genes are candidates for OCD susceptibility. Childhood trauma has been linked OCD psychopathology, but little attention has been paid to the interactions between genes and environment in OCD aetiology. This pilot study investigated gene-by-environment interactions between childhood trauma and polymorphisms in the MAOA, MAOB and COMT genes in OCD. Ten polymorphisms (MAOA: 3 variants, MAOB: 4 variants, COMT: 3 variants) were genotyped in a cohort of OCD patients and controls. Early-life trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Gene-by-gene (GxG) and gene-by-environment interactions (GxE) of the variants and childhood trauma were assessed using logistic regression models. Significant GxG interactions were found between rs362204 (COMT) and two independent polymorphisms in the MAOB gene (rs1799836 and rs6651806). Haplotype associations for OCD susceptibility were found for MAOB. Investigation of GxE interactions indicated that the sexual abuse sub-category was significantly associated with all three genes in haplotype x environment interaction analyses. Preliminary findings indicate that polymorphisms within the MAOB and COMT genes interact resulting in risk for OCD. Childhood trauma interacts with haplotypes in COMT, MAOA and MAOB, increasing risk for OCD. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Association Between Single Nucleotide Polymorphism +276G > T (rs1501299) in ADIPOQ and Endometrial Cancer.

PubMed

Bieńkiewicz, Jan; Smolarz, Beata; Malinowski, Andrzej

2016-01-01

Current literature gives evidence of an indisputable role adiponectin plays in adipose tissue metabolism and obesity-related diseases. Moreover, latest research efforts focus on linking genetic markers of this adipocytokine's gene (ADIPOQ) with cancer. Aim of this study was to determine the genotype distribution of single nucleotide polymorphism +276G > T (rs1501299) in ADIPOQ and an attempt to identify the impact this polymorphism exerts on endometrial cancer risk in obese females. The test group comprised 90 women treated surgically for endometrial cancer between 2000 and 2012 in the Department of Surgical & Endoscopic Gynecology and Gynecologic Oncology, Polish Mothers' Memorial Hospital - Research Institute, Lodz, Poland. 90 individuals treated in the parallel period for uterine fibroids constituted the control group. Patients within both groups were stratified according to BMI into: lean, overweight and obese subjects. Statistical analysis was performed between two major groups and, furthermore, within the abovementioned subgroups. The analysis revealed that allele G of the investigated polymorphism in obese women with endometrial cancer is significantly more frequent, and allele T is significantly less frequent than in lean controls. However, no significant correlation was observed between the polymorphism and endometrial cancer in lean and overweight females. Single nucleotide polymorphism +276G > T (rs1501299) in ADIPOQ may be considered to be a risk factor of endometrial cancer. Further research on SNP in EC is warranted to obtain more conclusive outcomes.

Testing for genetic association taking into account phenotypic information of relatives.

PubMed

Uh, Hae-Won; Wijk, Henk Jan van der; Houwing-Duistermaat, Jeanine J

2009-12-15

We investigated efficient case-control association analysis using family data. The outcome of interest was coronary heart disease. We employed existing and new methods that take into account the correlations among related individuals to obtain the proper type I error rates. The methods considered for autosomal single-nucleotide polymorphisms were: 1) generalized estimating equations-based methods, 2) variance-modified Cochran-Armitage (MCA) trend test incorporating kinship coefficients, and 3) genotypic modified quasi-likelihood score test. Additionally, for X-linked single-nucleotide polymorphisms we proposed a two-degrees-of-freedom test. Performance of these methods was tested using Framingham Heart Study 500 k array data.

UGT1A1*6 polymorphism is most predictive of severe neutropenia induced by irinotecan in Japanese cancer patients.

PubMed

Onoue, Masahide; Terada, Tomohiro; Kobayashi, Masahiko; Katsura, Toshiya; Matsumoto, Shigemi; Yanagihara, Kazuhiro; Nishimura, Takafumi; Kanai, Masashi; Teramukai, Satoshi; Shimizu, Akira; Fukushima, Masanori; Inui, Ken-ichi

2009-04-01

Gene polymorphisms of the UDP-glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) contribute to individual variations in adverse events among patients administered irinotecan, and the distribution of the polymorphisms shows large interethnic differences. Variation in the solute carrier organic anion-transporter family, member 1B1 (SLCO1B1) gene also has a significant effect on the disposition of irinotecan in Asian cancer patients. In the present study, we evaluated the association of genetic polymorphisms of UGT1A1 and SLCO1B1 with irinotecanrelated neutropenia in Japanese cancer patients. One hundred and thirty-five consecutive patients treated with irinotecan were enrolled. Genotypes of UGT1A1 (*60, *28, *6, and *27) and SLCO1B1 (*1b, *5, and haplotype *15) were determined by direct sequencing. Severe neutropenia refers to events observed during the first cycle of irinotecan treatment. Severe neutropenia was observed in 29 patients (22%). Six patients were homozygous and 48 heterozygous for UGT1A1*6. Only 1 patient was homozygous for UGT1A1*28. Homozygosity for UGT1A1*6 was associated with a high risk of severe neutropenia (odds ratio [OR], 7.78; 95% confidence interval [CI], 1.36 to 44.51). No significant association was found between severe neutropenia and other UGT1A1 polymorphisms or SLCO1B1 polymorphisms. These findings suggest that the UGT1A1*6 polymorphism is a potential predictor of severe neutropenia caused by irinotecan in Japanese cancer patients.

Gene polymorphisms associated with functional dyspepsia.

PubMed

Kourikou, Anastasia; Karamanolis, George P; Dimitriadis, George D; Triantafyllou, Konstantinos

2015-07-07

Functional dyspepsia (FD) is a constellation of functional upper abdominal complaints with poorly elucidated pathophysiology. However, there is increasing evidence that susceptibility to FD is influenced by hereditary factors. Genetic association studies in FD have examined genotypes related to gastrointestinal motility or sensation, as well as those related to inflammation or immune response. G-protein b3 subunit gene polymorphisms were first reported as being associated with FD. Thereafter, several gene polymorphisms including serotonin transporter promoter, interlukin-17F, migration inhibitory factor, cholecystocynine-1 intron 1, cyclooxygenase-1, catechol-o-methyltransferase, transient receptor potential vanilloid 1 receptor, regulated upon activation normal T cell expressed and secreted, p22PHOX, Toll like receptor 2, SCN10A, CD14 and adrenoreceptors have been investigated in relation to FD; however, the results are contradictory. Several limitations underscore the value of current studies. Among others, inconsistencies in the definitions of FD and controls, subject composition differences regarding FD subtypes, inadequate samples, geographical and ethnical differences, as well as unadjusted environmental factors. Further well-designed studies are necessary to determine how targeted genes polymorphisms, influence the clinical manifestations and potentially the therapeutic response in FD.

Effect of the 5-HTTLPR polymorphism on posttraumatic stress disorder, depression, anxiety, and quality of life among Iraq and Afghanistan veterans.

PubMed

Kimbrel, Nathan A; Morissette, Sandra B; Meyer, Eric C; Chrestman, Roberta; Jamroz, Robert; Silvia, Paul J; Beckham, Jean C; Young, Keith A

2015-01-01

Posttraumatic stress disorder (PTSD), depression, anxiety, and stress are significant problems among returning veterans and are associated with reduced quality of life. A correlational design was used to examine the impact of a polymorphism (5-HTTLPR) in the serotonin transporter promoter gene on post-deployment adjustment among returning veterans. A total of 186 returning Iraq and Afghanistan veterans were genotyped for the 5-HTTLPR polymorphism. Symptoms of PTSD, depression, general stress, and anxiety were assessed along with quality of life. After controlling for combat exposure, age, sex of the participant, and race, 5-HTTLPR had a significant multivariate effect on post-deployment adjustment, such that S' carriers reported more post-deployment adjustment problems and worse quality of life than veterans homozygous for the L' allele. This effect was larger when the analyses were restricted to veterans of European ancestry. Our findings suggest that veterans who carry the S' allele of the 5-HTTLPR polymorphism may be at increased risk for adjustment problems and reduced quality of life following deployments to war zones.

Hemolysis and Mediterranean G6PD mutation (c.563 C>T) and c.1311 C>T polymorphism among Palestinians at Gaza Strip.

PubMed

Sirdah, Mahmoud; Reading, N Scott; Perkins, Sherrie L; Shubair, Mohammad; Aboud, Lina; Prchal, Josef T

2012-04-15

The G6PD c.563 C>T deficient mutation is endemic among Mediterranean populations but its clinical significance is not well delineated. We set up to estimate the proportion of G6PD deficient children presenting with hemolytic anemia at Al Nasser Pediatric Hospital at Gaza Strip, Palestine. We then established the prevalence of c.563T Mediterranean mutation and its linkage to c.1311 C>T polymorphism in this population. G6PD deficiency was identified in children presenting with hemolytic anemia at Al Nasser Pediatric Hospital by spectrophotometric measurement of G6PD activity. G6PD exon 6 and exon 11 were amplified from genomic DNA and evaluated for c.563T mutation by sequencing and the c.1311T polymorphism by restriction fragment analysis. Seventy X-chromosomes (60 males and 5 females) from G6PD deficient patients and 40 X-chromosomes from a control group known to be not G6PD deficient were tested. Over 80% of these children presenting with hemolytic anemia were G6PD deficient and 34% of these had the Mediterranean G6PD deficient variant. The allelic frequencies of Mediterranean c.563T and c.1311T polymorphisms among G6PD deficient patients were 0.33 and 0.38 respectively. The c.1311T polymorphism was linked in 95.2% of patients with the Mediterranean mutation, an allele frequency of 0.87, compared to the control non-G6PD deficient group with an allele frequency of 0.18. We conclude that G6PD deficiency accounts for majority of hemolytic anemia encountered in Gaza children treated at Al Nasser Pediatric Hospital Emergency department. The Mediterranean mutation c.563T, while not accounting for a majority of G6PD deficiency, is common among G6PD deficient Gaza Strip Palestinians and is frequently, but not always, linked to the c.1311T polymorphism. This work provides a foundation for the population screening of Palestinians for G6PD deficiency and for investigations of ancestral origin of the Mediterranean variant in world populations. Copyright © 2012 Elsevier Inc. All rights reserved.

Genomic introgression mapping of field-derived multiple-anthelmintic resistance in Teladorsagia circumcincta

PubMed Central

Hallsworth-Pepin, Kymberlie; Martin, John; Mitreva, Makedonka

2017-01-01

Preventive chemotherapy has long been practiced against nematode parasites of livestock, leading to widespread drug resistance, and is increasingly being adopted for eradication of human parasitic nematodes even though it is similarly likely to lead to drug resistance. Given that the genetic architecture of resistance is poorly understood for any nematode, we have analyzed multidrug resistant Teladorsagia circumcincta, a major parasite of sheep, as a model for analysis of resistance selection. We introgressed a field-derived multiresistant genotype into a partially inbred susceptible genetic background (through repeated backcrossing and drug selection) and performed genome-wide scans in the backcross progeny and drug-selected F2 populations to identify the major genes responsible for the multidrug resistance. We identified variation linking candidate resistance genes to each drug class. Putative mechanisms included target site polymorphism, changes in likely regulatory regions and copy number variation in efflux transporters. This work elucidates the genetic architecture of multiple anthelmintic resistance in a parasitic nematode for the first time and establishes a framework for future studies of anthelmintic resistance in nematode parasites of humans. PMID:28644839

Interaction of child maltreatment and 5-HTT polymorphisms: suicidal ideation among children from low-SES backgrounds.

PubMed

Cicchetti, Dante; Rogosch, Fred A; Sturge-Apple, Melissa; Toth, Sheree L

2010-06-01

To investigate whether genotypic variation of the serotonin transporter gene-linked promoter region (5-HTTLPR) moderates the effect of maltreatment on suicidal ideation in school-aged children. Eight hundred and fifty low-income children (478 maltreated; 372 non-maltreated) provided DNA samples and self-reported depressive and suicidal symptoms. Genotypes of 5-HTTLPR (s/s or s/l vs. l/l) were determined by fragment analyses. Higher suicidal ideation was found among maltreated than non-maltreated children; the groups did not differ in 5-HTTLPR genotype frequencies. Children with one to two maltreatment subtypes and s/s or s/l genotypes had higher suicidal ideation than those with the l/l genotype; suicidal ideation did not differ in non-maltreated children or children with three to four maltreatment subtypes based on 5-HTTLPR variation. The results were applicable to emotionally maltreated/neglected and to physically/sexually abused children. Gene-environment interaction was not found for depressive symptoms. The protective effect of the 5-HTTLPR l/l genotype on suicidal ideation was limited to maltreated children experiencing fewer subtypes.

Placental transfer of antidepressant medications: implications for postnatal adaptation syndrome.

PubMed

Ewing, Grace; Tatarchuk, Yekaterina; Appleby, Dina; Schwartz, Nadav; Kim, Deborah

2015-04-01

Seven to thirteen percent of women are either prescribed or taking (depending on the study) an antidepressant during pregnancy. Because antidepressants freely cross into the intrauterine environment, we aim to summarize the current findings on placental transfer of antidepressants. Although generally low risk, antidepressants have been associated with postnatal adaptation syndrome (PNAS). Specifically, we explore whether the antidepressants most closely associated with PNAS (paroxetine, fluoxetine, venlafaxine) cross the placenta to a greater extent than other antidepressants. We review research on antidepressants in the context of placental anatomy, placental transport mechanisms, placental metabolism, pharmacokinetics, as well as non-placental maternal and fetal factors. This provides insight into the complexity involved in understanding how placental transfer of antidepressants may relate to adverse perinatal outcomes. Ultimately, from this data there is no pattern in which PNAS is related to placental transfer of antidepressant medications. In general, there is large interindividual variability for each type of antidepressant. To make the most clinically informed decisions about the use of antidepressants in pregnancy, studies that link maternal, placental and fetal genetic polymorphisms, placental transfer rates and infant outcomes are needed.

Prolonged cholestasis triggered by hepatitis A virus infection and variants of the hepatocanalicular phospholipid and bile salt transporters.

PubMed

Krawczyk, Marcin; Grünhage, Frank; Langhirt, Miriam; Bohle, Raine M; Lammert, Frank

2012-01-01

Hepatitis A virus (HAV) infection resolves in most patients uneventfully within weeks from the onset of the disease. In rare cases, however, it may relapse or cause prolonged cholestasis. Here we present a case of a 36-year-old female patient who developed severe pruritus and jaundice three weeks after initially uncomplicated hepatitis A. A relapse of the infection was excluded. Since therapy with colestyramin, antihistaminics, naloxon and ursodeoxycholic acid (UDCA) did not improve symptoms, we decided to perform plasma absorption and to start rifampicin therapy. Under these measures, pruritus and jaundice, as well as serum bilirubin levels improved gradually and after four plasmapheresis sessions we were able to discharge the patient. Genetic testing showed the presence of two procholestatic polymorphisms, the c.3084 [GG] variant within the gene encoding the hepatocanalicular bile salt transporter ABCB11 and the c.711 [AT] variant of the phosphatidylcholine floppase ABCB4. We speculate that this compound ABCB4-ABCB11 genotype led to a severe intrahepatic cholestasis in the setting of HAV infection. In conclusion, our case suggests that polymorphisms within the hepatocanalicular transporters may contribute to a more pronounced course of HAV infection. Although dedicated studies in large cohorts of patients are needed to confirm this observation, we speculate that patients carrying procholestatic hepatobiliary transporter variants may benefit from vaccination against hepatitis A.

Depressive mood ratings are reduced by MDMA in female polydrug ecstasy users homozygous for the l-allele of the serotonin transporter.

PubMed

Kuypers, K P C; de la Torre, R; Farre, M; Xicota, L; de Sousa Fernandes Perna, E B; Theunissen, E L; Ramaekers, J G

2018-01-18

MDMA exerts its main effects via the serotonergic system and the serotonin transporter. The gene coding for this transporter determines the expression rate of the transporter. Previously it was shown that healthy individuals with the short allelic variant ('s-group') of the 5-HTTLPR-polymorphism displayed more anxiety and negative mood, and had a lower transcriptional efficiency compared to individuals who are homozygous for the l-allele ('l-group'). The present study aimed to investigate the role of the 5-HTTLPR polymorphism in MDMA-induced mood effects. Four placebo-controlled, within-subject studies were pooled, including in total 63 polydrug ecstasy users (N s-group  = 48; N l-group  = 15) receiving MDMA 75 mg and placebo on two test days, separated by minimally 7 days. Mood was assessed by means of the Profile of Mood States. Findings showed that MDMA induced -independent of sex- a positive mood state, and as a side effect also increased two negative affect states, anxiety and confusion. Anxiety ratings were higher in the l-group and independent of treatment or sex. Depression ratings were lowered by MDMA in the female l-group. Findings indicate that the MDMA-induced reduction in self-rated depressive feelings is sex- and genotype-dependent, with females homozygous for the l-allele showing this beneficial effect.

High-Pressure Polymorphism in Orthoamphiboles

NASA Astrophysics Data System (ADS)

Finkelstein, G. J.; Zhang, D.; Shelton, H.; Dera, P.

2017-12-01

Amphiboles are double-chain silicate minerals that are the structurally hydrated counterpart to single-chain, anhydrous pyroxenes. They may play an important role in the earth as a carrier for volatiles in subduction zones, as well as a generator for seismic anisotropy in the upper mantle. Recent work has described previously unrecognized high-pressure polymorphism at low temperatures in a variety of pyroxene minerals, which may be relevant for the structure and dynamics of thick, cold, subducted slabs. However, high-pressure polymorphism in amphiboles above a few GPa in pressure has not been well explored, and if similar polymorphism to pyroxenes exists in this mineral family, it may affect the extent and depth of volatile transport in amphiboles, as well as their rheological properties. At low temperatures and high pressures, orthopyroxenes undergo crystal structure transitions at lower pressures than clinopyroxenes (10-30 GPa vs. > 50 GPa), so for this study we have investigated polymorphism in the anthophyllite-gedrite (Al-free and Al rich) orthoamphibole solid solution series. Using neon gas-loaded diamond anvil cells, we compressed both phases to a maximum pressure of 31 GPa, and observed transitions to new monoclinic structures in both endmembers. In this presentation, we will discuss the details of these transitions and implications for the earth's interior.

[Family-based association study of a variable number of tandem repeat polymorphism of DAT1 gene with Tourette syndrome in a Chinese Han population].

PubMed

Zheng, Lanlan; Han, Zhen-liang; Zhang, Xin-hua; Wang, Xue-qin; Jiang, Wei-hua; Yi, Ming-ji; Liu, Shi-guo

2013-10-01

To assess the association of a 40 bp variable number of tandem repeat (VNTR) polymorphism within 3 untranslated region of dopamine transporter gene (DAT1) with Tourette syndrome (TS) in a Chinese Han population. A total of 160 TS patients and their parents were recruited. The VNTR polymorphism was detected with polymerase chain reaction-VNTR analysis, and its association with TS and its subtypes were assessed through a family-based association study comprising transmission disequilibrium test (TDT) and haplotype relative risk (HRR) analysis. The repeat numbers at the DAT1 40 bp locus were 11, 10, 9, 7.5 and 7 among the patients and their parents, with the most common type being a 10-repeat allele. No significant association was detected between the polymorphism and TS (TDT: X ² = 0.472, df = 1, P = 0.583; HRR: X ² = 0.313, P = 0.576, OR = 0.855, 95%CI: 0.493-1.481). Our data suggested that the VNTR polymorphism of DAT1 gene is not associated with susceptibility to TS in Chinese Han population. However, our results are to be validated in larger sets of patients collected from other populations.

ABCG8 polymorphisms and renal disease in type 2 diabetic patients.

PubMed

Nicolas, Anthony; Fatima, Sehrish; Lamri, Amel; Bellili-Muñoz, Naima; Halimi, Jean-Michel; Saulnier, Pierre-Jean; Hadjadj, Samy; Velho, Gilberto; Marre, Michel; Roussel, Ronan; Fumeron, Frédéric

2015-06-01

Sterols, bile acids and their receptors have been involved in diabetic nephropathy. The ATP-binding cassette transporters G5 and G8 (ABCG5 and ABCG8) play an important role in intestinal sterol absorption and bile acid secretion. The aim of our study was to assess the associations between two ABCG8 coding polymorphisms, T400K and D19H, and the incidence of renal events in type 2 diabetic subjects. Participants were the 3137 French type 2 diabetic subjects with micro- or macro-albuminuria from the genetic substudy of the DIABHYCAR trial. The mean duration of follow-up was 4years. Renal events were defined as a doubling of serum creatinine concentration or end-stage renal disease at follow-up. We then used a second population (DIAB2NEPHROGENE) of 2140 type 2 diabetic patients for the purpose of validation. In DIABHYCAR, the 400K allele was significantly associated with a higher risk of incident renal events in a multiple adjusted model (HR: 1.75 [95% CI 1.20-2.56], P=0.003). This association was still significant after further adjustments for baseline values of estimated glomerular filtration rate and urinary albumin excretion. In the validation population, the 400K allele was associated with the prevalence of end-stage renal disease (OR=2.01 [95% CI 1.15-3.54], P=0.015). No significant association was found between the D19H polymorphism and the risk of diabetic nephropathy. A polymorphism of the sterol transporter ABCG8 has been associated with the prevalence of end-stage renal disease and with the incidence of new renal events in type 2 diabetic patients. Copyright © 2015. Published by Elsevier Inc.

Dopamine transporter gene polymorphism in children with ADHD: A pilot study in Indonesian samples.

PubMed

Wiguna, Tjhin; Ismail, Raden Irawati; Winarsih, Noorhana Setyawati; Kaligis, Fransiska; Hapsari, Anggia; Budiyanti, Lina; Sekartini, Rini; Rahayu, Susan; Guerrero, Anthony P S

2017-10-01

Several studies showed that DAT1 polymorphism closed related with ADHD although the results were not consistently found. Studies in China, South Korea, Japan revealed that 10-repeat allele gave a risk for ADHD. Based on that understanding, this study tried to identify whether the similar polymorphism of DAT1 was also apparent in Indonesian children with ADHD. This was a case - control study. Case was 50 Indonesian origin children with ADHD and without any other mental disorders and metal retardation. Control is Indonesian origin children without ADHD, other mental disorders and mental retardation. ADHD diagnosis was taken after doing the psychiatric interview and observation based on the DSM-IV TR diagnostic criteria for ADHD at the Child and Adolescent Psychiatry Out-patient Clinic, Dr. Cipto Mangunkusumo National Referral Hospital - Faculty of Medicine Universitas Indonesia. DNA isolation, DNA purity and concentration were measured. PCR was done by using a primer based on Homo sapiens solute carrier family 6 (neurotransmitter transporter), member 3 (SLC6A3), RefSeq Gene on chromosome 5 with accession number NG_015885.1. To identify the serial of repeated allele, we used the sequencing technique. There were 47 children with ADHD and 48 children without ADHD that involved in the final analysis. The mean of age amongst ADHD group was 9.18 (2.42) and 8.10 (2.46) years old in non-ADHD group. The 10-repeated allele of DAT1 was the highest proportion in both. This finding was apparently similar with other studies on DAT1 polymorphism across Asian. Copyright © 2017 Elsevier B.V. All rights reserved.

Drug metabolism and transport gene polymorphisms and efavirenz adverse effects in Brazilian HIV-positive individuals.

PubMed

de Almeida, Tailah Bernardo; de Azevedo, Marcelo Costa Velho Mendes; Pinto, Jorge Francisco da Cunha; Ferry, Fernando Rafael de Almeida; da Silva, Guilherme Almeida Rosa; de Castro, Izana Junqueira; Baker, Paxton; Tanuri, Amilcar; Haas, David W; Cardoso, Cynthia C

2018-06-03

There are limited data regarding efavirenz pharmacogenetics in admixed populations. The Brazilian population is highly admixed. In a Brazilian cohort, we sought to characterize associations between efavirenz adverse effects (all-cause and CNS) and polymorphisms in seven genes known or suspected to affect efavirenz metabolism and transport. We studied 225 HIV-positive individuals who had been prescribed efavirenz-containing regimens at a hospital in Rio de Janeiro, Brazil. Eighty-nine cases had efavirenz adverse effects, including 43 with CNS adverse effects, while 136 controls had no adverse effect of any antiretroviral after treatment for at least 6 months. A total of 67 candidate polymorphisms in ABCB1, CYP2A6, CYP2B6, CYP3A4, CYP3A5, NR1I2 and NR1I3 genes were selected for association analysis. Admixture was assessed using 28 ancestry-informative polymorphisms previously validated for the Brazilian population. Associations were evaluated with logistic regression models adjusted for sex and genetic ancestry. There was extensive African, European and Native American admixture in the cohort. Increased all-cause adverse effects were associated with the CYP2B6 genotype combination 15582CC-516TT-983TT (OR = 7.26, P = 0.003) and with the CYP2B6 slow metabolizer group 516TT or 516GT-983CT (OR = 3.10, P = 0.04). CNS adverse effects were nominally associated with CYP3A4 rs4646437 (OR = 4.63, P = 0.014), but not after adjusting for multiple comparisons. In a highly admixed Brazilian cohort, the CYP2B6 slow metabolizer genotype was associated with an increased risk of efavirenz adverse effects.

Candidate genes for alcohol dependence: A genetic association study from India.

PubMed

Malhotra, Savita; Basu, Debasish; Khullar, Madhu; Ghosh, Abhishek; Chugh, Neera

2016-11-01

Search for candidate genes for alcohol dependence (AD) has been inconsistent and inconclusive. Moreover, most of the research has been confined to a few specific ethnic groups. Hence, the aim of our study was to explore specific candidate genes for AD in north Indian male population. In this clinic-based genetic association study, 210 males with AD and 200 controls matched for age, gender and ethnicity were recruited from the clinic and the general population, respectively. Cases were diagnosed with Semi-structured Assessment for Genetics of Alcoholism-II (SSAGA-II). Single-nucleotide polymorphism genotyping was done by real-time quantitative-polymerase chain reaction (PCR) using Taq Man assay (ABI 7500) fast real-time PCR system. Both at the genotypic level and at allelic frequency, Met158 variant of catechol-O-methyl transferase (COMT) showed significant increase in cases as compared to controls. The frequency of heterozygous genotype (A/G) of gamma-aminobutyric acid receptor A1 (GABRA1) was significantly lower in cases as compared to controls. Likewise, for GABRA2, the frequency of homozygous recessive genotype (G/G) was significantly higher in the control group. With respect to the 5-hydroxytryptamine (5HT) transporter long promoter region (5HTTLPR), cholinergic receptor muscarinic (CHRM2) and alcohol dehydrogenase 1B (ADH1B) genes, there was no significant difference between the cases and the controls. Aldehyde dehydrogenase (ALDH2) gene was found to be monomorphic in our study population. Our study findings showed COMT polymorphism conferring risk and GABRA polymorphism as a protective genotype for Indian male with AD. Genes for alcohol metabolism, serotonin transporter and cholinergic receptor gene polymorphism were perhaps not contributory to AD for Indian population.

LRP-1 polymorphism is associated with global and regional amyloid load in Alzheimer's disease in humans in-vivo

PubMed Central

Grimmer, Timo; Goldhardt, Oliver; Guo, Liang-Hao; Yousefi, Behrooz H.; Förster, Stefan; Drzezga, Alexander; Sorg, Christian; Alexopoulos, Panagiotis; Förstl, Hans; Kurz, Alexander; Perneczky, Robert

2014-01-01

Objective Impaired amyloid clearance has been proposed to contribute to β-amyloid deposition in sporadic late-onset Alzheimer's disease (AD). Low density lipoprotein receptor-related protein 1 (LRP-1) is involved in the active outward transport of β-amyloid across the blood–brain barrier (BBB). The C667T polymorphism (rs1799986) of the LRP-1 gene has been inconsistently associated with AD in genetic studies. We aimed to elucidate the association of this polymorphism with in-vivo brain amyloid load of AD patients using amyloid PET with [11C]PiB. Materials and methods 72 patients with very mild to moderate AD were examined with amyloid PET and C667T polymorphism was obtained using TaqMan PCR assays. The association of C667T polymorphism with global and regional amyloid load was calculated using linear regression and voxel based analysis, respectively. The effect of the previously identified modulator of amyloid uptake, the apolipoprotein E genotype, on this association was also determined. Results The regression analysis between amyloid load and C667T polymorphism was statistically significant (p = 0.046, β = 0.236). In an additional analysis ApoE genotype and gender were identified to explain further variability of amyloid load. Voxel based analysis revealed a significant (p < 0.05) association between C667T polymorphism and amyloid uptake in the temporo-parietal cortex bilaterally. ApoE did not interact significantly with the LRP-1 polymorphism. Discussion In conclusion, C667T polymorphism of LRP-1 is moderately but significantly associated with global and regional amyloid deposition in AD. The relationship appears to be independent of the ApoE genotype. This finding is compatible with the hypothesis that impaired amyloid clearance contributes to amyloid deposition in late-onset sporadic AD. PMID:24596678

Using next generation sequencing for multiplexed trait-linked markers in wheat

USDA-ARS?s Scientific Manuscript database

With the advent of next generation sequencing (NGS) technologies, single nucleotide polymorphisms (SNPs) have become the major type of marker for genotyping in many crops. However, the availability of SNP markers for important traits of bread wheat (Triticum aestivum L.) that can be effectively used...

The folate hydrolase 1561 C>T polymorphism is associated with depressive symptoms in Puerto Rican adults

USDA-ARS?s Scientific Manuscript database

Low plasma folate has been associated with depression. Variants of genes involved in the uptake, retention and metabolism of folate have been linked with plasma folate and homocysteine concentrations. It remains unclear whether such variants are also associated with depressive symptoms, directly or ...

Malaria severity: Possible influence of the E670G PCSK9 polymorphism: A preliminary case-control study in Malian children.

PubMed

Arama, Charles; Diarra, Issa; Kouriba, Bourèma; Sirois, Francine; Fedoryak, Olesya; Thera, Mahamadou A; Coulibaly, Drissa; Lyke, Kirsten E; Plowe, Christopher V; Chrétien, Michel; Doumbo, Ogobara K; Mbikay, Majambu

2018-01-01

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is a hepatic secretory protein which promotes the degradation of low-density lipoprotein receptors leading to reduced hepatic uptake of plasma cholesterol. Non-synonymous single-nucleotide polymorphisms in its gene have been linked to hypo- or hyper- cholesterolemia, depending on whether they decrease or increase PCSK9 activity, respectively. Since the proliferation and the infectivity of Plasmodium spp. partially depend on cholesterol from the host, we hypothesize that these PCSK9 genetic polymorphisms could influence the course of malaria infection in individuals who carry them. Here we examined the frequency distribution of one dominant (C679X) and two recessive (A443T, I474V) hypocholesterolemic polymorphisms as well as that of one recessive hypercholesterolemic polymorphism (E670G) among healthy and malaria-infected Malian children. Dried blood spots were collected in Bandiagara, Mali, from 752 age, residence and ethnicity-matched children: 253 healthy controls, 246 uncomplicated malaria patients and 253 severe malaria patients. Their genomic DNA was extracted and genotyped for the above PCSK9 polymorphisms using Taqman assays. Associations of genotype distributions and allele frequencies with malaria were evaluated. The minor allele frequency of the A443T, I474V, E670G, and C679X polymorphisms in the study population sample was 0.12, 0.20, 0.26, and 0.02, respectively. For each polymorphism, the genotype distribution among the three health conditions was statistically insignificant, but for the hypercholesterolemic E670G polymorphism, a trend towards association of the minor allele with malaria severity was observed (P = 0.035). The association proved to be stronger when allele frequencies between healthy controls and severe malaria cases were compared (Odd Ratio: 1.34; 95% Confidence Intervals: 1.04-1.83); P = 0.031). Carriers of the minor allele of the E670G PCSK9 polymorphism might be more susceptible to severe malaria. Further investigation of the cholesterol regulating function of PCSK9 in the pathophysiology of malaria is needed.

Effects of CYP2C19 and P2Y12 Gene Polymorphisms on Clinical Results of Patients Using Clopidogrel after Acute Ischemic Cerebrovascular Disease

PubMed Central

Sen, HM; Silan, F; Silan, C; Degirmenci, Y; Ozisik Kamaran, HI

2014-01-01

The CY2C19 and P2Y12 gene polymorphisms are responsible for resistance to clopidogrel, known as drug unresponsiveness. In this study we researched the effect of gene polymorphism on clinical results of patients who began clopidogrel therapy after acute ischemic cerebrovascular disease. The study included 51 patients. The patient group included patients who had begun prophylactic clopidogrel due to acute ischemic cerebrovascular disease in the last 2 years. All patients were monitored by the Neurology Outpatient Clinic at Çanakkale Onsekiz Mart Üniversity Research Hospital, Çanakkale, Turkey, and only those monitored for at least 1 year were included in the study. When the *1, *2 and *3 alleles of the CYP2C19 gene polymorphism were evaluated, two patients were homozygotes for *2/*2, 13 patients were heterozygous for *1/*2 and 36 patients were homozygotes for the wild type *1/*1. No patient had the *3 allele. Three heterozygous patients, one for *2/*2 and two for *1/*2, stopped clopidogrel therapy due to repeated strokes and began taking warfarin. When evaluating P2Y12 52 (G>T) and 34 (C>T) polymorphisms, all alleles were of the wild type. The CYP2C19 and P2Y12 gene polymorphisms may cause recurring strokes linked to insufficient response to treatment of ischemic cerebrovascular disease. In our patient group, three patients suffered repeated strokes and these patients had the CYP2C19*2 gene polymorphism. As a result, before medication use, genetic testing is important for human life, quality of life and economic burden. PMID:25937796

Subsets of Inflammatory Cytokine Gene Polymorphisms are Associated with Risk of Carcinogenic Liver Fluke Opisthorchis viverrini-Associated Advanced Periductal Fibrosis and Cholangiocarcinoma.

PubMed

Surapaitoon, Arpa; Suttiprapa, Sutas; Mairiang, Eimorn; Khuntikeo, Narong; Pairojkul, Chawalit; Bethony, Jeffrey; Brindley, Paul J; Sripa, Banchob

2017-06-01

Opisthorchis viverrini infection induces chronic inflammation, and a minor proportion of infected individuals develop advanced periductal fibrosis (APF) and cholangiocarcinoma (CCA). Inflammatory cytokines and/or their gene polymorphisms may link to these biliary pathologies. We therefore investigated associations among cytokine gene polymorphisms and cytokine production in 510 Thai cases infected with O. viverrini who presented with APF+ or APF-, as established by abdominal ultrasonography as well as in patients diagnosed with CCA. Levels of pro-inflammatory and anti-inflammatory cytokines were determined in culture supernatants after stimulation of peripheral blood mononuclear cells (PBMCs) with O. viverrini excretory-secretory (ES) products. Pro-inflammatory cytokines, IL-1β, IL-6, IFN-γ, LT-α, and TNF-α were significantly increased in CCA patients compared with non-CCA (APF- and APF+) cases. Polymorphisms in genes encoding IL-1β-511C/T, IL-6-174G/C, IFN-γ +874T/A, LT-α +252A/G, and TNF-α -308G/A were then investigated by using PCR-RFLP or allele specific-PCR (AS-PCR) analyses. In the CCA cases, LT-α +252A/G and TNF-α -308G/A heterozygous and homozygous variants showed significantly higher levels of these cytokines than the wild type. By contrast, levels of cytokines in wild type of IFN-γ +874T/A were significantly higher than the variants in CCA cases. IFN-γ +874T/A polymorphisms were associated with advanced periductal fibrosis, whereas IL-6 -174G/C polymorphisms were associated with CCA. To our knowledge, these findings provide the first demonstration that O. viverrini infected individuals carrying several specific cytokine gene polymorphisms are susceptible to develop fibrosis and CCA.

Subsets of Inflammatory Cytokine Gene Polymorphisms are Associated with Risk of Carcinogenic Liver Fluke Opisthorchis viverrini-Associated Advanced Periductal Fibrosis and Cholangiocarcinoma

PubMed Central

Surapaitoon, Arpa; Suttiprapa, Sutas; Mairiang, Eimorn; Khuntikeo, Narong; Pairojkul, Chawalit; Bethony, Jeffrey; Brindley, Paul J.; Sripa, Banchob

2017-01-01

Opisthorchis viverrini infection induces chronic inflammation, and a minor proportion of infected individuals develop advanced periductal fibrosis (APF) and cholangiocarcinoma (CCA). Inflammatory cytokines and/or their gene polymorphisms may link to these biliary pathologies. We therefore investigated associations among cytokine gene polymorphisms and cytokine production in 510 Thai cases infected with O. viverrini who presented with APF+ or APF−, as established by abdominal ultrasonography as well as in patients diagnosed with CCA. Levels of pro-inflammatory and anti-inflammatory cytokines were determined in culture supernatants after stimulation of peripheral blood mononuclear cells (PBMCs) with O. viverrini excretory-secretory (ES) products. Pro-inflammatory cytokines, IL-1β, IL-6, IFN-γ, LT-α, and TNF-α were significantly increased in CCA patients compared with non-CCA (APF− and APF+) cases. Polymorphisms in genes encoding IL-1β-511C/T, IL-6-174G/C, IFN-γ +874T/A, LT-α +252A/G, and TNF-α −308G/A were then investigated by using PCR-RFLP or allele specific-PCR (AS-PCR) analyses. In the CCA cases, LT-α +252A/G and TNF-α −308G/A heterozygous and homozygous variants showed significantly higher levels of these cytokines than the wild type. By contrast, levels of cytokines in wild type of IFN-γ +874T/A were significantly higher than the variants in CCA cases. IFN-γ +874T/A polymorphisms were associated with advanced periductal fibrosis, whereas IL-6 −174G/C polymorphisms were associated with CCA. To our knowledge, these findings provide the first demonstration that O. viverrini infected individuals carrying several specific cytokine gene polymorphisms are susceptible to develop fibrosis and CCA. PMID:28719954

ERCC1 rs3212986 A/C polymorphism is not associated with chemotherapy treatment outcomes in gastric cancer patients: evidence from 11 publications in Chinese populations

PubMed Central

Wang, Yuemei; Wang, Xiaowei

2018-01-01

Background A number of studies have investigated the roles of excision repair cross-complementation group 1 (ERCC1) gene rs3212986 polymorphisms as potential biomarkers in gastric cancer (GC). However, the results were inconsistent. Here, we performed a meta-analysis to explore ERCC1 rs3212986 polymorphisms in the chemotherapy response and clinical outcome of GC. Methods PubMed, Embase, and Web of Science were searched up to July 28, 2017, for studies on the association between ERCC1 rs3212986 A/C polymorphisms and response to chemotherapy as well as overall survival time of GC. A fixed-effect or random-effect model was used to calculate the pooled odds ratios (ORs) based on the results from the heterogeneity tests. Results The result revealed that there was no significant association between the ERCC1 rs3212986 A/C polymorphism and response to chemotherapy in GC under comparison models (AA + CA versus CC, OR 0.95, P=0.80, AA versus CA, OR 0.85, P=0.55, AA versus CC, OR 0.74, P=0.47). Further identification suggested that ERCC1 rs3212986 A/C polymorphisms were not linked with the overall survival of GC (AA + CA versus CC, OR 1.09, P=0.52, AA versus CA, OR 1.05, P=0.85, AA versus CC, OR 1.43, P=0.23). Conclusion Our meta-analysis indicated that the ERCC1 rs3212986 A/C polymorphism was not associated with response to chemotherapy or overall survival time in GC. Well-designed studies with larger sample sizes and more ethnic groups should be performed to further validate our results. PMID:29302191

Polymorphisms in CD14 Gene May Modify Soluble CD14 Levels and Represent Risk Factors for Multiple Sclerosis.

PubMed

Farrokhi, Mehrdad; Moeini, Pedram; Fazilati, Mohammad; Nazem, Habibollah; Faraji, Shahla; Saadatpour, Zahra; Fadaei, Elyas; Saadatpour, Leila; Rezaei, Ali; Ansaripour, Sadra; Amani-Beni, Ali

2016-11-07

Besides the central role of the adaptive immune system, a disturbance of innate immune system is also suggested to be involved in the pathogenesis of multiple sclerosis (MS). CD14, a receptor upregulated in activated microglia, is known to be an essential mediator of inflammation in innate immune responses. Therefore, in this study we aimed to assess possible roles of CD14-159 and -260 gene polymorphisms in MS susceptibility and the effects of those polymorphisms to its protein producing capacity in Iranian population. In this case control study, CD14-159 and -260 polymorphisms were genotyped using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) in 200 MS patients and 200 healthy controls matched in age and gender. Serum levels of soluble CD14 (sCD14) was determined by enzyme-linked immunosorbent assay (ELISA). There were significant differences in genotype distribution of CD14-159 and -260 polymorphisms between patients and controls (P = 0.01, for-both). Mean serum level of sCD14 was significantly higher in MS patients than in control subjects (3340.30 ± 612.50 ng/ml vs 2353.73 ± 539.07 ng/ml; P < 0.01). In summary, we conclude that CD14-159 and -260 polymorphisms are associated with the risk of MS in Iranian population and affects CD14 promoter activity, thereby regulating CD14 expression. Furthermore, our study provides preliminary evidence for the activation of innate immunity in the pathogenesis of MS. In addition, the findings of the present study suggest serum level of sCD14 as candidate biomarker of MS severity.

Evaluation of cellular immunological responses in mono- and polymorphic clinical forms of post-kala-azar dermal leishmaniasis in India.

PubMed

Kaushal, H; Bras-Gonçalves, R; Avishek, K; Kumar Deep, D; Petitdidier, E; Lemesre, J-L; Papierok, G; Kumar, S; Ramesh, V; Salotra, P

2016-07-01

Post-kala-azar dermal leishmaniasis (PKDL) is a chronic dermal complication that occurs usually after recovery from visceral leishmaniasis (VL). The disease manifests into macular, papular and/or nodular clinical types with mono- or polymorphic presentations. Here, we investigated differences in immunological response between these two distinct clinical forms in Indian PKDL patients. Peripheral blood mononuclear cells of PKDL and naive individuals were exposed in vitro to total soluble Leishmania antigen (TSLA). The proliferation index was evaluated using an enzyme-linked immunosorbent assay (ELISA)-based lymphoproliferative assay. Cytokines and granzyme B levels were determined by cytometric bead array. Parasite load in tissue biopsy samples of PKDL was quantified by quantitative polymerase chain reaction (qPCR). The proportion of different lymphoid subsets in peripheral blood and the activated T cell population were estimated using flow cytometry. The study demonstrated heightened cellular immune responses in the polymorphic PKDL group compared to the naive group. The polymorphic group showed significantly higher lymphoproliferation, increased cytokines and granzyme B levels upon TSLA stimulation, and a raised proportion of circulating natural killer (NK) T cells against naive controls. Furthermore, the polymorphic group showed a significantly elevated proportion of activated CD4(+) and CD8(+) T cells upon in-vitro TSLA stimulation. Thus, the polymorphic variants showed pronounced cellular immunity while the monomorphic form demonstrated a comparatively lower cellular response. Additionally, the elevated level of both activated CD4(+) and CD8(+) T cells, coupled with high granzyme B secretion upon in-vitro TSLA stimulation, indicated the role of cytotoxic cells in resistance to L. donovani infection in polymorphic PKDL. © 2016 British Society for Immunology.

Tetra primer ARMS-PCR relates folate/homocysteine pathway genes and ACE gene polymorphism with coronary artery disease.

PubMed

Masud, Rizwan; Qureshi, Irfan Zia

2011-09-01

Cardiovascular disorders and coronary artery disease (CAD) are significant contributors to morbidity and mortality in heart patients. As genes of the folate/homocysteine pathway have been linked with the vascular disease, we investigated association of these gene polymorphisms with CAD/myocardial infarction (MI) using the novel approach of tetraprimer ARMS-PCR. A total of 230 participants (129 MI cases, 101 normal subjects) were recruited. We genotyped rs1801133 and rs1801131 SNPs in 5'10' methylenetetrahydrofolate reductase (MTHFR), rs1805087 SNP in 5' methyltetrahydrofolate homocysteine methyltransferase (MTR), rs662 SNP in paroxanse1 (PON1), and rs5742905 polymorphism in cystathionine beta synthase (CBS). Angiotensin converting enzyme (ACE) insertion/deletion polymorphism was detected through conventional PCR. Covariates included blood pressure, fasting blood sugar, serum cholesterol, and creatinine concentrations. Our results showed allele frequencies at rs1801133, rs1801131, rs1805087 and the ACE insertion/deletion (I/D) polymorphism varied between cases and controls. Logistic regression, after adjusting for covariates, demonstrated significant associations of rs1801133 and rs1805087 with CAD in the additive, dominant, and genotype model. In contrast, ACE I/D polymorphism was significantly related with CAD where recessive model was applied. Gene-gene interaction against the disease status revealed two polymorphism groups: rs1801133, rs662, and rs1805087; and rs1801131, rs662, and ACE I/D. Only the latter interaction maintained significance after adjusted for covariates. Our study concludes that folate pathway variants exert contributory influence on susceptibility to CAD. We further suggest that tetraprimer ARMS-PCR successfully resolves the genotypes in selected samples and might prove to be a superior technique compared to the conventional approach.

Evaluation of Glutathione-S-Transferase P1 Polymorphism and its Relation to Bone Mineral Density in Egyptian Children and Adolescents with Beta-Thalassemia Major

PubMed Central

Ragab, Seham M.; Badr, Eman A.; Ibrahim, Ahmed S.

2016-01-01

Background Osteoporosis is a major complication of beta thalassemia major (TM). Increased oxidative stress and its controlling genes were linked to osteoporosis. Ile105 Val variant is a functional polymorphism of Glutathione S-transferase P1 (GSTP1), with reduced anti-oxidative property. No data are available about this variant or its association with osteoporosis among thalassemia patients yet. Objectives To investigate Ile105Val polymorphism and its possible association with bone mineral density (BMD) values in a group of TM children. Methods Thirty five TM children and 30 age and sex matched healthy controls were included. Liver and renal functions, serum ferritin, calcium, phosphorous, alkaline phosphatase and osteocalcin were assayed. BMD was determined by DXA with calculation of Z-scores at lumbar spine (LS) and femoral neck (FN). Height for age Z- score (HAZ) adjusted BMD Z-scores were calculated. GSTP1 Ile105Val polymorphism was studied by polymerase chain reaction-restriction fragment length polymorphism. Results The relative frequency of 105 Val allele was significantly higher in TM patients than the controls (p<0.0001). Significant association between genotype subgroups and BMD parameters was detected. Compared to wild homozygotes, polymorphic homozygotes had lower LS-BMD (p =0.029), LS-BMD Z –score (p=0.008 ), LS- BMD haz - Z-score (p=0.011), FN- BMD (p= 0.001), FN- BMD Z –score (p=0.02) and FN-BMD haz - Z-score (p=0.001). They exhibited higher osteocalcin levels compared to heterozygotes and wild homozygotes (p=0.012, p=0.013, respectively). Conclusion Ile105Val polymorphism was frequent among TM patients and could increase their susceptibility to reduced BMD. Large sample studies are required to confirm these findings. PMID:26740865

Mismatch repair polymorphisms and the risk of colorectal cancer.

PubMed

Berndt, Sonja I; Platz, Elizabeth A; Fallin, M Daniele; Thuita, Lucy W; Hoffman, Sandra C; Helzlsouer, Kathy J

2007-04-01

Rare germline variants in mismatch repair genes have been linked to hereditary nonpolyposis colorectal cancer; however, it is unknown whether common polymorphisms in these genes alter the risk of colorectal cancer. To examine the association between common variants in mismatch repair genes and colorectal cancer, we conducted a case-cohort study within the CLUE II cohort. Four single nucleotide polymorphisms in 3 mismatch repair genes (MSH3 R940Q, MSH3 T1036A, MSH6 G39E and MLH1 I219V) were genotyped in 237 colorectal cancer cases and a subcohort of 2,189 participants. Incidence rate ratios (RRs) and 95% confidence intervals (95% CIs) for each polymorphism were estimated. The MSH3 1036A variant was found to be associated with an increased risk of colorectal cancer (RR=1.28, 95% CI: 0.94-1.74 and RR=1.65, 95% CI: 1.01-2.70 for the AT and TT genotypes, respectively, with p(trend)=0.02), particularly proximal colon cancer. Although the MSH3 940Q variant was only weakly associated with colorectal cancer overall (p(trend)=0.07), it was associated with a significant increased risk of proximal colon cancer (RR=1.69, 95% CI: 1.10-2.61 and RR=2.68, 95% CI: 0.96-7.47 for the RQ and QQ genotypes, respectively with p(trend)=0.005). Processed meat intake appeared to modify the association between the MSH3 polymorphisms and colorectal cancer (p(interaction) < 0.10 for both). No association was observed with the MSH6 and MLH1 polymorphisms overall. This study suggests that common polymorphisms in the mismatch repair gene, MSH3, may increase the risk of colorectal cancer, especially proximal colon cancer. (c) 2006 Wiley-Liss, Inc.

Methylenetetrahydrofolate reductase gene polymorphisms contribute to acute myeloid leukemia and chronic myeloid leukemia susceptibilities: evidence from meta-analyses.

PubMed

He, Hairong; He, Gonghao; Wang, Taotao; Cai, Jiangxia; Wang, Yan; Zheng, Xiaowei; Dong, Yalin; Lu, Jun

2014-10-01

The expression of methylenetetrahydrofolate reductase (MTHFR) is associated with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). Most studies have linked the common functional C677T and A1298C polymorphisms of the MTHFR gene and susceptibility to AML and CML, but the results were not consistent. The aim of the present study was to derive a more precise estimation of the relationship. Meta-analyses assessing the association of MTHFR C677T and A1298C variations with AML and CML were conducted. Eligible articles were identified from the PubMed and EMBASE databases. All statistical analyses were conducted using Review Manager Software. 10 and 10 studies were included in the meta-analysis about the role of C677T polymorphism on the AML and CML risks, respectively; 6 and 4 studies were included about the role of A1298C polymorphism on the AML and CML risks, respectively. Overall, both the C677T and A1298C polymorphisms were significantly associated with CML risk under the recessive model (P=0.04, OR=1.35, 95% CI=1.02-1.79 for C677T and P=0.003, OR=2.17, 95% CI=1.29-3.63 for A1298C). In addition, the risk of CML was higher in 1298CC genotype carriers than in 1298AA genotype carriers (P=0.004, OR=2.17, 95%=1.28-3.69). Conversely, the overall data failed to indicate a significant association of C677T or A1298C polymorphisms with AML risk under any model. The findings provide evidence that C677T and A1298C polymorphisms are risk factors for CML risk. Copyright © 2014 Elsevier Ltd. All rights reserved.

Polymorphisms in the circadian expressed genes PER3 and ARNTL2 are associated with diurnal preference and GNβ3 with sleep measures

PubMed Central

Parsons, Michael J; Lester, Kathryn J; Barclay, Nicola L; Archer, Simon N; Nolan, Patrick M; Eley, Thalia C; Gregory, Alice M

2014-01-01

Sleep and circadian rhythms are intrinsically linked, with several sleep traits, including sleep timing and duration, influenced by both sleep homeostasis and the circadian phase. Genetic variation in several circadian genes has been associated with diurnal preference (preference in timing of sleep), although there has been limited research on whether they are associated with other sleep measurements. We investigated whether these genetic variations were associated with diurnal preference (Morningness–Eveningness Questionnaire) and various sleep measures, including: the global Pittsburgh Sleep Quality index score; sleep duration; and sleep latency and sleep quality. We genotyped 10 polymorphisms in genes with circadian expression in participants from the G1219 sample (n = 966), a British longitudinal population sample of young adults. We conducted linear regressions using dominant, additive and recessive models of inheritance to test for associations between these polymorphisms and the sleep measures. We found a significant association between diurnal preference and a polymorphism in period homologue 3 (PER3) (P < 0.005, recessive model) and a novel nominally significant association between diurnal preference and a polymorphism in aryl hydrocarbon receptor nuclear translocator-like 2 (ARNTL2) (P < 0.05, additive model). We found that a polymorphism in guanine nucleotide binding protein beta 3 (GNβ3) was associated significantly with global sleep quality (P < 0.005, recessive model), and that a rare polymorphism in period homologue 2 (PER2) was associated significantly with both sleep duration and quality (P < 0.0005, recessive model). These findings suggest that genes with circadian expression may play a role in regulating both the circadian clock and sleep homeostasis, and highlight the importance of further studies aimed at dissecting the specific roles that circadian genes play in these two interrelated but unique behaviours. PMID:24635757

A66G and C524T polymorphisms of methionine synthase reductase gene are linked to the development of acyanotic congenital heart diseases in Egyptian children.

PubMed

Hassan, Fahima M; Khattab, Ahmad A; Abo El Fotoh, Wafaa Moustafa M; Zidan, Reham S

2017-09-20

Methionine synthase reductase (MTRR) is one of the main regulatory enzymes in the homocysteine/folate pathway. Genes involved in this pathway may play an important role in the development of congenital heart diseases (CHDs). C524T and A66G polymorphisms of MTRR gene may play an imperative role in the development of acyanotic CHDs. This study carried out on 200 children equally divided into 2 groups: group I: 100 children with acyanotic CHDs; and group II: 100 healthy children served as controls. PCR-RFLP method carried out to amplify the A66G and C524T polymorphisms of MTRR gene digested with Xho1and NdeI enzymes. A significant difference(P=0.015) in genotype frequencies of C524T polymorphism between cases and controls, where CC, CT, and TT were 14.0%, 40.0% and 46.0% in patients compared to 38.0,36.0% and 26.0% in controls. Again, a significant difference (P=0.010) in genotype frequencies of A66G polymorphism between the two groups as AA, AG and GG were 26.0%, 32.0% and42.0% in patients compared to 48.0, 36.0% and 16.0% in controls. Also, MTRR A66G and C524T polymorphisms were associated with a higher CHD risk in the homozygote comparison of wild and mutant genotypes and also in heterozygote and mutant comparison. So A66G and C524T polymorphisms of MTRR gene are associated with increased risk of acyanotic CHDs. Copyright © 2017 Elsevier B.V. All rights reserved.

Association of the Plasminogen Activator Inhibitor-1 (PAI-1) Gene -675 4G/5G and -844 A/G Promoter Polymorphism with Risk of Keloid in a Chinese Han Population

PubMed Central

Wang, Yongjie; Long, Jianhong; Wang, Xiaoyan; Sun, Yang

2014-01-01

Background A keloid is pathological scar caused by aberrant response to skin injuries, characterized by excessive accumulation of histological extracellular matrix, and occurs in genetically susceptible individuals. Plasminogen activator inhibitor-1 (PAI-1) has been implicated in the pathogenesis of keloid. We investigated the association between PAI-1 polymorphisms and plasma PAI-1 level with keloid risk. Material/Methods A total of 242 Chinese keloid patients and 207 controls were enrolled in this study. Polymerase chain reaction-restriction technique was used to determine PAI-1 promoter polymorphism (-675 4G/5G and -844 A/G) distribution. Plasma PAI-1 levels were detected using enzyme-linked immunosorbent assay (ELISA). Results There was a statistically significant difference in the distribution of PAI-1 -675 4G/5G polymorphism between keloid patients and healthy controls. 4G/4G carriers were more likely to develop keloid. In contrast, the -844 A/G polymorphism distribution did not vary significantly between keloid patients and controls. The keloid patients group had a significantly higher plasma PAI-1 level than the control group. In the -675 4G/4G carrier population, the plasma PAI-1 levels were significant higher in keloid patients compared with controls. Conclusions Our study provides evidence that PAI-1 promoter polymorphism -675 4G/5G and plasma PAI-1 level are associated with keloid risk. PAI-1 -675 4G/5G polymorphism may be an important hereditary factor responsible for keloid development in the Chinese Han population. PMID:25350781

The serotonin transporter 5-HTTPR polymorphism is associated with current and lifetime depression in persons with chronic psychotic disorders.

PubMed

Contreras, J; Hare, L; Camarena, B; Glahn, D; Dassori, A; Medina, R; Contreras, S; Ramirez, M; Armas, R; Munoz, R; Mendoza, R; Raventos, H; Ontiveros, A; Nicolini, H; Palmer, R; Escamilla, M

2009-02-01

Variation in the serotonin transporter gene (SLC6A4) promoter region has been shown to influence depression in persons who have been exposed to a number of stressful life events. We evaluated whether genetic variation in 5-HTTLPR, influences current depression, lifetime history of depression and quantitative measures of depression in persons with chronic psychotic disorders. This is an association study of a genetic variant with quantitative and categorical definitions of depression conducted in the southwest US, Mexico and Costa Rica. We analyzed 260 subjects with a history of psychosis, from a sample of 129 families. We found that persons carrying at least one short allele had a statistically significant increased lifetime risk for depressive syndromes (P < 0.02, odds ratio 2.18, 95% CI 1.10-4.20). The 'ss' or 'sl' genotype at the 5-HTTLPR promoter polymorphic locus increases the risk of psychotic individuals to develop major depression during the course of their illness.

Short report: polymorphisms in the chloroquine resistance transporter gene in Plasmodium falciparum isolates from Lombok, Indonesia.

PubMed

Huaman, Maria Cecilia; Yoshinaga, Kazumi; Suryanatha, Aan; Suarsana, Nyoman; Kanbara, Hiroji

2004-07-01

The polymorphisms in the Plasmodium falciparum multidrug resistance 1 (pfmdr1) and P. falciparum chloroquine resistance transporter (pfcrt) genes, which are associated with chloroquine resistance, were examined in 48 P. falciparum isolates from uncomplicated malaria patients from the West Lombok District in Indonesia. The point mutation N86Y in pfmdr1 was present in 35.4% of the isolates and mutation K76T in pfcrt was found in all but one of the samples studied. Identified pfcrt haplotypes were mainly identical to the Papua New Guinea type S(agt)VMNT (42 of 48, 87.5%), and a few isolates had the Southeast Asia type CVIET (5 of 48, 10.4%). Moreover, one P. falciparum isolate harbored the K76N mutation, giving rise to the haplotype CVMNN, which was not previously reported in field isolates. Our findings suggest that chloroquine resistance in this area might have the same origin as in Papua New Guinea.

[Role of Serotonin Transporter Gene in Eating Disorders].

PubMed

Hernández-Muñoz, Sandra; Camarena-Medellin, Beatriz

2014-01-01

The serotoninergic system has been implicated in mood and appetite regulation, and the serotonin transporter gene (SLC6A4) is a commonly studied candidate gene for eating disorders. However, most studies have focused on a single polymorphism (5-HTTLPR) in SLC6A4. We present the studies published on the association between eating disorders (ED) and 5-HTTLPR polymorphism in anorexia nervosa (AN), bulimia nervosa (BN), and eating disorders not otherwise specified (EDNOS). Search of databases: MEDLINE, ISI, and PubMed for SLC6A4 and ED. From a review of 37 original articles, it was suggested that carriers of S allele is a risk factor for eating disorders, especially for AN. However, BN did not show any association. Also, BMI, impulsivity, anxiety, depression, and age of onset have been associated with S allele in ED patients. Copyright © 2013 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

Refining the Candidate Environment: Interpersonal Stress, the Serotonin Transporter Polymorphism, and Gene-Environment Interactions in Major Depression.

PubMed

Vrshek-Schallhorn, Suzanne; Mineka, Susan; Zinbarg, Richard E; Craske, Michelle G; Griffith, James W; Sutton, Jonathan; Redei, Eva E; Wolitzky-Taylor, Kate; Hammen, Constance; Adam, Emma K

2014-05-01

Meta-analytic evidence supports a gene-environment (G×E) interaction between life stress and the serotonin transporter polymorphism (5-HTTLPR) on depression, but few studies have examined factors that influence detection of this effect, despite years of inconsistent results. We propose that the "candidate environment" (akin to a candidate gene) is key. Theory and evidence implicate major stressful life events (SLEs)-particularly major interpersonal SLEs-as well as chronic family stress. Participants ( N = 400) from the Youth Emotion Project (which began with 627 high school juniors oversampled for high neuroticism) completed up to five annual diagnostic and life stress interviews and provided DNA samples. A significant G×E effect for major SLEs and S -carrier genotype was accounted for significantly by major interpersonal SLEs but not significantly by major non-interpersonal SLEs. S -carrier genotype and chronic family stress also significantly interacted. Identifying such candidate environments may facilitate future G×E research in depression and psychopathology more broadly.

Relationship between ABCB1 gene polymorphisms and severe neutropenia in patients with breast cancer treated with doxorubicin/cyclophosphamide chemotherapy.

PubMed

Ikeda, Midori; Tsuji, Daiki; Yamamoto, Keisuke; Kim, Yong-Il; Daimon, Takashi; Iwabe, Yutaro; Hatori, Masahiro; Makuta, Ryo; Hayashi, Hideki; Inoue, Kazuyuki; Nakamichi, Hidenori; Shiokawa, Mitsuru; Itoh, Kunihiko

2015-04-01

Chemotherapy-induced neutropenia is one of the major adverse events which results in the reduction of chemotherapy. Doxorubicin is a substrate of the adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) transporter; reportedly, ABCB1 polymorphisms influence doxorubicin pharmacokinetics. We evaluated the association between chemotherapy-induced neutropenia and ABCB1 polymorphisms in patients with breast cancer. We investigated 141 patients with breast cancer treated with doxorubicin and cyclophosphamide (AC) chemotherapy. Peripheral blood samples obtained from patients were genotyped for the ABCB1 2677G>T/A and 3435C>T polymorphisms. The genotypes were then investigated for their association with grade 3 or greater neutropenia, and further their risk factors were examined using a multivariate logistic regression. The proportion of patients with grade 3 or greater neutropenia was 85.7% in the homozygous variant group, and 80% and 58.6% in the heterozygous variant and GG genotype groups, respectively (p = 0.021). The multivariate logistic regression analysis revealed that the ABCB1 2677G>T/A polymorphism was a strong predictor of grade 3 or greater neutropenia (odds ratio: 3.76; 95% confidence interval: 1.44-9.81; p = 0.007). ABCB1 polymorphisms may influence the extent of chemotherapy-induced neutropenia in AC combination-treated patients with breast cancer. Copyright © 2014 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Interindividual Variability in Hepatic Organic Anion-Transporting Polypeptides and P-Glycoprotein (ABCB1) Protein Expression: Quantification by Liquid Chromatography Tandem Mass Spectroscopy and Influence of Genotype, Age, and Sex

PubMed Central

Prasad, Bhagwat; Evers, Raymond; Gupta, Anshul; Hop, Cornelis E. C. A.; Salphati, Laurent; Shukla, Suneet; Ambudkar, Suresh V.

2014-01-01

Interindividual variability in protein expression of organic anion-transporting polypeptides (OATPs) OATP1B1, OATP1B3, OATP2B1, and multidrug resistance-linked P-glycoprotein (P-gp) or ABCB1 was quantified in frozen human livers (n = 64) and cryopreserved human hepatocytes (n = 12) by a validated liquid chromatography tandem mass spectroscopy (LC-MS/MS) method. Membrane isolation, sample workup, and LC-MS/MS analyses were as described before by our laboratory. Briefly, total native membrane proteins, isolated from the liver tissue and cryopreserved hepatocytes, were trypsin digested and quantified by LC-MS/MS using signature peptide(s) unique to each transporter. The mean ± S.D. (maximum/minimum range in parentheses) protein expression (fmol/µg of membrane protein) in human liver tissue was OATP1B1- 2.0 ± 0.9 (7), OATP1B3- 1.1 ± 0.5 (8), OATP2B1- 1 1.7 ± 0.6 (5), and P-gp- 0.4 ± 0.2 (8). Transporter expression in the liver tissue was comparable to that in the cryopreserved hepatocytes. Most important is that livers with SLCO1B1 (encoding OATP1B1) haplotypes *14/*14 and *14/*1a [i.e., representing single nucleotide polymorphisms (SNPs), c.388A > G, and c.463C > A] had significantly higher (P < 0.0001) protein expression than the reference haplotype (*1a/*1a). Based on these genotype-dependent protein expression data, we predicted (using Simcyp) an up to ∼40% decrease in the mean area under the curve of rosuvastatin or repaglinide in subjects harboring these variant alleles compared with those harboring the reference alleles. SLCO1B3 (encoding OATP1B3) SNPs did not significantly affect protein expression. Age and sex were not associated with transporter protein expression. These data will facilitate the prediction of population-based human transporter-mediated drug disposition, drug-drug interactions, and interindividual variability through physiologically based pharmacokinetic modeling. PMID:24122874

The impact of N- and O-glycosylation on the functions of Glut-1 transporter in human thyroid anaplastic cells.

PubMed

Samih, Nezha; Hovsepian, Sonia; Notel, Frédéric; Prorok, Maëlle; Zattara-Cannoni, Hélène; Mathieu, Sylvie; Lombardo, Dominique; Fayet, Guy; El-Battari, Assou

2003-04-07

It has been previously shown that glucose transporter Glut-1 expression was detectable by immunostaining in tissue sections from anaplastic carcinoma, but not in normal thyroid tissue. Using human thyroid anaplastic carcinoma cells, we studied the mechanism by which Glut-1 molecules are translocated from the endoplasmic reticulum to the cell surface. The contribution of N- and O-linked glycans for the translocation and activity of Glut-1 transporter is emphasized. The inhibition of N-glycosylation with tunicamycin (TM) led to a 50% decrease in glucose transport while glycosylated and unglycosylated forms of Glut-1 were found at the cell surface. However, the inhibition of N-linked oligosaccharide processing with deoxymannojirimycin (dMJ) and swainsonine (SW) influenced neither the intracellular trafficking nor the activity of the transporter. On the other hand, Glut-1 bound to the O-linked glycan-specific lectin jacalin and the O-glycosylation inhibitor benzyl-N-acetylgalactosamine dramatically inhibited glucose transport. These results show that O- and N-linked oligosaccharides arbored by Glut-1 are essential for glucose transport in anaplastic carcinoma cells. The quantitative and qualitative alterations of Glut-1 glycosylation and the increase in glucose transport are associated with the anaplastic phenotype of human thyroid cells.

Organic Ion Transporters and Statin Drug Interactions.

PubMed

Kellick, Kenneth

2017-11-25

Statin drug-drug interactions (DDIs) are both troublesome to patients as well as costly to medical resources. The ability to predict and avoid these events could lead to improved outcomes as well as patient satisfaction. This review will explore efforts to better understand and predict these interactions specifically related to one drug transport system, the organic anion-transporting polypeptides (OATPs) specifically OATP1B1 and OATP1B3. Since the publication of the discovery of OATPs, there have been various pharmacokinetic models that have been proposed to explain the variation in pharmacokinetic and clinical effects related to the OATPs. The effects in transport activity appear to be partially related to the individual polymorphisms studied. Drug-drug interactions can occur when other drugs compete for the metabolic site on the OATPs. Various medications are identified as substrates and/or inhibitors of the OATPs, thereby complicating the ability to fully predict the impact on levels and effects. All of the models reviewed claim successes but show limited clinical utility. There are specific populations that have been identified, predominately various Asian descendants that require lower doses of statins to avoid adverse events. The concept of attributing these actions to the OATPs has been explored, but current models cannot accurately predict statin blood levels or elimination constants. The current research only points to the differences in the human genome and the single-nucleotide polymorphisms that exist between us. Based upon the currently available studies, there is beginning to be a glimmer in the understanding how different populations respond to statin transport and elimination. Additionally and unfortunately, there are other enzymes to be studied to better predict patient differences. Clearly, there has been much work completed, yet many more questions require answering to better understand these transport proteins.

More Power to OATP1B1: An Evaluation of Sample Size in Pharmacogenetic Studies Using a Rosuvastatin PBPK Model for Intestinal, Hepatic, and Renal Transporter‐Mediated Clearances

PubMed Central

Burt, Howard; Abduljalil, Khaled; Neuhoff, Sibylle

2016-01-01

Abstract Rosuvastatin is a substrate of choice in clinical studies of organic anion‐transporting polypeptide (OATP)1B1‐ and OATP1B3‐associated drug interactions; thus, understanding the effect of OATP1B1 polymorphisms on the pharmacokinetics of rosuvastatin is crucial. Here, physiologically based pharmacokinetic (PBPK) modeling was coupled with a power calculation algorithm to evaluate the influence of sample size on the ability to detect an effect (80% power) of OATP1B1 phenotype on pharmacokinetics of rosuvastatin. Intestinal, hepatic, and renal transporters were mechanistically incorporated into a rosuvastatin PBPK model using permeability‐limited models for intestine, liver, and kidney, respectively, nested within a full PBPK model. Simulated plasma rosuvastatin concentrations in healthy volunteers were in agreement with previously reported clinical data. Power calculations were used to determine the influence of sample size on study power while accounting for OATP1B1 haplotype frequency and abundance in addition to its correlation with OATP1B3 abundance. It was determined that 10 poor‐transporter and 45 intermediate‐transporter individuals are required to achieve 80% power to discriminate the AUC0‐48h of rosuvastatin from that of the extensive‐transporter phenotype. This number was reduced to 7 poor‐transporter and 40 intermediate‐transporter individuals when the reported correlation between OATP1B1 and 1B3 abundance was taken into account. The current study represents the first example in which PBPK modeling in conjunction with power analysis has been used to investigate sample size in clinical studies of OATP1B1 polymorphisms. This approach highlights the influence of interindividual variability and correlation of transporter abundance on study power and should allow more informed decision making in pharmacogenomic study design. PMID:27385171

The Gain-of-Function Integrin β3 Pro33 Variant Alters the Serotonin System in the Mouse Brain.

PubMed

Dohn, Michael R; Kooker, Christopher G; Bastarache, Lisa; Jessen, Tammy; Rinaldi, Capria; Varney, Seth; Mazalouskas, Matthew D; Pan, Hope; Oliver, Kendra H; Velez Edwards, Digna R; Sutcliffe, James S; Denny, Joshua C; Carneiro, Ana M D

2017-11-15

Engagement of integrins by the extracellular matrix initiates signaling cascades that drive a variety of cellular functions, including neuronal migration and axonal pathfinding in the brain. Multiple lines of evidence link the ITGB3 gene encoding the integrin β3 subunit with the serotonin (5-HT) system, likely via its modulation of the 5-HT transporter (SERT). The ITGB3 coding polymorphism Leu33Pro (rs5918, Pl A2 ) produces hyperactive αvβ3 receptors that influence whole-blood 5-HT levels and may influence the risk for autism spectrum disorder (ASD). Using a phenome-wide scan of psychiatric diagnoses, we found significant, male-specific associations between the Pro33 allele and attention-deficit hyperactivity disorder and ASDs. Here, we used knock-in (KI) mice expressing an Itgb3 variant that phenocopies the human Pro33 variant to elucidate the consequences of constitutively enhanced αvβ3 signaling to the 5-HT system in the brain. KI mice displayed deficits in multiple behaviors, including anxiety, repetitive, and social behaviors. Anatomical studies revealed a significant decrease in 5-HT synapses in the midbrain, accompanied by decreases in SERT activity and reduced localization of SERTs to integrin adhesion complexes in synapses of KI mice. Inhibition of focal adhesion kinase (FAK) rescued SERT function in synapses of KI mice, demonstrating that constitutive active FAK signaling downstream of the Pro32Pro33 integrin αvβ3 suppresses SERT activity. Our studies identify a complex regulation of 5-HT homeostasis and behaviors by integrin αvβ3, revealing an important role for integrins in modulating risk for neuropsychiatric disorders. SIGNIFICANCE STATEMENT The integrin β3 Leu33Pro coding polymorphism has been associated with autism spectrum disorders (ASDs) within a subgroup of patients with elevated blood 5-HT levels, linking integrin β3, 5-HT, and ASD risk. We capitalized on these interactions to demonstrate that the Pro33 coding variation in the murine integrin β3 recapitulates the sex-dependent neurochemical and behavioral attributes of ASD. Using state-of-the-art techniques, we show that presynaptic 5-HT function is altered in these mice, and that the localization of 5-HT transporters to specific compartments within the synapse, disrupted by the integrin β3 Pro33 mutation, is critical for appropriate reuptake of 5-HT. Our studies provide fundamental insight into the genetic network regulating 5-HT neurotransmission in the CNS that is also associated with ASD risk. Copyright © 2017 the authors 0270-6474/17/3711272-14$15.00/0.

Association of genotypes and haplotypes of multi-drug transporter genes ABCB1 and ABCG2 with clinical response to imatinib mesylate in chronic myeloid leukemia patients.

PubMed

Au, Anthony; Aziz Baba, Abdul; Goh, Ai Sim; Wahid Fadilah, S Abdul; Teh, Alan; Rosline, Hassan; Ankathil, Ravindran

2014-04-01

The introduction and success of imatinib mesylate (IM) has become a paradigm shift in chronic myeloid leukemia (CML) treatment. However, the high efficacy of IM has been hampered by the issue of clinical resistance that might due to pharmacogenetic variability. In the current study, the contribution of three common single nucleotide polymorphisms (SNPs) of ABCB1 (T1236C, G2677T/A and C3435T) and two SNPs of ABCG2 (G34A and C421A) genes in mediating resistance and/or good response among 215 CML patients on IM therapy were investigated. Among these patients, the frequency distribution of ABCG2 421 CC, CA and AA genotypes were significantly different between IM good response and resistant groups (P=0.01). Resistance was significantly associated with patients who had homozygous ABCB1 1236 CC genotype with OR 2.79 (95%CI: 1.217-6.374, P=0.01). For ABCB1 G2677T/A polymorphism, a better complete cytogenetic remission was observed for patients with variant TT/AT/AA genotype, compared to other genotype groups (OR=0.48, 95%CI: 0.239-0.957, P=0.03). Haplotype analysis revealed that ABCB1 haplotypes (C1236G2677C3435) was statistically linked to higher risk to IM resistance (25.8% vs. 17.4%, P=0.04), while ABCG2 diplotype A34A421 was significantly correlated with IM good response (9.1% vs. 3.9%, P=0.03). In addition, genotypic variant in ABCG2 421C>A was associated with a major molecular response (MMR) (OR=2.20, 95%CI: 1.273-3.811, P=0.004), whereas ABCB1 2677G>T/A variant was associated with a significantly lower molecular response (OR=0.49, 95%CI: 0.248-0.974, P=0.04). However, there was no significant correlation of these SNPs with IM intolerance and IM induced hepatotoxicity. Our results suggest the usefulness of genotyping of these single nucleotide polymorphisms in predicting IM response among CML patients. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Population and allelic variation of A-to-I RNA editing in human transcriptomes.

PubMed

Park, Eddie; Guo, Jiguang; Shen, Shihao; Demirdjian, Levon; Wu, Ying Nian; Lin, Lan; Xing, Yi

2017-07-28

A-to-I RNA editing is an important step in RNA processing in which specific adenosines in some RNA molecules are post-transcriptionally modified to inosines. RNA editing has emerged as a widespread mechanism for generating transcriptome diversity. However, there remain significant knowledge gaps about the variation and function of RNA editing. In order to determine the influence of genetic variation on A-to-I RNA editing, we integrate genomic and transcriptomic data from 445 human lymphoblastoid cell lines by combining an RNA editing QTL (edQTL) analysis with an allele-specific RNA editing (ASED) analysis. We identify 1054 RNA editing events associated with cis genetic polymorphisms. Additionally, we find that a subset of these polymorphisms is linked to genome-wide association study signals of complex traits or diseases. Finally, compared to random cis polymorphisms, polymorphisms associated with RNA editing variation are located closer spatially to their respective editing sites and have a more pronounced impact on RNA secondary structure. Our study reveals widespread cis variation in RNA editing among genetically distinct individuals and sheds light on possible phenotypic consequences of such variation on complex traits and diseases.

Comparative assessment of genetic and epigenetic variation among regenerants of potato (Solanum tuberosum) derived from long-term nodal tissue-culture and cell selection.

PubMed

Dann, Alison L; Wilson, Calum R

2011-04-01

Three long-term nodal tissued cultured Russet Burbank potato clones and nine thaxtomin A-treated regenerant lines, derived from the nodal lines, were assessed for genetic and epigenetic (in the form of DNA methylation) differences by AFLP and MSAP. The treated regenerant lines were originally selected for superior resistance to common scab disease and acceptable tuber yield in pot and field trials. The long-term, tissue culture clone lines exhibited genetic (8.75-15.63% polymorphisms) and epigenetic (12.56-26.13% polymorphisms) differences between them and may represent a stress response induced by normal plant growth disruption. The thaxtomin A-treated regenerant lines exhibited much higher significant (p < 0.05) genetic (2-29.38%) and epigenetic (45.22-51.76%) polymorphisms than the nodal cultured parent clones. Methylation-sensitive mutations accumulated within the regenerant lines are significantly correlated (p < 0.05) to disease resistance. However, linking phenotypic differences that could be of benefit to potato growers, to single gene sequence polymorphisms in a tetraploid plant such as the potato would be extremely difficult since it is assumed many desirable traits are under polygenic control.

Korean, Japanese, and Chinese populations featured similar genes encoding drug-metabolizing enzymes and transporters: a DMET Plus microarray assessment.

PubMed

Yi, SoJeong; An, Hyungmi; Lee, Howard; Lee, Sangin; Ieiri, Ichiro; Lee, Youngjo; Cho, Joo-Youn; Hirota, Takeshi; Fukae, Masato; Yoshida, Kenji; Nagatsuka, Shinichiro; Kimura, Miyuki; Irie, Shin; Sugiyama, Yuichi; Shin, Dong Wan; Lim, Kyoung Soo; Chung, Jae-Yong; Yu, Kyung-Sang; Jang, In-Jin

2014-10-01

Interethnic differences in genetic polymorphism in genes encoding drug-metabolizing enzymes and transporters are one of the major factors that cause ethnic differences in drug response. This study aimed to investigate genetic polymorphisms in genes involved in drug metabolism, transport, and excretion among Korean, Japanese, and Chinese populations, the three major East Asian ethnic groups. The frequencies of 1936 variants representing 225 genes encoding drug-metabolizing enzymes and transporters were determined from 786 healthy participants (448 Korean, 208 Japanese, and 130 Chinese) using the Affymetrix Drug-Metabolizing Enzymes and Transporters Plus microarray. To compare allele or genotype frequencies in the high-dimensional data among the three East Asian ethnic groups, multiple testing, principal component analysis (PCA), and regularized multinomial logit model through least absolute shrinkage and selection operator were used. On microarray analysis, 1071 of 1936 variants (>50% of markers) were found to be monomorphic. In a large number of genetic variants, the fixation index and Pearson's correlation coefficient of minor allele frequencies were less than 0.034 and greater than 0.95, respectively, among the three ethnic groups. PCA identified 47 genetic variants with multiple testing, but was unable to discriminate ethnic groups by the first three components. Multinomial least absolute shrinkage and selection operator analysis identified 269 genetic variants that showed different frequencies among the three ethnic groups. However, none of those variants distinguished between the three ethnic groups during subsequent PCA. Korean, Japanese, and Chinese populations are not pharmacogenetically distant from one another, at least with regard to drug disposition, metabolism, and elimination.

Prognostic role of the CDNK1B V109G polymorphism in multiple endocrine neoplasia type 1.

PubMed

Circelli, Luisa; Ramundo, Valeria; Marotta, Vincenzo; Sciammarella, Concetta; Marciello, Francesca; Del Prete, Michela; Sabatino, Lina; Pasquali, Daniela; Izzo, Francesco; Scala, Stefania; Colao, Annamaria; Faggiano, Antongiulio; Colantuoni, Vittorio

2015-07-01

CDKN1B encodes the cyclin-dependent kinase inhibitor p27/Kip1. CDKN1B mutations and polymorphisms are involved in tumorigenesis; specifically, the V109G single nucleotide polymorphism has been linked to different tumours with controversial results. Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant syndrome, characterized by the development of different types of neuroendocrine tumours and increased incidence of other malignancies. A clear genotype-phenotype correlation in MEN1 has not been established yet. In this study, we assessed whether the CDKN1B V109G polymorphism was associated with the development of aggressive tumours in 55 consecutive patients affected by MEN1. The polymorphism was investigated by PCR amplification of germline DNA followed by direct sequencing. Baseline and follow-up data of tumour types and their severity were collected and associated with the genetic data. MEN1-related aggressive and other malignant tumours of any origin were detected in 16.1% of wild-type and 33.3% of polymorphism allele-bearing patients (P = NS). The time interval between birth and the first aggressive tumour was significantly shorter in patients with the CDKN1B V109G polymorphism (median 46 years) than in those without (median not reached; P = 0.03). Similarly, shorter was the time interval between MEN1 diagnosis and age of the first aggressive tumour (P = 0.02). Overall survival could not be estimated as 96% patients were still alive at the time of the study. In conclusion, CDKN1B V109G polymorphism seems to play a role in the development of aggressive tumours in MEN1. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Sequence diversity patterns suggesting balancing selection in partially sex-linked genes of the plant Silene latifolia are not generated by demographic history or gene flow.

PubMed

Guirao-Rico, Sara; Sánchez-Gracia, Alejandro; Charlesworth, Deborah

2017-03-01

DNA sequence diversity in genes in the partially sex-linked pseudoautosomal region (PAR) of the sex chromosomes of the plant Silene latifolia is higher than expected from within-species diversity of other genes. This could be the footprint of sexually antagonistic (SA) alleles that are maintained by balancing selection in a PAR gene (or genes) and affect polymorphism in linked genome regions. SA selection is predicted to occur during sex chromosome evolution, but it is important to test whether the unexpectedly high sequence polymorphism could be explained without it, purely by the combined effects of partial linkage with the sex-determining region and the population's demographic history, including possible introgression from Silene dioica. To test this, we applied approximate Bayesian computation-based model choice to autosomal sequence diversity data, to find the most plausible scenario for the recent history of S. latifolia and then to estimate the posterior density of the most relevant parameters. We then used these densities to simulate variation to be expected at PAR genes. We conclude that an excess of variants at high frequencies at PAR genes should arise in S. latifolia populations only for genes with strong associations with fully sex-linked genes, which requires closer linkage with the fully sex-linked region than that estimated for the PAR genes where apparent deviations from neutrality were observed. These results support the need to invoke selection to explain the S. latifolia PAR gene diversity, and encourage further work to test the possibility of balancing selection due to sexual antagonism. © 2016 John Wiley & Sons Ltd.

Promoter polymorphisms in the ATP binding cassette transporter gene influence production of cell-derived microparticles and are highly associated with susceptibility to severe malaria in humans.

PubMed

Sahu, Upasana; Mohapatra, Biranchi N; Kar, Shantanu K; Ranjit, Manoranjan

2013-04-01

Microparticle (MP) efflux is known to be mediated by the ABCA1 protein, and the plasma level of these cell-derived MPs is elevated considerably during human malarial infection. Therefore, two polymorphisms at positions -477 and -320 in the promoter of the ABCA1 gene were genotyped and tested for association with the plasma MP level in four groups of malaria patients segregated according to the clinical severity, i.e., cerebral malaria (CM), multiorgan dysfunction (MOD), noncerebral severe malaria, and uncomplicated malaria (UM). The TruCount tube-based flow cytometric method was used for the exact quantification of different cell-derived MPs in patients. Polymorphisms in the ABCA1 gene promoter were analyzed by use of the PCR/two-primer-pair method, followed by restriction fragment length polymorphism, in 428 malaria patients. The level of circulating plasma MPs was significantly higher in febrile patients with Plasmodium falciparum infection, especially in CM patients compared to healthy individuals. The homozygous wild-type -477 and -320 genotype was observed to be significantly higher in patients with severe malaria. These patients also showed marked increases in the plasma MP numbers compared to UM patients. We report here for the first time an association of ABCA1 promoter polymorphisms with susceptibility to severe malaria, especially to CM and MOD, indicating the protective effect of the mutant variant of the polymorphism. We hypothesize that the -477T and -320G polymorphisms affect the downregulation of MP efflux and may be a predictor of organ complication during P. falciparum malarial infections.

Association of the -1082 G/A promoter polymorphism of interleukin-10 gene with the autoantibodies production in patients with rheumatoid arthritis.

PubMed

Nemec, Petr; Pavkova-Goldbergova, Monika; Gatterova, Jindra; Fojtik, Zdenek; Vasku, Anna; Soucek, Miroslav

2009-08-01

Interleukin-10 (IL-10) is an immunoregulatory cytokine, usually considered to mediate the downregulation of the inflammatory response in rheumatoid arthritis (RA). Some effects of IL-10 are not anti-inflammatory; for example, the activation of B cells to promote autoantibody production. Allelic polymorphisms located in the promoter region of the IL-10 gene may contribute to the regulation of autoantibodies production. To examine the putative association between the -1082 G/A polymorphism in the promoter region of the IL-10 gene and the susceptibility to disease onset and severity of RA, a total of 144 patients with RA diagnosed according to the revised criteria of the American College of Rheumatology for RA were consecutively recruited into the study. Radiographic progression of RA was scored according to the Sharp/van der Heijde method. Serum levels of rheumatoid factors (RFs) were measured by enzyme-linked immunosorbent assay. Polymerase chain reaction amplification was used for the analysis of the promoter polymorphism of the IL-10 gene. We observed significant differences in genotype distribution of the -1082 G/A polymorphism between IgM RF, IgA RF, and IgG RF positive/negative subgroups of RA patients, with higher prevalence of the GG genotype within IgM RF (Pg = 0.006), IgA RF (Pg = 0.05), and IgG RF (Pg = 0.007) negative RA patients. Results obtained in this study provide the evidence of an association between the -1082 G/A polymorphism in the IL-10 gene promoter and the production of RFs in RA patients.

PvuII and XbaI polymorphisms of estrogen receptor-α and the results of estroprogestagen therapy in girls with functional hypothalamic amenorrhea – preliminary study

PubMed Central

Syrenicz, Anhelli; Friebe, Zbigniew; Jarząbek-Bielecka, Grażyna; Chełstowski, Kornel

2012-01-01

Introduction The aim of this study was the long-term prospective evaluation of the effects of estroprogestagen (EP) therapy on the bone mineral density (BMD) of girls with functional hypothalamic amenorrhea (FHA) carrying various PvuII and XbaI polymorphisms of ER-α. Material and methods Prospective observation included 84 FHA girls and 50 controls. The FHA patients were subjected to 4-year sequential therapy with 17β estradiol (2 mg from the 2nd to 25th day of the menstrual cycle) and dydrogesterone (10 mg from the 16th to the 25th day). Hormonal parameters, serum concentration of the bone fraction of alkaline phosphatase (BALP), urine concentration of cross-linked n-telopeptide of type I collagen (Ntx) and BMD were determined before and after the treatment. Results Six-month treatment resulted in a marked increase in estradiol (p = 0.001), testosterone and prolactin levels (p = 0.01 both) and a significant decrease in BALP and Ntx (p = 0.001 both). Patients with the PP polymorphism had significantly lower baseline BMD compared to carriers of other polymorphic variants of PvuII (p = 0.003). A significant increase in BMD was observed throughout the entire therapy period, with no significant differences in the yearly dynamics of BMD changes observed amongst various polymorphic variants and haplotypes of ER-α. Conclusions The EP therapy is effective in the treatment of BMD disorders associated with FHA, and treatment results do not depend on PvuII and XbaI polymorphisms of ER-α. PMID:23185193

PvuII and XbaI polymorphisms of estrogen receptor-α and the results of estroprogestagen therapy in girls with functional hypothalamic amenorrhea - preliminary study.

PubMed

Sowińska-Przepiera, Elżbieta; Syrenicz, Anhelli; Friebe, Zbigniew; Jarząbek-Bielecka, Grażyna; Chełstowski, Kornel

2012-11-09

The aim of this study was the long-term prospective evaluation of the effects of estroprogestagen (EP) therapy on the bone mineral density (BMD) of girls with functional hypothalamic amenorrhea (FHA) carrying various PvuII and XbaI polymorphisms of ER-α. Prospective observation included 84 FHA girls and 50 controls. The FHA patients were subjected to 4-year sequential therapy with 17β estradiol (2 mg from the 2(nd) to 25(th) day of the menstrual cycle) and dydrogesterone (10 mg from the 16(th) to the 25(th) day). Hormonal parameters, serum concentration of the bone fraction of alkaline phosphatase (BALP), urine concentration of cross-linked n-telopeptide of type I collagen (Ntx) and BMD were determined before and after the treatment. Six-month treatment resulted in a marked increase in estradiol (p = 0.001), testosterone and prolactin levels (p = 0.01 both) and a significant decrease in BALP and Ntx (p = 0.001 both). Patients with the PP polymorphism had significantly lower baseline BMD compared to carriers of other polymorphic variants of PvuII (p = 0.003). A significant increase in BMD was observed throughout the entire therapy period, with no significant differences in the yearly dynamics of BMD changes observed amongst various polymorphic variants and haplotypes of ER-α. The EP therapy is effective in the treatment of BMD disorders associated with FHA, and treatment results do not depend on PvuII and XbaI polymorphisms of ER-α.

Human cancer xenografts in outbred nude mice can be confounded by polymorphisms in a modifier of tumorigenesis.

PubMed

Zeineldin, Maged; Jensen, Derek; Paranjape, Smita R; Parelkar, Nikhil K; Jokar, Iman; Vielhauer, George A; Neufeld, Kristi L

2014-08-01

Tumorigenicity studies often employ outbred nude mice, in the absence of direct evidence that this mixed genetic background will negatively affect experimental outcome. Here we show that outbred nude mice carry two different alleles of Pla2g2a, a genetic modifier of intestinal tumorigenesis in mice. Here, we identify previous unreported linked polymorphisms in the promoter, noncoding and coding sequences of Pla2g2a and show that outbred nude mice from different commercial providers are heterogeneous for this polymorphic Pla2g2a allele. This heterogeneity even extends to mice obtained from a single commercial provider, which display mixed Pla2g2a genotypes. Notably, we demonstrated that the polymorphic Pla2g2a allele affects orthotopic xenograft establishment of human colon cancer cells in outbred nude mice. This finding establishes a non-cell-autonomous role for Pla2g2a in suppressing intestinal tumorigenesis. Using in vitro reporter assays and pharmacological inhibitors, we show promoter polymorphisms and nonsense-mediated RNA decay (NMD) as underlying mechanisms that lead to low Pla2g2a mRNA levels in tumor-sensitive mice. Together, this study provides mechanistic insight regarding Pla2g2a polymorphisms and demonstrates a non-cell-autonomous role for Pla2g2a in suppressing tumors. Moreover, our direct demonstration that mixed genetic backgrounds of outbred nude mice can significantly affect baseline tumorigenicity cautions against future use of outbred mice for tumor xenograft studies. Copyright © 2014 by the Genetics Society of America.

Human Cancer Xenografts in Outbred Nude Mice Can Be Confounded by Polymorphisms in a Modifier of Tumorigenesis

PubMed Central

Zeineldin, Maged; Jensen, Derek; Paranjape, Smita R.; Parelkar, Nikhil K.; Jokar, Iman; Vielhauer, George A.; Neufeld, Kristi L.

2014-01-01

Tumorigenicity studies often employ outbred nude mice, in the absence of direct evidence that this mixed genetic background will negatively affect experimental outcome. Here we show that outbred nude mice carry two different alleles of Pla2g2a, a genetic modifier of intestinal tumorigenesis in mice. Here, we identify previous unreported linked polymorphisms in the promoter, noncoding and coding sequences of Pla2g2a and show that outbred nude mice from different commercial providers are heterogeneous for this polymorphic Pla2g2a allele. This heterogeneity even extends to mice obtained from a single commercial provider, which display mixed Pla2g2a genotypes. Notably, we demonstrated that the polymorphic Pla2g2a allele affects orthotopic xenograft establishment of human colon cancer cells in outbred nude mice. This finding establishes a non-cell-autonomous role for Pla2g2a in suppressing intestinal tumorigenesis. Using in vitro reporter assays and pharmacological inhibitors, we show promoter polymorphisms and nonsense-mediated RNA decay (NMD) as underlying mechanisms that lead to low Pla2g2a mRNA levels in tumor-sensitive mice. Together, this study provides mechanistic insight regarding Pla2g2a polymorphisms and demonstrates a non-cell-autonomous role for Pla2g2a in suppressing tumors. Moreover, our direct demonstration that mixed genetic backgrounds of outbred nude mice can significantly affect baseline tumorigenicity cautions against future use of outbred mice for tumor xenograft studies. PMID:24913681

The Association of Plasminogen Activator Inhibitor Type 1 (PAI-1) Level and PAI-1 4G/5G Gene Polymorphism with the Formation and the Grade of Endometrial Cancer.

PubMed

Yıldırım, Malik Ejder; Karakuş, Savas; Kurtulgan, Hande Küçük; Kılıçgün, Hasan; Erşan, Serpil; Bakır, Sevtap

2017-08-01

Plasminogen activator inhibitor type 1 (PAI-1) is a serine protease inhibitor (Serpine 1), and it inhibits both tissue plasminogen activator and urokinase plasminogen activator which are important in fibrinolysis. We aimed to find whether there is a possible association between PAI-1 level, PAI-1 4G/5G polymorphism, and endometrial cancer. PAI-1 levels in peripheral blood were determined in 82 patients with endometrial carcinoma and 76 female healthy controls using an enzyme-linked immunoassay (ELISA). Then, the genomic DNA was extracted and screened by reverse hybridization procedure (Strip assay) to detect PAI 1 4G/5G polymorphism. The levels of PAI-1 in the patients were higher statistically in comparison to controls (P < 0.001). The distribution of PAI-1 4G/5G polymorphism was quite different between patients and controls (P = 0.008), and 4G allelic frequency was significantly higher in the patients of endometrial cancer than in controls (P = 0.026). We found significant difference between Grade 1 and Grade 2+3 patients in terms of the PAI-1 levels (P = 0.047). There was no association between PAI-1 4G/5G polymorphism and the grades of endometrial cancer (P = 0.993). Our data suggest that the level of PAI-1 and PAI-1 4G/5G gene polymorphism are effective in the formation of endometrial cancer. PAI-1 levels are also associated with the grades of endometrial cancer.