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Sample records for genotype relative risks

  1. How to Relate Complex DNA Repair Genotypes to Pathway Function and, Ultimately, Health Risk

    SciTech Connect

    Jones, IM

    2002-01-09

    Exposure to ionizing radiation increases the incidence of cancer. However, predicting which individuals are at most risk from radiation exposure is a distant goal. Predictive ability is needed to guide policies that regulate radiation exposure and ensure that medical treatments have maximum benefit and minimum risk. Differences between people in susceptibility to radiation are largely based on their genotype, the genes inherited from their parents. Among the important genes are those that produce proteins that repair DNA damaged by radiation. Base Excision Repair (BER) proteins repair single strand breaks and oxidized bases in DNA. Double Strand Break Repair proteins repair broken chromosomes. Using technologies and information from the Human Genome Project, we have previously determined that the DNA sequence of DNA repair genes varies within the human population. An average of 3-4 different variants were found that affect the protein for each of 37 genes studied. The average frequency of these variants is 5%. Given the many genes in each DNA repair pathway and their many variants, technical ability to determine an individual's repair genotype greatly exceeds ability to interpret the information. A long-term goal is to relate DNA repair genotypes to health risk from radiation. This study focused on the BER pathway. The BER genes are known, variants of the genes have been identified at LLNL, and LLNL had recently developed an assay for BER function using white blood cells. The goal of this initial effort was to begin developing data that could be used to test the hypothesis that many different genotypes have similar DNA repair capacity phenotypes (function). Relationships between genotype and phenotype could then be used to group genotypes with similar function and ultimately test the association of groups of genotypes with health risk from radiation. Genotypes with reduced repair function are expected to increase risk of radiation-induced health effects. The goal

  2. Interleukin-6-related genotypes, body mass index, and risk of multiple myeloma and plasmacytoma.

    PubMed

    Cozen, Wendy; Gebregziabher, Mulugeta; Conti, David V; Van Den Berg, David J; Coetzee, Gerhard A; Wang, Sophia S; Rothman, Nathaniel; Bernstein, Leslie; Hartge, Patricia; Morhbacher, Ann; Coetzee, Simon G; Salam, Muhammad T; Wang, Wei; Zadnick, John; Ingles, Sue A

    2006-11-01

    Interleukin-6 (IL-6) promotes normal plasma cell development and proliferation of myeloma cells in culture. We evaluated IL-6 genotypes and body mass index (BMI) in a case-control study of multiple myeloma and plasmacytoma. DNA samples and questionnaires were obtained from incident cases of multiple myeloma (n = 134) and plasmacytoma (n = 16; plasma cell neoplasms) ascertained from the Los Angeles County population-based cancer registry and from siblings or cousins of cases (family controls, n = 112) and population controls (n = 126). Genotypes evaluated included IL-6 promoter gene single nucleotide polymorphisms (SNP) at positions -174, -572, and -597; one variable number of tandem repeats (-373 A(n)T(n)); and one SNP in the IL-6 receptor (IL-6ralpha) gene at position -358. The variant allele of the IL-6 promoter SNP -572 was associated with a roughly 2-fold increased risk of plasma cell neoplasms when cases were compared with family [odds ratio (OR), 1.8; 95% confidence interval (95% CI), 0.7-4.7] or population controls (OR, 2.4; 95% CI, 1.2-4.7). The -373 9A/9A genotype was associated with a decreased risk compared with the most common genotype (OR for cases versus family controls, 0.4; 95% CI, 0.1-1.7; OR for cases versus population controls, 0.3; 95% CI, 0.1-0.9). No other SNPs were associated with risk. Obesity (BMI >or= 30 kg/m(2)) increased risk nonsignificantly by 40% and 80% when cases were compared with family controls or population controls, respectively, relative to persons with a BMI of <25 kg/m(2). These results suggest that IL-6 promoter genotypes may be associated with increased risk of plasma cell neoplasms.

  3. Oxidative stress-related genotypes, fruit and vegetable consumption and breast cancer risk.

    PubMed

    Li, Yulin; Ambrosone, Christine B; McCullough, Marjorie J; Ahn, Jiyoung; Stevens, Victoria L; Thun, Michael J; Hong, Chi-Chen

    2009-05-01

    Dietary antioxidants may interact with endogenous sources of pro- and antioxidants to impact breast cancer risk. A nested case-control study of postmenopausal women (505 cases and 502 controls) from the Cancer Prevention Study-II Nutrition Cohort was conducted to examine the interaction between oxidative stress-related genes and level of vegetable and fruit intake on breast cancer risk. Genetic variations in catalase (CAT) (C-262T), myeloperoxidase (MPO) (G-463A), endothelial nitric oxide synthase (NOS3) (G894T) and heme oxygenase-1 (HO-1) [(GT)(n) dinucleotide length polymorphism] were not associated with breast cancer risk. Women carrying the low-risk CAT CC [odds ratio (OR) = 0.75, 95% confidence interval (CI) 0.50-1.11], NOS3 TT (OR = 0.54, 95% CI = 0.26-1.12, P-trend = 0.10) or HO-1 S allele and MM genotype (OR = 0.56, 95% CI = 0.37-0.55), however, were found to be at non-significantly reduced breast cancer risk among those with high vegetable and fruit intake (> or = median; P-interactions = 0.04 for CAT, P = 0.005 for NOS3 and P = 0.07 for HO-1). Furthermore, those with > or = 4 putative low-risk alleles in total had significantly reduced risk (OR = 0.53, 95% CI = 0.32-0.88, P-interaction = 0.006) compared with those with < or = 2 low-risk alleles. In contrast, among women with low vegetable and fruit intake (< median), the low-risk CAT CC (OR = 1.33, 95% CI = 0.89-1.99), NOS3 TT (OR = 2.93, 95% CI = 1.38-6.22) and MPO AA (OR = 2.09, 95% CI = 0.73-5.95) genotypes appeared to be associated with raised breast cancer risk, with significantly increased risks observed in those with > or = 4 low-risk alleles compared with participants with < or = 2 low-risk alleles (OR = 1.77, 95% CI = 1.05-2.99, P-interaction = 0.006). Our results support the hypothesis that there are joint effects of endogenous and exogenous antioxidants.

  4. Genotype distribution and the relative risk factors for human papillomavirus in Urumqi, China.

    PubMed

    Chen, Zhifang; Meng, Wei; DU, Rong; Zhu, Yuejie; Zhang, Yi; Ding, Yan

    2013-07-01

    The aim of this study was to investigate human papillomavirus (HPV) infection and HPV genotype distributions in Urumqi, Xinjiang, China. The related risk factors for high-risk HPV infection was also analyzed. A stratified cluster sampling method was used for the population-based cervical cancer screening of women aged 18-69 years in the Urumqi Saybagh district. Exfoliated cervical cell samples were collected for liquid-based cytology detection and HPV genotyping DNA microarrays. Education level, number of sexual partners, condom use and occupation were used in the multivariate analysis model. The HPV infection rate of women working in service industries was significantly higher compared with those of white-collar workers, community residents and migrant workers. The 35-44-year-old migrant worker group had the highest HPV infection rates among all of the groups in the three different age ranges. The number of marriages, education level, smoking history, number of abortions, use of condoms, number of sexual partners, number of sexual partners in the past five years and occupation were all associated with female HPV infection rate (P<0.05). The 35-44-year-old women were the age group with the highest HPV infection rate. The HPV infection rate of females in service industries was the highest. Education level and condom use were protective factors of HPV infection, while the number of sexual partners and occupation were risk factors for HPV infection.

  5. MIR137HG risk variant rs1625579 genotype is related to corpus callosum volume in schizophrenia.

    PubMed

    Patel, Veena S; Kelly, Sinead; Wright, Carrie; Gupta, Cota Navin; Arias-Vasquez, Alejandro; Perrone-Bizzozero, Nora; Ehrlich, Stefan; Wang, Lei; Bustillo, Juan R; Morris, Derek; Corvin, Aiden; Cannon, Dara M; McDonald, Colm; Donohoe, Gary; Calhoun, Vince D; Turner, Jessica A

    2015-08-18

    Genome-wide association studies implicate the MIR137HG risk variant rs1625579 (MIR137HGrv) within the host gene for microRNA-137 as a potential regulator of schizophrenia susceptibility. We examined the influence of MIR137HGrv genotype on 17 subcortical and callosal volumes in a large sample of individuals with schizophrenia and healthy controls (n=841). Although the volumes were overall reduced relative to healthy controls, for individuals with schizophrenia the homozygous MIR137HGrv risk genotype was associated with attenuated reduction of mid-posterior corpus callosum volume (p=0.001), along with trend-level effects in the adjacent central and posterior corpus callosum. These findings are unique in the literature and remain robust after analysis in ethnically homogenous and single-scanner subsets of the larger sample. Thus, our study suggests that the mechanisms whereby MIR137HGrv works to increase schizophrenia risk are not those that generate the corpus callosum volume reductions commonly found in the disorder.

  6. Genotype relative risks: Methods for design and analysis of candidate-gene association studies

    SciTech Connect

    Shaid, D.J.; Sommer, S.S. )

    1993-11-01

    Design and analysis methods are presented for studying the association of a candidate gene with a disease by using parental data in place of nonrelated controls. This alternating design eliminates spurious differences in allele frequencies between cases and nonrelated controls resulting from different ethnic origins and population stratification for these two groups. The authors present analysis methods which are based on two genetic relative risks: (1) the relative risk of disease for homozygotes with two copies of the candidate gene versus homozygotes without the candidate gene and (2) the relative risk for heterozygotes with one copy of the candidate gene versus homozygotes without the candidate gene. In addition to estimating the magnitude of these relative risks, likelihood methods allow specific hypotheses to be tested, namely, a test for overall association of the candidate gene with disease, as well as specific genetic hypotheses, such as dominant or recessive inheritance. Two likelihood methods are presented: (1) a likelihood method appropriate when Hardy-Weinberg equilibrium holds and (2) a likelihood method in which the authors condition on parental genotype data when Hardy-Weinberg equilibrium does not hold. The results for the relative efficiency of these two methods suggest that the conditional approach may at times be preferable, even when equilibrium holds. Sample-size and power calculations are presented for a multitiered design. Tier 1 detects the presence of an abnormal sequence for a postulated candidate gene among a small group of cases. Tier 2 tests for association of the abnormal variant with disease, such as by the likelihood methods presented. Tier 3 confirms positive results from tier 2. Results indicate that required sample sizes are smaller when expression of disease is recessive, rather than dominant, and that, for recessive disease and large relative risks, necessary sample sizes may be feasible. 19 refs., 2 figs., 2 tabs.

  7. The relation between apolipoprotein E (APOE) genotype and peripheral artery disease in patients at high risk for cardiovascular disease.

    PubMed

    Koopal, Charlotte; Geerlings, Mirjam I; Muller, Majon; de Borst, G J; Algra, Ale; van der Graaf, Yolanda; Visseren, Frank L J

    2016-03-01

    The apolipoprotein E gene (APOE) is associated with coronary heart disease and stroke, but the relation with peripheral artery disease (PAD) is unknown. We investigated the relation of APOE genotype with PAD and other types of vascular disease. The cross-sectional association between APOE genotype and ankle-brachial index (ABI) and vascular disease prevalence; and the prospective relation with incident PAD and other types of vascular disease (coronary artery disease, stroke and vascular mortality) were evaluated in 7418 patients from the Secondary Manifestations of ARTerial disease (SMART) study. This is a prospective cohort study in patients with cardiovascular disease or a cardiovascular risk factor. Analyses were adjusted for age and sex. Mean age was 56.7 ± 12.4 years and 68% of the patients was male. APOE genotype frequencies were ε2ε2 1.3%; ε2ε3 9.9%; ε2ε4 2.4%; ε3ε3 56.9%; ε3ε4 26.7% and ε4ε4 2.8%. Median follow-up time was 8.1 years (IQR 5.4-11.4) in which 452 new PAD events occurred. The ε2ε2 genotype was significantly associated with a lower ABI (regression coefficient -0.04, 95%CI -0.07 to -0.01), increased PAD prevalence (prevalence ratio 1.54, 95%CI 1.01-2.17) and a higher risk of incident PAD (HR 2.31, 95%CI 1.29-4.12) compared with ε3ε3. No relations between APOE genotypes and other vascular disease were observed. Of the six APOE genotypes, the ε2ε2 variant is associated with an increased risk for PAD in patients at high risk for cardiovascular disease. No association was observed between APOE genotype and coronary artery disease, stroke or vascular mortality in this population. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  8. Functional effect of Saffron supplementation and risk genotypes in early age-related macular degeneration: a preliminary report

    PubMed Central

    2013-01-01

    Background To determine whether the functional effects of oral supplementation with Saffron, a natural compound that proved to be neuroprotective in early age-related macular degeneration, are influenced by complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) risk genotypes. Methods Thirty-three early AMD patients, screened for CFH (rs1061170) and ARMS2 (rs10490924) polymorphisms and receiving Saffron oral supplementation (20 mg/day) over an average period of treatment of 11 months (range, 6–12), were longitudinally evaluated by clinical examination and focal electroretinogram (fERG)-derived macular (18°) flicker sensitivity estimate. fERG amplitude and macular sensitivity, the reciprocal value of the estimated fERG amplitude threshold, were the main outcome measures. Results After three months of supplementation, mean fERG amplitude and fERG sensitivity improved significantly when compared to baseline values (p < 0.01). These changes were stable throughout the follow-up period. No significant differences in clinical and fERG improvements were observed across different CFH or ARMS2 genotypes. Conclusions The present results indicate that the functional effect of Saffron supplementation in individual AMD patients is not related to the major risk genotypes of disease. PMID:24067115

  9. Functional effect of Saffron supplementation and risk genotypes in early age-related macular degeneration: a preliminary report.

    PubMed

    Marangoni, Dario; Falsini, Benedetto; Piccardi, Marco; Ambrosio, Lucia; Minnella, Angelo Maria; Savastano, Maria Cristina; Bisti, Silvia; Maccarone, Rita; Fadda, Antonello; Mello, Enrica; Concolino, Paola; Capoluongo, Ettore

    2013-09-25

    To determine whether the functional effects of oral supplementation with Saffron, a natural compound that proved to be neuroprotective in early age-related macular degeneration, are influenced by complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) risk genotypes. Thirty-three early AMD patients, screened for CFH (rs1061170) and ARMS2 (rs10490924) polymorphisms and receiving Saffron oral supplementation (20 mg/day) over an average period of treatment of 11 months (range, 6-12), were longitudinally evaluated by clinical examination and focal electroretinogram (fERG)-derived macular (18°) flicker sensitivity estimate. fERG amplitude and macular sensitivity, the reciprocal value of the estimated fERG amplitude threshold, were the main outcome measures. After three months of supplementation, mean fERG amplitude and fERG sensitivity improved significantly when compared to baseline values (p < 0.01). These changes were stable throughout the follow-up period. No significant differences in clinical and fERG improvements were observed across different CFH or ARMS2 genotypes. The present results indicate that the functional effect of Saffron supplementation in individual AMD patients is not related to the major risk genotypes of disease.

  10. The "thermolabile" variant of methylenetetrahydrofolate reductase and neural tube defects: An evaluation of genetic risk and the relative importance of the genotypes of the embryo and the mother.

    PubMed Central

    Shields, D C; Kirke, P N; Mills, J L; Ramsbottom, D; Molloy, A M; Burke, H; Weir, D G; Scott, J M; Whitehead, A S

    1999-01-01

    Recent reports have implicated the "thermolabile" (T) variant of methylenetetrahydrofolate reductase (MTHFR) in the causation of folate-dependent neural tube defects (NTDs). We report herein the largest genetic study of NTD cases (n=271) and families (n=218) to date, establishing that, in Ireland, the "TT" genotype is found in 18.8% of cases versus 8.3% of controls (odds ratio 2.57; confidence interval [CI] 1.48-4.45; P=.0005). The maternal and paternal TT genotypes have intermediate frequencies of 13.8% and 11.9%, respectively, indicating that the predominant MTHFR-related genetic effect acts via the TT genotype of the developing embryo. Analysis of the 218 family triads of mother, father, and affected child with log-linear models supports this interpretation, providing significant evidence that the case TT genotype is associated with NTDs (P=.02) but no evidence of a maternal TT genotypic effect (P=. 83). The log-linear model predicted that the risk of NTDs conferred by the case TT genotype is 1.61 (CI 1.06-2.46), consistent with the paramount importance of the case TT genotype in determining risk. There is no compelling evidence for more than a modest additional risk conferred by a maternal TT genotype. These results favor a biological model of MTHFR-related NTD pathogenesis in which suboptimal maternal folate status imposes biochemical stress on the developing embryo, a stress it is ill-equipped to tolerate if it has a TT genotype. PMID:10090889

  11. Relative risk of Alzheimer disease and age-at-onset distributions, based on APOE genotypes among elderly African Americans, caucasians, and hispanics in New York City

    SciTech Connect

    Tang, M.X.; Liu, X.H.; Stern, Y.

    1996-03-01

    Apolipoprotein-E {epsilon}4 (APOE-{epsilon}4) has been consistently associated with Alzheimer disease (AD) and may be responsible for an earlier age at onset. We have previously reported a diminished association between APOE-{epsilon}4 and AD in African Americans. Using a new method, which allows inclusion of censored information, we compared relative risks by APOE genotypes in an expanded collection of cases and controls from three ethnic groups in a New York community. The relative risk for AD associated with APOE-{epsilon}4 homozygosity was increased in all ethnic groups (African American relative risk [RR] = 3.0; 95% confidence interval [CI] = 1.5-5.9; Caucasian RR = 7.3, 95% CI = 2.5-21.6; and Hispanic RR = 2.5, 95% CI = 1.1-5.7), compared with those with APOE-{epsilon}3/{epsilon}3 genotypes. The risk was also increased for APOE-{epsilon}4 heterozygous Caucasians (RR = 2.9, 95% CI = 1.7-5.1) and Hispanics (RR = 1.6,95% CI = 1.1-2.3), but not for African Americans (RR = 0.6, 95% CI = 0.4-0.9). The age distribution of the proportion of Caucasians and Hispanics without AD was consistently lower for APOE-{epsilon}4 homozygous and APOE-{epsilon}4 heterozygous individuals than for those with other APOE genotypes. In African Americans this relationship was observed only in APOE-{epsilon}4 homozygotes. These results confirm that APOE genotypes influence the RR of AD in Caucasians and Hispanics. Differences in risk among APOE-{epsilon}4 heterozygote African Americans suggest that other genetic or environmental factors may modify the effect of APOE-{epsilon}4 in some populations. 58 refs., 3 figs., 4 tabs.

  12. Correlations between major risk factors and closely related Mycobacterium tuberculosis isolates grouped by three current genotyping procedures: a population-based study in northeast Mexico.

    PubMed

    Peñuelas-Urquides, Katia; Martínez-Rodríguez, Herminia Guadalupe; Enciso-Moreno, José Antonio; Molina-Salinas, Gloria María; Silva-Ramírez, Beatriz; Padilla-Rivas, Gerardo Raymundo; Vera-Cabrera, Lucio; Torres-de-la-Cruz, Víctor Manuel; Martínez-Martínez, Yazmin Berenice; Ortega-García, Jorge Luis; Garza-Treviño, Elsa Nancy; Enciso-Moreno, Leonor; Saucedo-Cárdenas, Odila; Becerril-Montes, Pola; Said-Fernández, Salvador

    2014-09-01

    The characteristics of tuberculosis (TB) patients related to a chain of recent TB transmissions were investigated. Mycobacterium tuberculosis (MTB) isolates (120) were genotyped using the restriction fragment length polymorphism-IS6110 (R), spacer oligotyping (S) and mycobacterial interspersed repetitive units-variable number of tandem repeats (M) methods. The MTB isolates were clustered and the clusters were grouped according to the similarities of their genotypes. Spearman's rank correlation coefficients between the groups of MTB isolates with similar genotypes and those patient characteristics indicating a risk for a pulmonary TB (PTB) chain transmission were ana- lysed. The isolates showing similar genotypes were distributed as follows: SMR (5%), SM (12.5%), SR (1.67%), MR (0%), S (46.67%), M (5%) and R (0%). The remaining 35 cases were orphans. SMR exhibited a significant correlation (p < 0.05) with visits to clinics, municipalities and comorbidities (primarily diabetes mellitus). S correlated with drug consumption and M with comorbidities. SMR is needed to identify a social network in metropolitan areas for PTB transmission and S and M are able to detect risk factors as secondary components of a transmission chain of TB.

  13. Associations of Polymorphisms in MTHFR Gene with the Risk of Age-Related Cataract in Chinese Han Population: A Genotype-Phenotype Analysis

    PubMed Central

    Wei, Li; Han, Ya-di; Cui, Ning-hua; Huang, Zhu-liang; Li, Zu-hua; Zheng, Fang; Yan, Ming

    2015-01-01

    Homocysteine (Hcy) is a potential risk factor for age-related cataract (ARC). Methylenetetrahydrofolate reductase (MTHFR) is the key enzyme for Hcy metabolism, and variants of MTHFR may affect MTHFR enzyme activity. This study mainly evaluated the associations between variants in MTHFR gene, plasma MTHFR enzyme activity, total Hcy (tHcy) levels and ARC risk in Chinese population. Four single nucleotide polymorphisms (SNPs) in MTHFR gene were genotyped using the high-resolution melting (HRM) method in 502 ARC patients (mean age, 70.2 [SD, 9.0], 46.0% male) and 890 healthy controls (mean age, 67.1 [SD, 11.1], 47.6% male). The plasma MTHFR activity, folic acid (FA), vitamins B12 and B6 levels were detected by enzyme-linked immunosorbent assays (ELISA). The plasma tHcy levels were measured by an automated enzymatic assay. After the Bonferroni correction, the minor allele T of SNP rs1801133 showed a significant association with an increased risk of overall ARC (OR = 1.26, P = 0.003). Consistent association was also found between SNP rs1801133 and cortical ARC risk (OR = 1.44, P = 0.003). Haplotype analyses revealed an adverse effect of the haplotype "C-A-T-C" (alleles in order of SNPs rs3737967, rs1801131, rs1801133 and rs9651118) on ARC risk (OR = 1.55, P = 0.003). Moreover, in a joint analysis of SNPs rs9651118 and rs1801133, subjects with two unfavorable genotypes had a 1.76-fold increased risk of ARC compared with the reference group, and a statistically significant dose-response trend (Ptrend = 0.001) was also observed. Further, in healthy controls and patients with cortical ARC, the allele T of SNP rs1801133 and the increasing number of unfavorable genotypes were significantly correlated with decreased MTHFR activity as well as increased tHcy levels. However, there was no significant association between FA, vitamins B12, B6 levels and MTHFR variants. Our data indicated that variants in MTHFR gene might individually and jointly influence susceptibility to ARC by

  14. HCV genotype distribution and possible transmission risks in Lahore, Pakistan.

    PubMed

    Ahmad, Waqar; Ijaz, Bushra; Javed, Fouzia-Tahir; Jahan, Shah; Shahid, Imran; Khan, Fawad-Mumtaz; Hassan, Sajida

    2010-09-14

    To investigate the prevalence of hepatitis C virus (HCV) genotypes and their association with possible transmission routes in the general population of Lahore, as the data exclusively related to this city is limited. Complete data regarding patient's history, possible route of infection and biochemical tests was collected from the public hospital for 1364 patients. SPSS version 16 windows software was used for data analysis by univariate and multivariate techniques. Age range < or = 40 years showed high prevalence of HCV infection. HCV genotype 3a was dominant (55.9%), followed by 1a (23.6%), 4a (12.5%), 3b (3.2%), untypable (2.5%), 4b (1.2%) and mixed type (1.2%). Blood transfusion, dental surgery and barber shops were the main risk factors for HCV transmission. Genotype prevalence was independent of age (P = 0.971) and gender (P = 0.122) while risk factors showed a significant association with age (P = 0.000) and genotypes (P = 0.000). We observed an independent association of risk factors and genotype 3a, while patients with genotype 1 and 4 were mostly infected due to dental surgery blood transfusion and barber shops. Risk factors of intravenous drug use and sexual exposure were exclusively found in < or = 40 years age group. An increase in genotypes 1a and 4a suggest migration of people, possibly from Balochistan and the northern war-zone area. Government should focus on public education regarding infection routes.

  15. The NEI/NCBI dbGAP database: genotypes and haplotypes that may specifically predispose to risk of neovascular age-related macular degeneration.

    PubMed

    Zhang, Hong; Morrison, Margaux A; Dewan, Andy; Adams, Scott; Andreoli, Michael; Huynh, Nancy; Regan, Maureen; Brown, Alison; Miller, Joan W; Kim, Ivana K; Hoh, Josephine; Deangelis, Margaret M

    2008-06-09

    To examine if the significantly associated SNPs derived from the genome wide allelic association study on the AREDS cohort at the NEI (dbGAP) specifically confer risk for neovascular age-related macular degeneration (AMD). We ascertained 134 unrelated patients with AMD who had one sibling with an AREDS classification 1 or less and was past the age at which the affected sibling was diagnosed (268 subjects). Genotyping was performed by both direct sequencing and Sequenom iPLEX system technology. Single SNP analyses were conducted with McNemar's Test (both 2 x 2 and 3 x 3 tests) and likelihood ratio tests (LRT). Conditional logistic regression was used to determine significant gene-gene interactions. LRT was used to determine the best fit for each genotypic model tested (additive, dominant or recessive). Before release of individual data, p-value information was obtained directly from the AREDS dbGAP website. Of the 35 variants with P < 10-6 examined, 23 significantly modified risk of neovascular AMD. Many variants located in tandem on 1q32-q22 including those in CFH, CFHR4, CFHR2, CFHR5, F13B, ASPM and ZBTB were significantly associated with AMD risk. Of these variants, single SNP analysis revealed that CFH rs572515 was the most significantly associated with AMD risk (P < 10-6). Haplotype analysis supported our findings of single SNP association, demonstrating that the most significant haplotype, GATAGTTCTC, spanning CFH, CFHR4, and CFHR2 was associated with the greatest risk of developing neovascular AMD (P < 10-6). Other than variants on 1q32-q22, only two SNPs, rs9288410 (MAP2) on 2q34-q35 and rs2014307 (PLEKHA1/HTRA1) on 10q26 were significantly associated with AMD status (P = .03 and P < 10-6 respectively). After controlling for smoking history, gender and age, the most significant gene-gene interaction appears to be between rs10801575 (CFH) and rs2014307 (PLEKHA1/HTRA1) (P < 10-11). The best genotypic fit for rs10801575 and rs2014307 was an additive model based

  16. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci.

    PubMed

    Cortes, Adrian; Hadler, Johanna; Pointon, Jenny P; Robinson, Philip C; Karaderi, Tugce; Leo, Paul; Cremin, Katie; Pryce, Karena; Harris, Jessica; Lee, Seunghun; Joo, Kyung Bin; Shim, Seung-Cheol; Weisman, Michael; Ward, Michael; Zhou, Xiaodong; Garchon, Henri-Jean; Chiocchia, Gilles; Nossent, Johannes; Lie, Benedicte A; Førre, Øystein; Tuomilehto, Jaakko; Laiho, Kari; Jiang, Lei; Liu, Yu; Wu, Xin; Bradbury, Linda A; Elewaut, Dirk; Burgos-Vargas, Ruben; Stebbings, Simon; Appleton, Louise; Farrah, Claire; Lau, Jonathan; Kenna, Tony J; Haroon, Nigil; Ferreira, Manuel A; Yang, Jian; Mulero, Juan; Fernandez-Sueiro, Jose Luis; Gonzalez-Gay, Miguel A; Lopez-Larrea, Carlos; Deloukas, Panos; Donnelly, Peter; Bowness, Paul; Gafney, Karl; Gaston, Hill; Gladman, Dafna D; Rahman, Proton; Maksymowych, Walter P; Xu, Huji; Crusius, J Bart A; van der Horst-Bruinsma, Irene E; Chou, Chung-Tei; Valle-Oñate, Raphael; Romero-Sánchez, Consuelo; Hansen, Inger Myrnes; Pimentel-Santos, Fernando M; Inman, Robert D; Videm, Vibeke; Martin, Javier; Breban, Maxime; Reveille, John D; Evans, David M; Kim, Tae-Hwan; Wordsworth, Bryan Paul; Brown, Matthew A

    2013-07-01

    Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to HLA-B*27 alleles, 12 loci have previously been identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12 additional ankylosing spondylitis-associated haplotypes at 11 loci. Two ankylosing spondylitis-associated regions have now been identified encoding four aminopeptidases that are involved in peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and with MHC class I cell surface expression.

  17. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci

    PubMed Central

    Cortes, Adrian; Hadler, Johanna; Pointon, Jenny P; Robinson, Philip C; Karaderi, Tugce; Leo, Paul; Cremin, Katie; Pryce, Karena; Harris, Jessica; lee, Seunghun; Joo, Kyung Bin; Shim, Seung-Cheol; Weisman, Michael; Ward, Michael; Zhou, Xiaodong; Garchon, Henri-Jean; Chiocchia, Gilles; Nossent, Johannes; Lie, Benedicte A; Førre, Øystein; Tuomilehto, Jaakko; Laiho, Kari; Jiang, Lei; Liu, Yu; Wu, Xin; Bradbury, Linda A; Elewaut, Dirk; Burgos-Vargas, Ruben; Stebbings, Simon; Appleton, Louise; Farrah, Claire; Lau, Jonathan; Kenna, Tony J; Haroon, Nigil; Ferreira, Manuel A; Yang, Jian; Mulero, Juan; Fernandez-Sueiro, Jose Luis; Gonzalez-Gay, Miguel A; lopez-Larrea, Carlos; Deloukas, Panos; Donnelly, Peter; Bowness, Paul; Gafney, Karl; Gaston, Hill; Gladman, Dafna D; Rahman, Proton; Maksymowych, Walter P; Xu, Huji; Crusius, J Bart A; van der Horst-Bruinsma, Irene E; Chou, Chung-Tei; Valle-Oñate, Raphael; Romero-Sánchez, Consuelo; Hansen, Inger Myrnes; Pimentel-Santos, Fernando M; Inman, Robert D; Videm, Vibeke; Martin, Javier; Breban, Maxime; Reveille, John D; Evans, David M; Kim, Tae-Hwan; Wordsworth, Bryan Paul; Brown, Matthew A

    2013-01-01

    Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to HLA-B*27 alleles, 12 loci have previously been identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12 additional ankylosing spondylitis–associated haplotypes at 11 loci. Two ankylosing spondylitis–associated regions have now been identified encoding four aminopeptidases that are involved in peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and with MHC class I cell surface expression. PMID:23749187

  18. HCV genotype distribution and possible transmission risks in Lahore, Pakistan

    PubMed Central

    Ahmad, Waqar; Ijaz, Bushra; Javed, Fouzia Tahir; Jahan, Shah; Shahid, Imran; Khan, Fawad Mumtaz; Hassan, Sajida

    2010-01-01

    AIM: To investigate the prevalence of hepatitis C virus (HCV) genotypes and their association with possible transmission routes in the general population of Lahore, as the data exclusively related to this city is limited. METHODS: Complete data regarding patient’s history, possible route of infection and biochemical tests was collected from the public hospital for 1364 patients. SPSS version 16 windows software was used for data analysis by univariate and multivariate techniques. RESULTS: Age range ≤ 40 years showed high prevalence of HCV infection. HCV genotype 3a was dominant (55.9%), followed by 1a (23.6%), 4a (12.5%), 3b (3.2%), untypable (2.5%), 4b (1.2%) and mixed type (1.2%). Blood transfusion, dental surgery and barber shops were the main risk factors for HCV transmission. Genotype prevalence was independent of age (P = 0.971) and gender (P = 0.122) while risk factors showed a significant association with age (P = 0.000) and genotypes (P = 0.000). We observed an independent association of risk factors and genotype 3a, while patients with genotype 1 and 4 were mostly infected due to dental surgery blood transfusion and barber shops. Risk factors of intravenous drug use and sexual exposure were exclusively found in ≤ 40 years age group. CONCLUSION: An increase in genotypes 1a and 4a suggest migration of people, possibly from Balochistan and the northern war-zone area. Government should focus on public education regarding infection routes. PMID:20818816

  19. Genotyping of celiac disease-related-risk haplotypes using a closed-tube polymerase chain reaction analysis of dried blood and saliva disk samples.

    PubMed

    Ollikka, Pia; Raussi, Hanna-Mari; Laitala, Ville; Jaakkola, Lassi; Hovinen, Jari; Hemmilä, Ilkka; Ylikoski, Alice

    2009-03-01

    Expansion of molecular diagnostics more widely into clinical routines requires simplified methods allowing automation. We developed a homogeneous, multilabel polymerase chain reaction (PCR) method based on time-resolved fluorometry, and studied the use of dried disk samples in PCR. Celiac disease-related HLA-DQA1*05, HLA-DQB1*02, and HLA-DQB1*0302 genotyping was used to verify the method with blood and saliva samples dried on S&S 903 and IsoCode sample collection papers. Three sample preparation procedures, including manufacturer's manual elution, an automated elution, and direct use of disk samples, were compared using dried disk samples. The three procedures gave successful amplification and correct genotyping results. Owing to the simplicity of the direct use of disk samples in PCR, this method was chosen for the subsequent homogeneous analysis of blood (n=194) and saliva (n=30) disk samples on S&S 903 paper. The results revealed that, in addition to DNA samples (n=29), both blood and saliva disk samples were successfully amplified and genotyped using the homogeneous PCR assays for HLA-DQA1 and HLA-DQB1. The homogeneous PCR assays developed provide a useful tool to genotype celiac disease-related HLA-DQA1*05, HLA-DQB1*02, and HLA-DQB1*0302 alleles. Furthermore, the method provides a direct way to perform a closed-tube PCR analysis of dried blood and saliva disk samples enabling simple automation.

  20. Disclosure of APOE genotype for risk of Alzheimer's disease.

    PubMed

    Green, Robert C; Roberts, J Scott; Cupples, L Adrienne; Relkin, Norman R; Whitehouse, Peter J; Brown, Tamsen; Eckert, Susan LaRusse; Butson, Melissa; Sadovnick, A Dessa; Quaid, Kimberly A; Chen, Clara; Cook-Deegan, Robert; Farrer, Lindsay A

    2009-07-16

    The apolipoprotein E (APOE) genotype provides information on the risk of Alzheimer's disease, but the genotyping of patients and their family members has been discouraged. We examined the effect of genotype disclosure in a prospective, randomized, controlled trial. We randomly assigned 162 asymptomatic adults who had a parent with Alzheimer's disease to receive the results of their own APOE genotyping (disclosure group) or not to receive such results (nondisclosure group). We measured symptoms of anxiety, depression, and test-related distress 6 weeks, 6 months, and 1 year after disclosure or nondisclosure. There were no significant differences between the two groups in changes in time-averaged measures of anxiety (4.5 in the disclosure group and 4.4 in the nondisclosure group, P=0.84), depression (8.8 and 8.7, respectively; P=0.98), or test-related distress (6.9 and 7.5, respectively; P=0.61). Secondary comparisons between the nondisclosure group and a disclosure subgroup of subjects carrying the APOE epsilon4 allele (which is associated with increased risk) also revealed no significant differences. However, the epsilon4-negative subgroup had a significantly lower level of test-related distress than did the epsilon4-positive subgroup (P=0.01). Subjects with clinically meaningful changes in psychological outcomes were distributed evenly among the nondisclosure group and the epsilon4-positive and epsilon4-negative subgroups. Baseline scores for anxiety and depression were strongly associated with post-disclosure scores of these measures (P<0.001 for both comparisons). The disclosure of APOE genotyping results to adult children of patients with Alzheimer's disease did not result in significant short-term psychological risks. Test-related distress was reduced among those who learned that they were APOE epsilon4-negative. Persons with high levels of emotional distress before undergoing genetic testing were more likely to have emotional difficulties after disclosure

  1. Disclosure of APOE Genotype for Risk of Alzheimer's Disease

    PubMed Central

    Green, Robert C.; Roberts, J. Scott; Cupples, L. Adrienne; Relkin, Norman R.; Whitehouse, Peter J.; Brown, Tamsen; Eckert, Susan LaRusse; Butson, Melissa; Sadovnick, A. Dessa; Quaid, Kimberly A.; Chen, Clara; Cook-Deegan, Robert; Farrer, Lindsay A.; Annas, G.; Bhatt, D.; Biesecker, B.; Blacker, D.; Cox, E.; Christensen, K.; Davis, J.G.; Fasaye, G.-A.; Griffith, P.; Hiraki, S.; Juengst, E.; Karlawish, J.; Linnenbringer, E.; Marteau, T.; Neimeister, E.; Obisesan, T.; Petersen, R.; Post, S.; Ravdin, L.; Reilly, R.P.; Roter, D.; Royal, C.; Stern, R.; Topol, E.; Uhlmann, W.; Williams, M.; Wright, L.

    2009-01-01

    Background The apolipoprotein E (APOE) genotype provides information on the risk of Alzheimer's disease, but the genotyping of patients and their family members has been discouraged. We examined the effect of genotype disclosure in a prospective, randomized, controlled trial. Methods We randomly assigned 162 asymptomatic adults who had a parent with Alzheimer's disease to receive the results of their own APOE genotyping (disclosure group) or not to receive such results (nondisclosure group). We measured symptoms of anxiety, depression, and test-related distress 6 weeks, 6 months, and 1 year after disclosure or nondisclosure. Results There were no significant differences between the two groups in changes in time-averaged measures of anxiety (4.5 in the disclosure group and 4.4 in the nondisclosure group, P = 0.84), depression (8.8 and 8.7, respectively; P = 0.98), or test-related distress (6.9 and 7.5, respectively; P=0.61). Secondary comparisons between the non-disclosure group and a disclosure subgroup of subjects carrying the APOE ε4 allele (which is associated with increased risk) also revealed no significant differences. However, the ε4-negative subgroup had a significantly lower level of test-related distress than did the ε4-positive subgroup (P=0.01). Subjects with clinically meaningful changes in psychological outcomes were distributed evenly among the nondisclosure group and the ε4-positive and ε4-negative subgroups. Baseline scores for anxiety and depression were strongly associated with post-disclosure scores of these measures (P<0.001 for both comparisons). Conclusions The disclosure of APOE genotyping results to adult children of patients with Alzheimer's disease did not result in significant short-term psychological risks. Test-related distress was reduced among those who learned that they were APOE ε4–negative. Persons with high levels of emotional distress before undergoing genetic testing were more likely to have emotional difficulties after

  2. Assessment of the association between GSTM1 null genotype and risk of type 2 diabetes.

    PubMed

    Yi, Ran; Liu, Bin; Dong, Qi

    2013-06-01

    Many studies have investigated the association between Glutathione S-Transferase M1 (GSTM1) null genotype and risk of diabetes mellitus, but the impact of GSTM1 null genotype on diabetes mellitus is unclear owing to the obvious inconsistence among those studies. This study aimed to quantify the strength of association between GSTM1 null genotype and risk of diabetes mellitus. We searched the PubMed, Embase and Wangfang databases for studies relating the association between GSTM1 null genotype and risk of diabetes mellitus. We estimated summary odds ratio (OR) with their 95 % confidence interval (95 % CI) to assess the association. Subgroup analyses were performed by type of diabetes and ethnicity. 10 case-control studies with 7, 054 subjects were included into this meta-analysis. Meta-analysis of total 10 studies showed GSTM1 null genotype was associated increased risk of diabetes mellitus (OR = 1.59, 95 % CI 1.14-2.22, P = 0.007). Subgroup analyses by type of diabetes mellitus suggested GSTM1 null genotype was associated increased risk of type 2 diabetes (OR = 1.90, 95 % CI 1.37-2.64, P < 0.001), but was not associated with risk of type 1 diabetes (OR = 0.84, 95 % CI 0.66-1.07, P = 0.153). Subgroup analysis by ethnicity further identified the obvious association between GSTM1 null genotype and increased risk of type 2 diabetes. The cumulative meta-analyses showed a trend of obvious association between GSTM1 null genotype and risk of type 2 diabetes as information accumulated. No evidence of publication bias was observed. Thus, evidence from current meta-analysis suggests an association between GSTM1 null genotype and risk of type 2 diabetes.

  3. Adipose tissue PCB levels and CYP1B1 and COMT genotypes in relation to breast cancer risk in postmenopausal Danish women.

    PubMed

    Bräuner, Elvira V; Loft, Steffen; Wellejus, Anja; Autrup, Herman; Tjønneland, Anne; Raaschou-Nielsen, Ole

    2014-01-01

    Exposure to PCBs may be an etiologic factor for breast cancer. The cytochrome P450 1B1 (CYP1B1) and catechol-O-methyltransferase (COMT) enzymes are involved in estrogen metabolism and PCB metabolism, both of which may relate to breast cancer susceptibility. Polymorphisms in genes regulating these enzymes control efficiency. Our objective was to assess whether CYP1B1 and COMT gene polymorphisms modulate the effect of PCBs in breast cancer risk, among postmenopausal Danish women. Neither CYP1B1 Leu432Val polymorphisms nor adipose tissue PCBs were independently associated with breast cancer risk. When assessing the independent effect of the COMT Val158Met polymorphism, we observed reduced risk for breast cancer amongst hormone replacement therapy using women who were homozygous carriers of the variant allele compared with those carrying the wild-type variant (RR = 0.41; 95% CI: 0.29-0.89). We found no statistically significant interactions between any of the PCB groups and CYP1B1 or COMT polymorphisms on the risk of breast cancer.

  4. Understanding the relative contributions of direct environmental effects and passive genotype-environment correlations in the association between familial risk factors and child disruptive behavior disorders.

    PubMed

    Bornovalova, M A; Cummings, J R; Hunt, E; Blazei, R; Malone, S; Iacono, W G

    2014-03-01

    Previous work reports an association between familial risk factors stemming from parental characteristics and offspring disruptive behavior disorders (DBDs). This association may reflect (a) the direct effects of familial environment and (b) a passive gene-environment correlation (r(GE)), wherein the parents provide both the genes and the environment. The current study examined the contributions of direct environmental influences and passive r(GE) by comparing the effects of familial risk factors on child DBDs in genetically related (biological) and non-related (adoptive) families. Participants were 402 adoptive and 204 biological families. Familial environment was defined as maternal and paternal maladaptive parenting and antisociality, marital conflict and divorce; offspring DBDs included attention deficit hyperactivity disorder (ADHD), conduct disorder (CD) and oppositional defiant disorder (ODD). Mixed-level regressions estimated the main effects of familial environment, adoption status and the familial environment by adoption status interaction term, which tested for the presence of passive r(GE). There was a main effect of maternal and paternal maladaptive parenting and marital discord on child DBDs, indicating a direct environmental effect. There was no direct environmental effect of maternal or paternal antisociality, but maternal and paternal antisociality had stronger associations with child DBDs in biological families than adoptive families, indicating the presence of a passive r(GE). Many familial risk factors affected children equally across genetically related and non-related families, providing evidence for direct environmental effects. The relationship of parental antisociality and offspring DBDs was best explained by a passive r(GE), where a general vulnerability toward externalizing psychopathology is passed down by the parents to the children.

  5. Understanding the Relative Contributions of Direct Environmental Effects and Passive Genotype-Environment Correlations in the Association between Familial Risk Factors and Child Disruptive Behavior Disorders

    PubMed Central

    Bornovalova, Marina A.; Cummings, Jenna R.; Hunt, Elizabeth; Blazei, Ryan; Malone, Steve; Iacono, William G.

    2013-01-01

    Background: Previous work reports an association between familial risk factors stemming from parental characteristics and offspring disruptive behavior disorders (DBDs). This association may reflect a) the direct effects of familial environment, and b) a passive gene-environment correlation, wherein the parents provide both the genes and the environment. The current study examined the contributions of direct environmental influences and passive gene-environment correlations by comparing the effects of familial risk factors on child DBDs in genetically related (biological) and non-related (adoptive) families. Method: Participants were 402 adoptive and 204 biological families. Familial environment was defined as maternal and paternal maladaptive parenting and antisociality, marital conflict, and divorce; offspring DBDs included attention deficit/hyperactivity disorder, conduct disorder, and oppositional defiant disorder. Mixed-level regressions estimated the main effects of familial environment, adoption status, and the familial environment by adoption status interaction term, which tested for a presence of passive gene-environment correlations. Results: There was a main effect of maternal and paternal maladaptive parenting and marital discord on child DBDs, indicating a direct environmental effect. There was no direct environmental effect of maternal or paternal antisociality, but maternal and paternal antisociality had stronger associations with child DBDs in biological families than adoptive families, indicating the presence of a passive gene-environment correlation. Conclusions: Many familial risk factors affected children equally across genetically-related and non-related families, providing evidence for direct environmental effects. The relationship of parental antisociality and offspring DBDs was best explained by a passive gene-environment correlation, where a general vulnerability toward externalizing psychopathology is passed down by the parents to the

  6. Epidemiological manifestations of hepatitis C virus genotypes and its association with potential risk factors among Libyan patients.

    PubMed

    Elasifer, Hana A; Agnnyia, Yossif M; Al-Alagi, Basher A; Daw, Mohamed A

    2010-11-13

    The information on hepatitis C virus genotypes and subtypes among Libyan population and its association with various risk factors is not known. The objectives of this study were to determine the epidemiological manifestations of HCV genotypes among Libyan patients and their association with certain potential risk factors. A total of 1240 of HCV infected patients registered at Tripoli Medical Centre were studied in five years period from January 2005 to October 2009. The information were reviewed and the data were collected. A sample from each patient (785 male; 455 female) was analysed for genotyping and sub-typing using specific genotyping assay. The information was correlated with the risk factors studied and the statistical data were analyzed using SPSS version 11.5. Off the total patients studied, four different genotypes were reported, including genotypes 1, 2, 3, and 4. Genotype4 was the commonest (35.7%), followed by genotype1 (32.6%). According to subtypes 28% were unclassified genotype 4, 14.6% were genotype 1b and some patients infected with more than one subtype (2.3% genotype 4c/d, 1% genotype 2a/c). Genotypes 1 was the commonest among males, while genotype 4 among females. According to the risk factors studied, Genotype1 and genotype 4 were found with most of the risk factors. Though they were particularly evident surgical intervention, dental procedures and blood transfusion while genotype 1 was only followed by genotype 3 mainly which mainly associated with certain risk groups such as intravenous drug abusers. Here in we report on a detailed description of HCV genotype among Libyans. The most common genotype was type 4 followed by genotype 1, other genotypes were also reported at a low rate. The distribution of such genotypes were also variable according to gender and age. The commonly prevalent genotypes found to be attributable to the medical -related transmission of HCV, such as blood, surgery and dental procedures when compared with other risk

  7. The Relativity of Genotypes and Phenotypes.

    ERIC Educational Resources Information Center

    Willie, Charles Vert

    1995-01-01

    Asserts that Herrnstein and Murray's "The Bell Curve" (1994) is an attempt to influence and control public discourse about public policy and inequality. It examines four of the book's flaws in classification, analyses, research, and its failure to recognize intelligence as having both genotypic and phenotypic manifestations. (GR)

  8. FTO genotype and adiposity in children: physical activity levels influence the effect of the risk genotype in adolescent males

    PubMed Central

    Scott, Robert A; Bailey, Mark E S; Moran, Colin N; Wilson, Richard H; Fuku, Noriyuki; Tanaka, Masashi; Tsiokanos, Athanasios; Jamurtas, Athanasios Z; Grammatikaki, Evangelia; Moschonis, George; Manios, Yannis; Pitsiladis, Yannis P

    2010-01-01

    Studies of the fat mass and obesity-associated (FTO) gene provide compelling evidence of genetic variation in the general population that influences fat levels and obesity risk. Studies of the interaction between genetic and environmental factors such as physical activity (PA) will promote the understanding of how lifestyle can modulate genetic contributions to obesity. In this study, we investigated the effect of FTO genotype, and interactions with PA or energy intake, in young children and adolescents. In all, 1–5-year-old children from the Growth, Exercise and Nutrition Epidemiological Study in preSchoolers (GENESIS) study (N=1980) and 11–18-year-old Greek adolescents (N=949) were measured for adiposity-related phenotypes and genotyped at the FTO single-nucleotide polymorphism (SNP) marker, rs17817449. Adolescents were classified as physically active or inactive based on self-reported levels of PA. In adolescents, FTO genotype influenced weight (P=0.001) and BMI (P=0.007). There was also a significant SNP*PA*gender interaction (P=0.028) on BMI, which reflected the association between FTO genotype and BMI in males (P=0.016), but not females (P=0.15), and significant SNP*PA interaction in males (P=0.007), but not females (P=0.74). The FTO genotype effect was more pronounced in inactive than active males. Inactive males homozygous for the G allele had a mean BMI 3 kg/m2 higher than T carriers (P=0.008). In the GENESIS study, no significant association between FTO genotype and adiposity was found. The present findings highlight PA as an important factor modifying the effect of FTO genotype. PMID:20717169

  9. FTO genotype and adiposity in children: physical activity levels influence the effect of the risk genotype in adolescent males.

    PubMed

    Scott, Robert A; Bailey, Mark E S; Moran, Colin N; Wilson, Richard H; Fuku, Noriyuki; Tanaka, Masashi; Tsiokanos, Athanasios; Jamurtas, Athanasios Z; Grammatikaki, Evangelia; Moschonis, George; Manios, Yannis; Pitsiladis, Yannis P

    2010-12-01

    Studies of the fat mass and obesity-associated (FTO) gene provide compelling evidence of genetic variation in the general population that influences fat levels and obesity risk. Studies of the interaction between genetic and environmental factors such as physical activity (PA) will promote the understanding of how lifestyle can modulate genetic contributions to obesity. In this study, we investigated the effect of FTO genotype, and interactions with PA or energy intake, in young children and adolescents. In all, 1-5-year-old children from the Growth, Exercise and Nutrition Epidemiological Study in preSchoolers (GENESIS) study (N=1980) and 11-18-year-old Greek adolescents (N=949) were measured for adiposity-related phenotypes and genotyped at the FTO single-nucleotide polymorphism (SNP) marker, rs17817449. Adolescents were classified as physically active or inactive based on self-reported levels of PA. In adolescents, FTO genotype influenced weight (P=0.001) and BMI (P=0.007). There was also a significant SNP(*)PA(*)gender interaction (P=0.028) on BMI, which reflected the association between FTO genotype and BMI in males (P=0.016), but not females (P=0.15), and significant SNP(*)PA interaction in males (P=0.007), but not females (P=0.74). The FTO genotype effect was more pronounced in inactive than active males. Inactive males homozygous for the G allele had a mean BMI 3 kg/m(2) higher than T carriers (P=0.008). In the GENESIS study, no significant association between FTO genotype and adiposity was found. The present findings highlight PA as an important factor modifying the effect of FTO genotype.

  10. Geographic distribution of HCV genotypes in Libya and analysis of risk factors involved in their transmission.

    PubMed

    Daw, Mohamed A; El-Bouzedi, Abdallah; Dau, Aghnaya A

    2015-08-21

    Hepatitis C virus (HCV) genotypes have been shown to be differently distributed between distinct geographical areas. Libya is a large country has the longest coast in the Mediterranean basin. Information regarding hepatitis C genotypes and subtypes circulating in Libya are not well known. The objectives of this study were to determine the frequency of various HCV genotypes cross Libya and the demographic and attributable risk factors associated with HCV transmission among Libyan population. A cross-sectional study was carried out on patients with recently confirmed HCV infection. A total of 3,227 serum samples enrolled at 19 collection center cross Libya. 1,756 belonged to Tripoli region, 452 to West region 355 to North region, 181 South regions and 483 East region. The samples were tested by type specific genotyping assay and correlated with demographic and potential risk factors within the studied populations. A total of 20 discrete genotypes and subtypes were identified among the Libyan population ranging from 11.5 to 0.3% cross the country. Genotype 1 was the most frequent among all regions (19.7-40.5%), reaching the highest value in Tripoli region, followed by genotype 4 which was more prevalent in the South (49.3%) and West (40.0%) regions. Genotype 3, was higher in Tripoli (21.3%) and East (15.9%) regions while genotype 2, common in North (23.6%) and South (22.5%) regions. However, we found evidence that there is a changing relative prevalence of HCV genotypes in relation to age, gender and the mode of transmission which is reflected in the predominance of certain genotypes among Libyan population. Different HCV genotypes were isolated form Libyan population including newly emerged ones. The prevalence of the genotypes varied by geographic region and influenced by demographic and risk factors. Knowing the frequency and distribution of the genotypes would provide key information on understanding the spread of HCV in Libya and this could be greatly reflected

  11. Immune Response Genotypes and Risk of Young Adult Hodgkin Lymphoma

    DTIC Science & Technology

    2008-09-01

    1) To identify, enroll and collect blood specimens from 368 adolescents and young adults 18 years of age or older at the time of participation... Young Adult Hodgkin Lymphoma PRINCIPAL INVESTIGATOR: Wendy Cozen, Victoria Cortessis...COVERED 1 Sep 2007 – 31 Aug 2008 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Immune Response Genotypes and Risk of Young Adult Hodgkin Lymphoma 5b

  12. GSTM1 null genotype, red meat consumption and breast cancer risk (The Netherlands).

    PubMed

    van der Hel, Olga L; Peeters, Petra H M; Hein, David W; Doll, Mark A; Grobbee, Diederick E; Ocké, Marga; Bueno de Mesquita, H Bas

    2004-04-01

    We studied whether polymorphisms in N-acetyltransferase 1 and 2 and Glutathione S-transferase M1 and T1 genes modify the association between meat consumption and breast cancer. A nested case control was conducted in a Dutch prospective cohort. Breast cancer cases (229) and controls (264) were frequency matched on age, town and menopausal status. There is no relation between any type of meat consumption ( i.e., total meat, processed meat, fresh meat, red meat and white meat) and breast cancer risk. Neither presence of NAT1 or NAT2 rapid genotype, or GSTT1 null genotype, alone or in combination with meat consumption affects breast cancer risk. Absence of GSTM1 shows 46% increased breast cancer risk (OR = 1.46 (95% confidence interval, 95% CI = 1.02-2.09)). When stratifying according to combined 'GSTM1 genotype-meat consumption' categories, breast cancer risk is slightly increased with consumption of red meat both in women with genotype GSTM1 presence (OR = 1.49 and 1.75 for intermediate and high versus low consumption) and in GSTM1 null genotype (OR = 1.18 and 1.02). These increases are statistically not significant. In postmenopausal women a suggestion of an effect of red meat consumption is observed: effects are slightly stronger, although still not statistically significant and without a clear dose-response relation: OR = 1.79 (95% CI = 0.92-3.50) and 1.46 (1.46 (95% CI = 0.76-2.82) for intermediate and high compared to low red meat consumption respectively. Reliable evaluation of interaction is not possible due to the small number of cancers. GSTM1 null genotype increases breast cancer risk. Red meat consumption slightly increases breast cancer risk, but the relation is not statistically significant and GSTM1, NAT1, NAT2 and GSTT1 polymorphisms do not modify this relation. Copyright 2004 Kluwer Academic Publishers

  13. Relative Risk Aversion.

    DTIC Science & Technology

    1981-01-01

    strength of preference notion. Some of these developments relate to multiattribute utility theory and to the collective choice problem. In subsequent... multiattribute utility theory , utility func- tions have been assessed that indicate a decision maker is risk prone on one attribute and risk averse on...research with tradi- tional developments in utility theory . 3.1 Relative Risk Attitude We will introduce the concept of a relative risk attitude to analyze

  14. Epidemiological characteristics and risk factors of hepatitis C virus genotype 1 infection: a national epidemiological survey of Chinese Han population.

    PubMed

    Wang, C-B; Cheng, Z-X; Chen, J-J; Chen, Y-Y; Nie, H-M; Ling, Q-H; Dong, Y-N

    2016-01-01

    Hepatitis C virus (HCV) infection is a high morbidity disease in China. The aim of this study was to explore the latest distribution of HCV genotypes in China, mainly focusing on epidemiological characteristics and risk factors of HCV genotype 1 in Chinese Han population. 793 HCV-positive patients were enrolled from 21 hospitals across China. The association of epidemiological data with HCV genotype 1 and the potential risk factors was analyzed using univariate and multivariate logistic regression analysis. The HCV genotype 1b was detected in 66.9% of 793 patients. The way of infection, disease course, HCV RNA level, history of blood transfusion and smoking were found to be significantly different between patients infected with HCV genotype 1 and non-genotype 1. The result of univariate logistic regression analysis showed that HCV genotype 1 infection has a close relationship with age, gender, smoking history, the way of infection, allergy, disease course, and HCV RNA level. Moreover, the HCV RNA level, disease course, and blood transfusion history were the related risk factors for infection of HCV genotype 1 as demonstrated by multivariate logistic regression analysis. The HCV genotype 1 was still the main genotype of HCV infection in China. We should intensify HCV screening for those people who aged over 50 years and had a history of blood transfusion in China. The treatment of genotype 1 should be paid more attention in antiviral of HCV.

  15. Duarte GALT genotypes are not associated with ovarian cancer risk

    PubMed Central

    Merritt, Melissa A.; Kotsopoulos, Joanne; Cramer, Daniel W.; Hankinson, Susan E.; Terry, Kathryn L.; Tworoger, Shelley S.

    2012-01-01

    Objective To investigate whether Galactose-1-phosphate uridyl transferase (GALT) variant genotypes were associated with epithelial ovarian cancer risk and to determine if this association was modified by lactose intake. Design two prospective cohort studies and a case-control study. Setting Academic institution. Patient(s) 992 cases and 1050 population-based controls from a New England case-control study and 240 cases and 900 controls from the Nurses’ Health Studies. Intervention(s) None. Main Outcome Measure(s) Genotyping of the N314D variant and the 4-bp deletion (-119delGTCA) of GALT using the Taqman 5′ nuclease assay. Duarte1 (D1) genotype individuals have a missense mutation (N314D) associated with normal GALT activity unless it occurs together with an associated 4-bp deletion leading to reduced GALT activity (Duarte2 or D2). Result(s) Logistic regression analysis identified no association between D1/D2 genotypes and ovarian cancer risk (pooled RR, 1.1 (95% CI, 0.8–1.5) for D1 and 1.0 (95% CI, 0.7–1.4) for D2). We did not observe a significant interaction between D1 and D2 genotypes in analyses stratified by level of lactose intake (Pinteraction ≥ 0.3). Conclusion(s) D1 and D2 genotypes do not appear to play a role in the association between galactose intake, possible ovarian dysfunction and the link with ovarian cancer. PMID:22749219

  16. Apolipoprotein E genotype and the cardiovascular disease risk phenotype: impact of sex and adiposity (the FINGEN study).

    PubMed

    Kofler, Bettina M; Miles, Elizabeth A; Curtis, Peter; Armah, Christopher K; Tricon, Sabine; Grew, Jilly; Napper, Frances L; Farrell, Leslie; Lietz, Georg; Packard, Christopher J; Caslake, Muriel J; Mathers, John C; Williams, Christine M; Calder, Philip C; Minihane, Anne Marie

    2012-04-01

    Here the impact of APOE genotype on CHD risk in UK adults is reported, along with an analysis of APOE genotype × BMI/age/sex interactions. APOE genotype had a significant impact on fasting total:LDL-cholesterol (TC:LDL-C) ratio, triglycerides, % HDL3, and the Framingham 10-year CVD risk score (P<0.05), with an overall trend towards lower and higher risk in E2- and E4-carriers, respectively, relative to the wild-type E3/E3 genotype. A greater impact of genotype on TC:HDL-C was observed in females, which explained 16% of the variability in this outcome versus 6% in males. APOE genotype was also associated with plasma C-reactive protein and adhesion molecule concentrations (P<0.05), with significant genotype × BMI interactions observed. Our observations indicate that the association between the APOE genotype and CHD risk is unlikely to be homogenous and highlights the risk of inaccurate estimations of genotype-phenotype associations in population subgroups without appropriate stratification for sex and adiposity. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  17. Immune Response Genotypes and Risk of Young Adult Hodgkin Lymphoma

    DTIC Science & Technology

    2007-09-01

    TECHNICAL OBJECTIVES 1) To identify, enroll and collect blood specimens from 368 adolescents and young adults 18-to 45 years old diagnosed with Hodgkin... Young Adult Hodgkin Lymphoma PRINCIPAL INVESTIGATOR: Wendy Cozen Victoria Cortessis, Ph.D. David Conti, Ph.D. David...Genotypes and Risk of Young Adult Hodgkin Lymphoma 5b. GRANT NUMBER W81XWH-06-1-0683 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Wendy Cozen

  18. Contribution of double strand break repair gene XRCC3 genotypes to nasopharyngeal carcinoma risk in Taiwan.

    PubMed

    Liu, Juhn-Cherng; Tsai, Chia-Wen; Hsu, Chin-Mu; Chang, Wen-Shin; Li, Chi-Yuan; Liu, Shih-Ping; Shen, Wu-Chung; Bau, Da-Tian

    2015-02-28

    The DNA double strand break repair protein XRCC3 plays a central role in removing double strand breaks from the genome and defects in cellular repair capacity is closely related to human cancer initiation. Therefore, we aimed to investigate the contribution of XRCC3 genotypes to individual nasopharyngeal carcinoma (NPC) susceptibility. In this hospital-based population research, the genotyping and analyzing of XRCC3 rs1799794, rs45603942, rs861530, rs3212057, rs1799796, rs861539, rs28903081 in a large Taiwanese population was performed. Totally, 176 NPC patients and 880 age- and gender-matched healthy controls were genotyped and analyzed by PCR-RFLP method. The results showed that there was a differential distribution among NPC and control subjects in the genotypic (P = 0.000488) and allelic (P = 0.0002) frequencies of XRCC3 rs861539. As for the gene-environment interaction, we have firstly provided evidence showing that there is an obvious joint effect of XRCC3 rs861539 CT and TT genotypes with individual smoking habits on increased NPC risk. In conclusion, the T allele of XRCC3 rs861539, interacts with smoking habit in increasing NPC risk, may be an early detection marker for NPC.

  19. Newcastle disease: evolution of genotypes and the related diagnostic challenges.

    PubMed

    Miller, Patti J; Decanini, Eduardo Lucio; Afonso, Claudio L

    2010-01-01

    Since the discovery of Newcastle disease virus (NDV) in 1926, nine genotypes of class I viruses and ten of class II have been identified, representing a diverse and continually evolving group of viruses. The emergence of new virulent genotypes from global epizootics and the year-to-year changes observed in the genomic sequence of NDV of low and high virulence implies that distinct genotypes of NDV are simultaneously evolving at different geographic locations across the globe. This vast genomic diversity may be favored by the large variety of avian species susceptible to NDV infection and by the availability of highly mobile wild bird reservoirs. The genomic diversity of NDV increases the possibility of diagnostic failures, resulting in unidentified infections. Constant epidemiological surveillance and pro-active characterization of circulating strains are needed to ensure that the immunological and PCR reagents are effective in identifying NDV circulating worldwide. For example, in the United States, the widely used real-time reverse transcription polymerase chain reaction (RRT-PCR) matrix gene assay for the identification of NDV often fails to detect low virulence APMV-1 from waterfowl, while the RRT-PCR fusion gene assay, used to identify virulent isolates, often fails to detect certain virulent NDV genotypes. A new matrix-polymerase multiplex test that detects most of the viruses currently circulating worldwide and a modified fusion test for the identification of virulent pigeon viruses circulating in the U.S. and Europe have recently been developed. For newly isolated viruses with unknown sequences, recently developed random priming sequencing methods need to be incorporated into the diagnostic arsenal. In addition, the current system of classifying NDV into genotypes or lineages is inadequate. Here, we review the molecular epidemiology and recent diagnostic problems related to viral evolution of NDV and explain why a new system, based on objective criteria, is

  20. Genotype-defined cancer risk in juvenile polyposis syndrome.

    PubMed

    Aytac, E; Sulu, B; Heald, B; O'Malley, M; LaGuardia, L; Remzi, F H; Kalady, M F; Burke, C A; Church, J M

    2015-01-01

    Germline mutations in SMAD4 and BMPR1A disrupt the transforming growth factor β signal transduction pathway, and are associated with juvenile polyposis syndrome. The effect of genotype on the pattern of disease in this syndrome is unknown. This study evaluated the differential impact of SMAD4 and BMPR1A gene mutations on cancer risk and oncological phenotype in patients with juvenile polyposis syndrome. Patients with juvenile polyposis syndrome and germline SMAD4 or BMPR1A mutations were identified from a prospectively maintained institutional registry. Medical records were reviewed and the clinical patterns of disease were analysed. Thirty-five patients had germline mutations in either BMPR1A (8 patients) or SMAD4 (27). Median follow-up was 11 years. Colonic phenotype was similar between patients with SMAD4 and BMPR1A mutations, whereas SMAD4 mutations were associated with larger polyp numbers (number of patients with 50 or more gastric polyps: 14 versus 0 respectively). The numbers of patients with rectal polyps was comparable between BMPR1A and SMAD4 mutation carriers (5 versus 17). No patient was diagnosed with cancer in the BMPR1A group, whereas four men with a SMAD4 mutation developed gastrointestinal (3) or extraintestinal (1) cancer. The gastrointestinal cancer risk in patients with juvenile polyposis syndrome and a SMAD4 mutation was 11 per cent (3 of 27). The SMAD4 genotype is associated with a more aggressive upper gastrointestinal malignancy risk in juvenile polyposis syndrome. © 2014 BJS Society Ltd. Published by John Wiley & Sons Ltd.

  1. Quantitative assessment of the association between the GSTM1-null genotype and the risk of childhood asthma.

    PubMed

    Li, Fang; Li, Shizhi; Chang, Hongyu; Nie, Yaling; Zeng, Li; Zhang, Xia; Wang, Yi

    2013-09-01

    Many studies investigated the association between the glutathione S-transferase M 1 (GSTM1)-null genotype and childhood asthma risk, but there was obvious inconsistence among those studies. The aim of this meta-analysis was to quantify the strength of association between the GSTM1-null genotype and risk of childhood asthma. We searched the PubMed, Embase, and Wangfang databases for studies relating the association between the GSTM1-null genotype and risk of childhood asthma. We estimated the pooled odds ratio (OR) with its 95% confidence interval (95% CI) to assess the association. Nineteen case-control studies with 4,543 childhood asthma cases and 19,394 controls were included into this meta-analysis. Meta-analysis of all 19 studies showed that the GSTM1-null genotype was associated with increased risk of childhood asthma (OR=1.17, 95% CI 1.03-1.34, p=0.017). Subgroup analyses by ethnicity suggested that the GSTM1-null genotype was associated with an increased risk of childhood asthma in Caucasians and Africans (for Caucasians, fixed-effects OR=1.16, 95% CI 1.07-1.27, p=0.001; for Africans, fixed-effects OR=1.92, 95% CI 1.35-2.74, p<0.001). The cumulative meta-analyses showed a trend of obvious association between the GSTM1-null genotype and risk of childhood asthma as information accumulated in the analyses of both total studies and Caucasians. No evidence of publication bias was observed. Meta-analyses of available data suggest a significant association between the GSTM1-null genotype and the risk of childhood asthma, and the GSTM1-null genotype contributes to increased risk of childhood asthma, especially in Caucasians and Africans.

  2. Glutathione S-transferase M1 null genotype related to poor prognosis of colorectal cancer.

    PubMed

    Yan, Shushan; Wang, Zengfang; Wang, Zengyan; Duan, Quanhong; Wang, Xiaochen; Li, Jun; Sun, Beicheng

    2016-08-01

    Published studies showed controversial findings about the relationship between glutathione S-transferase M1 (GSTM1) null genotype and clinical outcomes of patients with colorectal cancer. We performed a meta-analysis to quantitatively assess the association between GSTM1 null genotype and prognosis of patients with colorectal cancer. We systematically searched Pubmed, Embase, and Web of Science to identify prospective or retrospective cohort studies assessing the association of GSTM1 null genotype with overall survival (OS) or disease-free survival (DFS) in colorectal cancer. The hazard ratios (HRs) and 95 % confidence intervals (95 % CIs) were used to assess the association of GSTM1 null genotype with OS or DFS. Finally, 15 studies from 14 publications with 4326 colorectal cancer patients were included into the meta-analysis. There was no heterogeneity in the meta-analysis relating OS (I (2) = 0 %) and DFS (I (2) = 0 %). Overall, GSTM1 null genotype was significantly associated with poor OS in patients with colorectal cancer (HR = 1.18, 95 % CI 1.07-1.30, P = 0.001). In addition, GSTM1 null genotype was also significantly associated with poor DFS in patients with colorectal cancer (HR = 1.15, 95 % CI 1.03-1.28, P = 0.015). No obvious risk of publication bias was observed. GSTM1 null genotype is significantly associated with poor OS and DFS in patients with colorectal cancer, which suggests that GSTM1 null genotype confers poor effect on the prognosis of colorectal cancer.

  3. Body mass index and obesity- and diabetes-associated genotypes and risk for pancreatic cancer.

    PubMed

    Tang, Hongwei; Dong, Xiaoqun; Hassan, Manal; Abbruzzese, James L; Li, Donghui

    2011-05-01

    The genetic factors predisposing individuals with obesity or diabetes to pancreatic cancer have not been identified. To investigate the hypothesis that obesity- and diabetes-related genes modify the risk of pancreatic cancer. We genotyped 15 single nucleotide polymorphisms of fat mass and obesity-associated (FTO), peroxisome proliferators-activated receptor gamma (PPARγ), nuclear receptor family 5 member 2 (NR5A2), AMPK, and ADIPOQ genes in 1,070 patients with pancreatic cancer and 1,175 cancer-free controls. Information on risk factors was collected by personal interview. Adjusted ORs (AOR) and 95% CIs were calculated using unconditional logistic regression. The PPARγ P12A GG genotype was inversely associated with risk of pancreatic cancer (AOR, 0.21; 95% CI, 0.07-0.62). Three NR5A2 variants that were previously identified in a genome-wide association study were significantly associated with reduced risk of pancreatic cancer, AORs ranging from 0.57 to 0.79. Two FTO gene variants and one ADIPOQ variant were differentially associated with pancreatic cancer according to levels of body mass index (BMI; P(interaction) = 0.0001, 0.0015, and 0.03). For example, the AOR (95% CI) for FTO IVS1-2777AC/AA genotype was 0.72 (0.55-0.96) and 1.54 (1.14-2.09) in participants with a BMI of less than 25 or 25 kg/m(2) or more, respectively. We observed no significant association between AMPK genotype and pancreatic cancer and no genotype interactions with diabetes or smoking. Our findings suggest the PPARγ P12A GG genotype and NR5A2 variants may reduce the risk for pancreatic cancer. A positive association of FTO and ADIPOQ gene variants with pancreatic cancer may be limited to persons who are overweight. The discovery of genetic factors modifying the risk of pancreatic cancer may help to identify high-risk individuals for prevention efforts. ©2011 AACR.

  4. Propositional Density and Apolipoprotein E Genotype among Persons at Risk for Familial Alzheimer's Disease

    PubMed Central

    Medina, Luis D.; Rodriguez-Agudelo, Yaneth; Geschwind, Daniel H.; Gilbert, Paul E.; Liang, Li-Jung; Cummings, Jeffrey L.; Ringman, John M.

    2011-01-01

    Background/Aims A relationship between decreased propositional density (p-density) in young adulthood and future risk for Alzheimer's disease (AD) has been postulated, but multiple interpretations of the nature of this relationship are possible. This study explored the relationship between familial AD (FAD) mutation status, apolipoprotein E (APOE) genotype, and p-density. Methods Thirty-five non-demented persons at risk for FAD mutations were recruited. Subjects wrote brief biographical essays from which p-density, the ratio of the number of unique ideas to the number of words in the text, was calculated. Mixed-effects regression models were used to examine the relationship of p-density and FAD mutation status and APOE genotype. Results FAD mutation status was not significantly associated with p-density. However, results from both models indicated that the presence of the APOE ∊4 allele was significantly associated with p-density (p < 0.0001), with APOE ∊4 carriers having lower p-density than non-carriers. Conclusions Our results are consistent with an influence of APOE status on p-density in young adulthood that is independent of the AD risk per se and suggest the previous finding of increased risk for the development of AD in persons with decreased p-density may be related to APOE genotype. PMID:22134129

  5. MAOA genotype, family relations and sexual abuse in relation to adolescent alcohol consumption.

    PubMed

    Nilsson, Kent W; Comasco, Erika; Åslund, Cecilia; Nordquist, Niklas; Leppert, Jerzy; Oreland, Lars

    2011-04-01

    The aim of the present study was to investigate MAOA gene-environment (G*E) interactions in relation to adolescent alcohol consumption. In the county of Västmanland, Sweden, all 17-18-year-old students were asked to complete an anonymous questionnaire and provide a saliva sample during class hours. A total of 2263 students completed the questionnaire (77.4%) and a saliva sample was provided by 2131 participants. Failed MAOA u-variable number of tandem repeats (VNTR) genotype analyses and internal non-responses left 851 boys and 735 girls (total n=1586) to be investigated. Alcohol use disorder identification test was used to measure hazardous alcohol consumption. MAOA u-VNTR was used to measure biological risk in interaction with poor family relations and experience of sexual abuse. The model was also adjusted for non-independent socioeconomic variables, separated parents, type of housing and parental unemployment. Results showed that the MAOA u-VNTR, in interaction with psychosocial risk factors, such as the quality of family relations and sexual abuse, was related to high alcohol consumption among adolescents. Girls, carrying the long MAOA u-VNTR variant showed a higher risk of being high alcohol consumers, whereas among boys, the short allele was related to higher alcohol consumption. The present study supports the hypothesis that there is a relation between MAOA u-VNTR and alcohol consumption and that this relation is modulated by environmental factors. Furthermore, the present study also supports the hypothesis that there is a sex difference in the G*E interaction. © 2010 The Authors, Addiction Biology © 2010 Society for the Study of Addiction.

  6. Association between dietary intake of folate and MTHFR and MTR genotype with risk of breast cancer.

    PubMed

    He, J M; Pu, Y D; Wu, Y J; Qin, R; Zhang, Q J; Sun, Y S; Zheng, W W; Chen, L P

    2014-10-31

    We investigated the association between dietary intake of folate, vitamin B6, and the 5,10-methylenetetrahydrofolate reductase (MTHFR) genotype with breast cancer. A matched case-control study was conducted, and 413 patients with newly diagnosed and histologically confirmed breast cancer and 436 controls were recruited. Folate intake, vitamin B6, and vitamin B12 levels were calculated, and the MTHFR C677T and A1298C and MTR A2756G polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism. Breast cancer cases were generally older, older at first live birth, and younger at menarche, had a higher body mass index, were smokers, had higher energy intake, and more first-degree relatives with breast cancer as well as more live births compared to controls. With respect to energy intake, we found that higher energy intake were more likely to increase the risk of breast cancer. The MTHFR 667TT genotype was associated with a moderately increased risk of breast cancer when compared with the CC genotype, and a significant odds ratio (OR; 95% confidence interval, CI) was found (OR = 1.70, 95%CI = 1.06-2.73). Individuals carrying T allele were associated with higher risk of breast cancer when compared with C allele (OR = 1.34, 95%CI = 1.06-1.70). We did not find a significant effect of the MTHFR A1298C and MTR A2756G on the risk of breast cancer. We did not find any association between folate intake and MTHFR C677T polymorphisms. In conclusion, we found that the MTHFR C667T polymorphism is associated with the risk of breast cancer, indicating that this genotype plays a role in breast cancer development.

  7. War exposure, 5-HTTLPR genotype and lifetime risk of depression.

    PubMed

    Artero, Sylvaine; Touchon, Jacques; Dupuy, Anne-Marie; Malafosse, Alain; Ritchie, Karen

    2011-07-01

    In 1962 approximately 1.5 million French people living in Algeria were repatriated to France in very poor and often life-threatening conditions. These people constitute a cohort for the study of the long-term impact of gene-environment interaction on depression. To examine the interaction between a highly stressful life event and subsequent depression, and its modulation by a length polymorphism of the serotonin transporter gene (5-HTTLPR). A community sample of people aged 65 years and over residing in the Montpellier region of the south of France was randomly recruited from electoral rolls. Genotyping was performed on 248 repatriated persons and 632 controls. Current and lifetime major and minor depressive disorders were assessed according to DSM-IV criteria. A significant relationship was observed between exposure to repatriation and subsequent depression (P<0.002), but there was no significant effect of gene alone (P = 0.62). After controlling for age, gender, education, disability, recent life events and cognitive function, the gene-environment interaction (repatriation × 5-HTTLPR) was globally significant (P<0.002; OR = 3.21, 95% CI 2.48-5.12). Individuals carrying the two short (s) alleles of 5-HTTLPR were observed to be at higher risk (P<0.005; OR = 2.34, 95% CI 1.24-4.32), particularly when repatriation occurred before age 35 years (P<0.002; OR = 2.91, 95% CI 1.44-5.88), but this did not reach significance in those who were older at the time of the event (P = 0.067). The association between depression and war repatriation was significantly modulated by 5-HTTLPR genotype but this appeared to occur only in people who were younger at the time of exposure.

  8. War exposure, 5-HTTLPR genotype and lifetime risk of depression

    PubMed Central

    Artero, Sylvaine; Touchon, Jacques; Dupuy, Anne-Marie; Malafosse, Alain; Ritchie, Karen

    2011-01-01

    Background in 1962, during the Algerian war, approximately one and a half million French people living in Algeria were repatriated to France in very poor and often life-threatening conditions. These subjects constitute a cohort for the study of the long term impact of gene-environment interaction on depression. Aims To examine the interaction between a highly stressful life event and subsequent depression, and its modulation by the serotonin transporter gene (5-HTTLPR). Method A community sample of elderly persons aged 65 years and over residing in the Montpellier region of the South of France was randomly recruited from electoral rolls. Genotyping was performed on 248 repatriated persons and 632 controls. Current and lifetime major and minor depressions were assessed according to DSM-IV criteria. Results A significant relationship was observed between exposure to repatriation and subsequent depression (p<0.002), but there was no significant effect of gene alone (p=0.62). After controlling for age, gender, education, disability, recent life events and cognitive function, the gene-environment interaction (Repatriation X 5-HTTLPR) was globally significant (p<0.002; OR= 3.21 [2.48–5.12]). Subjects carrying the two short ( S ) alleles of 5-HTTLPR were observed to be at higher risk (p<0.005; OR=2.34 [1.24–4.32]) and particularly when the repatriation occurred before the age of 35 (p<0.002; OR=2.91 [1.44–5.88]) but did not reach significance in subjects who were older at the time of the event (p=0.067). Conclusion The association between depression and war repatriation is significantly modulated by 5-HTTLPR genotype but this appears to occur only in persons who were younger at the time of exposure. PMID:21593514

  9. Genotype-phenotype correlations in recessive RYR1-related myopathies

    PubMed Central

    2013-01-01

    Background RYR1 mutations are typically associated with core myopathies and are the most common overall cause of congenital myopathy. Dominant mutations are most often associated with central core disease and malignant hyperthermia, and genotype-phenotype patterns have emerged from the study of these mutations that have contributed to the understanding of disease pathogenesis. The recent availability of genetic testing for the entire RYR1 coding sequence has led to a dramatic expansion in the identification of recessive mutations in core myopathies and other congenital myopathies. To date, no clear patterns have been identified in these recessive mutations, though no systematic examination has yet been performed. Methods In this study, we investigated genotype-phenotype correlations in a large combined cohort of unpublished (n = 14) and previously reported (n = 92) recessive RYR1 cases. Results Overall examination of this cohort revealed nearly 50% of cases to be non-core myopathy related. Our most significant finding was that hypomorphic mutations (mutations expected to diminish RyR1 expression) were enriched in patients with severe clinical phenotypes. We also determined that hypomorphic mutations were more likely to be encountered in non-central core myopathies. With analysis of the location of non-hypomorphic mutations, we found that missense mutations were generally enriched in the MH/CCD hotspots and specifically enriched in the selectivity filter of the channel pore. Conclusions These results support a hypothesis that loss of protein function is a key predictive disease parameter. In addition, they suggest that decreased RyR1 expression may dictate non-core related pathology though, data on protein expression was limited and should be confirmed in a larger cohort. Lastly, the results implicate abnormal ion conductance through the channel pore in the pathogenesis in recessive core myopathies. Overall, our findings represent a comprehensive analysis of

  10. Does Apolipoprotein E Genotype Increase Risk of Postoperative Delirium?

    PubMed Central

    Vasunilashorn, Sarinnapha; Ngo, Long; Kosar, Cyrus M.; Fong, Tamara G.; Jones, Richard N.

    2015-01-01

    Objectives To determine whether Apolipoprotein E (ApoE) is associated with postoperative delirium incidence, severity, and duration in older patients free of dementia at baseline. Design, Setting, Participants We examined 557 non-demented patients age ≥70 undergoing major non-cardiac surgery enrolled in the Successful Aging after Elective Surgery (SAGES) Study. Measurements We considered three ApoE measures: ε2, ε4 carriers vs. non-carriers, and a three-category ApoE measure. Delirium was determined using the Confusion Assessment Method (CAM) and chart review. We used generalized linear models to estimate the association between ApoE and delirium incidence, severity (peak CAM Severity [CAM-S] score), and days. Results ApoE ε2 and ε4 was present in 15% and 19% respectively, and postoperative delirium occurred in 24%. Among patients with delirium, the mean peak CAM-S score was 8.0 (standard deviation 4), with most patients experiencing one or two delirium days (51% or 28%, respectively). After adjusting for age, sex, surgical procedure, and preoperative cognitive function, ApoE ε4 and ε2 carrier status were not associated with postoperative delirium: RR for ε4=1.0, 95% confidence interval (CI) 0.7-1.5 and RR for ε2=0.9, 95% CI 0.6-1.4. No association between ApoE and delirium severity or number of delirium days was observed. Conclusions In older surgery patients free of dementia, our findings do not support the hypothesis that the ApoE genotype does not confer either risk or protection in postoperative delirium incidence, severity, or duration. Thus, an important genetic risk factor for Alzheimer's Disease does not affect risk of delirium. PMID:26238230

  11. Childhood adversity, monoamine oxidase a genotype, and risk for conduct disorder.

    PubMed

    Foley, Debra L; Eaves, Lindon J; Wormley, Brandon; Silberg, Judy L; Maes, Hermine H; Kuhn, Jonathan; Riley, Brien

    2004-07-01

    Very little is known about how different sets of risk factors interact to influence risk for psychiatric disorder. To replicate a recent report of a genotype-environment interaction that predicts risk for antisocial behavior in boys. Characterizing risk for conduct disorder in boys in association with monoamine oxidase A genotype and exposure to familial adversity, defined by interparental violence, parental neglect, and inconsistent discipline. A community-based sample of twin boys. Five hundred fourteen male twins aged 8 to 17 years. Conduct disorder. There was a main effect of adversity but not of monoamine oxidase A on risk for conduct disorder. Low monoamine oxidase A activity increased risk for conduct disorder only in the presence of an adverse childhood environment. Neither a passive nor an evocative genotype-environment correlation accounted for the interaction. This study replicates a recent report of a genotype-environment interaction that predicts individual variation in risk for antisocial behavior in boys.

  12. Cigarette smoking, N-acetyltransferase 2 genotypes, and breast cancer risk: pooled analysis and meta-analysis.

    PubMed

    Ambrosone, Christine B; Kropp, Silke; Yang, Jun; Yao, Song; Shields, Peter G; Chang-Claude, Jenny

    2008-01-01

    Approximately 10 years ago, it was noted that smoking increased risk of breast cancer among women with N-acetyltransferase 2 (NAT2) slow acetylation genotypes. This report was followed by a number of studies to address this question. We pooled data from 10 existing studies and also conducted a meta-analysis of 13 studies published from 1996 to October 2006 that were conducted among women, were published in English, and had adequate information on smoking and NAT2 genotyping. Raw data were requested from authors. Unconditional logistic regression was done for pooled analysis, and random effect models was done for meta-analysis. Study heterogeneity was assessed, and sensitivity tests were done when subgroups were excluded from the analysis. In the pooled analysis, there was a significant interaction between smoking, NAT2 genotype, and risk of breast cancer [pack-years (continuous variable, P(interaction) = 0.03)], with higher pack-years significantly associated with an increased risk of breast cancer among women with NAT2 slow genotypes (pooled analysis relative risk, 1.49; 95% confidence interval, 1.08-2.04). These findings were supported by the meta-analysis including all studies; pack-years were significantly associated with risk among slow acetylators in a dose-dependent fashion (meta-analysis relative risk, 1.44; 95% confidence interval, 1.23-1.68 for > or =20 pack-years versus never smokers), but not among rapid acetylators. Similar relationships were noted for smoking status (ever, never) and duration of smoking. Our results show that cigarette smoking is associated with an increase in breast cancer risk among women with NAT2 slow acetylation genotypes. Because slow NAT2 genotypes are present in 50% to 60% of Caucasian populations, smoking is likely to play an important role in breast cancer etiology.

  13. FTO genotype, physical activity, and coronary heart disease risk in Swedish men and women.

    PubMed

    Gustavsson, Jaana; Mehlig, Kirsten; Leander, Karin; Lissner, Lauren; Björck, Lena; Rosengren, Annika; Nyberg, Fredrik

    2014-04-01

    Variants in the fat mass- and obesity-associated gene (FTO) predisposing to obesity and diabetes mellitus have also been associated with cardiovascular disease. Physical activity has been suggested to attenuate the FTO effect on obesity, but it is unknown whether this is also true for cardiovascular disease. Therefore, we explored whether physical activity modifies the FTO association with coronary heart disease (CHD). FTO rs9939609 (T>A) polymorphism was genotyped in 2 Swedish population-based case-control studies with 1743 CHD cases and 4402 population controls (25-74 years of age; 41% women). Leisure time physical activity was assessed by questionnaires, and 3 levels were defined: low, medium, and high. Overall, carriers of the FTO A allele had an increased risk of CHD (odds ratio, 1.20; 95% confidence interval, 1.06-1.37) adjusted for age, sex, study, and body mass index. Although A-allele carriers with low physical activity had the highest CHD risk (odds ratio, 3.30; 95% confidence interval, 2.44-4.46) compared with those with TT genotype and high activity, the effects of FTO genotype and physical activity on CHD risk were approximately additive, indicating the absence of additive interaction. The stratum-specific relative risks of CHD from the A allele in subjects with low, medium, and high physical activity were odds ratio 1.11 (95% confidence interval, 0.77-1.60), 1.22 (1.04-1.44), and 1.38 (1.06-1.80), respectively, but the suggested multiplicative interaction was not significant. FTO rs9939609 A-allele carriers have an increased CHD risk, and the association is not counteracted by increased physical activity.

  14. Progression of Geographic Atrophy and Genotype in Age-Related Macular Degeneration

    PubMed Central

    Klein, Michael L.; Ferris, Frederick L.; Francis, Peter J.; Lindblad, Anne S.; Chew, Emily Y.; Hamon, Sara C.; Ott, Jurg

    2009-01-01

    Purpose To determine if genotype is associated with rate of growth of geographic atrophy (GA) in eyes with age-related macular degeneration (AMD). Design Prospective analysis of participants in a randomized controlled clinical trial. Participants 114 eyes of 114 participants in the Age-Related Eye Disease Study (AREDS). Methods Fundus photographs from AREDS participants with GA from whom a DNA specimen had been obtained and serial photographs had been taken over a minimum of 2 years were evaluated for progression as determined by change in cumulative area of GA. All fundus photographs were scanned, digitized, and centrally graded longitudinally for area of GA. The relationship of GA progression with previously identified genetic variants associated with AMD was assessed. Main Outcome Measures Genotype frequencies and change in cumulative area of GA. Results The mean growth rate of geographic atrophy for the 114 eyes was 1.79 mm2/year (range= 0.17–4.76 mm2/year). No association between growth rate and genotype was present for variants in the CFH, C2, C3, APOE, and TLR3genes. For the single nucleotide polymorphism (SNP) rs10490924 in LOC387715/ARMS2, there was a significant association of GA growth rate, both adjusted and unadjusted for initial lesion size, with the homozygous risk genotype as compared to the homozygous non-risk genotype (unadjusted p-value = 0.002; Bonferroni corrected p-value = 0.014) and for allelic association(Bonferroni corrected p-value = 0.011). Analyses of other measures of geographic atrophy progression (progression to central GA from extrafoveal GA and development of bilateral GA in those initially with unilateral GA) showed no statistically significant association between progression and the LOC387715/ARMS2/HTRA1 genotype. Conclusion GA growth rates calculated from digitized serial fundus photographs showed no association with variants in the CFH, C2, C3, APOE, and TLR3 genes. There was a nominally statistically significant association

  15. Integrative Genomics Identifies Novel Associations with APOL1 Risk Genotypes in Black NEPTUNE Subjects.

    PubMed

    Sampson, Matthew G; Robertson, Catherine C; Martini, Sebastian; Mariani, Laura H; Lemley, Kevin V; Gillies, Christopher E; Otto, Edgar A; Kopp, Jeffrey B; Randolph, Anne; Vega-Warner, Virginia; Eichinger, Felix; Nair, Viji; Gipson, Debbie S; Cattran, Daniel C; Johnstone, Duncan B; O'Toole, John F; Bagnasco, Serena M; Song, Peter X; Barisoni, Laura; Troost, Jonathan P; Kretzler, Matthias; Sedor, John R

    2016-03-01

    APOL1 variants have been associated with renal phenotypes in blacks. To refine clinical outcomes and discover mechanisms of APOL1-associated kidney injury, we analyzed clinical and genomic datasets derived from 90 black subjects in the Nephrotic Syndrome Study Network (NEPTUNE), stratified by APOL1 risk genotype. Ninety subjects with proteinuria ≥0.5 g/d were enrolled at first biopsy for primary nephrotic syndrome and followed. Clinical outcomes were determined, and renal histomorphometry and sequencing of Mendelian nephrotic syndrome genes were performed. APOL1 variants were genotyped, and glomerular and tubulointerstitial transcriptomes from protocol renal biopsy cores were analyzed for differential and correlative gene expression. Analyses were performed under the recessive model (high-risk genotype defined by two risk alleles). APOL1 high-risk genotype was significantly associated with a 17 ml/min per 1.73 m(2) lower eGFR and a 69% reduction in the probability of complete remission at any time, independent of histologic diagnosis. Neither APOL1 risk group was enriched for Mendelian mutations. On renal biopsy, high-risk genotype was associated with increased fractional interstitial area, interstitial fibrosis, and tubular atrophy. Risk genotype was not associated with intrarenal APOL1 mRNA expression levels. Differential expression analysis demonstrated an increased steady-state level of five genes associated with the high-risk genotype (CXCL9, CXCL11, and UBD in glomerulus; SNOR14B and MUC13 in tubulointerstitium). APOL1 tubulointerstitial coexpression analysis showed coexpression of APOL1 mRNA levels with a group of intrarenal transcripts that together were associated with increased interstitial fibrosis and tubular atrophy. These data indicate the high-risk APOL1 genotype confers renal risk across histopathologic diagnoses. Copyright © 2016 by the American Society of Nephrology.

  16. Threat-related amygdala functional connectivity is associated with 5-HTTLPR genotype and neuroticism.

    PubMed

    Madsen, Martin Korsbak; Mc Mahon, Brenda; Andersen, Sofie Bech; Siebner, Hartwig Roman; Knudsen, Gitte Moos; Fisher, Patrick MacDonald

    2016-01-01

    Communication between the amygdala and other brain regions critically regulates sensitivity to threat, which has been associated with risk for mood and affective disorders. The extent to which these neural pathways are genetically determined or correlate with risk-related personality measures is not fully understood. Using functional magnetic resonance imaging, we evaluated independent and interactive effects of the 5-HTTLPR genotype and neuroticism on amygdala functional connectivity during an emotional faces paradigm in 76 healthy individuals. Functional connectivity between left amygdala and medial prefrontal cortex (mPFC) and between both amygdalae and a cluster including posterior cingulate cortex, precuneus and visual cortex was significantly increased in 5-HTTLPR S' allele carriers relative to L(A)L(A) individuals. Neuroticism was negatively correlated with functional connectivity between right amygdala and mPFC and visual cortex, and between both amygdalae and left lateral orbitofrontal (lOFC) and ventrolateral prefrontal cortex (vlPFC). Notably, 5-HTTLPR moderated the association between neuroticism and functional connectivity between both amygdalae and left lOFC/vlPFC, such that S' carriers exhibited a more negative association relative to L(A)L(A) individuals. These findings provide novel evidence for both independent and interactive effects of 5-HTTLPR genotype and neuroticism on amygdala communication, which may mediate effects on risk for mood and affective disorders.

  17. Risk factors for hepatitis C virus infection among Koreans according to the hepatitis C virus genotype.

    PubMed Central

    Kim, Young Sik; Ahn, Yoon-Ok; Lee, Hyo Suk

    2002-01-01

    To investigate risk factors for HCV infection according to the genotype, we studied 178 patients positive for HCV-PCR and 226 controls that were negative for the anti-HCV antibody. One hundred and twenty five controls (community control) were recruited from spouses of HCV-PCR-positive patients and the other 101 from hospital visitors (hospital control). HCV genotyping was performed by PCR, and epidemiological data were obtained from all participants. The distribution of HCV genotypes was as follows -- 1a (0.6%), 1b (39.9%), 2a (38.2%), 2b (0%), 3 (1.1%), and unclassified (20.2%). By multivariate analysis, blood transfusion (OR 2.90) and endoscopy (OR 2.80) were found to be risk factors for HCV genotype 1b versus the community control. Similarly, blood transfusion (OR 3.17) was found to be risk factors for HCV genotype 1b versus the hospital control. Blood transfusion (OR 2.75) and endoscopy (OR 3.57) were risk factors for HCV genotype 2a versus the community control, and blood transfusion (OR 4.55) and endoscopy (OR 2.16) were those versus the hospital control. Our results suggest that the risk factors for HCV infection are similar among the different genotypes. Blood transfusion and endoscopy were found to be associated with HCV infection. PMID:11961301

  18. Estrogen receptor-alpha genotype affects exercise-related reduction of arterial stiffness.

    PubMed

    Hayashi, Koichiro; Maeda, Seiji; Iemitsu, Motoyuki; Otsuki, Takeshi; Sugawara, Jun; Tanabe, Takumi; Miyauchi, Takashi; Kuno, Shinya; Ajisaka, Ryuichi; Matsuda, Mitsuo

    2008-02-01

    Arterial stiffness, an independent risk factor for cardiovascular disease, increases with advancing age. Arterial stiffness is improved by regular exercise, but individual responses to exercise training are variable. Given that estrogen and estrogen receptor-alpha (ER-alpha) can induce vasodilation and can exert an antiatherosclerotic effect in vessels, we hypothesized that gene polymorphisms of ER-alpha might influence the ability of regular exercise to improve arterial stiffness in postmenopausal women. One hundred ninety-five healthy postmenopausal women (62 +/- 6 yr, mean +/- SD) participated in our cross-sectional study. We determined the genotype of single-nucleotide polymorphisms (SNP) at -401T/C of intron 1 of the ER-alpha gene. Arterial stiffness was measured by brachial-ankle pulse wave velocity (baPWV), and daily physical activity was estimated by a uniaxial accelerometer. Subjects were divided into active and inactive groups according to the median value (200 kcal.d(-1)) of energy expenditure. baPWV in individuals with the TT variant of -401T/C genotype were significantly higher than for individuals with the TC+CC genotype. No significant differences in mean baPWV values were found between the active group and the inactive group (P = 0.09). A significant reduction of baPWV secondary to increased daily physical activity was observed in individuals with the TC+CC genotype but not in individuals with the TT genotype (TT/active: 1470 +/- 36 cm.s(-1); TT/inactive: 1457 +/- 34 cm.s(-1); TC+CC/active: 1359 +/- 21 cm.s(-1); TC+CC/inactive: 1433 +/- 24 cm.s(-1)). These results suggest that ER-alpha polymorphism affects the regular exercise-related reduction in arterial stiffness in healthy postmenopausal women.

  19. Dopamine Transporter Genotype Conveys Familial Risk of Attention-Deficit/Hyperactivity Disorder through Striatal Activation

    ERIC Educational Resources Information Center

    Durston, Sarah; Fossella, John A.; Mulder, Martijn J.; Casey B. J.; Ziermans, Tim B.; Vessaz, M. Nathalie; Van Engeland, Herman

    2008-01-01

    The study examines the effect of the dopamine transporter (DAT1) genotype in attention-deficit/hyperactivity disorder (ADHD). The results confirm that DAT1 translates the genetic risk of ADHD through striatal activation.

  20. Dopamine Transporter Genotype Conveys Familial Risk of Attention-Deficit/Hyperactivity Disorder through Striatal Activation

    ERIC Educational Resources Information Center

    Durston, Sarah; Fossella, John A.; Mulder, Martijn J.; Casey B. J.; Ziermans, Tim B.; Vessaz, M. Nathalie; Van Engeland, Herman

    2008-01-01

    The study examines the effect of the dopamine transporter (DAT1) genotype in attention-deficit/hyperactivity disorder (ADHD). The results confirm that DAT1 translates the genetic risk of ADHD through striatal activation.

  1. Newborn APOE genotype influences maternal lipid profile and the severity of high-risk pregnancy - preeclampsia: Interaction with maternal genotypes as a modulating risk factor in preeclampsia.

    PubMed

    Procopciuc, Lucia Maria; Caracostea, Gabriela; Zaharie, Gabriela; Stamatian, Florin

    2015-01-01

    To establish the role of the interaction between maternal and newborn apolipoprotein E (APOE) genotypes on the risk, lipid profile and prognosis of preeclampsia (PE). Forty-seven preeclamptic women and 94 normotensive pregnant women and their newborns were genotyped for APOE using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Maternal APOE-ε4 allele was associated with an about eight times higher risk of PE (adjusted OR = 8.4, 95% CI: 2.51-28.17, p = 0.001). The multivariate logistic regression model showed that the newborn APOE-ε4 allele was associated with an about six times higher risk of PE (adjusted OR = 5.6, 95% CI: 2.09-15.21, p = 0.001) for the given gestational age levels. Pregnant women with severe PE whose newborns carried the APOE-ε4 allele delivered at earlier gestational ages neonates with a lower birth weight compared to pregnant women with newborns negative for this allele. Higher TG and LDL-C levels and lower HDL-C levels were found in pregnant women with severe PE whose newborns were carriers of the APOE-ε4 allele compared to preeclamptic women whose newborns were carriers of the ε3/ε3 genotype. If we checked the combined effect of the mother/newborn genotypes on the risk of PE, we found that the risk to develop PE was 15.4-fold (p < 0.001) increased if mothers or newborns were carriers of the APOE-ε4 allele. The risk increased to 20.02 (p < 0.001) if both the mother and newborn were carriers of the APOE-ε4 allele. Our study confirms the maternal/newborn APOE genotype interaction influences the risk for PE, as well as prognosis and lipid profile.

  2. Dense Genotyping of Immune-Related Loci in the Idiopathic Inflammatory Myopathies Confirms HLA alleles as Strongest Genetic Risk Factor and Suggests Different Genetic Background for Major Clinical Subgroups

    PubMed Central

    Rothwell, Simon; Cooper, Robert G.; Lundberg, Ingrid E.; Miller, Frederick W.; Gregersen, Peter K.; Bowes, John; Vencovsky, Jiri; Danko, Katalin; Limaye, Vidya; Selva-O’Callaghan, Albert; Hanna, Michael G.; Machado, Pedro M.; Pachman, Lauren M.; Reed, Ann M.; Rider, Lisa G.; Cobb, Joanna; Platt, Hazel; Molberg, Øyvind; Benveniste, Olivier; Mathiesen, Pernille; Radstake, Timothy; Doria, Andrea; De Bleecker, Jan; De Paepe, Boel; Maurer, Britta; Ollier, William E.; Padyukov, Leonid; O’Hanlon, Terrance P.; Lee, Annette; Amos, Christopher I.; Gieger, Christian; Meitinger, Thomas; Winkelmann, Juliane; Wedderburn, Lucy R; Chinoy, Hector; Lamb, Janine A

    2017-01-01

    The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of rare autoimmune diseases characterized by muscle weakness and extramuscular manifestations such as skin rashes and interstitial lung disease. We genotyped 2,566 IIM cases of Caucasian descent using the Immunochip; a custom array covering 186 established autoimmune susceptibility loci. The cohort was predominantly comprised of dermatomyositis (DM, n=879), juvenile dermatomyositis (JDM, n=481), polymyositis (PM, n=931) and inclusion body myositis (IBM, n=252) patients collected from 14 countries through the Myositis Genetics Consortium. The human leukocyte antigen (HLA) and PTPN22 regions reached genome-wide significance (p<5×10−8). Nine regions were associated at a significance level of p<2.25×10−5, including UBE2L3, CD28 and TRAF6, with evidence of independent effects within STAT4. Analysis of clinical subgroups revealed distinct differences between PM, and DM and JDM. PTPN22 was associated at genome-wide significance with PM, but not DM and JDM, suggesting this effect is driven by PM. Additional suggestive associations including IL18R1 and RGS1 in PM and GSDMB in DM were identified. HLA imputation confirmed that alleles HLA-DRB1*03:01 and HLA-B*08:01 of the 8.1 ancestral haplotype (8.1AH) are most strongly associated with IIM, and provides evidence that amino acids within the HLA, such as HLA-DQB1 position 57 in DM, may explain part of the risk in this locus. Associations with alleles outside the 8.1AH reveal differences between PM, DM, and JDM. This work represents the largest IIM genetic study to date, reveals new insights into the genetic architecture of these rare diseases and suggests different predominating pathophysiology in different clinical subgroups. PMID:26362759

  3. Strict blood pressure control associates with decreased mortality risk by APOL1 genotype.

    PubMed

    Ku, Elaine; Lipkowitz, Michael S; Appel, Lawrence J; Parsa, Afshin; Gassman, Jennifer; Glidden, David V; Smogorzewski, Miroslaw; Hsu, Chi-Yuan

    2017-02-01

    Although APOL1 high-risk genotype partially accounts for the increased susceptibility of blacks to chronic kidney disease (CKD), whether APOL1 associates differentially with mortality risk remains controversial. Here we evaluate the association between APOL1 genotype and risk of death and determine whether APOL1 status modifies the association between strict versus usual blood pressure control and mortality risk. We performed a retrospective analysis of the African American Study of Kidney Disease and Hypertension trial that randomized black participants with CKD to strict versus usual blood pressure control from 1995 to 2001. This included 682 participants with known APOL1 genotype (157 with high-risk genotype) previously assigned to either strict (mean arterial pressure [MAP] 92 mm Hg or less) versus usual blood pressure control (MAP 102-107 mm Hg) during the trial. During a median follow-up of 14.5 years, risk of death did not differ between individuals with high- versus low-risk APOL1 genotypes (unadjusted hazard ratio 1.00 [95% confidence interval 0.76-1.33]). However, a significant interaction was detected between the APOL1 risk group and blood pressure control strategy. In the APOL1 high-risk group, the risk of death was 42% lower comparing strict versus usual blood pressure control (0.58 [0.35-0.97]). In the APOL1 low-risk group, the risk of death comparing strict versus usual blood pressure control was not significantly different (1.09 [0.84-1.43]). Thus, strict blood pressure control during CKD associates with a lower risk of death in blacks with the high-risk CKD APOL1 genotype. Knowledge of APOL1 status could inform selection of blood pressure treatment targets in black CKD patients. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  4. Head injury and risk of Alzheimer's disease by apolipoprotein E genotype.

    PubMed

    O'Meara, E S; Kukull, W A; Sheppard, L; Bowen, J D; McCormick, W C; Teri, L; Pfanschmidt, M; Thompson, J D; Schellenberg, G D; Larson, E B

    1997-09-01

    Head injury and apolipoprotein E (APOE)-epsilon 4 (e4) genotype have each been associated with increased risk of Alzheimer's disease. If APOE-e4 affects neuronal viability and branching, and if response to head injury differs in e4 patients, then the association between head injury and Alzheimer's disease may vary with the presence of the e4 allele. The authors examined this association in a case-control study conducted between 1987 and 1995 among enrollees of the Group Health Cooperative of Puget Sound, a health maintenance organization in Seattle, Washington. Proxy informants reported prior head injury with loss of consciousness for 32 of 349 patients with probable Alzheimer's disease and for 16 of 342 control subjects of similar age and sex who had been randomly selected from the same population (odds ratio (OR) = 2.1, 95% confidence interval (CI) 1.1-3.8). Elevated risk was observed among men (OR = 4.2, 95% CI 1.5-11.5) but not among women (OR = 1.1, 95% CI 0.5-2.6). No significant variation in the head injury-Alzheimer's disease risk relation by APOE-e4 genotype was found among 230 cases and 309 controls (OR = 3.1 (95% CI 0.7-14.6) for persons with at least one e4 allele and OR = 2.0 (95% CI 0.8-5.2) for those without e4). Neither age, education, race, type of proxy informant, nor duration of relationship with the proxy confounded the association. Head injury with loss of consciousness, although uncommon in this sample, was associated with increased risk of Alzheimer's disease. APOE-e4 was an independent risk factor which neither modified nor confounded the association. Susceptibility to Alzheimer's disease as conferred by APOE-e4 does not appear to increase the risk associated with head injury.

  5. The TT genotype of the MTHFR 677C > T polymorphism increases susceptibility to premature coronary artery disease in interaction with some of the traditional risk factors.

    PubMed

    Sarecka-Hujar, Beata; Zak, Iwona; Krauze, Jolanta

    2012-01-01

    The presence of several risk factors (genetic and non-genetic) has greater impact on the risk of premature coronary artery disease (CAD) than single risk factor. The aim of the study was to establish possible relations between genotypes and alleles of 677C>T polymorphism of MTHFR gene and some traditional risk factors e.g. elevated levels of lipid parameters and smoking in development of premature CAD. The groups comprised 152 patients with angiographically documented premature CAD (aged 42.9 +/- 5.5) and 121 age-matched blood donors (aged 42.3 +/- 6.5) were studied. The MTHFR 677C>T polymorphism was genotyped with Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. Patients with TT genotype who simultaneously smoked had increased risk of premature CAD compared to non-smoking cases with CC genotype (OR = 24.62). We also found that individuals with TT genotype and elevated LDL-cholesterol (LDL-chol.) level had significantly higher risk of CAD (OR = 9.92) than individuals with normal LDL-chol. level and CC genotype. The present study shows that simultaneous presence of MTHFR TT genotype and smoking or elevated levels of LDL-chol. influences the risk of premature CAD. This findings give interesting contribution to gene-environment interaction problem that may have clinical implications in the future.

  6. Association between dietary intake of folate, vitamin B6, B12 & MTHFR, MTR Genotype and breast cancer risk

    PubMed Central

    Weiwei, Zheng; Liping, Chen; Dequan, Li

    2014-01-01

    Objective: we conducted a case-control study to investigate the association between dietary folate, vitamin B6 and vitamin B12 intake, MTHFR and MTR genotype, and breast cancer risk. Methods: Genotyping for MTHFR C677T and A1298C and MTR A2756G polymorphisms were performed using polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP) method. The intake of folate, vitamin B6 and vitamin B12 were calculated by each food item from questionnaire. Results: Subjects with breast cancer tended to have more first-degree relatives (χ2=30.77, P<0.001) and have high intake of folate (t=2.42, P=0.008) and Vitamin B6 (t=2.94, P=0.002). Compared to the reference group, women with MTHFR 677 TT genotype and T allele had a significantly increased risk of breast cancer, with ORs (95%CI) of 1.8(1.08-2.27) and 1.39(1.02-1.92), respectively. For those who had folate intake<450 ug/day, MTHFR 667TT genotype was associated with a higher risk of breast cancer (OR=2.45, 95% CI=1.09-5.82, P=0.02). Similarly, subjects with Vitamin B6 intake<0.84 mg/day and MTHFR 667T allele genotype was correlated with a marginally increased risk of breast cancer. A significant interaction was observed between MTHFR C667T polymorphism and folate intake on the risk of breast cancer (P for interaction was 0.025). Conclusion: This case-control study found a significant association between MTHFR C667T polymorphism, folate intake and vitamin B6 and breast cancer risk, and a significant interaction was observed between MTHFR C667T polymorphism and folate intake on the risk of breast cancer. PMID:24639841

  7. Candida albicans: genotyping methods and clade related phenotypic characteristics

    PubMed Central

    Lyon, Juliana P.; Moraes, Karen C.M.; Moreira, Leonardo M.; Aimbire, Flávio; de Resende, Maria Aparecida

    2010-01-01

    Several molecular methods, such as Southern blotting hybridization, Multilocus Sequence Typing, and DNA microsatellite analysis, have been employed to genotype Candida albicans. The genotype analysis allows to group strains in clades, that is, a group composed of one ancestor and its descendants. These genotype studies demonstrate that clades distribution is influenced by geographic area as well as that antifungal resistance is associated with particular clades. These findings suggested that C. albicans reproduces mainly in a clonal manner, with certain degree of DNA microevolution. Additionally, virulence factors and site of isolation have also been associated with clade specificity. The present article is a brief review about the methods used for Candida genotyping and the correlated clade systems established. Special emphasis is given to Ca3 hybridization, MLST, and Microsatellites. The present work is also focused on the phenotypic and physiological traits associated with Candida clades. PMID:24031564

  8. TGF-alpha genotypes, oral clefts, and environmental risk factors: A population-based California study

    SciTech Connect

    Shaw, G.M.; Wasserman, C.R.; Lammer, E.J.

    1994-09-01

    Several studies have shown a relation between genetic variation at the TGF-alpha locus and oral clefts. These studies had limited sample sizes and also lacked data on additional factors potentially related to clefting. We investigated the influence on clefting from risk factors, such as maternal smoking, dependent on TFG-alpha genotype. This was accomplished using a large population-bases case-control study of fetuses and liveborn infants with oral clefts among a 1987-89 cohort of California births (N=548,844). To obtain data on potential risk factors, telephone interviews were conducted with mothers of 731 (84.5% of eligible) cleft cases, and 734 (78.2%) nonmalformed controls. DNA was obtained from newborn screening bloodspots and genotyped by using SSCP designed to detect the Taq1 RFLP. Among mothers who completed an interview, genotyping results were available for 571 (78.1%) cases and 640 (87.2%) controls. Compared to controls, the risk estimate for TGF-alpha polymorphism as measured by the odds ratio was: 0.99 (95% confidence interval 0.64, 1.5) for isolated cleft lip {plus_minus}palate; 0.88 (0.33, 2.2) for nonisolated cleft lip {plus_minus}palate; 1.6 (0.94, 2.8) for isolated cleft palate; 1.9 (0.82, 4.3) for nonisolated cleft palate; and 2.2 (0.99, 5.0) for clefts with known etiology. This dataset also revealed 1.4 to 2-fold increased risks for maternal cigarette smoking > 19 cigs/day in early pregnancy. Among these heavy smokers, risk of clefting was even more increased for infants with the TGF-alpha polymorphism. Our data suggest an association between the TGF-alpha uncommon allele and some phenotypic subgroups as well as provide evidence for a genetic-environment interaction between maternal smoking and the variant in the etiology of clefting. The fraction of cases possibly attributed to this interaction, however, was small.

  9. Molecular genotyping of HPV L1 gene in low-risk and high-risk populations in Bangkok

    PubMed Central

    Leaungwutiwong, Pornsawan; Bamrungsak, Busara; Jittmittraphap, Akanitt; Maneekan, Pannamas; Kosoltanapiwat, Nathamon; Kalambaheti, Thareerat; Kelley, James F.

    2015-01-01

    Background Human papillomavirus (HPV) infections in Thailand are a public health concern but information on HPV infection in sex workers and men who have sex with men (MSM) is limited. The aim of this study was to measure the prevalence and genotype distribution of HPV among low- and high-risk, HIV-negative populations. Methods A total of 300 participants were categorized as general women, female sex workers, MSM, and MSM sex workers. HPV infections were identified by the Papanicolaou (Pap) test and nested-PCR. A phylogenetic analysis of partial HPV L1 genes was performed. Results Abnormal cytology was found in 5% of general women, 10% of female sex workers, 24% of MSM and 28% of MSM sex workers. HPV was detected in 9% of general women, 13% of female sex workers and 30% in both MSM and the MSM sex workers. The prevalence of HPV high-risk genotypes was significantly higher in female sex workers and MSM while low-risk genotypes and genital warts were significantly higher in MSM sex workers. Significantly more patients with genital warts and CIN I/AIN I harbored low-risk genotypes while those with CIN II/AIN II harbored high-risk genotypes. Conclusion High- and low-risk HPV genotypes persist in high-risk groups in Bangkok. Some genotypes infecting at-risk populations are not vaccine-preventable. These findings may help to elucidate the prevalence of HPV infections in Thailand and serve as the basis for additional investigations into risk factors for these populations. PMID:25763674

  10. Molecular genotyping of human papillomavirus l1 gene in low-risk and high-risk populations in Bangkok.

    PubMed

    Leaungwutiwong, Pornsawan; Bamrungsak, Busara; Jittmittraphap, Akanitt; Maneekan, Pannamas; Kosoltanapiwat, Nathamon; Kalambaheti, Thareerat; Kelley, James F

    2015-04-01

    Human papillomavirus (HPV) infections in Thailand are a public health concern, but information on HPV infection in sex workers and men who have sex with men (MSM) is limited. The aim of this study was to measure the prevalence and genotype distribution of HPV among low- and high-risk, HIV-negative populations. A total of 300 participants were categorized as general women, female sex workers, MSM, and MSM sex workers. Human papillomavirus infections were identified by the Papanicolaou test and nested polymerase chain reaction. A phylogenetic analysis of partial HPV L1 genes was performed. Abnormal cytology was found in 5% of general women, 10% of female sex workers, 24% of MSM, and 28% of MSM sex workers. Human papillomavirus was detected in 9% of general women, 13% of female sex workers, and 30% in both MSM and the MSM sex workers. The prevalence of HPV high-risk genotypes was significantly higher in female sex workers and MSM, whereas low-risk genotypes and genital warts were significantly higher in MSM sex workers. Significantly more patients with genital warts and cervical intraepithelial neoplasia I/anal intraepithelial neoplasia I harbored low-risk genotypes, whereas those with cervical intraepithelial neoplasia II/anal intraepithelial neoplasia II harbored high-risk genotypes. High- and low-risk HPV genotypes persist in high-risk groups in Bangkok. Some genotypes infecting at-risk populations are not vaccine preventable. These findings may help to elucidate the prevalence of HPV infections in Thailand and serve as the basis for additional investigations into risk factors for these populations.

  11. ABO Genotype, ‘Blood-Type’ Diet and Cardiometabolic Risk Factors

    PubMed Central

    Wang, Jingzhou; García-Bailo, Bibiana; Nielsen, Daiva E.; El-Sohemy, Ahmed

    2014-01-01

    Background The ‘Blood-Type’ diet advises individuals to eat according to their ABO blood group to improve their health and decrease risk of chronic diseases such as cardiovascular disease. However, the association between blood type-based dietary patterns and health outcomes has not been examined. The objective of this study was to determine the association between ‘blood-type’ diets and biomarkers of cardiometabolic health and whether an individual's ABO genotype modifies any associations. Methods Subjects (n = 1,455) were participants of the Toronto Nutrigenomics and Health study. Dietary intake was assessed using a one-month, 196-item food frequency questionnaire and a diet score was calculated to determine relative adherence to each of the four ‘Blood-Type’ diets. ABO blood group was determined by genotyping rs8176719 and rs8176746 in the ABO gene. ANCOVA, with age, sex, ethnicity, and energy intake as covariates, was used to compare cardiometabolic biomarkers across tertiles of each ‘Blood-Type’ diet score. Results Adherence to the Type-A diet was associated with lower BMI, waist circumference, blood pressure, serum cholesterol, triglycerides, insulin, HOMA-IR and HOMA-Beta (P<0.05). Adherence to the Type-AB diet was also associated with lower levels of these biomarkers (P<0.05), except for BMI and waist circumference. Adherence to the Type-O diet was associated with lower triglycerides (P<0.0001). Matching the ‘Blood-Type’ diets with the corresponding blood group did not change the effect size of any of these associations. No significant association was found for the Type-B diet. Conclusions Adherence to certain ‘Blood-Type’ diets is associated with favorable effects on some cardiometabolic risk factors, but these associations were independent of an individual's ABO genotype, so the findings do not support the ‘Blood-Type’ diet hypothesis. PMID:24454746

  12. HCV Genotype 6 Increased the Risk for Hepatocellular Carcinoma Among Asian Patients With Liver Cirrhosis.

    PubMed

    Lee, Mei-Hsuan; Hsiao, Tiffany I; Subramaniam, Shreenidhi R; Le, An K; Vu, Vinh D; Trinh, Huy N; Zhang, Jian; Jin, Mingjuan; Wong, Vincent Wai-Sun; Wong, Grace Lai-Hung; Nguyen, Mindie H

    2017-07-01

    Hepatitis C virus (HCV) infection is a well-documented risk factor for hepatocellular carcinoma (HCC). Seven HCV genotypes have been classified, and the genotypes show a great variety of geographic distribution. HCV genotype 6 is prevalent in Southeast Asia and has been less studied than the other genotypes. This follow-up study was designed to evaluate the natural history of HCV genotype 6. The cohort enrolled 851 Asian patients consisting of 222 with HCV genotype 6 and 629 with other genotypes. The incidence of HCC per 1,000 person-years of various HCV genotypes was estimated by dividing the new HCC cases to the person-years of follow-up. The adjusted hazards ratios (HRs) with 95% confidence intervals (CIs) were estimated by Cox's proportional hazards models. After 4072 person-years of follow-up, there were 96 newly-developed HCC cases, confirming an incidence of 23.6 per 1000 person-years. By stratifying cirrhosis at study entry, the cumulative risk of HCC among HCV genotype 6 vs. non-6 was 2.9 vs. 2.2% for those without cirrhosis (P=0.45) and 76.2% (95% CI: 55.6-96.8%) vs. 36.2% (95% CI: 28.7-39.1%) for those with cirrhosis (P<0.05), respectively. Among patients with cirrhosis, HCV genotype 6 was significantly associated with HCC compared to patients with non-6 genotypes, with the adjusted HR=2.12 (1.33-3.39), P<0.05. In a model treating patients with genotypes other than 1 or 6 as the reference, the adjusted HR for HCC for HCV genotypes 1 and 6 were 1.13 (0.56-2.27) and 2.34 (1.12-4.86), respectively. Among patients with cirrhosis, those with HCV genotype 6 infection should be given high priority for antiviral therapy to decrease HCC risk and for vigilant adherence to HCC surveillance.

  13. Relating Single Cell Heterogeneity To Genotype During Cancer Progression

    NASA Astrophysics Data System (ADS)

    Rajaram, Satwik

    2013-03-01

    Progression of normal cells towards cancer is driven by a series of genetic changes. Traditional population-averaged measurements have found that cell signalling activities are increasingly altered during this progression. Despite the fact that cancer cells are known to be highly heterogeneous, the response of individual pathways to specific genetic changes remains poorly characterized at a single cell level. Do signalling alterations in a pathway reflect a shift of the whole population, or changes to specific subpopulations? Are alterations to pathways independent, or are cells with alterations in one pathway more likely to be abnormal in another due to crosstalk? We are building a computational framework that analyzes immunofluorescence microscopy images of cells to identify alterations in individual pathways at a single-cell level. A primary novelty of our approach is a ``change of basis'' that allows us to understand signalling in cancer cells in terms of the much better understood patterns of signalling in normal cells. This allows us to model heterogeneous populations of cancer cells as a mixture of distinct subpopulations, each with a specific combination of signalling pathways altered beyond the normal baseline. We used this framework to analyze human bronchial epithelial cell lines containing a series of genetic modifications commonly seen in lung cancer. We confirmed expected trends (such as a population-wide epithelial mesenchymal transition following the last of our series of modifications) and are presently studying the relation between the mutational profiles of cancer cells and pathway crosstalk. Our framework will help establish a more natural basis for future investigations into the phenotype-genotype relationship in heterogeneous populations.

  14. Phylogenetic Analysis of Hepatitis B Virus Genotypes Circulating in Different Risk Groups of Panama, Evidence of the Introduction of Genotype A2 in the Country.

    PubMed

    Martínez, Alexander A; Zaldívar, Yamitzel; Arteaga, Griselda; de Castillo, Zoila; Ortiz, Alma; Mendoza, Yaxelis; Castillero, Omar; Castillo, Juan A; Cristina, Juan; Pascale, Juan M

    2015-01-01

    The Hepatitis B Virus (HBV) can cause acute or chronic infection it is also associated with the development of liver cancer, thousands of new infections occur on a yearly basis, and many of these cases are located in certain areas of the Caribbean and Latin America. In these areas, the HBV prevalence is still high which makes this virus a serious public health concern to the entire region. Studies performed in Panama suggest a complex pattern in the distribution of HBV among the country's different risk groups. We use phylogenetic analysis in order to determine which HBV genotypes were circulating in these specific groups; for this we used a fragment of the PreS2/2 region of the HBV genome. Subsequently whole HBV genome sequences were used for Bayesian analysis of phylodynamics and phylogeography. Two main genotypes were found: genotype A (54.5%) and genotype F (45.5%). There was a difference in the distribution of genotypes according to risk groups: 72.9% of high risk groups were associated to genotype A, and 55.0% of samples of genotype F were associated to the low risk group (p<0.002). The Bayesian analysis of phylogeny-traits association revealed a statistically significant geographical association (p<0.0001) with both genotypes and different regions of the country. The Bayesian time of most recent common ancestor analysis (tMRCA) revealed a recent tMRCA for genotype A2 circulating in Panama (1997, 95% HPD: 1986-2005), when it is compared with Panamanian genotype F1c sequences (1930, 95% HPD: 1810 - 2005). These results suggest a possible change in the distribution of HBV genotypes in Panama and Latin America as a whole. They also serve to encourage the implementation of vaccination programs in high-risk groups, in order to prevent an increase in the number of new HBV cases in Latin America and worldwide.

  15. Phylogenetic Analysis of Hepatitis B Virus Genotypes Circulating in Different Risk Groups of Panama, Evidence of the Introduction of Genotype A2 in the Country

    PubMed Central

    Martínez, Alexander A.; Zaldívar, Yamitzel; Arteaga, Griselda; de Castillo, Zoila; Ortiz, Alma; Mendoza, Yaxelis; Castillero, Omar; Castillo, Juan A.; Cristina, Juan; Pascale, Juan M.

    2015-01-01

    The Hepatitis B Virus (HBV) can cause acute or chronic infection it is also associated with the development of liver cancer, thousands of new infections occur on a yearly basis, and many of these cases are located in certain areas of the Caribbean and Latin America. In these areas, the HBV prevalence is still high which makes this virus a serious public health concern to the entire region. Studies performed in Panama suggest a complex pattern in the distribution of HBV among the country’s different risk groups. We use phylogenetic analysis in order to determine which HBV genotypes were circulating in these specific groups; for this we used a fragment of the PreS2/2 region of the HBV genome. Subsequently whole HBV genome sequences were used for Bayesian analysis of phylodynamics and phylogeography. Two main genotypes were found: genotype A (54.5%) and genotype F (45.5%). There was a difference in the distribution of genotypes according to risk groups: 72.9% of high risk groups were associated to genotype A, and 55.0% of samples of genotype F were associated to the low risk group (p<0.002). The Bayesian analysis of phylogeny-traits association revealed a statistically significant geographical association (p<0.0001) with both genotypes and different regions of the country. The Bayesian time of most recent common ancestor analysis (tMRCA) revealed a recent tMRCA for genotype A2 circulating in Panama (1997, 95% HPD: 1986—2005), when it is compared with Panamanian genotype F1c sequences (1930, 95% HPD: 1810 – 2005). These results suggest a possible change in the distribution of HBV genotypes in Panama and Latin America as a whole. They also serve to encourage the implementation of vaccination programs in high-risk groups, in order to prevent an increase in the number of new HBV cases in Latin America and worldwide. PMID:26230260

  16. Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk.

    PubMed

    Walsh, Kyle M; Codd, Veryan; Rice, Terri; Nelson, Christopher P; Smirnov, Ivan V; McCoy, Lucie S; Hansen, Helen M; Elhauge, Edward; Ojha, Juhi; Francis, Stephen S; Madsen, Nils R; Bracci, Paige M; Pico, Alexander R; Molinaro, Annette M; Tihan, Tarik; Berger, Mitchel S; Chang, Susan M; Prados, Michael D; Jenkins, Robert B; Wiemels, Joseph L; Samani, Nilesh J; Wiencke, John K; Wrensch, Margaret R

    2015-12-15

    Telomere maintenance has emerged as an important molecular feature with impacts on adult glioma susceptibility and prognosis. Whether longer or shorter leukocyte telomere length (LTL) is associated with glioma risk remains elusive and is often confounded by the effects of age and patient treatment. We sought to determine if genotypically-estimated LTL is associated with glioma risk and if inherited single nucleotide polymorphisms (SNPs) that are associated with LTL are glioma risk factors. Using a Mendelian randomization approach, we assessed differences in genotypically-estimated relative LTL in two independent glioma case-control datasets from the UCSF Adult Glioma Study (652 patients and 3735 controls) and The Cancer Genome Atlas (478 non-overlapping patients and 2559 controls). LTL estimates were based on a weighted linear combination of subject genotype at eight SNPs, previously associated with LTL in the ENGAGE Consortium Telomere Project. Mean estimated LTL was 31bp (5.7%) longer in glioma patients than controls in discovery analyses (P = 7.82x10-8) and 27bp (5.0%) longer in glioma patients than controls in replication analyses (1.48x10-3). Glioma risk increased monotonically with each increasing septile of LTL (O.R.=1.12; P = 3.83x10-12). Four LTL-associated SNPs were significantly associated with glioma risk in pooled analyses, including those in the telomerase component genes TERC (O.R.=1.14; 95% C.I.=1.03-1.28) and TERT (O.R.=1.39; 95% C.I.=1.27-1.52), and those in the CST complex genes OBFC1 (O.R.=1.18; 95% C.I.=1.05-1.33) and CTC1 (O.R.=1.14; 95% C.I.=1.02-1.28). Future work is needed to characterize the role of the CST complex in gliomagenesis and further elucidate the complex balance between ageing, telomere length, and molecular carcinogenesis.

  17. Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk

    PubMed Central

    Walsh, Kyle M.; Codd, Veryan; Rice, Terri; Nelson, Christopher P.; Smirnov, Ivan V.; McCoy, Lucie S.; Hansen, Helen M.; Elhauge, Edward; Ojha, Juhi; Francis, Stephen S.; Madsen, Nils R.; Bracci, Paige M.; Pico, Alexander R.; Molinaro, Annette M.; Tihan, Tarik; Berger, Mitchel S.; Chang, Susan M.; Prados, Michael D.; Jenkins, Robert B.; Wiemels, Joseph L.; Samani, Nilesh J.; Wiencke, John K.; Wrensch, Margaret R.

    2015-01-01

    Telomere maintenance has emerged as an important molecular feature with impacts on adult glioma susceptibility and prognosis. Whether longer or shorter leukocyte telomere length (LTL) is associated with glioma risk remains elusive and is often confounded by the effects of age and patient treatment. We sought to determine if genotypically-estimated LTL is associated with glioma risk and if inherited single nucleotide polymorphisms (SNPs) that are associated with LTL are glioma risk factors. Using a Mendelian randomization approach, we assessed differences in genotypically-estimated relative LTL in two independent glioma case-control datasets from the UCSF Adult Glioma Study (652 patients and 3735 controls) and The Cancer Genome Atlas (478 non-overlapping patients and 2559 controls). LTL estimates were based on a weighted linear combination of subject genotype at eight SNPs, previously associated with LTL in the ENGAGE Consortium Telomere Project. Mean estimated LTL was 31bp (5.7%) longer in glioma patients than controls in discovery analyses (P = 7.82×10-8) and 27bp (5.0%) longer in glioma patients than controls in replication analyses (1.48×10-3). Glioma risk increased monotonically with each increasing septile of LTL (O.R.=1.12; P = 3.83×10-12). Four LTL-associated SNPs were significantly associated with glioma risk in pooled analyses, including those in the telomerase component genes TERC (O.R.=1.14; 95% C.I.=1.03-1.28) and TERT (O.R.=1.39; 95% C.I.=1.27-1.52), and those in the CST complex genes OBFC1 (O.R.=1.18; 95% C.I.=1.05-1.33) and CTC1 (O.R.=1.14; 95% C.I.=1.02-1.28). Future work is needed to characterize the role of the CST complex in gliomagenesis and further elucidate the complex balance between ageing, telomere length, and molecular carcinogenesis. PMID:26646793

  18. Television food advertisement exposure and FTO rs9939609 genotype in relation to excess consumption in children

    PubMed Central

    Gilbert-Diamond, Diane; Emond, Jennifer A.; Lansigan, Reina K.; Rapuano, Kristina M.; Kelley, William M.; Heatherton, Todd F.; Sargent, James D.

    2016-01-01

    BACKGROUND/OBJECTIVE Exposure to food advertisements may cue overeating among children, especially among those genetically predisposed to respond to food cues. We aimed to assess how television food advertisements affect eating in the absence of hunger among children in a randomized trial. We hypothesized that the Fat Mass and Obesity Associated Gene (FTO) rs9939609 single nucleotide polymorphism would modify the effect of food advertisements. SUBJECTS/METHODS In this randomized experiment, 200 children aged 9–10 years old were served a standardized lunch and then shown a 34-minute television show embedded with either food or toy advertisements. Children were provided with snack food to consume ad libitum while watching the show and we measured caloric intake. Children were genotyped for rs9939609 and analyses were conducted in the overall sample and stratified by genotype. A formal test for interaction of the food ad effect on consumption by rs9939609 was conducted. RESULTS 172 unrelated participants were included in this analysis. Children consumed on average 453 (SD=185) kCals during lunch and 482 (SD=274) kCals during the experimental exposure. Children who viewed food advertisements consumed an average of 48 kCals (95% CI: 10, 85; P=0.01) more of a recently advertised food than those who viewed toy advertisements. There was a statistically significant interaction between genotype and food advertisement condition (P for interaction = 0.02), where the difference in consumption of a recently advertised food related to food advertisement exposure increased linearly with each additional FTO risk allele, even after controlling for BMI percentile. CONCLUSIONS Food advertisement exposure was associated with greater caloric consumption of a recently advertised food, and this effect was modified by an FTO genotype. Future research is needed to understand the neurological mechanism underlying these associations. PMID:27654143

  19. Television food advertisement exposure and FTO rs9939609 genotype in relation to excess consumption in children.

    PubMed

    Gilbert-Diamond, D; Emond, J A; Lansigan, R K; Rapuano, K M; Kelley, W M; Heatherton, T F; Sargent, J D

    2017-01-01

    Exposure to food advertisements may cue overeating among children, especially among those genetically predisposed to respond to food cues. We aimed to assess how television food advertisements affect eating in the absence of hunger among children in a randomized trial. We hypothesized that the fat mass and obesity-associated gene (FTO) rs9939609 single-nucleotide polymorphism would modify the effect of food advertisements. In this randomized experiment, 200 children aged 9-10 years were served a standardized lunch and then shown a 34-min television show embedded with either food or toy advertisements. Children were provided with snack food to consume ad libitum while watching the show and we measured caloric intake. Children were genotyped for rs9939609 and analyses were conducted in the overall sample and stratified by genotype. A formal test for interaction of the food advertisement effect on consumption by rs9939609 was conducted. About 172 unrelated participants were included in this analysis. Children consumed on average 453 (s.d.=185) kcals during lunch and 482 (s.d.=274) kcals during the experimental exposure. Children who viewed food advertisements consumed an average of 48 kcals (95% confidence interval: 10, 85; P=0.01) more of a recently advertised food than those who viewed toy advertisements. There was a statistically significant interaction between genotype and food advertisement condition (P for interaction=0.02), where the difference in consumption of a recently advertised food related to food advertisement exposure increased linearly with each additional FTO risk allele, even after controlling for body mass index percentile. Food advertisement exposure was associated with greater caloric consumption of a recently advertised food, and this effect was modified by an FTO genotype. Future research is needed to understand the neurological mechanism underlying these associations.

  20. Enterocytozoon bieneusi Genotypes in Children in Northeast China and Assessment of Risk of Zoonotic Transmission

    PubMed Central

    Yang, Jinping; Song, Mingxin; Wan, Qiang; Li, Yijing; Lu, Yixin; Jiang, Yanxue; Tao, Wei

    2014-01-01

    The prevalence (7.5%, 19/255) and genotypes of Enterocytozoon bieneusi in children of various age categories and clinical presentations were determined herein. The co-occurrence of the known genotypes (CS-4, EbpC, and Henan-IV) in children and pigs in the same study area, the phylogenetic characterization of novel genotypes (NEC1 to NEC5), and the assessment of potential risk factors associated with zoonotic transmission robustly suggested that pigs could be a significant source of human E. bieneusi infections in northeast China. PMID:25274994

  1. Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk.

    PubMed

    Permuth, Jennifer B; Pirie, Ailith; Ann Chen, Y; Lin, Hui-Yi; Reid, Brett M; Chen, Zhihua; Monteiro, Alvaro; Dennis, Joe; Mendoza-Fandino, Gustavo; Anton-Culver, Hoda; Bandera, Elisa V; Bisogna, Maria; Brinton, Louise; Brooks-Wilson, Angela; Carney, Michael E; Chenevix-Trench, Georgia; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Cybulski, Cezary; D'Aloisio, Aimee A; Anne Doherty, Jennifer; Earp, Madalene; Edwards, Robert P; Fridley, Brooke L; Gayther, Simon A; Gentry-Maharaj, Aleksandra; Goodman, Marc T; Gronwald, Jacek; Hogdall, Estrid; Iversen, Edwin S; Jakubowska, Anna; Jensen, Allan; Karlan, Beth Y; Kelemen, Linda E; Kjaer, Suzanne K; Kraft, Peter; Le, Nhu D; Levine, Douglas A; Lissowska, Jolanta; Lubinski, Jan; Matsuo, Keitaro; Menon, Usha; Modugno, Rosemary; Moysich, Kirsten B; Nakanishi, Toru; Ness, Roberta B; Olson, Sara; Orlow, Irene; Pearce, Celeste L; Pejovic, Tanja; Poole, Elizabeth M; Ramus, Susan J; Anne Rossing, Mary; Sandler, Dale P; Shu, Xiao-Ou; Song, Honglin; Taylor, Jack A; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Tworoger, Shelley S; Webb, Penelope M; Wentzensen, Nicolas; Wilkens, Lynne R; Winham, Stacey; Woo, Yin-Ling; Wu, Anna H; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Phelan, Catherine M; Schildkraut, Joellen M; Berchuck, Andrew; Goode, Ellen L; Pharoah, Paul D P; Sellers, Thomas A

    2016-08-15

    Rare and low frequency variants are not well covered in most germline genotyping arrays and are understudied in relation to epithelial ovarian cancer (EOC) risk. To address this gap, we used genotyping arrays targeting rarer protein-coding variation in 8,165 EOC cases and 11,619 controls from the international Ovarian Cancer Association Consortium (OCAC). Pooled association analyses were conducted at the variant and gene level for 98,543 variants directly genotyped through two exome genotyping projects. Only common variants that represent or are in strong linkage disequilibrium (LD) with previously-identified signals at established loci reached traditional thresholds for exome-wide significance (P < 5.0 × 10 (-)  (7)). One of the most significant signals (Pall histologies = 1.01 × 10 (-)  (13);Pserous = 3.54 × 10 (-)  (14)) occurred at 3q25.31 for rs62273959, a missense variant mapping to the LEKR1 gene that is in LD (r(2 )=( )0.90) with a previously identified 'best hit' (rs7651446) mapping to an intron of TIPARP. Suggestive associations (5.0 × 10 (-)  (5 )>( )P≥5.0 ×10 (-)  (7)) were detected for rare and low-frequency variants at 16 novel loci. Four rare missense variants were identified (ACTBL2 rs73757391 (5q11.2), BTD rs200337373 (3p25.1), KRT13 rs150321809 (17q21.2) and MC2R rs104894658 (18p11.21)), but only MC2R rs104894668 had a large effect size (OR = 9.66). Genes most strongly associated with EOC risk included ACTBL2 (PAML = 3.23 × 10 (-)  (5); PSKAT-o = 9.23 × 10 (-)  (4)) and KRT13 (PAML = 1.67 × 10 (-)  (4); PSKAT-o = 1.07 × 10 (-)  (5)), reaffirming variant-level analysis. In summary, this large study identified several rare and low-frequency variants and genes that may contribute to EOC susceptibility, albeit with possible small effects. Future studies that integrate epidemiology, sequencing, and functional assays are needed to further

  2. Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk

    PubMed Central

    Permuth, Jennifer B.; Pirie, Ailith; Ann Chen, Y.; Lin, Hui-Yi; Reid, Brett M.; Chen, Zhihua; Monteiro, Alvaro; Dennis, Joe; Mendoza-Fandino, Gustavo; Anton-Culver, Hoda; Bandera, Elisa V.; Bisogna, Maria; Brinton, Louise; Brooks-Wilson, Angela; Carney, Michael E.; Chenevix-Trench, Georgia; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; D’Aloisio, Aimee A.; Anne Doherty, Jennifer; Earp, Madalene; Edwards, Robert P.; Fridley, Brooke L.; Gayther, Simon A.; Gentry-Maharaj, Aleksandra; Goodman, Marc T.; Gronwald, Jacek; Hogdall, Estrid; Iversen, Edwin S.; Jakubowska, Anna; Jensen, Allan; Karlan, Beth Y.; Kelemen, Linda E.; Kjaer, Suzanne K.; Kraft, Peter; Le, Nhu D.; Levine, Douglas A.; Lissowska, Jolanta; Lubinski, Jan; Matsuo, Keitaro; Menon, Usha; Modugno, Rosemary; Moysich, Kirsten B.; Nakanishi, Toru; Ness, Roberta B.; Olson, Sara; Orlow, Irene; Pearce, Celeste L.; Pejovic, Tanja; Poole, Elizabeth M.; Ramus, Susan J.; Anne Rossing, Mary; Sandler, Dale P.; Shu, Xiao-Ou; Song, Honglin; Taylor, Jack A.; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Tworoger, Shelley S.; Webb, Penelope M.; Wentzensen, Nicolas; Wilkens, Lynne R.; Winham, Stacey; Woo, Yin-Ling; Wu, Anna H.; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Phelan, Catherine M.; Schildkraut, Joellen M.; Berchuck, Andrew; Goode, Ellen L.; Pharoah, Paul D. P.; Sellers, Thomas A.

    2016-01-01

    Rare and low frequency variants are not well covered in most germline genotyping arrays and are understudied in relation to epithelial ovarian cancer (EOC) risk. To address this gap, we used genotyping arrays targeting rarer protein-coding variation in 8,165 EOC cases and 11,619 controls from the international Ovarian Cancer Association Consortium (OCAC). Pooled association analyses were conducted at the variant and gene level for 98,543 variants directly genotyped through two exome genotyping projects. Only common variants that represent or are in strong linkage disequilibrium (LD) with previously-identified signals at established loci reached traditional thresholds for exome-wide significance (P < 5.0 × 10 − 7). One of the most significant signals (Pall histologies = 1.01 × 10 − 13;Pserous = 3.54 × 10 − 14) occurred at 3q25.31 for rs62273959, a missense variant mapping to the LEKR1 gene that is in LD (r2 = 0.90) with a previously identified ‘best hit’ (rs7651446) mapping to an intron of TIPARP. Suggestive associations (5.0 × 10 − 5 > P≥5.0 ×10 − 7) were detected for rare and low-frequency variants at 16 novel loci. Four rare missense variants were identified (ACTBL2 rs73757391 (5q11.2), BTD rs200337373 (3p25.1), KRT13 rs150321809 (17q21.2) and MC2R rs104894658 (18p11.21)), but only MC2R rs104894668 had a large effect size (OR = 9.66). Genes most strongly associated with EOC risk included ACTBL2 (PAML = 3.23 × 10 − 5; PSKAT-o = 9.23 × 10 − 4) and KRT13 (PAML = 1.67 × 10 − 4; PSKAT-o = 1.07 × 10 − 5), reaffirming variant-level analysis. In summary, this large study identified several rare and low-frequency variants and genes that may contribute to EOC susceptibility, albeit with possible small effects. Future studies that integrate epidemiology, sequencing, and functional assays are needed to further unravel the unexplained

  3. Prevalence and Genotyping of High Risk Human Papillomavirus in Cervical Cancer Samples from Punjab, Pakistan

    PubMed Central

    Siddiqa, Abida; Zainab, Maidah; Qadri, Ishtiaq; Bhatti, Muhammad Faraz; Parish, Joanna L.

    2014-01-01

    Cervical cancer is the third most common cause of cancer-related death in women worldwide. Infection with high-risk human papillomavirus (HPV) is established as the cause of cervical carcinoma, therefore, high risk HPV detection may have prognostic significance for the women who are at increased risk of disease progression. The paucity of data on the incidence of cervical cancer in Pakistan makes it difficult to determine disease burden. Even less information is available regarding the prevalent HPV strains in cervical specimens collected from this region. Cervical cancer is a neglected disease in Pakistan in terms of screening, prevention, and vaccination. Identification and accurate genotyping of the virus burden in cancer specimens is important to inform intervention policies for future management of HPV associated disease and to potentially stratify patients dependent on HPV status. In this study, detection and genotyping of HPV types 16 and 18 from 77 cervical specimens were carried out. Consensus primers GP5+/GP6+, which detect 44 genital HPV types, and type specific primers (TS16 and TS18) were used in conjunction with newly designed type specific primers. Using a combination of these methods of detection, a total of 94.81% (95% CI ±4.95) of cervical lesions were positive for HPV. Single infections of HPV16 were detected in 24.68% (95% CI ±9.63) of total samples and HPV18 was found in 25.97% (95% CI ±9.79) samples. Interestingly, a high proportion of samples (40.26%, 95% CI ±10.95) was positive for both HPV16 and 18, indicating a higher incidence of co-infection than previously reported for similar ethnic regions. The HPV genotype of 3.90% of HPV positive samples remained undetected, although these samples were positive with the GP5+/GP6+ primer set indicating infection with an HPV type other than 16 or 18. These data indicate that the overall incidence of high risk HPV infection in cervical cancer and intraepithelial neoplasia specimens in Punjab

  4. Prevalence and genotyping of high risk human papillomavirus in cervical cancer samples from Punjab, Pakistan.

    PubMed

    Siddiqa, Abida; Zainab, Maidah; Qadri, Ishtiaq; Bhatti, Muhammad Faraz; Parish, Joanna L

    2014-07-17

    Cervical cancer is the third most common cause of cancer-related death in women worldwide. Infection with high-risk human papillomavirus (HPV) is established as the cause of cervical carcinoma, therefore, high risk HPV detection may have prognostic significance for the women who are at increased risk of disease progression. The paucity of data on the incidence of cervical cancer in Pakistan makes it difficult to determine disease burden. Even less information is available regarding the prevalent HPV strains in cervical specimens collected from this region. Cervical cancer is a neglected disease in Pakistan in terms of screening, prevention, and vaccination. Identification and accurate genotyping of the virus burden in cancer specimens is important to inform intervention policies for future management of HPV associated disease and to potentially stratify patients dependent on HPV status. In this study, detection and genotyping of HPV types 16 and 18 from 77 cervical specimens were carried out. Consensus primers GP5+/GP6+, which detect 44 genital HPV types, and type specific primers (TS16 and TS18) were used in conjunction with newly designed type specific primers. Using a combination of these methods of detection, a total of 94.81% (95% CI ±4.95) of cervical lesions were positive for HPV. Single infections of HPV16 were detected in 24.68% (95% CI ±9.63) of total samples and HPV18 was found in 25.97% (95% CI ±9.79) samples. Interestingly, a high proportion of samples (40.26%, 95% CI ±10.95) was positive for both HPV16 and 18, indicating a higher incidence of co-infection than previously reported for similar ethnic regions. The HPV genotype of 3.90% of HPV positive samples remained undetected, although these samples were positive with the GP5+/GP6+ primer set indicating infection with an HPV type other than 16 or 18. These data indicate that the overall incidence of high risk HPV infection in cervical cancer and intraepithelial neoplasia specimens in Punjab

  5. Triad of Risk for Late Onset Alzheimer’s: Mitochondrial Haplotype, APOE Genotype and Chromosomal Sex

    PubMed Central

    Wang, Yiwei; Brinton, Roberta D.

    2016-01-01

    Brain is the most energetically demanding organ of the body, and is thus vulnerable to even modest decline in ATP generation. Multiple neurodegenerative diseases are associated with decline in mitochondrial function, e.g., Alzheimer’s, Parkinson’s, multiple sclerosis and multiple neuropathies. Genetic variances in the mitochondrial genome can modify bioenergetic and respiratory phenotypes, at both the cellular and system biology levels. Mitochondrial haplotype can be a key driver of mitochondrial efficiency. Herein, we focus on the association between mitochondrial haplotype and risk of late onset Alzheimer’s disease (LOAD). Evidence for the association of mitochondrial genetic variances/haplotypes and the risk of developing LOAD are explored and discussed. Further, we provide a conceptual framework that suggests an interaction between mitochondrial haplotypes and two demonstrated risk factors for Alzheimer’s disease (AD), apolipoprotein E (APOE) genotype and chromosomal sex. We posit herein that mitochondrial haplotype, and hence respiratory capacity, plays a key role in determining risk of LOAD and other age-associated neurodegenerative diseases. Further, therapeutic design and targeting that involve mitochondrial haplotype would advance precision medicine for AD and other age related neurodegenerative diseases. PMID:27757081

  6. Estrogen Metabolism and Exposure in a Genotypic-Phenotypic Model for Breast Cancer Risk Prediction

    PubMed Central

    Crooke, Philip S.; Justenhoven, Christina; Brauch, Hiltrud; Dawling, Sheila; Roodi, Nady; Higginbotham, Kathryn S. P.; Plummer, W. Dale; Schuyler, Peggy A.; Sanders, Melinda E; Page, David L.; Smith, Jeffrey R.; Dupont, William D.; Parl, Fritz F.

    2012-01-01

    Background Current models of breast cancer risk prediction do not directly reflect mammary estrogen metabolism or genetic variability in exposure to carcinogenic estrogen metabolites. Methods We developed a model that simulates the kinetic effect of genetic variants of the enzymes CYP1A1, CYP1B1, and COMT on the production of the main carcinogenic estrogen metabolite, 4-hydroxyestradiol (4-OHE2), expressed as area under the curve metric (4-OHE2-AUC). The model also incorporates phenotypic factors (age, body mass index, hormone replacement therapy, oral contraceptives, family history), which plausibly influence estrogen metabolism and the production of 4-OHE2. We applied the model to two independent, population-based breast cancer case-control groups, the German GENICA study (967 cases, 971 controls) and the Nashville Breast Cohort (NBC; 465 cases, 885 controls). Results In the GENICA study, premenopausal women at the 90th percentile of 4-OHE2-AUC among control subjects had a risk of breast cancer that was 2.30 times that of women at the 10th control 4-OHE2-AUC percentile (95% CI 1.7 – 3.2, P = 2.9 × 10−7). This relative risk was 1.89 (95% CI 1.5 – 2.4, P = 2.2 × 10−8) in postmenopausal women. In the NBC, this relative risk in postmenopausal women was 1.81 (95% CI 1.3 – 2.6, P = 7.6 × 10−4), which increased to 1.83 (95% CI 1.4 – 2.3, P = 9.5 × 10−7) when a history of proliferative breast disease was included in the model. Conclusions The model combines genotypic and phenotypic factors involved in carcinogenic estrogen metabolite production and cumulative estrogen exposure to predict breast cancer risk. Impact The estrogen carcinogenesis-based model has the potential to provide personalized risk estimates. PMID:21610218

  7. Easy and fast detection and genotyping of high-risk human papillomavirus by dedicated DNA microarrays.

    PubMed

    Albrecht, Valérie; Chevallier, Anne; Magnone, Virginie; Barbry, Pascal; Vandenbos, Fanny; Bongain, André; Lefebvre, Jean-Claude; Giordanengo, Valérie

    2006-11-01

    Persistent cervical high-risk human papillomavirus (HPV) infection is correlated with an increased risk of developing a high-grade cervical intraepithelial lesion. A two-step method was developed for detection and genotyping of high-risk HPV. DNA was firstly amplified by asymmetrical PCR in the presence of Cy3-labelled primers and dUTP. Labelled DNA was then genotyped using DNA microarray hybridization. The current study evaluated the technical efficacy of laboratory-designed HPV DNA microarrays for high-risk HPV genotyping on 57 malignant and non-malignant cervical smears. The approach was evaluated for a broad range of cytological samples: high-grade squamous intraepithelial lesions (HSIL), low-grade squamous intraepithelial lesions (LSIL) and atypical squamous cells of high-grade (ASC-H). High-risk HPV was also detected in six atypical squamous cells of undetermined significance (ASC-US) samples; among them only one cervical specimen was found uninfected, associated with no histological lesion. The HPV oligonucleotide DNA microarray genotyping detected 36 infections with a single high-risk HPV type and 5 multiple infections with several high-risk types. Taken together, these results demonstrate the sensitivity and specificity of the HPV DNA microarray approach. This approach could improve clinical management of patients with cervical cytological abnormalities.

  8. The Association of Methylenetetrahydrofolate Reductase Genotypes with the Risk of Childhood Leukemia in Taiwan

    PubMed Central

    Chang, Wen-Shin; Ji, Hong-Xue; Hsiao, Chieh-Lun; Miao, Chia-En; Hsu, Yuan-Nian; Bau, Da-Tian

    2015-01-01

    Background Acute lymphoblastic leukemia (ALL) is the most prevalent type of pediatric cancer, the causes of which are likely to involve an interaction between genetic and environmental factors. To evaluate the effects of the genotypic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) on childhood ALL risk in Taiwan, two well-known polymorphic genotypes of MTHFR, C677T (rs1801133) and A1298C (rs1801131), were analyzed to examine the extent of their associations with childhood ALL susceptibility and to discuss the MTHFR genotypic contribution to childhood ALL risk among different populations. Methodology/Principal Findings In total, 266 patients with childhood ALL and an equal number of non-cancer controls recruited were genotyped utilizing PCR-RFLP methodology. The MTHFR C677T genotype, but not the A1298C, was differently distributed between childhood ALL and control groups. The CT and TT of MTHFR C677T genotypes were significantly more frequently found in controls than in childhood ALL patients (odds ratios=0.60 and 0.48, 95% confidence intervals=0.42–0.87 and 0.24–0.97, respectively). As for gender, the boys carrying the MTHFR C677T CT or TT genotype conferred a lower odds ratio of 0.51 (95% confidence interval=0.32–0.81, P=0.0113) for childhood ALL. As for age, those equal to or greater than 3.5 years of age at onset of disease carrying the MTHFR C677T CT or TT genotype were of lower risk (odds ratio= 0.43 and 95% confidence interval=0.26–0.71, P=0.0016). Conclusions Our results indicated that the MTHFR C677T T allele was a protective biomarker for childhood ALL in Taiwan, and the association was more significant in male patients and in patients 3.5 years of age or older at onset of disease. PMID:25793509

  9. Genotype distribution characteristics of high-risk human papillomaviruses in women from Shanghai, China.

    PubMed

    Gu, Y; Yi, M; Xu, Y; Zhao, H; Fu, F; Zhang, Y

    2016-05-01

    High-risk human papillomaviruses (HPVs) are highly prevalent worldwide, and HPV genotype distribution varies regionally. Molecular surveys of HPVs are important for effective HPV control and prevention. Fifteen high-risk HPV strains (16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68) and six low-risk HPV strains (HPV6, 11, 42, 43, 44, CP8304) were detected by cervical cytology from 10 501 subjects. High-risk HPVs, low-risk HPVs, and both high- and low-risk HPVs were detected in 14·5%, 2·8%, and 2·4% of cases, respectively. Of 1782 subjects with high-risk HPV infection, 75·5%, 18·1%, and 6·4% were infected with one, two, and ⩾3 strains of high-risk HPVs, respectively. HPV52, HPV16, and HPV58 were the top three most dominant high-risk HPV genotypes in our population with positivity rates of 23·0%, 17·7% and 16·9%, respectively. Multiple infection was common, with significantly higher co-infection rates of HPV58/HPV33 (12·9%) and HPV58/HPV52 (11·3%). Further data comparisons showed that HPV genotype distribution varied markedly between domestic and international regions. In conclusion, a monolithic vaccination strategy is obviously impractical, and regional HPV surveillance is essential to optimize current HPV control and prevention.

  10. Prevalence, risk factors and multilocus genotyping of Enterocytozoon bieneusi in farmed foxes (Vulpes lagopus), Northern China.

    PubMed

    Zhang, Xiao-Xuan; Cong, Wei; Lou, Zhi-Long; Ma, Jian-Gang; Zheng, Wen-Bin; Yao, Qiu-Xia; Zhao, Quan; Zhu, Xing-Quan

    2016-02-05

    Microsporidiosis is a common disease in animals and humans around the world. Enterocytozoon bieneusi is the most common microsporidian species in humans. Many animal species may be a potential source of human microsporidiosis. However, information concerning prevalence and genotypes of E. bieneusi infection in farmed foxes (Vulpes lagopus) is scarce. Therefore, the present study examined prevalence, risk factors and genotypes of E. bieneusi in farmed foxes in northern China using a genetic approach. Of 302 fecal samples from farmed foxes, 37 (12.25%, 95% CI 8.55-15.95) were PCR-positive for E. bieneusi, and the prevalence was highly associated with the farming mode in that foxes raised outdoors (26.03% positive, 95% CI 18.91-33.15) had a significantly higher E. bieneusi prevalence than those raised indoors. Eleven internal transcribed spacer (ITS) genotypes were identified among the positive samples: four known E. bieneusi genotypes (Peru 8, Types IV, CHN-DC1 and D) and seven novel genotypes (NCF1-NCF7). Genotype NCF2 was the commonest (n = 13) and was found in five farms across three provinces (Jilin, Heilongjiang and Hebei). All genotypes belonged to phylogenetic group 1. Multilocus sequence typing (MLST) analyses revealed additional diversity. These findings indicate the presence of zoonotic E. bieneusi infection in farmed foxes in northern China. This is also the first report of genotypes Peru8, CHN-DC1 and Type IV, and seven novel genotypes (NCF1-NCF7) in farmed foxes by ITS combining with microsatellite and minisatellite markers for the first time. The results will provide baseline data for preventing and controlling E. bieneusi infection in farmed foxes, other animals and humans.

  11. Acanthamoeba keratitis in noncompliant soft contact lenses users: Genotyping and risk factors, a study from Cairo, Egypt.

    PubMed

    Taher, Eman E; Méabed, Eman M H; Abdallah, Islam; Abdel Wahed, Wafaa Y

    2017-09-28

    Acanthamoeba keratitis (AK) is a severe corneal infection that may occur as a serious outcome of improper use of contact lenses (CL). The study aimed to diagnose AK in soft CL users presenting with infectious keratitis, and to identify the prevalent genotypes isolated from different cases. Another aim was to determine the CL hygiene-related risk behaviors, and to explore the risk of water exposure for developing AK. A cross sectional study was performed. A questionnaire was carried out including 260 clinically diagnosed cases as infectious keratitis (170 females and 90 males); all of them were soft CL users for the suspected risk factors. Corneal scrapes from the affected eyes were cultured to diagnose bacterial and AK. PCR was performed and the amplified products were sequenced and compared with GenBank data. The parasite was positively amplified from 32 samples (12.3%). Acanthamoeba T4 genotype was identified in 27/32 (84.4%) of isolates. Other detected genotypes belonged to T5 and T3 genotypes at rates of 9.4%, and 6.25%, respectively. The most important risk factors associated with development of AK were female sex, sleeping while wearing CL, and exposure to water resources through different practices. These practices included rinsing the CL case in tap water, swimming and/or showering while wearing CL, using multipurpose solution for cleaning the lenses, using water from over-building tanks. Rubbing the eyes due to discomfort when applying CL was an additional important risk factor associated with AK. The protective factor was regular hand washing before using CL. CL users were more exposed to AK and should gain enough health education regarding proper lens hygiene and dangers of tap water exposure. Copyright © 2017. Published by Elsevier Ltd.

  12. Molecular detection of Rickettsia felis, Rickettsia typhi and two genotypes closely related to Bartonella elizabethae.

    PubMed

    De Sousa, Rita; Edouard-Fournier, Pierre; Santos-Silva, Margarida; Amaro, Fatima; Bacellar, Fatima; Raoult, Didier

    2006-10-01

    A total of 56 fleas were collected from mice, rats, and one hedgehog in national parks of mainland Portugal and the Madeira Island. All fleas were tested for the presence of bacteria of the genera Rickettsia and Bartonella using PCR assays. In fleas from mainland Portugal, we detected Rickettsia felis in one Archaeopsylla erinacei maura flea and in one Ctenophtalmus sp. In five Leptopsylla segnis fleas taken from rats in the Madeira Island, we identified Rickettsia typhi. In addition, in four fleas from the genera Ornithophaga and Stenoponia collect from mice and a rat in mainland Portugal, we detected the presence of two new Bartonella genotypes closely related to Bartonella elizabethae. Our findings emphasize the potential risk of flea-transmitted infections in mainland Portugal and the Madeira archipelago, and extend our knowledge of the potential flea vectors of human pathogens.

  13. Genotype and risk of major bleeding during warfarin treatment

    PubMed Central

    Kawai, Vivian K; Cunningham, Andrew; Vear, Susan I; Van Driest, Sara L; Oginni, Abimbola; Xu, Hua; Jiang, Min; Li, Chun; Denny, Joshua C; Shaffer, Christian; Bowton, Erica; Gage, Brian F; Ray, Wayne A; Roden, Dan M; Stein, C Michael

    2015-01-01

    Aim To determine whether genetic variants associated with warfarin dose variability were associated with increased risk of major bleeding during warfarin therapy. Materials & methods Using Vanderbilt’s DNA biobank we compared the prevalence of CYP2C9, VKORC1 and CYP4F2 variants in 250 cases with major bleeding and 259 controls during warfarin therapy. Results CYP2C9*3 was the only allele that differed significantly among cases (14.2%) and controls (7.8%; p = 0.022). In the 214 (85.6%) cases with a major bleed 30 or more days after warfarin initiation, CYP2C9*3 was the only variant associated with bleeding (adjusted odds ratio: 2.05; 95% CI: 1.04, 4.04). Conclusion The CYP2C9*3 allele may double the risk of major bleeding among patients taking warfarin for 30 or more days. PMID:25521356

  14. Plasma Complement Components and Activation Fragments: Associations with Age-Related Macular Degeneration Genotypes and Phenotypes

    PubMed Central

    Reynolds, Robyn; Hartnett, M. Elizabeth; Atkinson, John P.; Giclas, Patricia C.; Rosner, Bernard; Seddon, Johanna M.

    2010-01-01

    Purpose Several genes encoding complement system components and fragments are associated with age-related macular degeneration (AMD). This study was conducted to determine whether alterations in circulating levels of these markers of complement activation and regulation are also independently associated with advanced AMD and whether they are related to AMD genotypes. Methods Plasma and DNA samples were selected from individuals in our AMD registry who had progressed to or developed the advanced stages of AMD, including 58 with geographic atrophy and 62 with neovascular disease. Subjects of similar age and sex, but without AMD, and who did not progress were included as controls (n = 60). Plasma complment components (C3, CFB, CFI, CFH, and factor D) and activation fragments (Bb, C3a, C5a, iC3b, and SC5b-9) were analyzed. DNA samples were genotyped for seven single-nucleotide polymorphisms in six genes previously shown to be associated with AMD: CFB, CFH, C2, C3, and CFI and the LOC387715/ARMS2 gene region. The association between AMD and each complement biomarker was assessed by using logistic regression, controlling for age, sex, and proinflammatory risk factors: smoking and body mass index (BMI). Functional genomic analyses were performed to assess the relationship between the complement markers and genotypes. Concordance, or C, statistics were calculated to assess the effect of complement components and activation fragments in an AMD gene-environment prediction model. Results The highest quartiles of Bb and C5a were significantly associated with advanced AMD, when compared with the lowest quartiles. In multivariate models without genetic variants, the odds ratio (OR) for Bb was 3.3 (95% confidence interval [CI] = 1.3-8.6), and the OR for C5a was 3.6 (95% CI = 1.2-10.3). With adjustment for genetic variants, these ORs were substantially higher. The alternative pathway regulator CFH was inversely associated with AMD in the model without genotypes (OR = 0.3; P = 0

  15. Towards a more accurate quantitative assessment of seasonal Cryptosporidium infection risks in surface waters using species and genotype information.

    PubMed

    Lapen, D R; Schmidt, P J; Thomas, J L; Edge, T A; Flemming, C; Keithlin, J; Neumann, N; Pollari, F; Ruecker, N; Simhon, A; Topp, E; Wilkes, G; Pintar, K D M

    2016-11-15

    Many Cryptosporidium species/genotypes are not considered infectious to humans, and more realistic estimations of seasonal infection risks could be made using human infectious species/genotype information to inform quantitative microbial risk assessments (QMRA). Cryptosporidium oocyst concentration and species/genotype data were collected from three surface water surveillance programs in two river basins [South Nation River, SN (2004-09) and Grand River, GR (2005-13)] in Ontario, Canada to evaluate seasonal infection risks. Main river stems, tributaries, agricultural drainage streams, water treatment plant intakes, and waste water treatment plant effluent impacted sites were sampled. The QMRA employed two sets of exposure data to compute risk: one assuming all observed oocysts were infectious to humans, and the other based on the fraction of oocysts that were C. hominis and/or C. parvum (dominant human infectious forms of the parasite). Viability was not considered and relative infection risk was evaluated using a single hypothetical recreational exposure. Many sample site groupings for both river systems, had significant seasonality in Cryptosporidium occurrence and concentrations (p ≤ 0.05); occurrence and concentrations were generally highest in autumn for SN, and autumn and summer for GR. Mean risk values (probability of infection per exposure) for all sites combined, for each river system, were roughly an order of magnitude lower (avg. of SN and GR 5.3 × 10(-5)) when considering just C. parvum and C. hominis oocysts, in relation to mean infection risk (per exposure) assuming all oocysts were infectious to humans (5.5 × 10(-4)). Seasonality in mean risk (targeted human infectious oocysts only) was most strongly evident in SN (e.g., 7.9 × 10(-6) in spring and 8.1 × 10(-5) in summer). Such differences are important if QMRA is used to quantify effects of water safety/quality management practices where inputs from a vast array of fecal pollution

  16. Matrix Metalloproteinase-1 Genotype Contributes to the Risk of Non-solid Tumor in Childhood Leukemia.

    PubMed

    Pei, Jen-Sheng; Hsu, Pei-Chen; Chou, An-Kuo; Tsai, Chia-Wen; Chang, Wen-Shin; Hsiao, Chieh-Lun; Hsu, Yuan-Nian; Cheng, Shun-Ping; Bau, DA-Tian

    2016-10-01

    Up-regulation of metalloproteinase (MMPs) proteins have been shown in various types of solid cancers and the genotype of MMP1 has been associated with the risk of solid cancers. However, the contribution of MMP1 genotype to leukemia has never been investigated to our knowledge. Therefore, in this study we aimed to evaluate the contribution of the genotypic variants in the promoter region of MMP1 to childhood acute lymphoblastic leukemia (ALL) risk in Taiwan. In this case-control study, 266 patients with childhood ALL and 266 non-cancer controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism methodology. The distribution of 2G/2G, 1G/2G and 1G/1G for MMP1 promoter rs1799750 genotype was 49.2%, 39.5% and 11.3% in the childhood ALL group and 36.8%, 43.6% and 19.5% in the non-cancer control group, respectively (p for trend=0.0046), significantly differentially distributed between childhood ALL and control groups. The carrier comparisons in dominant and recessive models also support the findings that 1G appears to be the protective allele in childhood ALL. In genotype and gender interaction analysis, it was found that boys carrying the MMP1 rs1799750 1G/2G or 1G/1G genotypes had lower odds ratios(ORs) of 0.68 and 0.43 [95% confidence intervals (CI)=0.47-0.98 and 0.26-0.73, p=0.0395 and 0.0013, respectively] for childhood ALL than those carrying the 2G/2G genotype. Analysis of genotype inaction with age of onset age showed those aged less than 3.5 years at onset carrying the 1G/2G or 1G/1G genotypes had lower ORs (0.0183 and 0.0004, respectively) for childhood ALL, but there was no such difference for those having an age at onset of 3.5 years or more. Our results indicate that the MMP1 rs1799750 1G allele is a protective biomarker for childhood ALL. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  17. Comparing Human Metapneumovirus and Respiratory Syncytial Virus: Viral Co-Detections, Genotypes and Risk Factors for Severe Disease.

    PubMed

    Moe, Nina; Krokstad, Sidsel; Stenseng, Inger Heimdal; Christensen, Andreas; Skanke, Lars Høsøien; Risnes, Kari Ravndal; Nordbø, Svein Arne; Døllner, Henrik

    2017-01-01

    It is unclarified as to whether viral co-detection and human metapneumovirus (HMPV) genotypes relate to clinical manifestations in children with HMPV and lower respiratory tract infection (LRTI), and if the clinical course and risk factors for severe LRTI differ between HMPV and respiratory syncytial virus (RSV). We prospectively enrolled hospitalized children aged <16 years with LRTI from 2006 to 2015. Children were clinically examined, and nasopharyngeal aspirates were analyzed using semi-quantitative, real-time polymerase chain reaction tests for HMPV, RSV and 17 other pathogens. HMPV-positive samples were genotyped. A total of 171 children had HMPV infection. HMPV-infected children with single virus (n = 106) and co-detections (n = 65) had similar clinical manifestations. No clinical differences were found between HMPV genotypes A (n = 67) and B (n = 80). The HMPV-infected children were older (median 17.2 months) than RSV-infected children (median 7.3 months, n = 859). Among single virus-infected children, no differences in age-adjusted LRTI diagnoses were found between HMPV and RSV. Age was an important factor for disease severity among single virus-infected children, where children <6 months old with HMPV had a milder disease than those with RSV, while in children 12-23 months old, the pattern was the opposite. In multivariable logistic regression analysis for each virus type, age ≥12 months (HMPV), and age <6 months (RSV), prematurity, ≥1 chronic disease and high viral loads of RSV, but not high HMPV viral loads, were risk factors for severe disease. Among hospitalized children with LRTI, HMPV manifests independently of viral co-detections and HMPV genotypes. Disease severity in HMPV- and RSV-infected children varies in relation to age. A history of prematurity and chronic disease increases the risk of severe LRTI among HMPV- and RSV-infected children.

  18. Comparing Human Metapneumovirus and Respiratory Syncytial Virus: Viral Co-Detections, Genotypes and Risk Factors for Severe Disease

    PubMed Central

    Moe, Nina; Krokstad, Sidsel; Stenseng, Inger Heimdal; Christensen, Andreas; Skanke, Lars Høsøien; Risnes, Kari Ravndal; Nordbø, Svein Arne; Døllner, Henrik

    2017-01-01

    Background It is unclarified as to whether viral co-detection and human metapneumovirus (HMPV) genotypes relate to clinical manifestations in children with HMPV and lower respiratory tract infection (LRTI), and if the clinical course and risk factors for severe LRTI differ between HMPV and respiratory syncytial virus (RSV). Methods We prospectively enrolled hospitalized children aged <16 years with LRTI from 2006 to 2015. Children were clinically examined, and nasopharyngeal aspirates were analyzed using semi-quantitative, real-time polymerase chain reaction tests for HMPV, RSV and 17 other pathogens. HMPV-positive samples were genotyped. Results A total of 171 children had HMPV infection. HMPV-infected children with single virus (n = 106) and co-detections (n = 65) had similar clinical manifestations. No clinical differences were found between HMPV genotypes A (n = 67) and B (n = 80). The HMPV-infected children were older (median 17.2 months) than RSV-infected children (median 7.3 months, n = 859). Among single virus-infected children, no differences in age-adjusted LRTI diagnoses were found between HMPV and RSV. Age was an important factor for disease severity among single virus-infected children, where children <6 months old with HMPV had a milder disease than those with RSV, while in children 12–23 months old, the pattern was the opposite. In multivariable logistic regression analysis for each virus type, age ≥12 months (HMPV), and age <6 months (RSV), prematurity, ≥1 chronic disease and high viral loads of RSV, but not high HMPV viral loads, were risk factors for severe disease. Conclusions Among hospitalized children with LRTI, HMPV manifests independently of viral co-detections and HMPV genotypes. Disease severity in HMPV- and RSV-infected children varies in relation to age. A history of prematurity and chronic disease increases the risk of severe LRTI among HMPV- and RSV-infected children. PMID:28095451

  19. Cancer risk and genotype-phenotype correlations in PTEN hamartoma tumor syndrome.

    PubMed

    Nieuwenhuis, Marry H; Kets, C Marleen; Murphy-Ryan, Maureen; Yntema, Helger G; Evans, D Gareth; Colas, Chrystelle; Møller, Pal; Hes, Frederik J; Hodgson, Shirley V; Olderode-Berends, Maran J W; Aretz, Stefan; Heinimann, Karl; Gómez García, Encarna B; Douglas, Fiona; Spigelman, Allan; Timshel, Susanne; Lindor, Noralane M; Vasen, Hans F A

    2014-03-01

    Patients with germline PTEN mutations are at high risk of developing benign and malignant tumours. We aimed to evaluate the cumulative risk of several types of cancer and of dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease, LDD). In addition, genotype-phenotype correlations in PTEN hamartoma tumour syndrome (PHTS) were assessed. Data on patients with PTEN mutations were collected from clinical genetic centres in Western Europe, Australia, and the USA. The cumulative risk of developing cancers of the breast, thyroid, endometrium, skin, kidneys, colorectum, and lungs, and also LDD was calculated by Kaplan-Meier methods. Associations between mutations and cancer were assessed by Chi square means. A total of 180 germline PTEN mutation carriers, 81 males (45%), from nine countries were included. The cumulative risk of developing any cancer and/or LDD at age 60 was 56% for males and 87% for females (p = 0.001). Females had significant higher risks of developing breast cancer, thyroid cancer, and LDD than males. The only genotype-phenotype correlation identified was a lower frequency of thyroid cancer in patients with missense mutations (p = 0.014). In conclusion, PHTS patients, particularly females, have a substantial risk of developing one or more tumours from a broad tumour spectrum. Major genotype-phenotype associations could not be identified.

  20. Imputation of non-genotyped individuals based on genotyped relatives: assessing the imputation accuracy of a real case scenario in dairy cattle

    PubMed Central

    2014-01-01

    Background Imputation of genotypes for ungenotyped individuals could enable the use of valuable phenotypes created before the genomic era in analyses that require genotypes. The objective of this study was to investigate the accuracy of imputation of non-genotyped individuals using genotype information from relatives. Methods Genotypes were simulated for all individuals in the pedigree of a real (historical) dataset of phenotyped dairy cows and with part of the pedigree genotyped. The software AlphaImpute was used for imputation in its standard settings but also without phasing, i.e. using basic inheritance rules and segregation analysis only. Different scenarios were evaluated i.e.: (1) the real data scenario, (2) addition of genotypes of sires and maternal grandsires of the ungenotyped individuals, and (3) addition of one, two, or four genotyped offspring of the ungenotyped individuals to the reference population. Results The imputation accuracy using AlphaImpute in its standard settings was lower than without phasing. Including genotypes of sires and maternal grandsires in the reference population improved imputation accuracy, i.e. the correlation of the true genotypes with the imputed genotype dosages, corrected for mean gene content, across all animals increased from 0.47 (real situation) to 0.60. Including one, two and four genotyped offspring increased the accuracy of imputation across all animals from 0.57 (no offspring) to 0.73, 0.82, and 0.92, respectively. Conclusions At present, the use of basic inheritance rules and segregation analysis appears to be the best imputation method for ungenotyped individuals. Comparison of our empirical animal-specific imputation accuracies to predictions based on selection index theory suggested that not correcting for mean gene content considerably overestimates the true accuracy. Imputation of ungenotyped individuals can help to include valuable phenotypes for genome-wide association studies or for genomic prediction

  1. Alcohol consumption, alcohol dehydrogenase 1C (ADH1C) genotype, and risk of colorectal cancer in the Netherlands Cohort Study on diet and cancer.

    PubMed

    Bongaerts, Brenda W C; de Goeij, Anton F P M; Wouters, Kim A D; van Engeland, Manon; Gottschalk, Ralph W H; Van Schooten, Frederik J; Goldbohm, R Alexandra; van den Brandt, Piet A; Weijenberg, Matty P

    2011-05-01

    Within the Netherlands Cohort Study (1986), we examined associations between alcohol consumption, the alcohol dehydrogenase 1C (ADH1C) genotype, and risk of colorectal cancer (CRC). After a follow-up period of 7.3 years, 594 CRC cases with information on genotype and baseline alcohol intake were available for analyses. Adjusted incidence rate ratios (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. In subjects who reported to have consumed equal amounts of total alcohol both 5 years before baseline and at baseline, drinkers of ≥30g of alcohol per day with the ADH1C*2/*2 genotype were associated-although not statistically significant-with an increased risk of CRC relative to abstainers with the ADH1C*1/*1 genotype (RR: 1.91, 95% CI: 0.68, 5.34). The risk estimate in this exposure group increased slightly when compared with light drinkers of ≥0.5-<5g/day with the ADH1C*1/*1 genotype (RR: 2.32, 95% CI: 0.80, 6.72). The interaction term however, was not statistically significant (P>.05). In subjects who reported to have consumed equal amounts of total alcohol both 5 years before baseline and at baseline, drinkers of ≥30g of alcohol per day were associated-although not statistically significant-with an increased risk of CRC relative to abstainers (RR: 1.38, 95% CI: 0.80, 2.38). This risk estimate for high-level drinkers became stronger when compared with light drinkers (RR: 1.74, 95% CI: 1.01, 2.99). As main effect of genotype, we observed that the ADH1C*2/*2 genotype was associated with a 42% increase in risk of CRC when compared with the ADH1C*1/*1 genotype. In conclusion, both genotype and alcohol consumption were associated with an increased risk of CRC. Owing to limited statistical power, we found no apparent evidence for the ADH1C genotype as effect modifier of the relationship between alcohol intake and CRC. Nevertheless, the interaction deserves further investigation in larger genetic epidemiologic studies

  2. Microcystis genotype succession and related environmental factors in Lake Taihu during cyanobacterial blooms.

    PubMed

    Wang, Xingyu; Sun, Mengjia; Wang, Jinmei; Yang, Letian; Luo, Lan; Li, Pengfu; Kong, Fanxiang

    2012-11-01

    From spring to autumn, heavy Microcystis blooms always occur in Lake Taihu, although environmental conditions vary markedly. We speculated that Microcystis genotype succession could play an important role in adaptation to environmental changes and long-term maintenance of the high Microcystis biomass. In this study, we investigated Microcystis genotype succession pattern and the related environmental variables in Lake Taihu during cyanobacterial blooms. Denaturing gradient gel electrophoresis (DGGE) of polymerase chain reaction -amplified the genus-specific cpcBA and mcyJ gene fragments was used to monitor the variations of Microcystis genotype and potential microcystin (MC)-producing Microcystis genotype compositions during blooms biweekly in three sites (Meiliang Bay, lake center, and Gonghu Bay) and CANOCO 4.5 for Windows were used for the multivariate statistical analysis of their relationships to environmental variables. DGGE patterns indicated that the number of dominant cpcBA genotype per sample increased from spring to autumn. Principal component analysis ordination plots of DGGE profiles showed clear temporal distribution pattern, but not spatial distribution pattern based on both cpcBA and mcyJ genotype compositions. These results indicated there were relatively gradual successions of Microcystis cpcBA and mcyJ genotype compositions in each site, and no distinct spatial difference among the three sites. Redundancy analyses of the gel patterns showed that, in all the three sites, three environmental factors (nitrate, pH, and chemical oxygen demand) were correlated significantly to successions of both cpcBA and mcyJ genotypes except for mcyJ genotype in the lake center. Spearman's correlations indicated that the three environmental variables were also strongly correlated with chl a and MC concentrations. These results suggested that the environmental factors affecting succession of Microcystis community composition might also influence the growth of

  3. Genotypes of Mycobacterium tuberculosis in patients at risk of drug resistance in Bolivia.

    PubMed

    Monteserin, Johana; Camacho, Mirtha; Barrera, Lucía; Palomino, Juan Carlos; Ritacco, Viviana; Martin, Anandi

    2013-07-01

    Bolivia ranks among the 10 Latin American countries with the highest rates of tuberculosis (TB) and multidrug resistant (MDR) TB. In view of this, and of the lacking information on the population structure of Mycobacterium tuberculosis in the country, we explored genotype associations with drug resistance and clustering by analyzing isolates collected in 2010 from 100 consecutive TB patients at risk of drug resistance in seven of the nine departments in which Bolivia is divided. Fourteen isolates were MDR, 29 had other drug resistance profiles, and 57 were pansusceptible. Spoligotype family distribution was: Haarlem 39.4%, LAM 26.3%, T 22.2%, S 2.0%, X 1.0%, orphan 9.1%, with very low intra-family diversity and absence of Beijing genotypes. We found 66 different MIRU-VNTR patterns; the most frequent corresponded to Multiple Locus Variable Analysis (MLVA) MtbC15 patterns 860, 372 and 873. Twelve clusters, each with identical MIRU-VNTR and spoligotypes, gathered 35 patients. We found no association of genotype with drug resistant or MDR-TB. Clustering associated with SIT 50 and the H3 subfamily to which it belongs (p<0.0001). The largest cluster involved isolates from three departments and displayed a genotype (SIT 50/MLVA 860) previously identified in Bolivian migrants into Spain and Argentina suggesting that this genotype is widespread among Bolivian patients. Our study presents a first overview of M. tuberculosis genotypes at risk of drug resistance circulating in Bolivia. However, results should be taken cautiously because the sample is small and includes a particular subset of M. tuberculosis population. Copyright © 2013 Elsevier B.V. All rights reserved.

  4. AIDS-related Pneumocystis jirovecii genotypes in French Guiana.

    PubMed

    Le Gal, Solène; Blanchet, Denis; Damiani, Céline; Guéguen, Paul; Virmaux, Michèle; Abboud, Philippe; Guillot, Geneviève; Kérangart, Stéphane; Merle, Cédric; Calderon, Enrique; Totet, Anne; Carme, Bernard; Nevez, Gilles

    2015-01-01

    The study described Pneumocystis jirovecii (P. jirovecii) multilocus typing in seven AIDS patients living in French Guiana (Cayenne Hospital) and seven immunosuppressed patients living in Brest, metropolitan France (Brest Hospital). Archival P. jirovecii specimens were examined at the dihydropteroate synthase (DHPS) locus using a PCR-RFLP technique, the internal transcribed spacer (ITS) 1 and ITS 2 and the mitochondrial large subunit rRNA (mtLSUrRNA) gene using PCR and sequencing. Analysis of typing results were combined with an analysis of the literature on P. jirovecii mtLSUrRNA types and ITS haplotypes. A wild DHPS type was identified in six Guianese patients and in seven patients from metropolitan France whereas a DHPS mutant was infected in the remaining Guianese patient. Typing of the two other loci pointed out a high diversity of ITS haplotypes and an average diversity of mtLSUrRNA types in French Guiana with a partial commonality of these haplotypes and types described in metropolitan France and around the world. Combining DHPS, ITS and mtLSU types, 12 different multilocus genotypes (MLGs) were identified, 4 MLGs in Guianese patients and 8 MLGs in Brest patients. MLG analysis allows to discriminate patients in 2 groups according to their geographical origin. Indeed, none of the MLGs identified in the Guianese patients were found in the Brest patients and none of the MLGs identified in the Brest patients were found in the Guianese patients. These results show that in French Guiana (i) PCP involving DHPS mutants occur, (ii) there is a diversity of ITS and mtLSUrRNA types and (iii) although partial type commonality in this territory and metropolitan France can be observed, MLG analysis suggests that P. jirovecii organisms from French Guiana may present specific characteristics. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Large-scale genotyping identifies 41 new loci associated with breast cancer risk

    PubMed Central

    Michailidou, Kyriaki; Hall, Per; Gonzalez-Neira, Anna; Ghoussaini, Maya; Dennis, Joe; Milne, Roger L; Schmidt, Marjanka K; Chang-Claude, Jenny; Bojesen, Stig E; Bolla, Manjeet K; Wang, Qin; Dicks, Ed; Lee, Andrew; Turnbull, Clare; Rahman, Nazneen; Fletcher, Olivia; Peto, Julian; Gibson, Lorna; Silva, Isabel dos Santos; Nevanlinna, Heli; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Czene, Kamila; Irwanto, Astrid; Liu, Jianjun; Waisfisz, Quinten; Meijers-Heijboer, Hanne; Adank, Muriel; van der Luijt, Rob B; Hein, Rebecca; Dahmen, Norbert; Beckman, Lars; Meindl, Alfons; Schmutzler, Rita K; Müller-Myhsok, Bertram; Lichtner, Peter; Hopper, John L; Southey, Melissa C; Makalic, Enes; Schmidt, Daniel F; Uitterlinden, Andre G; Hofman, Albert; Hunter, David J; Chanock, Stephen J; Vincent, Daniel; Bacot, François; Tessier, Daniel C; Canisius, Sander; Wessels, Lodewyk F A; Haiman, Christopher A; Shah, Mitul; Luben, Robert; Brown, Judith; Luccarini, Craig; Schoof, Nils; Humphreys, Keith; Li, Jingmei; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Couch, Fergus J; Wang, Xianshu; Vachon, Celine; Stevens, Kristen N; Lambrechts, Diether; Moisse, Matthieu; Paridaens, Robert; Christiaens, Marie-Rose; Rudolph, Anja; Nickels, Stefan; Flesch-Janys, Dieter; Johnson, Nichola; Aitken, Zoe; Aaltonen, Kirsimari; Heikkinen, Tuomas; Broeks, Annegien; Van’t Veer, Laura J; van der Schoot, C Ellen; Guénel, Pascal; Truong, Thérèse; Laurent-Puig, Pierre; Menegaux, Florence; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Burwinkel, Barbara; Zamora, M Pilar; Perez, Jose Ignacio Arias; Pita, Guillermo; Alonso, M Rosario; Cox, Angela; Brock, Ian W; Cross, Simon S; Reed, Malcolm W R; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Lindblom, Annika; Margolin, Sara; Hooning, Maartje J; Hollestelle, Antoinette; van den Ouweland, Ans M W; Jager, Agnes; Bui, Quang M; Stone, Jennifer; Dite, Gillian S; Apicella, Carmel; Tsimiklis, Helen; Giles, Graham G; Severi, Gianluca; Baglietto, Laura; Fasching, Peter A; Haeberle, Lothar; Ekici, Arif B; Beckmann, Matthias W; Brenner, Hermann; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Jones, Michael; Figueroa, Jonine; Lissowska, Jolanta; Brinton, Louise; Goldberg, Mark S; Labrèche, France; Dumont, Martine; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Brauch, Hiltrud; Hamann, Ute; Brüning, Thomas; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Bonanni, Bernardo; Devilee, Peter; Tollenaar, Rob A E M; Seynaeve, Caroline; van Asperen, Christi J; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Bogdanova, Natalia V; Antonenkova, Natalia N; Dörk, Thilo; Kristensen, Vessela N; Anton-Culver, Hoda; Slager, Susan; Toland, Amanda E; Edge, Stephen; Fostira, Florentia; Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Sueta, Aiko; Wu, Anna H; Tseng, Chiu-Chen; Van Den Berg, David; Stram, Daniel O; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Teo, Soo Hwang; Yip, Cheng Har; Phuah, Sze Yee; Cornes, Belinda K; Hartman, Mikael; Miao, Hui; Lim, Wei Yen; Sng, Jen-Hwei; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Shen, Chen-Yang; Hsiung, Chia-Ni; Wu, Pei-Ei; Ding, Shian-Ling; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Blot, William J; Signorello, Lisa B; Cai, Qiuyin; Zheng, Wei; Deming-Halverson, Sandra; Shrubsole, Martha; Long, Jirong; Simard, Jacques; Garcia-Closas, Montse; Pharoah, Paul D P; Chenevix-Trench, Georgia; Dunning, Alison M; Benitez, Javier; Easton, Douglas F

    2013-01-01

    Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ~9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10−8). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility. PMID:23535729

  6. Norovirus genotypes implicated in two oyster-related illness outbreaks in Ireland.

    PubMed

    Rajko-Nenow, P; Keaveney, S; Flannery, J; McINTYRE, A; Doré, W

    2014-10-01

    We investigated norovirus (NoV) concentrations and genotypes in oyster and faecal samples associated with two separate oyster-related outbreaks of gastroenteritis in Ireland. Quantitative analysis was performed using real-time quantitative reverse transcription polymerase chain reaction and phylogenetic analysis was conducted to establish the NoV genotypes present. For both outbreaks, the NoV concentration in oysters was >1000 genome copies/g digestive tissue and multiple genotypes were identified. In faecal samples, GII.13 was the only genotype detected for outbreak 1, whereas multiple genotypes were detected in outbreak 2 following the application of cloning procedures. While various genotypes were identified in oyster samples, not all were successful in causing infection in consumers. In outbreak 2 NoV GII.1 was identified in all four faecal samples analysed and NoV GII concentrations in faecal samples were >108 copies/g. This study demonstrates that a range of NoV genotypes can be present in highly contaminated oysters responsible for gastroenteritis outbreaks.

  7. Identification of Alzheimer disease risk genotype that predicts efficiency of SORL1 expression in the brain.

    PubMed

    Caglayan, Safak; Bauerfeind, Anja; Schmidt, Vanessa; Carlo, Anne-Sophie; Prabakaran, Thaneas; Hübner, Norbert; Willnow, Thomas E

    2012-03-01

    To identify SORL1 risk genotypes that determine receptor protein expression in the human brain. DNA, RNA, and proteins were extracted from brain autopsies of Alzheimer disease cases and used for SORL1 genotyping, RNA profiling, and SORLA protein quantification, respectively. Specimens were provided by the MRC London Brain Bank for Neurodegenerative Diseases and the Netherlands Brain Bank. Brain autopsy material (frontal cortex) from 88 confirmed cases of sporadic Alzheimer disease. Our studies identified a SORL1 haplotype in the 3' gene region consisting of single-nucleotide polymorphisms rs1699102 and rs2070045 that is associated with poor receptor expression in the brain of patients with Alzheimer disease. These gene variations alter the SORL1 transcript sequence, resulting in a change from frequent to rare codon usage in the minor risk genotype. Studies in cultured cells confirm less efficient translation of the minor receptor transcripts into protein. Our findings suggest a functional mechanism that correlates SORL1 genotype with efficiency of receptor expression in the human brain.

  8. Association between Helicobacter pylori hopQI genotypes and human gastric cancer risk.

    PubMed

    Kazemi, E; Kahrizi, D; Moradi, M T; Sohrabi, M; Amini, S; Mousavi, S A R; Yari, K

    2016-01-11

    The Helicobacter pylori use a number of mechanisms to survive in the stomach lumen and can lead to gastritis and reduction in stomach acid secretion. It has been found that the risk of developing gastric carcinoma is associated to heterogeneity of H. pylori virulence factors such as HopQ. The HopQ is one of the outer membrane proteins involved in bacterial adherence to gastric mucosa and has been suggested to also main role in the virulence of H. pylori. The purpose of the current study was to investigate the association between different H. pylori virulence hopQI (types I) genotyping and patients with gastroduodenal disorders. For this purpose 58 stomach biopsies of the patients with gastric cancer and 100 saliva samples from healthy and H. pylori infected individuals were collected and studied. Then genomic DNA was purified and PCR was done for desired gene via specific primers. The H. pylori infections were diagnosed using PCR for GlmM gene. Then frequencies of hopQI+ and hopQI- genotypes were determined in H. pylori infected cases. Statistical analysis showed that there were not significant differences between healthy and diseased ones for genotypes hopQI+ and hopQI-. Then the hopQI+ cannot be as a risk factor genotype for gastric cancer.

  9. Meta-analysis of the association between GSTT1 null genotype and risk of nasopharyngeal carcinoma in Chinese.

    PubMed

    Jin, Bin; Dong, Pin; Li, Keyong; Shen, Bin; Xie, Jin

    2014-01-01

    Glutathione S-transferase T1 (GSTT1) null genotype has been proven to be associated with risks of many cancers. There were also many studies assessing on the association between GSTT1 null genotype and nasopharyngeal carcinoma risk in Chinese, but the findings from those studies were inconsistent. We performed a meta-analysis to provide a more precise assessment on the effect of GSTT1 null genotype on nasopharyngeal carcinoma risk. The PubMed and Wanfang databases were searched to identify eligible case-control studies on the association between GSTT1 null genotype and risk of nasopharyngeal carcinoma in Chinese. The pooled odds ratios (OR) with corresponding 95% confidence intervals (95% CI) were used to assess the association. Eight case-control studies with a total of 3,702 individuals were finally included in the meta-analysis. Meta-analysis of a total of eight studies showed that GSTT1 null genotype was significantly associated with increased risk of nasopharyngeal carcinoma in Chinese (OR = 2.27; 95% CI 1.41-3.67; P = 0.001). The finding from cumulative meta-analysis showed that there was a trend of more obvious association between GSTT1 null genotype and risk of nasopharyngeal carcinoma in Chinese as data accumulated by publication year. Therefore, the GSTT1 null genotype is significantly associated with increased risk of nasopharyngeal carcinoma in Chinese.

  10. Distribution and attribution of high-risk human papillomavirus genotypes in cervical precancerous lesions in China.

    PubMed

    Wang, Wenpeng; An, Jusheng; Song, Yan; Wang, Minjie; Huang, Manni; Wu, Lingying

    2017-07-01

    While human papillomavirus vaccine was recently approved by China Food and Drug Administration, mapping of high-risk human papillomavirus distribution and attribution in cervical precancerous lesions in China becomes critical in development of a high-risk human papillomavirus-based cervical cancer screening and prevention strategy. In total, 1016 patients with cervical precancerous lesions diagnosed in the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences were analyzed retrospectively, including 111 patients with low-grade squamous intraepithelial lesions and 905 patients with high-grade squamous intraepithelial lesions. HPV16, 58, 52, 33, and 31 were the most common high-risk human papillomavirus genotypes in order of decreasing frequency among high-risk human papillomavirus-positive high-grade squamous intraepithelial lesions; this differed from the high-risk human papillomavirus distribution in low-grade squamous intraepithelial lesions (HPV16, 52, 39, 56, and 58). The distribution of high-risk human papillomavirus genotypes in single-type infections for high-grade squamous intraepithelial lesions (HPV16, 58, 33, and 52) was similar to that in multiple-type infections (HPV16, 58, 52, and 33). By contrast, a more diverse distribution spectrum of high-risk human papillomavirus genotypes for low-grade squamous intraepithelial lesions was observed between single-type (HPV16, 52, 39, and 56) and multiple-type infection (HPV52, 68, 58, 59, 39 and 56). A previously published method was adopted to calculate the fractional proportion of individual high-risk human papillomavirus genotypes in multiple infections. For this proportional attribution, HPV16 (48.9%), 58 (10.0%), 33 (5.5%), and 52 (5.5%) were the most frequent among all high-grade squamous intraepithelial lesions, whereas HPV16 (13.2%), 52 (11.6%), 39 (9.5%), and 56 (7.6%) were the most frequent among all low-grade squamous intraepithelial lesions. Differences in high-risk human

  11. Mannose-binding lectin-deficient genotypes as a risk factor of pneumococcal meningitis in infants

    PubMed Central

    Bautista-Rodriguez, Carles; Launes, Cristian; Jordan, Iolanda; Andres, Maria; Arias, Maria Teresa; Lozano, Francisco; Garcia-Garcia, Juan Jose

    2017-01-01

    Objectives The objective of this study was to evaluate to evaluate the role of mannose-binding-lectin deficient genotypes in pneumococcal meningitis (PM) in children. Methods We performed a 16-year retrospective study (January 2001 to March 2016) including patients ≤ 18 years with PM. Variables including attack rate of pneumococcal serotype (high or low invasive capacity) and MBL2 genotypes associated with low serum MBL levels were recorded. Results Forty-eight patients were included in the study. Median age was 18.5 months and 17/48 episodes (35.4%) occurred in children ≤ 12 months old. Serotypes with high-invasive disease potential were identified in 15/48 episodes (31.2%). MBL2 deficient genotypes accounted for 18.8% (9/48). Children ≤ 12 months old had a 7-fold risk (95% CI: 1.6–29.9; p < 0.01) of having a MBL2 deficient genotype in comparison to those > 12 months old. A sub-analysis of patients by age group revealed significant proportions of carriers of MBL2 deficient genotypes among those ≤ 12 months old with PM caused by opportunistic serotypes (54.5%), admitted to the PICU (Pediatric Intensive Care Unit) (46.7%) and of White ethnicity (35.7%). These proportions were significantly higher than in older children (all p<0.05). Conclusions Our results suggest that differences in MBL2 genotype in children ≤12 months old affects susceptibility to PM, and it may have an important role in the episodes caused by non-high invasive disease potential serotypes. PMID:28562692

  12. Mannose-binding lectin-deficient genotypes as a risk factor of pneumococcal meningitis in infants.

    PubMed

    Bautista-Rodriguez, Carles; Launes, Cristian; Jordan, Iolanda; Andres, Maria; Arias, Maria Teresa; Lozano, Francisco; Garcia-Garcia, Juan Jose; Muñoz-Almagro, Carmen

    2017-01-01

    The objective of this study was to evaluate to evaluate the role of mannose-binding-lectin deficient genotypes in pneumococcal meningitis (PM) in children. We performed a 16-year retrospective study (January 2001 to March 2016) including patients ≤ 18 years with PM. Variables including attack rate of pneumococcal serotype (high or low invasive capacity) and MBL2 genotypes associated with low serum MBL levels were recorded. Forty-eight patients were included in the study. Median age was 18.5 months and 17/48 episodes (35.4%) occurred in children ≤ 12 months old. Serotypes with high-invasive disease potential were identified in 15/48 episodes (31.2%). MBL2 deficient genotypes accounted for 18.8% (9/48). Children ≤ 12 months old had a 7-fold risk (95% CI: 1.6-29.9; p < 0.01) of having a MBL2 deficient genotype in comparison to those > 12 months old. A sub-analysis of patients by age group revealed significant proportions of carriers of MBL2 deficient genotypes among those ≤ 12 months old with PM caused by opportunistic serotypes (54.5%), admitted to the PICU (Pediatric Intensive Care Unit) (46.7%) and of White ethnicity (35.7%). These proportions were significantly higher than in older children (all p<0.05). Our results suggest that differences in MBL2 genotype in children ≤12 months old affects susceptibility to PM, and it may have an important role in the episodes caused by non-high invasive disease potential serotypes.

  13. Can human papillomavirus (HPV) genotyping classify non-16/18 high-risk HPV infection by risk stratification?

    PubMed

    Sung, Yeoun Eun; Ki, Eun Young; Lee, Youn Soo; Hur, Soo Young; Lee, Ahwon; Park, Jong Sup

    2016-11-01

    Infection with high-risk genotypes of human papillomavirus (HR-HPV) is the major cause of invasive cervical cancers. HPV-16 and HPV-18 are known to be responsible for two-thirds of all invasive cervical carcinomas, followed by HPV-45, -31, and -33. Current guidelines only differentiate HPV-16/18 (+) by recommending direct colposcopy for treatment. We tried to evaluate whether there are differences in risk among 12 non-16/18 HR-HPV genotypes in this study. The pathology archive database records of 1,102 consecutive gynecologic patients, who had results for cervical cytology and histology and for HPV testing, as determined by HPV 9G DNA chip, were reviewed. Among the 1,102 patients, 346 were non-16/18 HR-HPV (+) and 231 were HPV-16/18 (+). We calculated the odds ratios for ≥cervical intraepithelial neoplasia 2 (CIN 2) of 14 groups of each HR-HPV genotype compared with a group of HR-HPV (-) patients. Based on the odds ratio of each genotype, we divided patients with non-16/18 HR-HPV genotypes (+) into two groups: HPV-31/33/35/45/52/58 (+) and HPV-39/51/56/59/66/68 (+). The age-adjusted odds ratios for ≥CIN 2 of the HPV-31/33/35/45/52/58 (+) and HPV-39/51/56/59/66/68 (+) groups compared with a HR-HPV (-) group were 11.9 (95% CI, 7.6 to 18.8; p<0.001) and 2.4 (95% CI, 1.4 to 4.3; p<0.001), respectively, while that of the HPV-16/18 (+) group was 18.1 (95% CI, 11.6 to 28.3; p=0.003). The 12 non-16/18 HR-HPV genotypes can be further categorized (HPV-31/33/35/45/52/58 vs. HPV-39/51/56/59/66/68) by risk stratification. The HPV-31/33/35/45/52/58 genotypes might need more aggressive action. Large scale clinical trials or cohort studies are necessary to confirm our suggestion.

  14. Contribution of DNA Repair Xeroderma Pigmentosum Group D Genotypes to Colorectal Cancer Risk in Taiwan.

    PubMed

    Chang, Wen-Shin; Yueh, Te-Cheng; Tsai, Chia-Wen; Ji, Hong-Xue; Wu, Cheng-Nan; Wang, Shou-Cheng; Lai, Yi-Liang; Hsu, Shih-Wei; Hsieh, Ming-Hao; Hsiao, Chieh-Lun; Hung, Yi-Wen; Shih, Tzu-Ching; Bau, Da-Tian

    2016-04-01

    It has been previously proposed that genetic variations on DNA repair genes confer susceptibility to cancer and the DNA repair gene Xeroderma Pigmentosum Group D (XPD) is thought to play the role of a helicase during excision repair and transcription. We investigated three genotypes of XPD, at promoter -114 (rs3810366), Asp312Asn (rs1799793) and Lys751Gln (rs13181), regarding their association with colorectal cancer susceptibility in a Taiwanese population. In total, 362 patients with colorectal cancer and 362 gender- and age-matched healthy controls were genotyped by polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP), and their XPD genotypes' association with colorectal cancer risk was investigated. The genotypes of XPD Asp312Asn (p=0.2493), Lys751Gln (p=0.7547) and promoter -114 (p=0.8702), were not associated with susceptibility for colorectal cancer. The Chi-square test revealed that the variant alleles of XPD Asp312Asn, Lys751Gln and promoter -114 was not associated with susceptibility for colorectal cancer either [p=0.1330, 0.3888 and 0.8740; odds ratio (OR)=1.20, 0.83 and 0.98; 95% confidence interval (95%CI)=0.95-1.52, 0.54-1.27 and 0.80-1.21, respectively]. The risk of A/G and A/A genotypes have no association with cancer risk among non-alcohol drinkers (OR=1.24, 95%, CI=0.90-1.72, p=0.2103) or alcohol drinkers (OR=1.51, 95% CI=0.64-3.55, p=0.4648). There exists no obvious contribution of XPD genotypes to tumor size (p=0.3531), location (p=0.3006) and lymph node metastasis (p=0.1061). Asp312Asn, Lys751Gln and promoter -114 of the XPD gene were not found to be adequate predictive markers for colorectal cancer risk in Taiwan. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  15. Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis.

    PubMed

    Neu, Scott C; Pa, Judy; Kukull, Walter; Beekly, Duane; Kuzma, Amanda; Gangadharan, Prabhakaran; Wang, Li-San; Romero, Klaus; Arneric, Stephen P; Redolfi, Alberto; Orlandi, Daniele; Frisoni, Giovanni B; Au, Rhoda; Devine, Sherral; Auerbach, Sanford; Espinosa, Ana; Boada, Mercè; Ruiz, Agustín; Johnson, Sterling C; Koscik, Rebecca; Wang, Jiun-Jie; Hsu, Wen-Chuin; Chen, Yao-Liang; Toga, Arthur W

    2017-10-01

    It is unclear whether female carriers of the apolipoprotein E (APOE) ε4 allele are at greater risk of developing Alzheimer disease (AD) than men, and the sex-dependent association of mild cognitive impairment (MCI) and APOE has not been established. To determine how sex and APOE genotype affect the risks for developing MCI and AD. Twenty-seven independent research studies in the Global Alzheimer's Association Interactive Network with data on nearly 58 000 participants. Non-Hispanic white individuals with clinical diagnostic and APOE genotype data. Homogeneous data sets were pooled in case-control analyses, and logistic regression models were used to compute risks. Age-adjusted odds ratios (ORs) and 95% confidence intervals for developing MCI and AD were calculated for men and women across APOE genotypes. Participants were men and women between ages 55 and 85 years. Across data sets most participants were white, and for many participants, racial/ethnic information was either not collected or not known. Men (OR, 3.09; 95% CI, 2.79-3.42) and women (OR, 3.31; CI, 3.03-3.61) with the APOE ε3/ε4 genotype from ages 55 to 85 years did not show a difference in AD risk; however, women had an increased risk compared with men between the ages of 65 and 75 years (women, OR, 4.37; 95% CI, 3.82-5.00; men, OR, 3.14; 95% CI, 2.68-3.67; P = .002). Men with APOE ε3/ε4 had an increased risk of AD compared with men with APOE ε3/ε3. The APOE ε2/ε3 genotype conferred a protective effect on women (OR, 0.51; 95% CI, 0.43-0.61) decreasing their risk of AD more (P value = .01) than men (OR, 0.71; 95% CI, 0.60-0.85). There was no difference between men with APOE ε3/ε4 (OR, 1.55; 95% CI, 1.36-1.76) and women (OR, 1.60; 95% CI, 1.43-1.81) in their risk of developing MCI between the ages of 55 and 85 years, but women had an increased risk between 55 and 70 years (women, OR, 1.43; 95% CI, 1.19-1.73; men, OR, 1.07; 95% CI, 0.87-1.30; P = .05). There were no significant

  16. PON1 Q192R genotype influences clopidogrel responsiveness by relative platelet inhibition instead of on-treatment platelet reactivity.

    PubMed

    Li, Xiaoqi; Zhang, Lanning; Chen, Xi; Qu, Fei; Li, Jiayue; Ma, Cong; Yang, Jie; Xu, Bin; Wang, Hongjuan; Xu, Qiang; Zhang, Yuxiao; Li, Yang; Lu, Caiyi; Yin, Tong

    2013-10-01

    paraoxonase-1 (PON1) was recently identified as the crucial enzyme for clopidogrel bioactivation, with PON1 Q192R (rs662) polymorphism determining the clopidogel antiplatelet efficacy. However, subsequent studies showed controversies over the findings. This study aimed to evaluate the impact of PON1 Q192R in parallel to that of CYP2C19*2 (rs4244285) on clopidogrel responsiveness in a cohort of Chinese patients with unstable angina pectoris. One hundred and eighty Chinese-Han patients diagnosed with unstable angina pectoris and treated with clopidogrel were consecutively recruited. Clopidogrel responsiveness, measured by relative platelet inhibition {RI=[(pretreatment aggregation-posttreatment aggregation at 5days)/(pretreatment aggregation)] x100%}, was assessed in relation to PON1 Q192R and CYP2C19*2 genotypes. RI values were stratified into four quartiles, with patients in quartile 1 defined as individuals of clopidogrel non-responsiveness. The contributions of PON1 Q192R and CYP2C19*2 to on-treatment platelet reactivity (OTPR) at 5days maintenance dose of clopidogrel were also evaluated. For PON1 Q192R genotypes, RI values were significantly lower in patients with QR and RR alleles than in patients with QQ alleles (p=0.01). OTPR values at 5days maintenance dose of clopidogrel were similar across all the PON1 Q192R genotypes (p=0.41). PON1 192 QR and RR conferred increased risks for clopidogrel non-responsiveness [OR 3.64; 95% CI (1.21-10.92), p=0.02]. For CYP2C19*2 genotypes, compared to CYP2C19*1/*1 wild type carriers, CYP2C19*2 carriers showed a significantly higher OTPR (p=0.009), and a trend for lower RI values (p=0.06). An increased risk for clopidogrel non-responsiveness was found in patients with CYP2C19*2 genotype [OR 2.02; 95% CI (1.03-3.96), p=0.04]. Both PON1 Q192R and CYP2C19*2 genotypes influence clopidogrel responsiveness, with the impact of PON1 Q192R mainly on relative platelet inhibition instead of OTPR of clopidogrel. © 2013.

  17. Leukocyte Telomere Length-Related rs621559 and rs398652 Genetic Variants Influence Risk of HBV-Related Hepatocellular Carcinoma

    PubMed Central

    Shi, Juan; Lu, Chao; Wei, Jinyu; Li, Lichao; Zhou, Changchun; Yuan, Qipeng; Zhou, Liqing; Yang, Ming

    2014-01-01

    Recent genome-wide association studies (GWAS) have identified eleven leukocyte telomere length (LTL)-related single nucleotide polymorphisms (SNPs). Since LTL has been associated with risk of many malignancies, LTL-related SNPs may contribute to cancer susceptibility. To test this hypothesis in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), we genotyped these eleven LTL-related SNPs in a case-control set including 1186 HBV-related HCC cases, 508 chronic HBV carriers and 1308 healthy controls at the discovery stage. The associations of HCC risk with these SNPs were further confirmed in an independent case-control set. We found that 1p34.2 rs621559 and 14q21 rs398652 were significantly associated with HBV-related HCC risk (both P<0.005 after Bonferroni corrections). There was no significant difference of either rs621559 or rs398652 genotypes between chronic HBV carriers and healthy controls, demonstrating that the association was not due to predisposition to HBV infection. In the pooled analyses (1806 HBV-related HCC cases and 1954 controls), we observed a decreased HCC risk, 0.72-times, associated with the 1p34.2 rs621559 AA genotype compared to the GG genotype (P = 1.6×10−6). Additionally, there was an increased HCC risk, 1.27-fold, associated with the rs398652 GG genotype (P = 3.3×10−6). A statistical joint effect between the rs621559 GG and rs398652 GG genotypes may exist in elevating risk of HBV-related HCC. We show, for the first time, that rs398652 and rs621559 might be marker genetic variants for risk of HBV-related HCC in the Chinese population. PMID:25365256

  18. Genotype-Environment Correlations for Language-Related Abilities: Implications for Typical and Atypical Learners.

    ERIC Educational Resources Information Center

    Gilger, Jeffrey W.; Ho, Hsiu-Zu; Whipple, Angela D.; Spitz, Romy

    2001-01-01

    This study examined passive genotype-environment correlations (GECs) for language related abilities by comparing environment-child language associations in adoptive and nonadoptive families. Findings indicate genetic mediation of the association between home environmental variables with children's language-related abilities. Implications for…

  19. Interleukin-6 genotype and risk for cerebral palsy in term and near-term infants.

    PubMed

    Wu, Yvonne W; Croen, Lisa A; Torres, Anthony R; Van De Water, Judy; Grether, Judith K; Hsu, Nathaniel N

    2009-11-01

    Chorioamnionitis is associated with increased risk for cerebral palsy (CP) in term infants. A functional polymorphism in the interleukin-6 (IL-6) gene has been implicated in newborn brain injury. We studied whether the IL-6 -174 G/C polymorphism confers increased risk for CP in term infants. This population-based case-control study included 334,333 live-born infants born at >or=36 weeks gestation within Kaiser Permanente Medical Care Program from 1991 to 2002. Case patients (n = 250) were identified from electronic records and confirmed by chart review, and comprised all infants with spastic or dyskinetic CP not caused by developmental abnormalities who had a neonatal blood specimen available for study. Control patients (n = 305) were randomly selected from the study population. Compared with genotype GG, the less common CC genotype was associated with increased risk for overall CP (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.5-4.6), quadriparetic CP (OR, 4.1; 95% CI, 1.8-9.3), and hemiparetic CP (OR, 2.7; 95% CI, 1.3-5.7), after controlling for race. The C allele conferred increased risk for CP in both recessive and additive genetic models. In multivariate analysis controlling for race, independent risk factors for CP included CC genotype compared with GG (OR, 2.4; 95% CI, 1.3-4.4), clinical chorioamnionitis (OR, 4.6; 95% CI, 2.1-10.4), maternal age >or= 35 (OR, 2.6; 95% CI, 1.6-4.1), and male sex (OR, 1.6; 95% CI, 1.1-2.4). Our data suggest that a functional polymorphism in the IL-6 gene is a risk factor for CP among term and near-term infants.

  20. Variation in the fat mass and obesity-related (FTO) genotype is not associated with body fatness in infants, but possibly with their length.

    PubMed

    Henriksson, P; Löf, M; Söderkvist, P; Forsum, E

    2014-10-01

    Data relating variation at the fat mass and obesity-related (FTO) locus (rs9939609) to fat mass in infancy are inconclusive. To study relationships between FTO genotype and infant size (at 1 and 12 weeks and at 1 year of age) and body composition (at 1 and 12 weeks). Body composition was assessed using air displacement plethysmography in 207 infants. FTO was genotyped using the TaqMan assay. The number of risk alleles was related to length at 1 and 12 weeks (P = 0.007-0.033) but not to fat mass. The relationship to length was stronger in boys than in girls. Our results suggest that the FTO genotype is not related during infancy to fat mass but is related to length in boys but not in girls. © 2014 The Authors. Pediatric Obesity © 2014 World Obesity.

  1. Evaluation of the modifying effects of unfavourable genotypes on classical clinical risk factors for ischaemic stroke

    PubMed Central

    Szolnoki, Z; Somogyvari, F; Kondacs, A; Szabo, M; Fodor, L; Bene, J; Melegh, B

    2003-01-01

    Objectives: Ischaemic stroke is a frequent heterogeneous multifactorial disease that is affected by a number of genetic mutations and environmental factors. We hypothesised the clinical importance of the interactions between common, unfavourable genetic mutations and clinical risk factors in the development of ischaemic stroke. Methods: The Factor V Leiden G1691A (Leiden V), the prothrombin G20210A, the methylenetetrahydrofolate reductase C677T (MTHFR C677T) mutations, the angiotensin converting enzyme I/D (ACE I/D), and apolipoprotein allele e4 (APO e4) genotypes were examined by the polymerase chain reaction (PCR) technique in 867 ischaemic stroke patients and 743 healthy controls. Logistic regression models were used to estimate the roles of the co-occurrences of the clinical risk factors and common genetic mutations in ischaemic stroke. Results: The Leiden V mutation in combination with hypertension or diabetes mellitus increased the risk of ischaemic stroke. We found synergistic effects between the ACE D/D and MTHFR 677TT genotypes and drinking or smoking. The presence of the APO e4 greatly facilitated the unfavourable effects of hypertension, diabetes mellitus, smoking, or drinking on the incidence of ischaemic stroke. Conclusion: In certain combinations, pairing of common unfavourable genetic factors, which alone confer only minor or non-significant risk, with clinical risk factors can greatly increase the susceptibility to ischaemic stroke. PMID:14638877

  2. GSTM1 null genotype and gastric cancer risk in the Chinese population: an updated meta-analysis and review.

    PubMed

    Zhang, Xi-Liang; Cui, Yong-Hui

    2015-01-01

    Although a number of studies have been conducted on the association between the GSTM1 null genotype and gastric cancer in People's Republic of China, this association remains elusive and controversial. To clarify the effects of the GSTM1 null genotype on the risk of gastric cancer, an updated meta-analysis was performed in the Chinese population. Related studies were identified from PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM) up to November 5, 2014. A total of 25 studies including 3,491 cases and 5,921 controls were included in this meta-analysis. Overall, a significant association (odds ratio [OR] =1.47, 95% CI: 1.28-1.69) was found between the null GSTM1 and gastric cancer risk when all studies in Chinese population were pooled into the meta-analysis. In subgroup analyses stratified by quality score, geographic area, and source of controls, the same results were observed. Additionally, a significant association was found both in smokers and non-smokers. This meta-analysis showed that the null GSTM1 may be a potential biomarker for gastric cancer risk in Chinese, and further studies with gene-gene and gene-environment interactions are required for definite conclusions.

  3. GSTM1 null genotype and gastric cancer risk in the Chinese population: an updated meta-analysis and review

    PubMed Central

    Zhang, Xi-Liang; Cui, Yong-Hui

    2015-01-01

    Although a number of studies have been conducted on the association between the GSTM1 null genotype and gastric cancer in People’s Republic of China, this association remains elusive and controversial. To clarify the effects of the GSTM1 null genotype on the risk of gastric cancer, an updated meta-analysis was performed in the Chinese population. Related studies were identified from PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM) up to November 5, 2014. A total of 25 studies including 3,491 cases and 5,921 controls were included in this meta-analysis. Overall, a significant association (odds ratio [OR] =1.47, 95% CI: 1.28–1.69) was found between the null GSTM1 and gastric cancer risk when all studies in Chinese population were pooled into the meta-analysis. In subgroup analyses stratified by quality score, geographic area, and source of controls, the same results were observed. Additionally, a significant association was found both in smokers and non-smokers. This meta-analysis showed that the null GSTM1 may be a potential biomarker for gastric cancer risk in Chinese, and further studies with gene–gene and gene–environment interactions are required for definite conclusions. PMID:25995643

  4. GSTT1 (rs4025935) null genotype is associated with increased risk of sickle cell disease in the populations of Tabuk-Northwestern region of Saudi Arabia.

    PubMed

    Abu-Duhier, Faisel; Mir, Rashid

    2017-04-01

    Glutathione system plays an important role in the protection of cells and tissue against damage from oxidative stress. Impairment of the glutathione system due to genetic polymorphism of GST genes may increase the risk and severity of sickle cell disease (SCD). Present study was, therefore, undertaken to examine the relative impact of the genetic polymorphism of GSTT1 and GSTM1 (rs4025935 and rs71748309) on susceptibility and hematological aspects of the patients with SCD. Present study included 100 patients with SCD and 200 healthy controls from northwestern region of Saudi Arabia. GSTM1 and GSTT1 (rs4025935 and rs71748309) genotypes were investigated by using single-tube multiplex PCR technique. It was observed that patients with SCD possessed significantly higher frequency of GSTT1 null genotype (26%) than healthy controls (15%), (P = 0.00001). Compared to the presence of GSTT1 genotype, the OR for the GSTT1 null genotype were estimated to be 4.3 (2.17-8.64, P = 0.00001). However, such association was not observed with respect to the presence of GSTM1 null genotype. In addition, it was observed that SCD in patients with GSTT1 genotype, the mean percentage levels for HbF and HbS were 0.48 and 35.4%, respectively; however, among SCD patients with GSTT1 null genotype, the mean percentage levels were significantly higher 1.62% (P = 0.004) and 39.38% (P = 0.02), respectively. GSTT1 null genotype is significantly associated with increased risk of SCD among the population of northwestern region of Saudi Arabia. In addition, it may be one of the important factors responsible for hematological manifestations of SCD.

  5. Effect of GABRA2 genotype on development of incentive-motivation circuitry in a sample enriched for alcoholism risk.

    PubMed

    Heitzeg, Mary M; Villafuerte, Sandra; Weiland, Barbara J; Enoch, Mary-Anne; Burmeister, Margit; Zubieta, Jon-Kar; Zucker, Robert A

    2014-12-01

    Heightened reactivity of the incentive-motivation system has been proposed to underlie adolescent-typical risky behaviors, including problem alcohol involvement. However, even in adolescence considerable individual variation in these behaviors exists, which may have genetic underpinnings and be related to variations in risk for later alcohol use disorder (AUD). Variants in GABRA2 have been associated with adult alcohol dependence as well as phenotypic precursors, including impulsiveness and externalizing behaviors. We investigated the impact of GABRA2 on the developmental trajectory of nucleus accumbens (NAcc) activation during anticipation of monetary reward from childhood to young adulthood. Functional MRI during a monetary incentive delay task was collected in 175 participants, with the majority (n = 151) undergoing repeated scanning at 1- to 2-year intervals. One group entered the study at age 8-13 years (n = 76) and another entered at age 18-23 years (n = 99). Most participants were children of alcoholics (79%) and thus at heightened risk for AUD. A total of 473 sessions were completed, covering ages 8-27 years. NAcc activation was heightened during adolescence compared with childhood and young adulthood. GABRA2 genotype (SNP rs279858) was associated with individual differences in NAcc activation specifically during adolescence, with the minor allele (G) associated with greater activation. Furthermore, NAcc activation mediated an effect of genotype on alcohol problems (n = 104). This work demonstrates an impact of GABRA2 genotype on incentive-motivation neurocircuitry in adolescence, with implications for vulnerability to alcoholism. These findings represent an important step toward understanding the genetic and neural basis of individual differences in how risk for addiction unfolds across development.

  6. Effect of GABRA2 Genotype on Development of Incentive-Motivation Circuitry in a Sample Enriched for Alcoholism Risk

    PubMed Central

    Heitzeg, Mary M; Villafuerte, Sandra; Weiland, Barbara J; Enoch, Mary-Anne; Burmeister, Margit; Zubieta, Jon-Kar; Zucker, Robert A

    2014-01-01

    Heightened reactivity of the incentive-motivation system has been proposed to underlie adolescent-typical risky behaviors, including problem alcohol involvement. However, even in adolescence considerable individual variation in these behaviors exists, which may have genetic underpinnings and be related to variations in risk for later alcohol use disorder (AUD). Variants in GABRA2 have been associated with adult alcohol dependence as well as phenotypic precursors, including impulsiveness and externalizing behaviors. We investigated the impact of GABRA2 on the developmental trajectory of nucleus accumbens (NAcc) activation during anticipation of monetary reward from childhood to young adulthood. Functional MRI during a monetary incentive delay task was collected in 175 participants, with the majority (n=151) undergoing repeated scanning at 1- to 2-year intervals. One group entered the study at age 8–13 years (n=76) and another entered at age 18–23 years (n=99). Most participants were children of alcoholics (79%) and thus at heightened risk for AUD. A total of 473 sessions were completed, covering ages 8–27 years. NAcc activation was heightened during adolescence compared with childhood and young adulthood. GABRA2 genotype (SNP rs279858) was associated with individual differences in NAcc activation specifically during adolescence, with the minor allele (G) associated with greater activation. Furthermore, NAcc activation mediated an effect of genotype on alcohol problems (n=104). This work demonstrates an impact of GABRA2 genotype on incentive-motivation neurocircuitry in adolescence, with implications for vulnerability to alcoholism. These findings represent an important step toward understanding the genetic and neural basis of individual differences in how risk for addiction unfolds across development. PMID:24975023

  7. Maternal depressive history, teen 5HTTLPR genotype, and the processing of emotional faces: Exploring mechanisms of risk

    PubMed Central

    Jacobs, Rachel H.; Pine, Daniel S.; Schoeny, Michael E.; Henry, David B.; Gollan, Jackie K.; Moy, Gregory; Cook, Edwin H.; Wakschlag, Lauren S.

    2010-01-01

    Variations in the serotonin transporter gene (5HTTLPR) and biased processing of face-emotion displays both have been implicated in the transmission of depression risk, but little is known about developmental influences on these relationships. Within a community sample of adolescents, we examine whether 5HTTLPR genotype moderates the link between maternal depressive history and errors in face-emotion labeling. When controlling for current levels of depression and anxiety among youth, a two-way interaction between maternal depressive history and 5HTTLPR genotype was detected. Specifically, adolescents whose mothers reported a depressive history and who had a low expressing genotype made more errors in classifying emotional faces when compared with adolescents with an intermediate or high expressing genotype, with or without maternal depression history. These findings highlight the complex manner in which maternal depression and genetic risk may interact to predict individual differences in social information processing, as it is moderated by the 5HTTLPR genotype. PMID:21092937

  8. Hepatitis B virus in Pakistan: a systematic review of prevalence, risk factors, awareness status and genotypes.

    PubMed

    Ali, Muhammad; Idrees, Muhammad; Ali, Liaqat; Hussain, Abrar; Ur Rehman, Irshad; Saleem, Sana; Afzal, Samia; Butt, Sadia

    2011-03-06

    In Pakistan, there are estimated 7-9 million carriers of hepatitis B virus (HBV) with a carrier rate of 3-5%. This article reviews the available literature about the prevalence, risk factors, awareness status and genotypes of the HBV in Pakistan by using key words; HBV prevalence, risk factors, awareness status and genotypes in Pakistani population in PubMed, PakMediNet, Directory of Open Access Journals (DOAJ) and Google Scholar. One hundred and six different studies published from 1998 to 2010 were included in this study. Weighted mean and standard deviation were determined for each population group. The percentage of hepatitis B virus infection in general population was 4.3318% ± 1.644%, healthy blood donors (3.93% ± 1.58%), military recruits (4.276% ± 1.646%), healthcare persons (3.25% ± 1.202%), pregnant women (5.872% ± 4.984), prisoners (5.75% ± 0.212%), surgical patients (7.397% ± 2.012%), patients with cirrhosis (28.87% ± 11.90%), patients with HCC (22% ± 2.645%), patients with hepatitis (15.896% ± 14.824%), patients with liver diseases (27.54% ± 6.385%), multiple transfused patients (6.223% ± 2.121%), opthalmic patients (3.89% ± 1.004%) and users of injectable drugs (14.95% ± 10.536%). Genotype D (63.71%) is the most prevalent genotype in Pakistani population. Mass vaccination and awareness programs should be initiated on urgent basis especially in populations with HBV infection rates of more than 5%.

  9. Hepatitis B virus in Pakistan: A systematic review of prevalence, risk factors, awareness status and genotypes

    PubMed Central

    2011-01-01

    In Pakistan, there are estimated 7-9 million carriers of hepatitis B virus (HBV) with a carrier rate of 3-5%. This article reviews the available literature about the prevalence, risk factors, awareness status and genotypes of the HBV in Pakistan by using key words; HBV prevalence, risk factors, awareness status and genotypes in Pakistani population in PubMed, PakMediNet, Directory of Open Access Journals (DOAJ) and Google Scholar. One hundred and six different studies published from 1998 to 2010 were included in this study. Weighted mean and standard deviation were determined for each population group. The percentage of hepatitis B virus infection in general population was 4.3318% ± 1.644%, healthy blood donors (3.93% ± 1.58%), military recruits (4.276% ± 1.646%), healthcare persons (3.25% ± 1.202%), pregnant women (5.872% ± 4.984), prisoners (5.75% ± 0.212%), surgical patients (7.397% ± 2.012%), patients with cirrhosis (28.87% ± 11.90%), patients with HCC (22% ± 2.645%), patients with hepatitis (15.896% ± 14.824%), patients with liver diseases (27.54% ± 6.385%), multiple transfused patients (6.223% ± 2.121%), opthalmic patients (3.89% ± 1.004%) and users of injectable drugs (14.95% ± 10.536%). Genotype D (63.71%) is the most prevalent genotype in Pakistani population. Mass vaccination and awareness programs should be initiated on urgent basis especially in populations with HBV infection rates of more than 5%. PMID:21375760

  10. [Apolipoprotein E (APOE) gene polymorphism and risk and prognosis in cerebral amyloid angiopathy-related haemorrhage].

    PubMed

    Mendel, Tadeusz; Gromadzka, Grażyna

    2010-01-01

    The authors present current opinions about the role of APOE (apolipoprotein E gene) genotype as a factor modifying risk, course and prognosis in haemorrhagic stroke of cerebral amyloid origin. The search for the role of genetics in haemorrhagic stroke has been ongoing for more than 15 years. One of the most frequently investigated genotypes in the context of intracerebral haemorrhages is the APOE genotype. Alleles APOE e2 and e4 have been established as risk factors for cerebral amyloid angiopathy (CAA), as well as for cerebral amyloid angiopathy-related haemorrhage (CAAH). Moreover, APOE genotype seems to determine prognosis in CAAH in terms of early mortality, as well as risk of recurrence. Current findings related to the association between different isoforms of apoE and haemorrhagic stroke due to CAA do not allow us to formulate any clinical recommendations yet.

  11. Comparative analysis of juice volatiles in selected mandarins, mandarin relatives and other citrus genotypes

    USDA-ARS?s Scientific Manuscript database

    Citrus fruit flavor is an important attribute prioritized in variety improvement. The objectives of this study were to compare aroma volatiles in juice samples from 13 selected genotypes of mandarins and mandarin relatives, including six mandarins, three sour oranges, one satsuma, one clementine, on...

  12. PrP genotype frequencies and risk evaluation for scrapie in dairy sheep breeds from southern Italy.

    PubMed

    Martemucci, Giovanni; Iamartino, Daniela; Blasi, Michele; D'Alessandro, Angela Gabriella

    2015-12-01

    Concerns regarding scrapie in sheep breeding have increased in the last few decades. The present study was carried out in dairy sheep breeds from southern Italy. In order to find breeding animals resistant to scrapie, the PrP genes of 1,205 animals from entire flocks of dairy native Apulian Leccese and Altamurana breeds, and Sicilian Comisana breed, were analysed for polymorphisms at codons 136, 154, and 171 related to scrapie resistance/susceptibility. The Altamurana breed was considered as two populations (Alt-Cav and Alt-Cra-Zoe), based on presumed cross-breeding. A total of five alleles and ten different genotypes were found. The ARQ allele was predominant for all breeds followed by ARR, the most resistant allele to scrapie, which was highly prevalent in Comisana (50%) and in native Alt-Cav (42.4%). The VRQ allele, associated with the highest susceptibility to scrapie, was detected at not negligeable levels in allocthonous Comisana (3.5%), at a low frequency (0.2%) in native Leccese and Alt-Cra-Zoe, while it was absent in Alt-Cav. The frequencies of PrP genotypes with a very low susceptibility risk to scrapie (R1) was higher in Comisana and Alt-Cav. The most susceptible genotype, ARQ/VRQ, was found only in Comisana. Within the Altamurana breed, there were notable differences between Alt-Cav and Alt-Cra-Zoe sheep. The Alt-Cav was characterised by the absence of VRQ and AHQ alleles and by the higher frequency of the ARR/ARR genotype (18.7%). Breeding programs, mainly in endangered breeds such as Altamurana, should be conducted gradually, combining resistance to scrapie, maintenance of genetic variability, and production.

  13. Genotypic variation in transpiration efficiency due to differences in photosynthetic capacity among sugarcane-related clones.

    PubMed

    Li, Chunjia; Jackson, Phillip; Lu, Xin; Xu, Chaohua; Cai, Qing; Basnayake, Jayapathi; Lakshmanan, Prakash; Ghannoum, Oula; Fan, Yuanhong

    2017-04-01

    Sugarcane, derived from the hybridization of Saccharum officinarum×Saccharum spontaneum, is a vegetative crop in which the final yield is highly driven by culm biomass production. Cane yield under irrigated or rain-fed conditions could be improved by developing genotypes with leaves that have high intrinsic transpiration efficiency, TEi (CO2 assimilation/stomatal conductance), provided this is not offset by negative impacts from reduced conductance and growth rates. This study was conducted to partition genotypic variation in TEi among a sample of diverse clones from the Chinese collection of sugarcane-related germplasm into that due to variation in stomatal conductance versus that due to variation in photosynthetic capacity. A secondary goal was to define protocols for optimized larger-scale screening of germplasm collections. Genotypic variation in TEi was attributed to significant variation in both stomatal and photosynthetic components. A number of genotypes were found to possess high TEi as a result of high photosynthetic capacity. This trait combination is expected to be of significant breeding value. It was determined that a small number of observations (16) is sufficient for efficiently screening TEi in larger populations of sugarcane genotypes The research methodology and results reported are encouraging in supporting a larger-scale screening and introgression of high transpiration efficiency in sugarcane breeding. However, further research is required to quantify narrow sense heritability as well as the leaf-to-field translational potential of genotypic variation in transpiration efficiency-related traits observed in this study. © The Author 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  14. Obesity and related risk factors.

    PubMed

    Mozaffari, H; Nabaei, B

    2007-03-01

    To study the prevalence of overweight and obesity among Iranian schoolgirls and to identify risk factors which lead to obesity. This cross-sectional study was conducted in 2002 and a sample of 1800 female students between 7-12 years old was obtained using a multistage cluster sampling method from Tehran. Height and weight were measured and related socio-economic information was collected. The overall percent of overweight and obesity was 13.3% and 7.7% respectively. BMI (Body Mass Index) was directly and significantly(r=+0.28, P< 0.001) correlated with increasing age. Physical activity was significantly different between obese and non-obese children. (P=0.03) Also, economical factors such as the type of school (private&public) were different in these children. (P=0.03) The statistical analysis of the data revealed a significant and inverse correlation(r=-0.03, P=0.04) between maternal education and occurrence of overweight and obesity in children. The prevalence of overweight and obesity in young Iranian girls was high. Advanced age, lack of physical inactivity, low economical factors and maternal educational status could be risk factors for obesity in children.

  15. The effect of cigarette smoke and arsenic exposure on urothelial carcinoma risk is modified by glutathione S-transferase M1 gene null genotype

    SciTech Connect

    Chung, Chi-Jung; Huang, Chao-Yuan; Pu, Yeong-Shiau; Shiue, Horng-Sheng; Su, Chien-Tien; Hsueh, Yu-Mei

    2013-01-15

    Inter-individual variation in the metabolism of xenobiotics, caused by factors such as cigarette smoking or inorganic arsenic exposure, is hypothesized to be a susceptibility factor for urothelial carcinoma (UC). Therefore, our study aimed to evaluate the role of gene–environment interaction in the carcinogenesis of UC. A hospital-based case–control study was conducted. Urinary arsenic profiles were measured using high-performance liquid chromatography–hydride generator-atomic absorption spectrometry. Genotyping was performed using a polymerase chain reaction-restriction fragment length polymorphism technique. Information about cigarette smoking exposure was acquired from a lifestyle questionnaire. Multivariate logistic regression was applied to estimate the UC risk associated with certain risk factors. We found that UC patients had higher urinary levels of total arsenic, higher percentages of inorganic arsenic (InAs%) and monomethylarsonic acid (MMA%) and lower percentages of dimethylarsinic acid (DMA%) compared to controls. Subjects carrying the GSTM1 null genotype had significantly increased UC risk. However, no association was observed between gene polymorphisms of CYP1A1, EPHX1, SULT1A1 and GSTT1 and UC risk after adjustment for age and sex. Significant gene–environment interactions among urinary arsenic profile, cigarette smoking, and GSTM1 wild/null polymorphism and UC risk were observed after adjustment for potential risk factors. Overall, gene–environment interactions simultaneously played an important role in UC carcinogenesis. In the future, large-scale studies should be conducted using tag-SNPs of xenobiotic-metabolism-related enzymes for gene determination. -- Highlights: ► Subjects with GSTM1 null genotype had significantly increased UC risk. ► UC patients had poor arsenic metabolic ability compared to controls. ► GSTM1 null genotype may modify arsenic related UC risk.

  16. A personalised approach to prostate cancer screening based on genotyping of risk founder alleles

    PubMed Central

    Cybulski, C; Wokołorczyk, D; Kluźniak, W; Kashyap, A; Gołąb, A; Słojewski, M; Sikorski, A; Puszyński, M; Soczawa, M; Borkowski, T; Borkowski, A; Antczak, A; Przybyła, J; Sosnowski, M; Małkiewicz, B; Zdrojowy, R; Domagała, P; Piotrowski, K; Menkiszak, J; Krzystolik, K; Gronwald, J; Jakubowska, A; Górski, B; Dębniak, T; Masojć, B; Huzarski, T; Muir, K R; Lophatananon, A; Lubiński, J; Narod, S A

    2013-01-01

    Background: To evaluate whether genotyping for 18 prostate cancer founder variants is helpful in identifying high-risk individuals and for determining optimal screening regimens. Methods: A serum PSA level was measured and a digital rectal examination (DRE) was performed on 2907 unaffected men aged 40–90. Three hundred and twenty-three men with an elevated PSA (⩾4 ng ml−1) or an abnormal DRE underwent a prostate biopsy. All men were genotyped for three founder alleles in BRCA1 (5382insC, 4153delA and C61G), for four alleles in CHEK2 (1100delC, IVS2+1G>A, del5395 and I157T), for one allele in NBS1 (657del5), for one allele in HOXB13 (G84E), and for nine low-risk single-nucleotide polymorphisms (SNPs). Results: On the basis of an elevated PSA or an abnormal DRE, prostate cancer was diagnosed in 135 of 2907 men (4.6%). In men with a CHEK2 missense mutation I157T, the cancer detection rate among men with an elevated PSA or an abnormal DRE was much higher (10.2%, P=0.0008). The cancer detection rate rose with the number of SNP risk genotypes observed from 1.2% for men with no variant to 8.6% for men who carried six or more variants (P=0.04). No single variant was helpful on its own in predicting the presence of prostate cancer, however, the combination of all rare mutations and SNPs improved predictive power (area under the curve=0.59; P=0.03). Conclusion: These results suggest that testing for germline CHEK2 mutations improves the ability to predict the presence of prostate cancer in screened men, however, the clinical utility of incorporating DNA variants in the screening process is marginal. PMID:23722471

  17. Rotavirus Diarrhea among Children in Taiz, Yemen: Prevalence—Risk Factors and Detection of Genotypes

    PubMed Central

    Al-Badani, Abdulmalik; Al-Areqi, Leena; Majily, Abdulatif; AL-Sallami, Saleh; AL-Madhagi, Anwar; Amood AL-Kamarany, Mohammed

    2014-01-01

    Diarrheal diseases are a great public health problem; they are among the most causes leading to morbidity and mortality of infants and children particularly in developing countries and even in developed countries. Rotavirus is the most common cause of severe gastroenteritis in infants and young children in both developed and developing countries. The purpose of this study was to determine the incidence rate of Rotavirus infection, its genotypes, and risk factors among children with diarrhea in Taiz, Yemen. 795 fecal samples were collected from children (less than 5 years old), suffering from diarrhea and attending the Yemeni-Swedish Hospital (YSH) in Taiz , Yemen, from November 2006 to February 2008. Rotavirus was detected by enzyme linkage immunosorbent assay (ELISA) on stool specimens of children. Genotypes of Rotavirus were characterized by reverse transcriptase-polymerase chain reaction (RT-PCR) and polyacrylamide gel electrophoresis (PAGE). The results showed that 358 (45.2%) were Rotavirus-positive and the most prevalent genotypes were G2P[4] (55%), followed by G1P[8] (15%). In addition, Rotavirus was found through the whole year; however, higher frequency during the summer season (53.4%) and lower frequency during the winter season (37.1%). PMID:25197286

  18. Water relations and leaf growth rate of three Agropyron genotypes under water stress.

    PubMed

    García, María G; Busso, Carlos A; Polci, Pablo; García Girou, Norberto L; Echenique, Viviana

    2002-12-01

    The effects of water stress on leaf water relations and growth are reported for three perennial tussock grass genotypes under glasshouse conditions. Studies were performed in genotypes El Palmar INTA and Selección Anguil of Agropyron scabrifolium (Döell) Parodi, and El Vizcachero of A. elongatum (Host) Beauv. Agropyron scabrifolium El Palmar INTA is native to a region with warm-temperate and humid climate without a dry season, and an average annual precipitation of 900 mm. Agropyron scabrifolium Selección Anguil comes from a region with a sub-humid, dry to semiarid climate and a mean annual precipitation of 600 mm. Agropyron elongatum is a widespread forage in semiarid Argentina with well-known water stress resistance. A mild water stress treatment was imposed slowly; plants reached a minimum pre-dawn leaf water potential of about -1.83 MPa by day 21 after watering was withheld. In all genotypes, water stress led to a reduction of leaf growth. There was a tendency for a greater epicuticular wax accumulation on water-stressed plants of A. scabrifolium Selección Anguil and A. elongatum than on those of A. scabrifolium El Palmar INTA. This may have contributed to obtain greater turgor pressures and relative water contents in the first two than in the later genotype. In turn, this may have contributed to determine smaller leaf growth rate reductions in A. scabrifolium Selección Anguil and A. elongatum than in A. scabrifolium El Palmar INTA under water stress. This study demonstrated variation in water stress resistance between genotypes in A. scabrifolium, and between A. scabrifolium Selección Anguil and A. elongatum versus A. scabrifolium El Palmar INTA, which was related to their differential responses in water relations.

  19. Association between glutathione S-transferase M1 null genotype and risk of gallbladder cancer: a meta-analysis.

    PubMed

    Sun, Hong-Li; Han, Bing; Zhai, Hong-Peng; Cheng, Xin-Hua; Ma, Kai

    2014-01-01

    Glutathione S-transferases (GSTs) are a family of enzymes which are involved in the detoxification of potential carcinogens. Glutathione S-transferase M1 (GSTM1) null genotype can impair the enzyme activity of GSTs and is suspected to increase the susceptibility to gallbladder cancer. Previous studies investigating the association between GSTM1 null genotype and risk of gallbladder cancer reported inconsistent findings. To quantify the association between GSTM1 null genotype and risk of gallbladder cancer, we performed a meta-analysis of published studies. We searched PubMed, Embase, and Wanfang databases for all possible studies. We estimated the pooled odds ratio (OR) with its 95% confidence interval (95% CI) to assess the association. Meta-analysis of total included studies showed that GSTM1 null genotype was not associated with gallbladder cancer risk (OR = 1.13, 95% CI 0.88-1.46, P = 0.332). Subgroup analysis by ethnicity showed that there was no association between GSTM1 null genotype and risk of gallbladder cancer in both Caucasians and Asians. However, meta-analysis of studies with adjusted estimations showed that GSTM1 null genotype was associated with increased risk of gallbladder cancer (OR = 1.46, 95% CI 1.02-2.09, P = 0.038). Thus, this meta-analysis shows that GSTM1 null genotype is likely to be associated with risk of gallbladder cancer. More studies with well design and large sample size are needed to further validate the association between GSTM1 null genotype and gallbladder cancer.

  20. Hepatitis B virus prevalence, risk factors and genotype distribution in HIV infected patients from West Java, Indonesia.

    PubMed

    Fibriani, Azzania; Wisaksana, Rudi; Alisjahbana, Bachti; Indrati, Agnes; Schutten, Martin; van Crevel, Reinout; van der Ven, Andre; Boucher, Charles A B

    2014-04-01

    Indonesia currently faces both an increasing HIV incidence and a high hepatitis B virus (HBV) burden. The objective of our study is to examine the prevalence, risk factors, and genotypic distribution of HBV infection among HIV infected patients in West Java, Indonesia. A cross sectional study was conducted among a cohort of HIV infected patients in 2008. Demographic and disease related variables were compared between HBV negative and positive patients. Logistic regression was applied to determine risk factors for HBV co-infection. HBV and HIV genotyping was performed in co-infected patients. Of 636 HIV-infected patients, the rate of HBV co-infection was 7%. The proportion of males was higher in HBV/HIV co-infected patients than in HIV mono-infected patients (93% vs. 72%, P=0.001). A history of injecting drug use (IDU), but not tattooing, was associated with HBV co-infection [P=0.035 OR 2.41 (95% CI 1.06-5.47)]. In the HIV and HBV treatment naive patients, CD4 cells counts <50cells/mm(3), HIV-RNA plasma ≥10,000copies/ml and AST level above normal were more often found in patients with high HBV-DNA levels (≥20,000IU/ml) as compared to those with low HBV DNA (<20.000IU/ml) (P<0.05). As in the general population, B3 was the dominant subtype in HBV co-infected patients. The prevalence of active HBV infection and the genotype distribution among HIV infected individuals is similar to the overall population in Java. However, an increased prevalence was observed in men with a history of IDU, underlining the need for routine HBV screening and monitoring. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Spatial Patterns of Ectomycorrhizal Assemblages in a Monospecific Forest in Relation to Host Tree Genotype

    PubMed Central

    Lang, Christa; Finkeldey, Reiner; Polle, Andrea

    2013-01-01

    Ectomycorrhizas (EcM) are important for soil exploration and thereby may shape belowground interactions of roots. We investigated the composition and spatial structures of EcM assemblages in relation to host genotype in an old-growth, monospecific beech (Fagus sylvatica) forest. We hypothesized that neighboring roots of different beech individuals are colonized by similar EcM assemblages if host genotype had no influence on the fungal colonization and that the similarity would decrease with increasing distance of the sampling points. The alternative was that the EcM species showed preferences for distinct beech genotypes resulting in intraspecific variation of EcM-host assemblages. EcM species identities, abundance and exploration type as well as the genotypes of the colonized roots were determined in each sampling unit of a 1 L soil core (r = 0.04 m, depth 0.2 m). The Morisita-Horn similarity indices (MHSI) based on EcM species abundance and multiple community comparisons were calculated. No pronounced variation of MHSI with increasing distances of the sampling points within a plot was found, but variations between plots. Very high similarities and no between plot variation were found for MHSI based on EcM exploration types suggesting homogenous soil foraging in this ecosystem. The EcM community on different root genotypes in the same soil core exhibited high similarity, whereas the EcM communities on the root of the same tree genotype in different soil cores were significantly dissimilar. This finding suggests that spatial structuring of EcM assemblages occurs within the root system of an individual. This may constitute a novel, yet unknown mechanism ensuring colonization by a diverse EcM community of the roots of a given host individual. PMID:23630537

  2. Genotyping of single nucleotide polymorphisms related to attention-deficit hyperactivity disorder.

    PubMed

    Tortajada-Genaro, Luis A; Mena, Salvador; Niñoles, Regina; Puigmule, Marta; Viladevall, Laia; Maquieira, Ángel

    2016-03-01

    Pharmacological treatment of several diseases, such as attention-deficit hyperactivity disorder (ADHD), presents marked variability in efficiency and its adverse effects. The genotyping of specific single nucleotide polymorphisms (SNPs) can support the prediction of responses to drugs and the genetic risk of presenting comorbidities associated with ADHD. This study presents two rapid and affordable microarray-based strategies to discriminate three clinically important SNPs in genes ADRA2A, SL6CA2, and OPRM1 (rs1800544, rs5569, and rs1799971, respectively). These approaches are allele-specific oligonucleotide hybridization (ASO) and a combination of allele-specific amplification (ASA) and solid-phase hybridization. Buccal swab and blood samples taken from ADHD patients and controls were analyzed by ASO, ASA, and a gold-reference method. The results indicated that ASA is superior in genotyping capability and analytical performance.

  3. Annual research review: Rare genotypes and childhood psychopathology--uncovering diverse developmental mechanisms of ADHD risk.

    PubMed

    Scerif, Gaia; Baker, Kate

    2015-03-01

    Through the increased availability and sophistication of genetic testing, it is now possible to identify causal diagnoses in a growing proportion of children with neurodevelopmental disorders. In addition to developmental delay and intellectual disability, many genetic disorders are associated with high risks of psychopathology, which curtail the wellbeing of affected individuals and their families. Beyond the identification of significant clinical needs, understanding the diverse pathways from rare genetic mutations to cognitive dysfunction and emotional-behavioural disturbance has theoretical and practical utility. We overview (based on a strategic search of the literature) the state-of-the-art on causal mechanisms leading to one of the most common childhood behavioural diagnoses - attention deficit hyperactivity disorder (ADHD) - in the context of specific genetic disorders. We focus on new insights emerging from the mapping of causal pathways from identified genetic differences to neuronal biology, brain abnormalities, cognitive processing differences and ultimately behavioural symptoms of ADHD. First, ADHD research in the context of rare genotypes highlights the complexity of multilevel mechanisms contributing to psychopathology risk. Second, comparisons between genetic disorders associated with similar psychopathology risks can elucidate convergent or distinct mechanisms at each level of analysis, which may inform therapeutic interventions and prognosis. Third, genetic disorders provide an unparalleled opportunity to observe dynamic developmental interactions between neurocognitive risk and behavioural symptoms. Fourth, variation in expression of psychopathology risk within each genetic disorder points to putative moderating and protective factors within the genome and the environment. A common imperative emerging within psychopathology research is the need to investigate mechanistically how developmental trajectories converge or diverge between and within

  4. Natural history of human papillomavirus infection in non-vaccinated young males: low clearance probability in high-risk genotypes.

    PubMed

    Cai, T; Perletti, G; Meacci, F; Magri, V; Verze, P; Palmieri, A; Mazzoli, S; Santi, R; Nesi, G; Mirone, V; Bartoletti, R

    2016-03-01

    In this study, we aimed to investigate the clearance of type-specific genital human papillomavirus (HPV) infection in heterosexual, non-HPV-vaccinated males whose female partners were positive to HPV DNA tests. All consecutive men attending the same sexually transmitted diseases (STD) centre between January 2005 and December 2006 were considered for this study. All subjects (n = 1009) underwent a urologic visit and microbiological tests on first void, midstream urine and total ejaculate samples. One hundred and five patients were positive for HPV DNA (10.4 %; mean age: 34.8 ± 5.8 years) and consented to clinical examination and molecular diagnostic assays for HPV detection scheduled every 6 months (median surveillance period of 53.2 months). HPV genotypes were classified as high risk, probable high risk and low risk. HPV-positive samples which did not hybridise with any of the type-specific probes were referred to as positive non-genotypeable. At enrollment, the distribution of HPV genotypes was as follows: high-risk HPV (n = 37), probable high-risk HPV (n = 6), low-risk HPV (n = 23) and non-genotypeable HPV (n = 39). A high HPV genotype concordance between stable sexual partners emerged (kappa = 0.92; p < 0.001). At the end of the study, 71/105 (67.6 %) subjects were negative for HPV (mean virus clearance time: 24.3 months). With regard to the HPV genotype, virus clearance was observed in 14/37 (37.8 %) high-risk HPV cases, 6/6 (100 %) probable high-risk HPV cases, 20/23 (86.9 %) low-risk HPV cases and 31/39 (79.5 %) non-genotypeable cases. The high-risk HPV genotypes showed the lowest rate and probability of viral clearance (p < 0.001). In our series, high-risk HPV infections were more likely to persist over time when compared with other HPV genotypes.

  5. Apolipoprotein E and Alzheimer disease: genotype-specific risks by age and sex.

    PubMed Central

    Bickeböller, H; Campion, D; Brice, A; Amouyel, P; Hannequin, D; Didierjean, O; Penet, C; Martin, C; Pérez-Tur, J; Michon, A; Dubois, B; Ledoze, F; Thomas-Anterion, C; Pasquier, F; Puel, M; Demonet, J F; Moreaud, O; Babron, M C; Meulien, D; Guez, D; Chartier-Harlin, M C; Frebourg, T; Agid, Y; Martinez, M; Clerget-Darpoux, F

    1997-01-01

    The distribution of apolipoprotein E (APOE) genotypes as a function of age and sex has been examined in a French population of 417 Alzheimer disease (AD) patients and 1,030 control subjects. When compared to the APOE epsilon3 allele, an increased risk associated with the APOE epsilon4 allele (odds ratio [OR] [epsilon4] = 2.7 with 95% confidence interval [CI] = 2.0-3.6; P < .001) and a protective effect of the APOE epsilon2 allele (OR[epsilon2] = 0.5 with 95% CI = 0.3-0.98; P = .012) were retrieved. An effect of the epsilon4 allele dosage on susceptibility was confirmed (OR[epsilon4/epsilon4] vs. the epsilon3/epsilon3 genotype = 11.2 [95% CI = 4.0-31.6]; OR[epsilon3/epsilon4] vs. the epsilon3/epsilon3 genotype = 2.2 [95% CI = 1.5-3.5]). The frequency of the epsilon4 allele was lower in male cases than in female cases, but, since a similar difference was found in controls, this does not lead to a difference in OR between sex. ORs for the epsilon4 allele versus the epsilon3 allele, OR(epsilon4), were not equal in all age classes: OR(epsilon4) in the extreme groups with onset at < 60 years or > 79 years were significantly lower than those from the age groups 60-79 years. In epsilon3/epsilon4 individuals, sex-specific lifetime risk estimates by age 85 years (i.e., sex-specific penetrances by age 85 years) were 0.14 (95% CI 0.04-0.30) for men and 0.17 (95% CI 0.09-0.28) for women. PMID:9012418

  6. Apolipoprotein E and Alzheimer disease: Genotype-specific risks by age and sex

    SciTech Connect

    Bickeboeller, H. |; Babron, M.C.; Clerget-Darpoux, F.

    1997-02-01

    The distribution of apolipoprotein E (APOE) genotypes as a function of age and sex has been examined in a French population of 417 Alzheimer disease (AD) patients and 1,030 control subjects. When compared to the APOE {epsilon}3 allele, an increased risk associated with the APOE {epsilon}4 allele (odds ratio [OR] [{epsilon}4] = 2.7 with 95% confidence interval [CI] = 2.0-3.6; P < .001) and a protective effect of the APOE {epsilon}2 allele (OR[{epsilon}2] = 0.5 with 95% CI = 0.3-0.98; P = .012) were retrieved. An effect of the {epsilon}4 allele dosage on susceptibility was confirmed (OR[{epsilon}4/{epsilon}4] vs. the {epsilon}3/{epsilon}3 genotype = 11.2 [95% CI = 4.0-31.6]; OR[{epsilon}3/{epsilon}4] vs. the {epsilon}3/{epsilon}3 genotype = 2.2 [95% Cl = 1.5-3.5]). The frequency of the {epsilon}4 allele was lower in male cases than in female cases, but, since a similar difference was found in controls, this does not lead to a difference in OR between sex. ORs for the {epsilon}4 allele versus the {epsilon}3 allele, OR({epsilon}4), were not equal in all age classes: OR({epsilon}4) in the extreme groups with onset at < 60 years or > 79 years were significantly lower than those from the age groups 60-79 years. In {epsilon}3/{epsilon}4 individuals, sex-specific lifetime risk estimates by age 85 years (i.e., sex-specific penetrances by age 85 years) were 0.14 (95% CI 0.04-0.30) for men and 0.17 (95% CI 0.09-0.28) for women. 53 refs., 1 fig., 3 tabs.

  7. Seroprevalence, risk factors, and hepatitis C virus genotypes in groups with high-risk sexual behavior in Croatia.

    PubMed

    Cavlek, Tatjana Vilibic; Margan, Ira Gjenero; Lepej, Snjezana Zidovec; Kolaric, Branko; Vince, Adriana

    2009-08-01

    The seroprevalence, risk factors and genotypes of hepatitis C virus (HCV) in groups with high-risk sexual behavior (persons with multiple sexual partners, men who have sex with men, commercial sex workers and their clients and persons with sexually transmitted diseases) in seven Croatian cities were analyzed. A total of 821 participants without history of injecting drug use were included in the study. Anti-HCV prevalence among risk groups varied from 2.9% to 8.5% with an overall prevalence of 4.6% (95% CI = 3.2-6.1) compared with 0.5% (95% CI = 0.0-1.5) in controls (pregnant females; OR = 9.66; 95% CI = 1.32-70.7). HCV-RNA was detected in 73.1% anti-HCV positive patients. Three of the seronegative cases (2.1%) were also found to be HCV-RNA positive ("window period"). Genotype 1 was most commonly detected (55.6%). The most prevalent subtypes were 1a (38.9%) and 3a (38.9%). Sociodemographic characteristics (age, gender, marital status and level of education) were not associated with anti-HCV seropositivity. Among sexually transmitted disease markers, a higher seroprevalence of HCV infection was found in subjects with a history of HBV infection (10.5% vs. 3.8%, P = 0.002) and gonorrhea (13.2% vs. 4.2%, P = 0.011). No other factors reflecting risk sexual behavior such as sexual orientation, number of sexual partners and number of risk behaviors were associated with HCV seroprevalence. 2009 Wiley-Liss, Inc.

  8. The Risk of Coronary Heart Disease Associated With Glycosylated Hemoglobin ≥ 6.5% is Pronounced in the Haptoglobin 2-2 Genotype

    PubMed Central

    Cahill, Leah E; Jensen, Majken K; Chiuve, Stephanie E; Shalom, Hadar; Pai, Jennifer K; Flint, Alan J; Mukamal, Kenneth J; Rexrode, Kathryn M; Levy, Andrew P; Rimm, Eric B

    2015-01-01

    BACKGROUND Research targeting glycosylated hemoglobin (HbA1c) to < 6.5% to prevent coronary heart disease (CHD) events has conflicting results. We previously observed the haptoglobin (Hp) Hp2-2 genotype is associated with a ~10-fold increased CHD risk among individuals with HbA1c ≥ 6.5%, and thus might be useful in identifying those at high risk of CHD who would benefit from maintaining HbA1c < 6.5%. OBJECTIVES We modeled whether HbA1c ≥ 6.5% in the Hp2-2 genotype is associated with CHD in a prospective case-control study nested within the Health Professionals Follow-Up Study (HPFS). METHODS HbA1c concentration and Hp genotype were determined for 695 incident cases of CHD from 1994–2010 and matched controls. Logistic regression models calculated relative risk (RR) and 95% confidence intervals (CI), for the first and second halves of follow-up, adjusting for confounding variables. A dataset from the Nurses’ Health Study (NHS) served as a replication cohort. RESULTS Prevalence of Hp2-2 genotype in HPFS was 39%. Compared to HbA1c < 6.5%, RR of CHD for HbA1c ≥ 6.5% for the Hp2-2 genotype over full follow-up was 3.07 (1.37–6.86)-- 3.88 (1.31–11.52) during the first half of follow-up and 2.16 (0.61–7.61) in the second half. The corresponding RRs (95% CI) for the Hp1-1 + Hp2-1 genotypes were 2.19 (1.14–4.24) (full follow-up), 1.60 (0.73–3.53) (first half), and 4.72 (1.26–17.65) (second half). CONCLUSIONS In 2 independent cohorts, risk of CHD associated with HbA1c ≥ 6.5% is pronounced in the Hp2-2 genotype, particularly in early cases. The Hp2-2 genotype may identify individuals at greatest CHD risk from hyperglycemia. PMID:26483103

  9. Contribution of DNA Double-strand Break Repair Gene XRCC3 Genotypes to Triple-negative Breast Cancer Risk.

    PubMed

    Su, Chen-Hsien; Chang, Wen-Shin; Hu, Pei-Shin; Hsiao, Chieh-Lun; Ji, Hong-Xue; Liao, Cheng-Hsi; Yueh, Te-Cheng; Chuang, Chin-Liang; Tsai, Chia-Wen; Hsu, Chin-Mu; Lane, Hsien-Yuan; Bau, Da-Tian

    2015-01-01

    The DNA-repair gene X-ray repair cross-complementing group 3 (XRCC3) is important in DNA double-strand break repair and plays a critical part in initiation of carcinogenesis. Triple-negative breast cancer (TNBC) is the most difficult breast cancer subtype with no existing gene-targeting drugs and little knowledge on its genetic etiology. This study aimed to investigate the contribution of the XRCC3 genotype to individual TNBC susceptibility. A total of 2,464 Taiwan citizens consisting of 1,232 breast cancer cases and 1,232 controls were enrolled in this case-control study, and genotyping of XRCC3 rs1799794, rs45603942, rs861530, rs3212057, rs1799796, rs861539 and rs28903081 were performed with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We also conducted risk-stratified sub-group analyses to determine the association between the genotype and age- and hormone-related characteristics of breast cancer sub-groups. There was no significant difference between breast cancer and control groups in the distributions of the genotypic or allelic frequencies as for the XRCC3 rs1799794 (p=0.5195 and 0.9545), rs45603942 (p=0.3478 and 0.1449), rs861530 (p=0.4567 and 0.5081), rs3212057 (p=1.0000 and 1.0000), rs1799796 (p=0.8487 and 0.7315) and rs28903081 (p=1.0000 and 1.0000), respectively. However, the XRCC3 rs861539 TT genotype was more prevalent in patients with breast cancer [odds ratio (OR)=2.99, 95% confidence interval (CI)=1.62-5.55; p=0.0002], and especially among those who were younger than 55 years (OR=2.61, 95% CI=1.82-3.73; p=0.0001), with first menarche earlier than 12.2 years (OR=2.47, 95% CI=1.74-3.52; p=0.0001), with menopause at 49.0 years old or later (OR=2.53, 95% CI=1.76-3.62; p=0.0001), or with TNBC (OR=2.05, 95% CI=1.46-4.28; p=4.63*10(-4)). XRCC3 rs861539 TT is a potential predictive marker for TNBC in Taiwanese women and investigations in other populations are warranted for further universal application in cancer detection

  10. Maternal depressive history, teen 5HTTLPR genotype, and the processing of emotional faces: Exploring mechanisms of risk.

    PubMed

    Jacobs, Rachel H; Pine, Daniel S; Schoeny, Michael E; Henry, David B; Gollan, Jackie K; Moy, Gregory; Cook, Edwin H; Wakschlag, Lauren S

    2011-01-01

    Variations in the serotonin transporter gene (5HTTLPR) and biased processing of face-emotion displays both have been implicated in the transmission of depression risk, but little is known about developmental influences on these relationships. Within a community sample of adolescents, we examine whether 5HTTLPR genotype moderates the link between maternal depressive history and errors in face-emotion labeling. When controlling for current levels of depression and anxiety among youth, a two-way interaction between maternal depressive history and 5HTTLPR genotype was detected. Specifically, adolescents whose mothers reported a depressive history and who had a low expressing genotype made more errors in classifying emotional faces when compared with adolescents with an intermediate or high expressing genotype, with or without maternal depression history. These findings highlight the complex manner in which maternal depression and genetic risk may interact to predict individual differences in social information processing. Copyright © 2010 Elsevier Ltd. All rights reserved.

  11. The UGT1A6_19_GG genotype is a breast cancer risk factor

    PubMed Central

    Justenhoven, Christina; Obazee, Ofure; Winter, Stefan; Rabstein, Sylvia; Lotz, Anne; Harth, Volker; Pesch, Beate; Brüning, Thomas; Baisch, Christian; Hartikainen, Jaana M.; Mannermaa, Arto; Kosma, Veli-Matti; Kataja, Vesa; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Fasching, Peter A.; Beckmann, Matthias; Ekici, Arif B.; Hein, Alexander; Hall, Per; Li, Jingmei; Chang-Claude, Jenny; Flesch-Janys, Dieter; Seibold, Petra; Rudolph, Anja; Hamann, Ute; Ko, Yon-Dschun; Brauch, Hiltrud

    2013-01-01

    Validation of an association between the UGT1A6_19_T>G (rs6759892) polymorphism and overall breast cancer risk. A pilot study included two population-based case-control studies from Germany (MARIE-GENICA). An independent validation study comprised four independent breast cancer case-control studies from Finland (KBCP, OBCS), Germany (BBCC), and Sweden (SASBAC). The pooled analysis included 7418 cases and 8720 controls from all six studies. Participants were of European descent. Genotyping was done by MALDI-TOF MS and statistical analysis was performed by logistic regression adjusted for age and study. The increased overall breast cancer risk for women with the UGT1A6_19_GG genotype which was observed in the pilot study was confirmed in the set of four independent study collections (OR 1.13, 95% CI 1.05–1.22; p = 0.001). The pooled study showed a similar effect (OR 1.09, 95% CI 1.04–1.14; p = 0.001). The risk effect on the basis of allele frequencies was highly significant, the pooled analysis showed an OR of 1.11 (95% CI 1.06–1.16; p = 5.8 × 10−6). We confirmed the association of UGT1A6_19_GG with increased overall breast cancer risk and conclude that our result from a well powered multi-stage study adds a novel candidate to the panel of validated breast cancer susceptibility loci. PMID:23781229

  12. Maternal serotonin transporter genotype affects risk for ASD with exposure to prenatal stress.

    PubMed

    Hecht, Patrick M; Hudson, Melissa; Connors, Susan L; Tilley, Michael R; Liu, Xudong; Beversdorf, David Q

    2016-11-01

    Stress exposure during gestation is implicated in several neuropsychiatric conditions, including autism spectrum disorder (ASD). Previous research showed that prenatal stress increases risk for ASD with peak exposure during the end of the second and the beginning of the third trimester. However, exposures to prenatal stress do not always result in ASD, suggesting that other factors may interact with environmental stressors to increase ASD risk. The present study examined a maternal genetic variation in the promoter region of the serotonin transporter gene (5-HTTLPR) affecting stress tolerance and its interaction with the effect of environmental stressors on risk for ASD. Two independent cohorts of mothers of ASD children recruited by the University of Missouri and Queen's University were surveyed regarding the prenatal environment and genotyping on 5-HTTLPR was performed to explore this relationship. In both samples, mothers of children with ASD carrying the stress susceptible short allele variant of 5-HTTLPR experienced a greater number of stressors and greater stress severity when compared to mothers carrying the long allele variant. The temporal peak of stressors during gestation in these mothers was consistent with previous findings. Additionally, increased exposure to prenatal stress was not reported in the pregnancies of typically developing siblings from the same mothers, regardless of maternal genotype, suggesting against the possibility that the short allele might increase the recall of stress during pregnancy. The present study provides further evidence of a specific maternal polymorphism that may affect the risk for ASD with exposure to prenatal stress. Autism Res 2016, 9: 1151-1160. © 2016 International Society for Autism Research, Wiley Periodicals, Inc. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

  13. Genomic characterization of Alzheimer's disease and genotype-related phenotypic analysis of biological markers in dementia.

    PubMed

    Cacabelos, Ramón

    2004-12-01

    More than 180 genes distributed across the human genome are potentially involved in the pathogenesis of Alzheimer's disease (AD). The AD population shows a higher genetic variation rate than the control population. Significant differences in allelic distribution and frequency exist when AD-related polygenic clusters are compared with other forms of dementia, indicating that the genetic component in neurodegenerative dementia differs from that of other CNS disorders. The characterization of AD genotype-related phenotypic profiles reveals substantial differences in biological markers among AD clusters associated with different genes and/or allelic combinations. AD and dementia with vascular component (DVC) are the most prevalent forms of dementia. Both clinical entities share many similarities, but they differ in their major phenotypic and genotypic profiles, as revealed by structural and functional genomics studies. Comparative phenotypic studies have identified significant differences in 25% of more than 100 parametric variables, including anthropometric values, cardiovascular function, blood pressure, lipid metabolism, uric acid metabolism, peripheral calcium homeostasis, liver function, alkaline phosphatase, lactate dehydrogenase, red and white blood cells, regional brain atrophy, and brain blood flow velocity. Functional genomic studies incorporating apolipoprotein E (APOE)-related changes in biological markers extended the difference between AD and DVC by up to 57%. Structural genomic studies with AD-related genes, including APP, MAPT, APOE, PS1, PS2, A2M, ACE, AGT, cFOS, and PRNP, demonstrate different genetic profiles in AD and DVC, with an absolute genetic variation rate in the range of 30-80%, depending upon genes and genetic clusters. The relative polymorphic variation in genetic clusters integrated by two, three or four genes associated with AD ranges from 1 to 3%. The main phenotypic differences in AD are genotype dependent, indicating a powerful

  14. The HLA-DQ2 genotype selects for early intestinal microbiota composition in infants at high risk of developing coeliac disease.

    PubMed

    Olivares, M; Neef, A; Castillejo, G; Palma, G De; Varea, V; Capilla, A; Palau, F; Nova, E; Marcos, A; Polanco, I; Ribes-Koninckx, C; Ortigosa, L; Izquierdo, L; Sanz, Y

    2015-03-01

    Intestinal dysbiosis has been associated with coeliac disease (CD), but whether the alterations are cause or consequence of the disease is unknown. This study investigated whether the human leukocyte antigen (HLA)-DQ2 genotype is an independent factor influencing the early gut microbiota composition of healthy infants at family risk of CD. As part of a larger prospective study, a subset (n=22) of exclusively breastfed and vaginally delivered infants with either high genetic risk (HLA-DQ2 carriers) or low genetic risk (non-HLA-DQ2/8 carriers) of developing CD were selected from a cohort of healthy infants with at least one first-degree relative with CD. Infant faecal microbiota was analysed by 16S rRNA gene pyrosequencing and real time quantitative PCR. Infants with a high genetic risk had significantly higher proportions of Firmicutes and Proteobacteria and lower proportions of Actinobacteria compared with low-risk infants. At genus level, high-risk infants had significantly less Bifidobacterium and unclassified Bifidobacteriaceae proportions and more Corynebacterium, Gemella, Clostridium sensu stricto, unclassified Clostridiaceae, unclassified Enterobacteriaceae and Raoultella proportions. Quantitative real time PCR also revealed lower numbers of Bifidobacterium species in infants with high genetic risk than in those with low genetic risk. In high-risk infants negative correlations were identified between Bifidobacterium species and several genera of Proteobacteria (Escherichia/Shigella) and Firmicutes (Clostridium). The genotype of infants at family risk of developing CD, carrying the HLA-DQ2 haplotypes, influences the early gut microbiota composition. This finding suggests that a specific disease-biased host genotype may also select for the first gut colonisers and could contribute to determining disease risk. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  15. Psychosis-inducing effects of cannabis are related to both childhood abuse and COMT genotypes.

    PubMed

    Alemany, S; Arias, B; Fatjó-Vilas, M; Villa, H; Moya, J; Ibáñez, M I; Ortet, G; Gastó, C; Fañanás, L

    2014-01-01

    To test whether the association between childhood abuse, cannabis use and psychotic experiences (PEs) was moderated by the COMT (catechol-O-methyltransferase) gene. Psychotic experiences (PEs), childhood abuse, cannabis use and COMT Val158Met genotypes were assessed in 533 individuals from the general population. Data were analysed hierarchically by means of multiple linear regression models. Childhood abuse showed a significant main effect on both positive (β = 0.09; SE = 0.04; P = 0.047) and negative PEs (β = 0.11; SE = 0.05; P = 0.038). A significant three-way interaction effect was found among childhood abuse, cannabis use and the COMT gene on positive PEs (β = -0.30; SE = 0.11; P = 0.006). This result suggests that COMT genotypes and cannabis use only influenced PE scores among individuals exposed to childhood abuse. Furthermore, exposure to childhood abuse and cannabis use increased PE scores in Val carriers. However, in individuals exposed to childhood abuse but who did not use cannabis, PEs increased as a function of the Met allele copies of the COMT gene. Cannabis use after exposure to childhood abuse may have opposite effects on the risk of PEs, depending on the COMT genotypes providing evidence for a qualitative interaction. Val carriers exposed to childhood abuse are vulnerable to the psychosis-inducing effects of cannabis. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Genetic variability on seed yield and related traits of elite faba bean (Vicia faba L.) genotypes.

    PubMed

    Fikreselassie, Million; Seboka, Habtamu

    2012-04-15

    Faba bean is one of the most important cool season crops in the highlands of Ethiopia and the country is considered as the secondary center of diversity. This study was conducted at Haramaya, Boreda and Hirna districts of Eastern Hararghe from 2006 to 2008 cropping season using twenty five elite genotypes of faba bean to determine the extent and pattern of genetic diversity for seed yield and related traits. The treatments were arranged in a randomized complete block design with three replications. The data were subjected to the analyses of variance using the SAS program. The mean squares due to genotypes were highly significant for seed yield (p < 0.01) indicating the existence of sufficient genetic variability for seed yield. Mean squares due to the interaction between year and location were highly significant for all the traits studied (p < 0.01). High genotypic coefficient of variation (10093.53%) was observed for seed yield followed by number of seeds per plant (325.45%). The estimated values of phenotypic variances were in the range of 0.60 for number of seeds per pods to 196564.64 for seed yield. Genetic gains that expected from selecting the top 5% of the genotypes, as a percent of the mean, varied from 12.32% for number of seeds per plant to 35.46% for seed yield. The average linkage technique of clustering produced a more understandable portrayal of the 25 faba bean genotypes by grouping them into five clusters. The maximum distance was found between cluster three and five (D2 = 691.47). Thus, the materials tested in the entire experiment will be maintained for further breeding program.

  17. Performance of risk prediction for inflammatory bowel disease based on genotyping platform and genomic risk score method.

    PubMed

    Chen, Guo-Bo; Lee, Sang Hong; Montgomery, Grant W; Wray, Naomi R; Visscher, Peter M; Gearry, Richard B; Lawrance, Ian C; Andrews, Jane M; Bampton, Peter; Mahy, Gillian; Bell, Sally; Walsh, Alissa; Connor, Susan; Sparrow, Miles; Bowdler, Lisa M; Simms, Lisa A; Krishnaprasad, Krupa; Radford-Smith, Graham L; Moser, Gerhard

    2017-08-29

    Predicting risk of disease from genotypes is being increasingly proposed for a variety of diagnostic and prognostic purposes. Genome-wide association studies (GWAS) have identified a large number of genome-wide significant susceptibility loci for Crohn's disease (CD) and ulcerative colitis (UC), two subtypes of inflammatory bowel disease (IBD). Recent studies have demonstrated that including only loci that are significantly associated with disease in the prediction model has low predictive power and that power can substantially be improved using a polygenic approach. We performed a comprehensive analysis of risk prediction models using large case-control cohorts genotyped for 909,763 GWAS SNPs or 123,437 SNPs on the custom designed Immunochip using four prediction methods (polygenic score, best linear genomic prediction, elastic-net regularization and a Bayesian mixture model). We used the area under the curve (AUC) to assess prediction performance for discovery populations with different sample sizes and number of SNPs within cross-validation. On average, the Bayesian mixture approach had the best prediction performance. Using cross-validation we found little differences in prediction performance between GWAS and Immunochip, despite the GWAS array providing a 10 times larger effective genome-wide coverage. The prediction performance using Immunochip is largely due to the power of the initial GWAS for its marker selection and its low cost that enabled larger sample sizes. The predictive ability of the genomic risk score based on Immunochip was replicated in external data, with AUC of 0.75 for CD and 0.70 for UC. CD patients with higher risk scores demonstrated clinical characteristics typically associated with a more severe disease course including ileal location and earlier age at diagnosis. Our analyses demonstrate that the power of genomic risk prediction for IBD is mainly due to strongly associated SNPs with considerable effect sizes. Additional SNPs that are

  18. GRECOS Project (Genotyping Recurrence Risk of Stroke): The Use of Genetics to Predict the Vascular Recurrence After Stroke.

    PubMed

    Fernández-Cadenas, Israel; Mendióroz, Maite; Giralt, Dolors; Nafria, Cristina; Garcia, Elena; Carrera, Caty; Gallego-Fabrega, Cristina; Domingues-Montanari, Sophie; Delgado, Pilar; Ribó, Marc; Castellanos, Mar; Martínez, Sergi; Freijo, Marimar; Jiménez-Conde, Jordi; Rubiera, Marta; Alvarez-Sabín, José; Molina, Carlos A; Font, Maria Angels; Grau Olivares, Marta; Palomeras, Ernest; Perez de la Ossa, Natalia; Martinez-Zabaleta, Maite; Masjuan, Jaime; Moniche, Francisco; Canovas, David; Piñana, Carlos; Purroy, Francisco; Cocho, Dolores; Navas, Inma; Tejero, Carlos; Aymerich, Nuria; Cullell, Natalia; Muiño, Elena; Serena, Joaquín; Rubio, Francisco; Davalos, Antoni; Roquer, Jaume; Arenillas, Juan Francisco; Martí-Fábregas, Joan; Keene, Keith; Chen, Wei-Min; Worrall, Bradford; Sale, Michele; Arboix, Adrià; Krupinski, Jerzy; Montaner, Joan

    2017-05-01

    Vascular recurrence occurs in 11% of patients during the first year after ischemic stroke (IS) or transient ischemic attack. Clinical scores do not predict the whole vascular recurrence risk; therefore, we aimed to find genetic variants associated with recurrence that might improve the clinical predictive models in IS. We analyzed 256 polymorphisms from 115 candidate genes in 3 patient cohorts comprising 4482 IS or transient ischemic attack patients. The discovery cohort was prospectively recruited and included 1494 patients, 6.2% of them developed a new IS during the first year of follow-up. Replication analysis was performed in 2988 patients using SNPlex or HumanOmni1-Quad technology. We generated a predictive model using Cox regression (GRECOS score [Genotyping Reurrence Risk of Stroke]) and generated risk groups using a classification tree method. The analyses revealed that rs1800801 in the MGP gene (hazard ratio, 1.33; P=9×10(-)(03)), a gene related to artery calcification, was associated with new IS during the first year of follow-up. This polymorphism was replicated in a Spanish cohort (n=1.305); however, it was not significantly associated in a North American cohort (n=1.683). The GRECOS score predicted new IS (P=3.2×10(-)(09)) and could classify patients, from low risk of stroke recurrence (1.9%) to high risk (12.6%). Moreover, the addition of genetic risk factors to the GRECOS score improves the prediction compared with previous Stroke Prognosis Instrument-II score (P=0.03). The use of genetics could be useful to estimate vascular recurrence risk after IS. Genetic variability in the MGP gene was associated with vascular recurrence in the Spanish population. © 2017 American Heart Association, Inc.

  19. Prevalence of high-risk human papilloma virus genotypes and associated risk of cervical precancerous lesions in a large U.S. screening population: data from the ATHENA trial.

    PubMed

    Monsonego, Joseph; Cox, J Thomas; Behrens, Catherine; Sandri, Maria; Franco, Eduardo L; Yap, Poh-Sin; Huh, Warner

    2015-04-01

    We assessed the age-related prevalence of high risk human papillomavirus (HR-HPV) genotypes and the genotype-associated risk for high-grade cervical intraepithelial neoplasia (CIN) in a large U.S. screening population. A total of 40,901 women aged ≥25 years were screened with liquid-based cytology and HPV testing in the ATHENA (Addressing the Need for Advanced HPV Diagnostics) trial. Genotyping was performed using the LINEAR ARRAY HPV Genotyping Test. HPV16 was the most prevalent genotype in all age groups, ranging from 3.5% to 0.8% in women aged 25-29 and ≥50 years, respectively. The next most prevalent genotypes were HPV52, HPV31 and HPV18. In the overall population, HPV16 conferred the greatest absolute risk of ≥CIN3 both in women aged 25-29 and ≥30 years (14.2% and 15.1%, respectively) followed by HPV31 (8.0% and 7.9%), HPV52 (6.7% and 4.4%) and HPV18 (2.7% and 9.0%). Similar trends were seen in women with negative cytology. The percent positivity increased markedly with disease progression for HPV16 and HPV18 which were responsible for 45.6% and 8.4% of ≥CIN3, respectively. Of note, HPV 18 was responsible for 50% of adenocarcinoma in situ (AIS) and 50% of invasive cancer cases. HPV16 played a major role in the development of ≥CIN3 irrespective of age, supporting the identification of HPV16 in primary screening for all women. Identification of HPV18 is also warranted, given its significant contribution to AIS and cancer. Identification of non-16/18 genotypes as a pool should provide sufficient information for screening. Copyright © 2015. Published by Elsevier Inc.

  20. MTHFR (C677T) CT genotype and CT-apoE3/3 genotypic combination predisposes the risk of ischemic stroke.

    PubMed

    Vijayan, Murali; Chinniah, Rathika; Ravi, Padma Malini; Sivanadham, Ramgopal; Mosses Joseph, Arun Kumar; Vellaiappan, Neethi Arasu; Krishnan, Jeyaram Illiayaraja; Karuppiah, Balakrishnan

    2016-10-15

    The predisposition to ischemic stroke (IS) might involve interactions of several genes and environmental factors. The present study was aimed to evaluate the influence of polymorphisms in methylenetetrahydrofolate reductase (MTHFR-C677T) and apolipoprotein-E (apo-E) as risk factors for IS patients in south Indian population. 200 IS patients and 193 age and sex matched controls were genotyped for MTHFR-C677T and apoE by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. Statistically significant association was observed for MTHFR CT genotype (IS-Pooled: OR=4.29; p=5.01×10(-5); IS-Males: OR=4.13; p=0.001; IS-Females: OR=8.62; p=0.027; IS-Large Vessel Disease (LVD)- Pooled: OR=4.14; p=0.0002) and T allele (IS-Pooled: OR=4.82; p=1.49×10(-5); IS-Males: OR=4.33; p=0.0002; IS-Females: OR=7.99; p=0.031; IS-LVD-Pooled: OR=4.13; p=0.0001). Further, reduced frequencies of CC genotype (IS-Pooled: OR=0.20; p=9.80×10(-6); IS-Males: OR=0.25; p=0.001; IS-Females: OR=0.12; p=0.027; IS-LVD-Pooled: OR=0.23; p=0.0001) and C allele (IS-Pooled: OR=0.21; p=1.49×10(-5); IS-Males: OR=0.23; p=0.0002; IS-Females: OR=0.13; p=0.031; IS-LVD-Pooled: OR=0.24; p=0.0001) were observed in IS patients than the controls. No association was observed for apoE genotypes/alleles in IS/LVD cases. Our study demonstrated the presence of risk for MTHFR CT genotype/T allele and 'CT-3/3' (n=33 vs. 5; OR=7.42; p=0.001) genotypic combination in the development of IS in south India. Further, follow-up study of these stroke cases i.e., in later stages of the disease whether they are developing the neurological disorders such as Alzheimer's Disease (AD) and vascular dementia (VaD) is needed to draw a fruitful conclusion in connection between neurological disorders and with these two polymorphisms, before translating it into clinical practice. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. RyR2 QQ2958 Genotype and Risk of Malignant Ventricular Arrhythmias.

    PubMed

    Galati, Francesca; Galati, Antonio; Massari, Serafina

    2016-01-01

    Ventricular arrhythmias are one of the most common causes of death in developed countries. The use of implantable cardiac defibrillators is the most effective treatment to prevent sudden cardiac death. To date, the ejection fraction is the only approved clinical variable used to determine suitability for defibrillator placement in subjects with heart failure. The purpose of this study was to assess whether genetic polymorphisms found in the ryanodine receptor type 2 (Q2958R) and histidine-rich calcium-binding protein (S96A) might serve as markers for arrhythmias. Genotyping was performed in 235 patients treated with defibrillator for primary and secondary prevention of arrhythmias. No significant association was found between the S96A polymorphism and arrhythmia onset, whereas the QQ2958 genotype in the ryanodine receptor gene was correlated with an increased risk of life-threatening arrhythmias. Concurrent stressor conditions, such as hypertension, seem to increase this effect. Our findings might help to better identify patients who could benefit from defibrillator implantation.

  2. RyR2 QQ2958 Genotype and Risk of Malignant Ventricular Arrhythmias

    PubMed Central

    Galati, Francesca; Galati, Antonio; Massari, Serafina

    2016-01-01

    Ventricular arrhythmias are one of the most common causes of death in developed countries. The use of implantable cardiac defibrillators is the most effective treatment to prevent sudden cardiac death. To date, the ejection fraction is the only approved clinical variable used to determine suitability for defibrillator placement in subjects with heart failure. The purpose of this study was to assess whether genetic polymorphisms found in the ryanodine receptor type 2 (Q2958R) and histidine-rich calcium-binding protein (S96A) might serve as markers for arrhythmias. Genotyping was performed in 235 patients treated with defibrillator for primary and secondary prevention of arrhythmias. No significant association was found between the S96A polymorphism and arrhythmia onset, whereas the QQ2958 genotype in the ryanodine receptor gene was correlated with an increased risk of life-threatening arrhythmias. Concurrent stressor conditions, such as hypertension, seem to increase this effect. Our findings might help to better identify patients who could benefit from defibrillator implantation. PMID:26904356

  3. RAD51 genotype and triple-negative breast cancer (TNBC) risk in Polish women.

    PubMed

    Smolarz, Beata; Zadrożny, Marek; Duda-Szymańska, Joanna; Makowska, Marianna; Samulak, Dariusz; Michalska, Magdalena M; Mojs, Ewa; Bryś, Magdalena; Forma, Ewa; Romanowicz-Makowska, Hanna

    2013-04-01

    The most lethal damage for the cell among all damage is double-strand breaks (DSB) of DNA. DSB cause development of cancer diseases including the triple-negative molecular subtype of breast cancer. The aim of this work was to evaluate the single nucleotide polymorphism -135G>C (rs1801320) of the RAD51 gene encoding DNA repair proteins by homologous recombination (HR) in triple-negative breast cancer (TNBC). We assessed the RAD51 -135G>C polymorphism in 50 women with triple-negative breast cancer and in 50 women from the control group. RAD51 polymorphism was analysed by the PCR-RFLP (restriction fragment length polymorphism) technique. Our results demonstrated a significant positive association between the RAD51 C/C genotype and TNBC, with an adjusted odds ratio (OR) of 5.95 (p = 0.002). The homozygous C/C genotype was found in 68% of breast cancer cases and 20% of controls. The variant 135C allele of RAD51 increased TNBC risk. This is the first study linking single nucleotide polymorphisms of the RAD51 gene with TNBC incidence in the population of Polish women. In conclusion, RAD51 polymorphisms may be regarded as predictive factors of triple-negative breast cancer in the female population. Large studies are needed to confirm our findings.

  4. Null genotypes of GSTM1 and GSTT1 contribute to increased risk of diabetes mellitus: a meta-analysis.

    PubMed

    Zhang, Jingwen; Liu, Hu; Yan, Hongyi; Huang, Guoliang; Wang, Bin

    2013-04-15

    Diabetes mellitus (DM) is a common disease which results from various causes including genetic and environmental factors. Glutathione S-Transferase M1 (GSTM1) and Glutathione S-Transferase T1 (GSTT1) genes are polymorphic in human and the null genotypes lead to the absence of enzyme function. Many studies assessed the associations between GSTM1/GSTT1 null genotypes and DM risk but reported conflicting results. In order to get a more precise estimate of the associations of GSTM1/GSTT1 null genotypes with DM risk, we performed this meta-analysis. Published literature from PubMed, Embase and China Biology Medicine (CBM) databases was searched for eligible studies. Pooled odds ratios (OR) and corresponding 95% confidence intervals (95%CI) were calculated using a fixed- or random-effects model. 11 publications (a total of 2577 cases and 4572 controls) were finally included into this meta-analysis. Meta-analyses indicated that null genotypes of GSTM1/GSTT1 and dual null genotype of GSTM1-GSTT1 were all associated with increased risk of DM (GSTM1: OR random-effects=1.60, 95%CI 1.10-2.34, POR=0.014; GSTT1: OR random-effects=1.47, 95%CI 1.12-1.92, POR=0.005; GSTM1-GSTT1: OR fixed-effects=1.83, 95%CI 1.30-2.59, POR=0.001). Subgroup by ethnicity suggested significant associations between null genotypes of GSTM1 and GSTT1 and DM risk among Asians (GSTM1: OR random-effects=1.77, 95%CI 1.24-2.53, POR=0.002; GSTT1: OR random-effects=1.58, 95%CI 1.09-2.27, POR=0.015). This meta-analysis suggests null genotypes of GSTM1/GSTT1 and dual null genotype of GSTM1-GSTT1 are all associated with increased risk of DM, and null genotypes of GSTM1/GSTT1 and dual null genotype of GSTM1-GSTT1 are potential biomarkers of DM.

  5. Methods for genomic evaluation of a relatively small genotyped dairy population and effect of genotyped cow information in multiparity analyses.

    PubMed

    Lourenco, D A L; Misztal, I; Tsuruta, S; Aguilar, I; Ezra, E; Ron, M; Shirak, A; Weller, J I

    2014-03-01

    Methods for genomic prediction were evaluated for an Israeli Holstein dairy population of 713,686 cows and 1,305 progeny-tested bulls with genotypes. Inclusion of genotypes of 343 elite cows in an evaluation method that considers pedigree, phenotypes, and genotypes simultaneously was also evaluated. Two data sets were available: a complete data set with production records from 1985 through 2011, and a reduced data set with records after 2006 deleted. For each production trait, a multitrait animal model was used to compute traditional genetic evaluations for parities 1 through 3 as separate traits. Evaluations were calculated for the reduced and complete data sets. The evaluations from the reduced data set were used to calculate parent average for validation bulls, which was the benchmark for comparing gain in predictive ability from genomics. Genomic predictions for bulls in 2006 were calculated using a Bayesian regression method (BayesC), genomic BLUP (GBLUP), single-step GBLUP (ssGBLUP), and weighted ssGBLUP (WssGBLUP). Predictions using BayesC and GBLUP were calculated either with or without an index that included parent average. Genomic predictions that included elite cow genotypes were calculated using ssGBLUP and WssGBLUP. Predictive ability was assessed by coefficients of determination (R(2)) and regressions of predictions of 135 validation bulls with no daughters in 2006 on deregressed evaluations of those bulls in 2011. A reduction in R(2) and regression coefficients was observed from parities 1 through 3. Fat and protein yields had the lowest R(2) for all the methods. On average, R(2) was lowest for parent averages, followed by GBLUP, BayesC, ssGBLUP, and WssGBLUP. For some traits, R(2) for direct genomic values from BayesC and GBLUP were lower than those for parent averages. Genomic estimated breeding values using ssGBLUP were the least biased, and this method appears to be a suitable tool for genomic evaluation of a small genotyped population, as it

  6. [Risks related to radiation therapy].

    PubMed

    Bey, Pierre

    2015-01-01

    Radiotherapy is used for about 60% of cancer patients, in 2/3rd of the cases with a curative intent. If the frequent early secondary effects are transitory and with a limited impact, some late effects, even rare as cardiac troubles and secondary tumors, are now more important due to the increase of cure rate and due to the improvement of life expectancy of cured patients. Technologic improvements of the last decades reduced some of these risks, as the strengthening of human resources and the development of quality assurance procedures have contributed to reduce the risk of major accidents.

  7. Relative risk regression analysis of epidemiologic data.

    PubMed

    Prentice, R L

    1985-11-01

    Relative risk regression methods are described. These methods provide a unified approach to a range of data analysis problems in environmental risk assessment and in the study of disease risk factors more generally. Relative risk regression methods are most readily viewed as an outgrowth of Cox's regression and life model. They can also be viewed as a regression generalization of more classical epidemiologic procedures, such as that due to Mantel and Haenszel. In the context of an epidemiologic cohort study, relative risk regression methods extend conventional survival data methods and binary response (e.g., logistic) regression models by taking explicit account of the time to disease occurrence while allowing arbitrary baseline disease rates, general censorship, and time-varying risk factors. This latter feature is particularly relevant to many environmental risk assessment problems wherein one wishes to relate disease rates at a particular point in time to aspects of a preceding risk factor history. Relative risk regression methods also adapt readily to time-matched case-control studies and to certain less standard designs. The uses of relative risk regression methods are illustrated and the state of development of these procedures is discussed. It is argued that asymptotic partial likelihood estimation techniques are now well developed in the important special case in which the disease rates of interest have interpretations as counting process intensity functions. Estimation of relative risks processes corresponding to disease rates falling outside this class has, however, received limited attention. The general area of relative risk regression model criticism has, as yet, not been thoroughly studied, though a number of statistical groups are studying such features as tests of fit, residuals, diagnostics and graphical procedures. Most such studies have been restricted to exponential form relative risks as have simulation studies of relative risk estimation

  8. Genotype-environment correlations for language-related abilities: implications for typical and atypical learners.

    PubMed

    Gilger, J W; Ho, H Z; Whipple, A D; Spitz, R

    2001-01-01

    Recent behavioral genetic research has shown that genetic propensities are associated with individual differences in experiences, and thus, what may appear to be environmental effects can reflect genetic influence. This study examines passive genotype-environment correlations (GECs) for language-related abilities by comparing environment-child language associations in adoptive and nonadoptive families. The results provide evidence for the genetic mediation of the association between home environmental variables, such as the provision of toys and games, maternal involvement, and degree of intellectual/cultural orientation with children's language-related abilities. Developmental changes in passive GECs are considered, and the implications for typical and atypical learners are discussed.

  9. Arrhythmia Phenotype during Fetal Life Suggests LQTS Genotype: Risk Stratification of Perinatal Long QT Syndrome

    PubMed Central

    Cuneo, Bettina F.; Etheridge, Susan P.; Horigome, Hitoshi; Sallee, Denver; Moon-Grady, Anita; Weng, Hsin-Yi; Ackerman, Michael J.; Benson, D. Woodrow

    2014-01-01

    Background Fetal arrhythmias characteristic of long QT syndrome (LQTS) include torsades de pointes (TdP) and/or 2° atrioventricular block (AVB), but sinus bradycardia, defined as fetal heart rate <3% for gestational age, is most common. We hypothesized that prenatal rhythm phenotype might predict LQTS genotype and facilitate improved risk stratification and management. Method and Results Records of subjects exhibiting LQTS fetal arrhythmias were reviewed. Fetal echocardiograms, neonatal ECG, and genetic testing were evaluated. We studied 43 subjects exhibiting fetal LQTS arrhythmias: TdP ± 2° AVB (Group 1, n=7), isolated 2° AVB (Group 2, n=4) and sinus bradycardia (Group 3, n=32). Mutations in known LQTS genes were found in 95% of subjects tested. SCN5A mutations occurred in 71% of Group 1 while 91% of subjects with KCNQ1 mutations were in Group 3. Small numbers of subjects with KCNH2 mutations (n=4) were scattered in all 3 groups. Age at presentation did not differ among groups, and most subjects (n=42) were live born with gestational ages of 37.5±2.8 wks (mean±SD). However, those with TdP were typically delivered earlier. Prenatal treatment in Group 1 terminated (n=2) or improved (n=4) TdP. The neonatal QTc (mean±SE) of Group 1 (664.7±24.9) was longer than neonatal QTc in both Group 2 (491.2±27.6, p=0.004) and Group 3 (483.1±13.7, p<0.001). Despite medical and pacemaker therapy, postnatal cardiac arrest (n=4) or sudden death (n=1) was common among subjects with fetal/neonatal TdP. Conclusions Rhythm phenotypes of fetal LQTS have genotype-suggestive features which, along with QTc duration, may risk stratify perinatal management. PMID:23995044

  10. Indoor tanning and the MC1R genotype: risk prediction for basal cell carcinoma risk in young people.

    PubMed

    Molinaro, Annette M; Ferrucci, Leah M; Cartmel, Brenda; Loftfield, Erikka; Leffell, David J; Bale, Allen E; Mayne, Susan T

    2015-06-01

    Basal cell carcinoma (BCC) incidence is increasing, particularly in young people, and can be associated with significant morbidity and treatment costs. To identify young individuals at risk of BCC, we assessed existing melanoma or overall skin cancer risk prediction models and built a novel risk prediction model, with a focus on indoor tanning and the melanocortin 1 receptor gene, MC1R. We evaluated logistic regression models among 759 non-Hispanic whites from a case-control study of patients seen between 2006 and 2010 in New Haven, Connecticut. In our data, the adjusted area under the receiver operating characteristic curve (AUC) for a model by Han et al. (Int J Cancer. 2006;119(8):1976-1984) with 7 MC1R variants was 0.72 (95% confidence interval (CI): 0.66, 0.78), while that by Smith et al. (J Clin Oncol. 2012;30(15 suppl):8574) with MC1R and indoor tanning had an AUC of 0.69 (95% CI: 0.63, 0.75). Our base model had greater predictive ability than existing models and was significantly improved when we added ever-indoor tanning, burns from indoor tanning, and MC1R (AUC = 0.77, 95% CI: 0.74, 0.81). Our early-onset BCC risk prediction model incorporating MC1R and indoor tanning extends the work of other skin cancer risk prediction models, emphasizes the value of both genotype and indoor tanning in skin cancer risk prediction in young people, and should be validated with an independent cohort.

  11. Genotypes and phenotypes in cystic fibrosis and cystic fibrosis transmembrane regulator-related disorders.

    PubMed

    Bombieri, Cristina; Seia, Manuela; Castellani, Carlo

    2015-04-01

    Cystic fibrosis (CF) is characterized by remarkable variability in severity, rate of disease progression, and organ involvement. In spite of the considerable amount of data collected on the relationship between genotype and phenotype in CF, this is still a challenging matter of debate. Barriers to the interpretation of this connection are the large number of mutations in the CF transmembrane regulator (CFTR) gene, the difficulties in attributing several of them to a specific mode of dysfunction, and a limited number of the almost 2,000 mutations so far detected, which have been clinically annotated. In addition to that, the heterogeneity of clinical manifestations in individuals with the same CFTR genotypes indicates that disease severity is modulated by other genes and by environmental factors, of which the most relevant is possibly treatment in its aspects of appropriateness, early start in life, and adherence. The phenotype variability extends to conditions, named CFTR-related disorders, which are connected with CFTR dysfunction, but do not satisfy diagnostic criteria for CF. The current level of knowledge does not allow use of the CFTR genotype to predict individual outcome and cannot be used as an indicator of CF prognosis. This might change with the development of treatments targeting specific mutations and possibly capable of changing the natural history of the disease.

  12. Campylobacter jejuni capsular genotypes are related to Guillain-Barré syndrome.

    PubMed

    Heikema, A P; Islam, Z; Horst-Kreft, D; Huizinga, R; Jacobs, B C; Wagenaar, J A; Poly, F; Guerry, P; van Belkum, A; Parker, C T; Endtz, H P

    2015-09-01

    In about one in a thousand cases, a Campylobacter jejuni infection results in the severe polyneuropathy Guillain-Barré syndrome (GBS). It is established that sialylated lipo-oligosaccharides (LOS) of C. jejuni are a crucial virulence factor in GBS development. Frequent detection of C. jejuni with sialylated LOS in stools derived from patients with uncomplicated enteritis implies that additional bacterial factors should be involved. To assess whether the polysaccharide capsule is a marker for GBS, the capsular genotypes of two geographically distinct GBS-associated C. jejuni strain collections and an uncomplicated enteritis control collection were determined. Capsular genotyping of C. jejuni strains from the Netherlands revealed that three capsular genotypes, HS1/44c, HS2 and HS4c, were dominant in GBS-associated strains and capsular types HS1/44c and HS4c were significantly associated with GBS (p 0.05 and p 0.01, respectively) when compared with uncomplicated enteritis. In a GBS-associated strain collection from Bangladesh, capsular types HS23/36c, HS19 and HS41 were most prevalent and the capsular types HS19 and HS41 were associated with GBS (p 0.008 and p 0.02, respectively). Next, specific combinations of the LOS class and capsular genotypes were identified that were related to the occurrence of GBS. Multilocus sequence typing revealed restricted genetic diversity for strain populations with the capsular types HS2, HS19 and HS41. We conclude that capsular types HS1/44c, HS2, HS4c, HS19, HS23/36c and HS41 are markers for GBS. Besides a crucial role for sialylated LOS of C. jejuni in GBS pathogenesis, the identified capsules may contribute to GBS susceptibility. Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. All rights reserved.

  13. The CC-genotype of the cyclooxygenase-2 gene associates with decreased risk of nasopharyngeal carcinoma in a Tunisian population.

    PubMed

    Mamoghli, T; Douik, H; Mehri, S; Ghanem, A; Ben Chaabane, A; Bouassida, J; Kablouti, G; Harzallah, L; Gritli, S; Guemira, F

    2015-02-01

    The cyclooxygenase-2 (cox-2) pathway is now recognized to be important in human cancer development and progression. The gene for cox-2 carries a common single nucleotide polymorphism, T8473C, located within a potential functional region in the 3'-UTR of cox-2 gene was identified. We have investigated the frequencies of cox-2 genotypes in Tunisian population to determine whether that polymorphism was associated with the risk of nasopharyngeal carcinoma (NPC) in Tunisian population. One hundred and eighty-nine NPC patients were compared to 237 healthy controls. The cox-2 T8473C polymorphism was significantly associated with NPC (P=0.031). The CC-genotype and C allele were more frequent in control compared to patients group [CC: OR=0.37; P=0.013; 95% CI: 0.17-0.81; C: OR=0.72; P=0.032; 95% CI: 0.53-0.97]. Multivariate logistic regression analyses revealed that the CC-genotype was associated with a significantly decreased risk of NPC (P=0.013). Tumor sizes, histologic grade, presence of primary lymph node metastases, age or sex were not associated with cox-2 genotypes. We conclude that the CC-genotype and C allele of cox-2 T8473C gene polymorphism are associated with decreased risk of nasopharyngeal carcinoma in a Tunisian population. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  14. Specific BACE1 genotypes provide additional risk for late-onset Alzheimer disease in APOE epsilon 4 carriers.

    PubMed

    Gold, Gabriel; Blouin, Jean-Louis; Herrmann, François R; Michon, Agnès; Mulligan, Reinhild; Duriaux Saïl, Geneviève; Bouras, Constantin; Giannakopoulos, Panteleimon; Antonarakis, Stylianos E

    2003-05-15

    Alzheimer disease (AD) is characterized neuropathologically by neurofibrillary tangles and senile plaques. A key component of plaques is A beta, a polypeptide derived from A beta-precursor protein (APP) through proteolytic cleavage catalyzed by beta and gamma-secretase. We hypothesized that sequence variation in genes BACE1 (on chromosome 11q23.3) and BACE2 (on chromosome 21q22.3), which encode two closely related proteases that seem to act as the APP beta-secretase, may represent a genetic risk factor for AD. We analyzed the frequencies of single nucleotide polymorphisms (SNPs) in BACE1 and BACE2 genes in a community-based sample of 96 individuals with late-onset AD and 170 controls selected randomly among residents of the same community. The genotype data in both study groups did not demonstrate any association between AD and BACE1 or BACE2. After stratification for APOE status, however, an association between a BACE1 polymorphism located within codon V262 and AD in APOE epsilon 4 carriers was observed (P = 0.03). We conclude that sequence variation in the BACE1 or BACE 2 gene is not a significant risk factor for AD; however, a combination of a specific BACE1 allele and APOE epsilon 4 may increase the risk for Alzheimer disease over and above that attributed to APOE epsilon 4 alone.

  15. Cost-utility analysis of genotype-guided antiplatelet therapy in patients with moderate-to-high risk acute coronary syndrome and planned percutaneous coronary intervention.

    PubMed

    Patel, Vardhaman; Lin, Fang-Ju; Ojo, Olaitan; Rao, Sapna; Yu, Shengsheng; Zhan, Lin; Touchette, Daniel R

    2014-07-01

    Prasugrel is recommended over clopidogrel in poor/intermediate CYP2C19 metabolizers with acute coronary syndrome (ACS) and planned percutaneous coronary intervention (PCI), reducing the risk of ischemic events. CYP2C19 genetic testing can guide antiplatelet therapy in ACS patients. The purpose of this study was to evaluate the cost-utility of genotype-guided treatment, compared with prasugrel or generic clopidogrel treatment without genotyping, from the US healthcare provider's perspective. A decision model was developed to project lifetime economic and humanistic burden associated with clinical outcomes (myocardial infarction [MI], stroke and major bleeding) for the three strategies in patients with ACS. Probabilities, costs and age-adjusted quality of life were identified through systematic literature review. Incremental cost-utility ratios (ICURs) were calculated for the treatment strategies, with quality-adjusted life years (QALYs) as the primary effectiveness outcome. Relative risk of developing myocardial infarction and stroke between patients with and without variant CYP2C19 when receiving clopidogrel were estimated to be 1.34 and 3.66, respectively. One-way and probabilistic sensitivity analyses were performed. Clopidogrel cost USD19,147 and provided 10.03 QALYs versus prasugrel (USD21,425, 10.04 QALYs) and genotype-guided therapy (USD19,231, 10.05 QALYs). The ICUR of genotype-guided therapy compared with clopidogrel was USD4,200. Genotype-guided therapy provided more QALYs at lower costs compared with prasugrel. Results were sensitive to the cost of clopidogrel and relative risk of myocardial infarction and stroke between CYP2C19 variant vs. non-variant. Net monetary benefit curves showed that genotype-guided therapy had at least 70% likelihood of being the most cost-effective alternative at a willingness-to-pay of USD100,000/QALY. In comparison with clopidogrel, prasugrel therapy was more cost-effective with <21% certainty at willingness-to-pay of >USD170

  16. Cost-utility analysis of genotype-guided antiplatelet therapy in patients with moderate-to-high risk acute coronary syndrome and planned percutaneous coronary intervention

    PubMed Central

    Patel, Vardhaman; Lin, Fang-Ju; Ojo, Olaitan; Rao, Sapna; Yu, Shengsheng; Zhan, Lin; Touchette, Daniel R.

    2014-01-01

    Background Prasugrel is recommended over clopidogrel in poor/intermediate CYP2C19 metabolizers with acute coronary syndrome (ACS) and planned percutaneous coronary intervention (PCI), reducing the risk of ischemic events. CYP2C19 genetic testing can guide antiplatelet therapy in ACS patients. Objective The purpose of this study was to evaluate the cost-utility of genotype-guided treatment, compared with prasugrel or generic clopidogrel treatment without genotyping, from the US healthcare provider’s perspective. Methods A decision model was developed to project lifetime economic and humanistic burden associated with clinical outcomes (myocardial infarction [MI], stroke and major bleeding) for the three strategies in patients with ACS. Probabilities, costs and age-adjusted quality of life were identified through systematic literature review. Incremental cost-utility ratios (ICURs) were calculated for the treatment strategies, with quality-adjusted life years (QALYs) as the primary effectiveness outcome. Relative risk of developing myocardial infarction and stroke between patients with and without variant CYP2C19 when receiving clopidogrel were estimated to be 1.34 and 3.66, respectively. One-way and probabilistic sensitivity analyses were performed. Results Clopidogrel cost USD19,147 and provided 10.03 QALYs versus prasugrel (USD21,425, 10.04 QALYs) and genotype-guided therapy (USD19,231, 10.05 QALYs). The ICUR of genotype-guided therapy compared with clopidogrel was USD4,200. Genotype-guided therapy provided more QALYs at lower costs compared with prasugrel. Results were sensitive to the cost of clopidogrel and relative risk of myocardial infarction and stroke between CYP2C19 variant vs. non-variant. Net monetary benefit curves showed that genotype-guided therapy had at least 70% likelihood of being the most cost-effective alternative at a willingness-to-pay of USD100,000/QALY. In comparison with clopidogrel, prasugrel therapy was more cost-effective with <21

  17. Characterization of Brassica napus L. genotypes utilizing sequence-related amplified polymorphism and genotyping by sequencing in association with cluster analysis.

    PubMed

    Lees, Corey J; Li, Genyi; Duncan, Robert W

    2016-01-01

    Identifying parental combinations that exhibit high heterosis is a constant target for commercial Brassica napus L. hybrid development programs. Finding high heterotic parental combinations can require hundreds of test crosses and years of yield evaluation. Heterotic pool development could be used to divide breeding material into specific breeding pools and focus the number of parental combinations created. Here, we report the genotypic characterization of 79 B. napus genotypes by calculating genetic distance based on sequence-related amplified polymorphism (SRAP) and genotyping by sequencing (GBS) in association with a neighbour-joining clustering algorithm. Despite the different genotypic analyses, neighbour-joining cluster analysis based on genetic distance of SRAP and GBS produced similar clusters. Homology between SRAP and GBS clusters was approximately 77 % when manually comparing clusters and 68 % when comparing clusters using Compare2Trees. This research demonstrates that SRAP can have similar efficacy when compared to next-generation sequencing technology for heterotic pool classification. This information may provide an important breeding scaffold for the development of hybrid cultivars based upon genetic distance and cluster analysis.

  18. Analytical Validation of a Personalized Medicine APOL1 Genotyping Assay for Nondiabetic Chronic Kidney Disease Risk Assessment

    PubMed Central

    Zhang, Jinglan; Fedick, Anastasia; Wasserman, Stephanie; Zhao, Geping; Edelmann, Lisa; Bottinger, Erwin P.; Kornreich, Ruth; Scott, Stuart A.

    2017-01-01

    The incidence of chronic kidney disease (CKD) varies by ancestry, with African Americans (AA) having a threefold to fourfold higher rate than whites. Notably, two APOL1 alleles, termed G1 [c.(1072A>G; 1200T>G)] and G2 (c.1212_1217del6), are strongly associated with higher rates of nondiabetic CKD and an increased risk for hypertensive end-stage renal disease. This has prompted the opportunity to implement APOL1 testing to identify at-risk patients and modify other risk factors to reduce the progression of CKD to end-stage renal disease. We developed an APOL1 genotyping assay using multiplex allele-specific primer extension, and validated using 58 positive and negative controls. Genotyping results were completely concordant with Sanger sequencing, and both triplicate interrun and intrarun genotyping results were completely concordant. Multiethnic APOL1 allele frequencies were also determined by genotyping 7059 AA, Hispanic, and Asian individuals from the New York City metropolitan area. The AA, Hispanic, and Asian APOL1 G1 and G2 allele frequencies were 0.22 and 0.13, 0.037 and 0.025, and 0.013 and 0.004, respectively. Notably, approximately 14% of the AA population carried two risk alleles and are at increased risk for CKD, compared with <1% of the Hispanic and Asian populations. This novel APOL1 genotyping assay is robust and highly accurate, and represents one of the first personalized medicine clinical genetic tests for disease risk prediction. PMID:26773863

  19. Candidate Gene Analysis Using Imputed Genotypes: Cell Cycle SNPs and Ovarian Cancer Risk

    PubMed Central

    Goode, Ellen L.; Fridley, Brooke L.; Vierkant, Robert A.; Cunningham, Julie M.; Phelan, Catherine M.; Anderson, Stephanie; Rider, David N.; White, Kristin L.; Pankratz, V. Shane; Song, Honglin; Hogdall, Estrid; Kjaer, Susanne K.; Whittemore, Alice S.; DiCioccio, Richard; Ramus, Susan J.; Gayther, Simon A.; Schildkraut, Joellen M.; Pharaoh, Paul P.D.; Sellers, Thomas A.

    2009-01-01

    Polymorphisms in genes critical to cell cycle control are outstanding candidates for association with ovarian cancer risk; numerous genes have been interrogated by multiple research groups using differing tagging SNP sets. In order to maximize information gleaned from existing genotype data, we conducted a combined analysis of five independent studies of invasive epithelial ovarian cancer. Up to 2,120 cases and 3,382 controls were genotyped in the course of two collaborations at a variety of SNPs in 11 cell cycle genes (CDKN2C, CDKN1A, CCND3, CCND1, CCND2, CDKN1B, CDK2, CDK4, RB1, CDKN2D, CCNE1) and one gene region (CDKN2A-CDKN2B). Because of the semi-overlapping nature of the 123 assayed tagging SNPs, we performed multiple imputation based on fastPHASE using data from White non-Hispanic study participants and participants in the international HapMap Consortium and NIEHS SNPs Program. Logistic regression assuming a log-additive model was performed on combined and imputed data. We observed strengthened signals in imputation-based analyses at several SNPs, particularly CDKN2A-CDKN2B rs3731239, CCND1 rs602652, rs3212879, rs649392, and rs3212891, CDK2 rs2069391, rs2069414, and rs17528736, and CCNE1 rs3218036. These results lend evidence to a role of cell cycle genes in ovarian cancer etiology, suggest a reduced set of SNPs to target in additional cases and controls, and exemplify the utility of imputation in candidate gene studies. PMID:19258477

  20. Candidate gene analysis using imputed genotypes: cell cycle single-nucleotide polymorphisms and ovarian cancer risk.

    PubMed

    Goode, Ellen L; Fridley, Brooke L; Vierkant, Robert A; Cunningham, Julie M; Phelan, Catherine M; Anderson, Stephanie; Rider, David N; White, Kristin L; Pankratz, V Shane; Song, Honglin; Hogdall, Estrid; Kjaer, Susanne K; Whittemore, Alice S; DiCioccio, Richard; Ramus, Susan J; Gayther, Simon A; Schildkraut, Joellen M; Pharaoh, Paul P D; Sellers, Thomas A

    2009-03-01

    Polymorphisms in genes critical to cell cycle control are outstanding candidates for association with ovarian cancer risk; numerous genes have been interrogated by multiple research groups using differing tagging single-nucleotide polymorphism (SNP) sets. To maximize information gleaned from existing genotype data, we conducted a combined analysis of five independent studies of invasive epithelial ovarian cancer. Up to 2,120 cases and 3,382 controls were genotyped in the course of two collaborations at a variety of SNPs in 11 cell cycle genes (CDKN2C, CDKN1A, CCND3, CCND1, CCND2, CDKN1B, CDK2, CDK4, RB1, CDKN2D, and CCNE1) and one gene region (CDKN2A-CDKN2B). Because of the semi-overlapping nature of the 123 assayed tagging SNPs, we performed multiple imputation based on fastPHASE using data from White non-Hispanic study participants and participants in the international HapMap Consortium and National Institute of Environmental Health Sciences SNPs Program. Logistic regression assuming a log-additive model was done on combined and imputed data. We observed strengthened signals in imputation-based analyses at several SNPs, particularly CDKN2A-CDKN2B rs3731239; CCND1 rs602652, rs3212879, rs649392, and rs3212891; CDK2 rs2069391, rs2069414, and rs17528736; and CCNE1 rs3218036. These results exemplify the utility of imputation in candidate gene studies and lend evidence to a role of cell cycle genes in ovarian cancer etiology, suggest a reduced set of SNPs to target in additional cases and controls.

  1. Apolipoprotein E4 Genotype Does Not Increase Risk of HIV-associated Neurocognitive Disorders

    PubMed Central

    Morgan, E.E.; Woods, S.P.; Letendre, S.L.; Franklin, D.R.; Bloss, C.; Goate, A.; Heaton, R.K.; Collier, A.C.; Marra, C.M.; Gelman, B.B.; McArthur, J.C.; Morgello, S.; Simpson, D.M.; McCutchan, J.A.; Ellis, R.J.; Abramson, I.; Gamst, A.; Fennema-Notestine, C.; Smith, D.M.; Grant, I.; Vaida, F.; Clifford, D.B.

    2013-01-01

    This is a cross-sectional, observational study to evaluate the hypothesis that HIV-seropositive (HIV+) apolipoprotein E4 (APOE4) carriers are at increased risk for HIV-associated Neurocognitive Disorders (HAND) compared to APOE4 noncarriers with HIV in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) Group sample. APOE genotype was determined in 466 CHARTER participants with varying disease stages and histories of antiretroviral treatment who did not have severe psychiatric or medical comorbid conditions that preclude diagnosis of HAND. HAND diagnoses were based on results of comprehensive neurobehavioral evaluation and use of current neuroAIDS diagnostic criteria. HAND status consisting of two levels: neuropsychologically normal status (i.e., no HAND) and any HAND diagnosis (i.e., asymptomatic neurocognitive impairment, minor neurocognitive disorder, HIV-associated dementia). Logistic regression analyses revealed no association between APOE4 carrier status and HAND, and there were no interactions between APOE4 carrier status and ethnicity, age, substance use disorders, duration of infection, or nadir CD4. Results did not differ when analysis was restricted to symptomatic HAND, and no APOE4 gene dose-dependent relationship to HAND emerged. APOE4 status was not associated with concurrent HAND in this large, well-characterized sample. This does not preclude emergence of an association between APOE4 status and HAND as this population ages. Prospective, longitudinal studies are needed to examine APOE4 as a risk factor for neurocognitive decline, incident HAND at older ages, and potential associations with CSF amyloid. PMID:23408335

  2. Impact of COX2 genotype, ER status and body constitution on risk of early events in different treatment groups of breast cancer patients.

    PubMed

    Markkula, Andrea; Simonsson, Maria; Rosendahl, Ann H; Gaber, Alexander; Ingvar, Christian; Rose, Carsten; Jernström, Helena

    2014-10-15

    The COX2 rs5277 (306G>C) polymorphism has been associated with inflammation-associated cancers. In breast cancer, tumor COX-2 expression has been associated with increased estrogen levels in estrogen receptor (ER)-positive and activated Akt-pathway in ER-negative tumors. Our study investigated the impact of COX2 genotypes on early breast cancer events and treatment response in relation to tumor ER status and body constitution. In Sweden, between 2002 and 2008, 634 primary breast cancer patients, aged 25-99 years, were included. Disease-free survival was assessed for 570 rs5277-genotyped patients. Body measurements and questionnaires were obtained preoperatively. Clinical data, patient- and tumor-characteristics were obtained from questionnaires, patients' charts, population registries and pathology reports. Minor allele(C) frequency was 16.1%. Genotype was not linked to COX-2 tumor expression. Median follow-up was 5.1 years. G/G genotype was not associated with early events in patients with ER-positive tumors, adjusted HR 0.77 (0.46-1.29), but conferred an over 4-fold increased risk in patients with ER-negative tumors, adjusted HR 4.41 (1.21-16.02)(p(interaction) = 0.015). Chemotherapy-treated G/G-carriers with a breast volume ≥ 850 ml had an increased risk of early events irrespective of ER status, adjusted HR 8.99 (1.14-70.89). Endocrine-treated C-allele carriers with ER-positive tumors and a breast volume ≥ 850 ml had increased risk of early events, adjusted HR 2.30 (1.12-4.75). COX2 genotype, body constitution and ER status had a combined effect on the risk of early events and treatment response. The high risk for early events in certain subgroups of patients suggests that COX2 genotype in combination with body measurements may identify patients in need of more personalized treatment.

  3. Genetic Risk Can Be Decreased: Quitting Smoking Decreases and Delays Lung Cancer for Smokers With High and Low CHRNA5 Risk Genotypes - A Meta-Analysis.

    PubMed

    Chen, Li-Shiun; Baker, Timothy; Hung, Rayjean J; Horton, Amy; Culverhouse, Robert; Hartz, Sarah; Saccone, Nancy; Cheng, Iona; Deng, Bo; Han, Younghun; Hansen, Helen M; Horsman, Janet; Kim, Claire; Rosenberger, Albert; Aben, Katja K; Andrew, Angeline S; Chang, Shen-Chih; Saum, Kai-Uwe; Dienemann, Hendrik; Hatsukami, Dorothy K; Johnson, Eric O; Pande, Mala; Wrensch, Margaret R; McLaughlin, John; Skaug, Vidar; van der Heijden, Erik H; Wampfler, Jason; Wenzlaff, Angela; Woll, Penella; Zienolddiny, Shanbeh; Bickeböller, Heike; Brenner, Hermann; Duell, Eric J; Haugen, Aage; Brüske, Irene; Kiemeney, Lambertus A; Lazarus, Philip; Le Marchand, Loic; Liu, Geoffrey; Mayordomo, Jose; Risch, Angela; Schwartz, Ann G; Teare, M Dawn; Wu, Xifeng; Wiencke, John K; Yang, Ping; Zhang, Zuo-Feng; Spitz, Margaret R; Amos, Christopher I; Bierut, Laura J

    2016-09-01

    Recent meta-analyses show that individuals with high risk variants in CHRNA5 on chromosome 15q25 are likely to develop lung cancer earlier than those with low-risk genotypes. The same high-risk genetic variants also predict nicotine dependence and delayed smoking cessation. It is unclear whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not. Meta-analyses examined the association between smoking cessation and lung cancer risk in 15 studies of individuals with European ancestry who possessed varying rs16969968 genotypes (N=12,690 ever smokers, including 6988 cases of lung cancer and 5702 controls) in the International Lung Cancer Consortium. Smoking cessation (former vs. current smokers) was associated with a lower likelihood of lung cancer (OR=0.48, 95%CI=0.30-0.75, p=0.0015). Among lung cancer patients, smoking cessation was associated with a 7-year delay in median age of lung cancer diagnosis (HR=0.68, 95%CI=0.61-0.77, p=4.9∗10(-10)). The CHRNA5 rs16969968 risk genotype (AA) was associated with increased risk and earlier diagnosis for lung cancer, but the beneficial effects of smoking cessation were very similar in those with and without the risk genotype. We demonstrate that quitting smoking is highly beneficial in reducing lung cancer risks for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Smokers with high-risk CHRNA5 genotypes, on average, can largely eliminate their elevated genetic risk for lung cancer by quitting smoking- cutting their risk of lung cancer in half and delaying its onset by 7years for those who develop it. These results: 1) underscore the potential value of smoking cessation for all smokers, 2) suggest that CHRNA5 rs16969968 genotype affects lung cancer diagnosis through its effects on smoking, and 3) have potential value for framing preventive interventions for those who smoke. Copyright © 2016

  4. Opioid neuropeptide genotypes in relation to heroin abuse: Dopamine tone contributes to reversed mesolimbic proenkephalin expression

    PubMed Central

    Nikoshkov, Andrej; Drakenberg, Katarina; Wang, Xinyu; Horvath, Monika Cs.; Keller, Eva; Hurd, Yasmin L.

    2008-01-01

    Striatal enkephalin and dynorphin opioid systems mediate reward and negative affect, respectively, relevant to addiction disorders. We examined polymorphisms of proenkephalin (PENK) and prodynorphin (PDYN) genes in relation to heroin abuse and gene expression in the human striatum and the relevance of genetic dopaminergic tone, critical for drug reward and striatal function. Heroin abuse was significantly associated with PENK polymorphic 3′ UTR dinucleotide (CA) repeats; 79% of subjects homozygous for the 79-bp allele were heroin abusers. Such individuals tended to express higher PENK mRNA than the 81-bp homozygotes, but PENK levels within the nucleus accumbens (NAc) shell were most strongly correlated to catecholamine-O-methyltransferase (COMT) genotype. Control Met/Met individuals expressed lower PENK mRNA than Val carriers, a pattern reversed in heroin users. Up-regulation of NAc PENK in Met/Met heroin abusers was accompanied by impaired tyrosine hydroxylase (TH) mRNA expression in mesolimbic dopamine neurons. In contrast to PENK, no association was detected between PDYN genotype (68-bp repeat element containing one to four copies of AP-1 binding sites in the promoter region) and heroin abuse, although there was a clear functional association with striatal PDYN mRNA expression: an increased number of inducible repeats (three and four) correlated with higher PDYN levels than adult or fetal subjects with noninducible (one and two) alleles. Moreover, PDYN expression was not related to COMT genotype. Altogether, the data suggest that dysfunction of the opioid reward system is significantly linked to opiate abuse vulnerability and that heroin use alters the apparent influence of heritable dopamine tone on mesolimbic PENK and TH function. PMID:18184800

  5. Vascular endothelial growth factor genotypes, haplotypes, gender, and the risk of non-small cell lung cancer.

    PubMed

    Zhai, Rihong; Liu, Geoffrey; Zhou, Wei; Su, Li; Heist, Rebecca Suk; Lynch, Thomas J; Wain, John C; Asomaning, Kofi; Lin, Xihong; Christiani, David C

    2008-01-15

    The vascular endothelial growth factor (VEGF) is a major mediator of angiogenesis involving tumor growth and metastasis. Polymorphisms in the VEGF gene may regulate VEGF production. In this large case-control study, we investigated whether functional polymorphisms (-460C/T, +405C/G, +936C/T) in the VEGF gene are associated with the risk of non-small cell lung cancer (NSCLC). VEGF genotypes and haplotypes were determined in 1,900 Caucasian patients with NSCLC and 1,458 healthy controls. The results were analyzed using logistic regression models, adjusting for age, gender, smoking status, pack-years of smoking, and years since smoking cessation (for ex-smokers). The false-positive report probability was estimated for the observed odds ratios (OR). There were no overall associations between individual VEGF genotypes and the risk of NSCLC. Stratified analysis suggested that the combined +405CC+CG genotype was significantly associated with increased risk of lung adenocarcinoma in males (adjusted OR, 1.40; 95% confidence interval, 1.03-1.87). In haplotype analysis, haplotypes were globally associated with differences between cases and controls in males (P = 0.03). Specifically, the -460T/+405G/+936C haplotype was significantly (P = 0.02) associated with decreased risk of adenocarcinoma in males when compared with the most common CGC haplotype (adjusted OR, 0.76; 95% confidence interval, 0.50-0.98). None of the VEGF genotypes and haplotypes studied significantly influenced the susceptibility to NSCLC in females. Polymorphisms of -460C/T, +405C/G, and +936C/T in the VEGF gene do not play a major role in NSCLC risk. However, we could not exclude a minor role for the +405CC+CG genotypes and the 460T/+405G/+936C haplotype in lung adenocarcinogenesis in male Caucasians.

  6. Variation at NRG1 genotype related to modulation of small-world properties of the functional cortical network.

    PubMed

    Lubeiro, Alba; Gomez-Pilar, Javier; Martín, Oscar; Palomino, Aitor; Fernández, Myriam; González-Pinto, Ana; Poza, Jesús; Hornero, Roberto; Molina, Vicente

    2017-02-01

    Functional brain networks possess significant small-world (SW) properties. Genetic variation relevant to both inhibitory and excitatory transmission may contribute to modulate these properties. In healthy controls, genotypic variation in Neuregulin 1 (NRG1) related to the risk of psychosis (risk alleles) would contribute to functional SW modulation of the cortical network. Electroencephalographic activity during an odd-ball task was recorded in 144 healthy controls. Then, small-worldness (SWn) was calculated in five frequency bands (i.e., theta, alpha, beta1, beta2 and gamma) for baseline (from -300 to the stimulus onset) and response (150-450 ms post-target stimulus) windows. The SWn modulation was defined as the difference in SWn between both windows. Association between SWn modulation and carrying the risk allele for three single nucleotide polymorphisms (SNP) of NRG1 (i.e., rs6468119, rs6994992 and rs7005606) was assessed. A significant association between three SNPs of NRG1 and the SWn modulation was found, specifically: NRG1 rs6468119 in alpha and beta1 bands; NRG1 rs6994992 in theta band; and NRG1 rs7005606 in theta and beta1 bands. Genetic variation at NRG1 may influence functional brain connectivity through the modulation of SWn properties of the cortical network.

  7. [Epidemiology and characterization of high-risk genotypes of human Papillomavirus in a population of sexually active adolescents in Ouagadougou].

    PubMed

    Ouédraogo, C M R; Rahimy, R M L; Zohoncon, T M; Djigma, F W; Yonli, A T; Ouermi, D; Sanni, A; Lankoande, J; Simpore, J

    2015-10-01

    This cross-sectional study was to determine the prevalence and characterization of high-risk HPV genotypes circulating among adolescents in Ouagadougou. From September to December 2013, 200 adolescents recruited from a youth counseling center have voluntarily accepted a swab of the endocervical canal. The identification of the genotypes of the human Papillomavirus (HPV) was performed by real-time polymerase chain reaction technique. The mean age of adolescents was 18.7±0.7 years and 83/200 adolescents were positive for at least one high-risk genotype HPV a prevalence of 41.5%. Twelve genotypes corresponding to 136 infections were characterized: HPV 52 (22.8%), HPV 59 (14.0%), HPV 39 (13.2%), HPV 35 (10.3%), HPV 51 (10.3%), HPV 56 (8.8%), HPV 16 (5.2%), HPV 18 (5.2%), HPV 58 (4.4%), HPV 31 (3.6%), HPV 45 (1.5%), HPV 33 (0.7%). Multiple infections (2-5 virus) statistically associated with age (p=0.0318) was detected in 42.2% of infected females. If the number of sexual partners was statistically associated with the porting of HPV (OR=2.18; 95% CI=1.17 to 4.09), early sexual intercourse and the recent change of sexual partner were not (p>0,05) CONCLUSION: The prevalence of carriage of HPV in this study is high, as described in young people at the start of sexual activity. Identified genotypes are different from those targeted by prophylactic vaccines currently available. A larger study to map genotypes of high-risk HPV circulating in West Africa is necessary for a suitable vaccine. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  8. Cytochrome CYP2E1 phenotyping and genotyping in the evaluation of health risks from exposure to polluted environments.

    PubMed

    Lucas, D; Ferrara, R; Gonzales, E; Albores, A; Manno, M; Berthou, F

    2001-10-15

    Humans are exposed to over 70,000 man-made chemicals including drugs, food additives, herbicides, pesticides, and industrial agents. It is well established that environmental chemicals are the cause of numerous human diseases including cancer. In most cases, chemical carcinogens require metabolic activation, which is mainly achieved by P450s enzymes. CYP2E1 is of clinical relevance because it is inducible by ethanol, and it metabolizes many common organic solvents such as benzene, alcohols and halogenated solvents. Therefore, alteration in the level of CYP2E1 might influence the health effects of the environmental pollutants. This hypothesis needs to be validated by epidemiological studies and the objective of the "Biomed-2" project was to develop new tests to assess the individual metabolic capacity of workers exposed to volatile organic compounds in order to predict their occupational risk. In vivo chlorzoxazone 6-hydroxylation was validated as a non-invasive and selective test for the determination of liver CYP2E1 activity. Preliminary data in workers exposed to organic solvents indicated that chlorzoxazone metabolism may be a biomarker of occupational exposure to organic solvents. Other approaches, such as use of salicylate as catalytic probe or measurement of catalytic activity in lymphocytes, were not conclusive. Attempts to use CYP2E1 genotyping for estimating human risks from chemical exposure did not bring convincing data as genetic polymorphism of CYP2E1 could not be clearly related to its catalytic activity.

  9. Occurrence, genotyping, shiga toxin genes and associated risk factors of E. coli isolated from dairy farms, handlers and milk consumers.

    PubMed

    Awadallah, M A; Ahmed, H A; Merwad, A M; Selim, M A

    2016-11-01

    The objectives of the current study were to determine the occurrence and genotypes of E. coli in dairy farms, workers and milk consumers and to evaluate risk factors associated with contamination of milk in dairy farms. Molecular characterization of shiga toxin associated genes and enterobacterial repetitive intergenic consensus-PCR (ERIC-PCR) finger printing of E. coli from different sources were also studied. Paired milk samples and rectal swabs from 125 dairy cows, rectal swabs from 82 calves and hand swabs from 45 dairy workers from five dairy farms were collected. In addition, 100 stool samples from 70 diarrheic and 30 healthy humans were collected and examined for the presence of E. coli. E. coli was isolated from milk (22.4%), dairy cattle feces (33.6%), calf feces (35.4%), dairy worker hand swabs (11.1%) and stools of milk consumers (2%, from diarrheic patients only). Only stx1 was identified in seven of 12 E. coli O125 isolated from different sources. High genetic diversity was determined (Simpson's index of diversity, D = 1) and E. coli O125 isolates were classified into 12 distinct profiles, E1-E12. The dendrogram analysis showed that two main clusters were generated. Mastitis in dairy cows was considered a risk factor associated with contamination of the produced milk with E. coli. The isolation of E. coli from rectal swabs of dairy cows and calves poses a zoonotic risk through consumption of unpasteurized contaminated dairy milk. Educational awareness should be developed to address risks related to consumption of raw milk.

  10. Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia, and Alzheimer disease in Northern Ireland.

    PubMed

    McIlroy, Stephen P; Dynan, Kevin B; Lawson, John T; Patterson, Christopher C; Passmore, A Peter

    2002-10-01

    Elevated plasma homocysteine level has been associated with increased risk for cardiovascular and cerebrovascular disease. Variation in the levels of this amino acid has been shown to be due to nutritional status and methylenetetrahydrofolate reductase (MTHFR) genotype. Under a case-control design we compared fasting levels of homocysteine and MTHFR genotypes in groups of subjects consisting of stroke, vascular dementia (VaD), and Alzheimer disease patients and normal controls from Northern Ireland. A significant increase in plasma homocysteine was observed in all 3 disease groups compared with controls. This remained significant after allowance for confounding factors (age, sex, hypertension, cholesterol, smoking, creatinine, and nutritional measures). MTHFR genotype was not found to influence homocysteine levels, although the T allele was found to increase risk for VaD and perhaps dementia after stroke. We report that moderately high plasma levels of homocysteine are associated with stroke, VaD, and Alzheimer disease. This is not due to vascular risk factors, nutritional status, or MTHFR genotype.

  11. Association of water spectral indices with plant and soil water relations in contrasting wheat genotypes

    PubMed Central

    Gutierrez, Mario; Reynolds, Matthew P.; Klatt, Arthur R.

    2010-01-01

    Spectral reflectance indices can be used to estimate the water status of plants in a rapid, non-destructive manner. Water spectral indices were measured on wheat under a range of water-deficit conditions in field-based yield trials to establish their relationship with water relations parameters as well as available volumetric soil water (AVSW) to indicate soil water extraction patterns. Three types of wheat germplasm were studied which showed a range of drought adaptation; near-isomorphic sister lines from an elite/elite cross, advanced breeding lines, and lines derived from interspecific hybridization with wild relatives (synthetic derivative lines). Five water spectral indices (one water index and four normalized water indices) based on near infrared wavelengths were determined under field conditions between the booting and grain-filling stages of crop development. Among all water spectral indices, one in particular, which was denominated as NWI-3, showed the most consistent associations with water relations parameters and demonstrated the strongest associations in all three germplasm sets. NWI-3 showed a strong linear relationship (r2 >0.6–0.8) with leaf water potential (ψleaf) across a broad range of values (–2.0 to –4.0 MPa) that were determined by natural variation in the environment associated with intra- and inter-seasonal affects. Association observed between NWI-3 and canopy temperature (CT) was consistent with the idea that genotypes with a better hydration status have a larger water flux (increased stomatal conductance) during the day. NWI-3 was also related to soil water potential (ψsoil) and AVSW, indicating that drought-adapted lines could extract more water from deeper soil profiles to maintain favourable water relations. NWI-3 was sufficiently sensitive to detect genotypic differences (indicated by phenotypic and genetic correlations) in water status at the canopy and soil levels indicating its potential application in precision phenotyping

  12. Inverse association of the obesity predisposing FTO rs9939609 genotype with alcohol consumption and risk for alcohol dependence.

    PubMed

    Sobczyk-Kopciol, Agnieszka; Broda, Grazyna; Wojnar, Marcin; Kurjata, Pawel; Jakubczyk, Andrzej; Klimkiewicz, Anna; Ploski, Rafal

    2011-04-01

    To investigate whether the FTO rs9939609 A allele (a risk factor for obesity) is associated with measures of alcohol consumption. Population-based cross-sectional study and two case-control studies. Poland and the Warsaw area. A total of 6584 subjects from the WOBASZ survey and two cohorts of alcohol-dependent patients (n = 145 and n = 148). Questionnaire data analysis, rs9939609 typing. Among individuals drinking alcohol, the obesity-associated AA genotype was also associated with lower total ethanol consumption [sex-, age- and body mass index (BMI)-adjusted difference: 0.21 g/day, P = 0.012] and distinct drinking habits with relatively low frequency of drinks but larger volume consumed at a time as evidenced by (i) association between AA and frequency/amount of typical drinks (P = 0.023, multiple logistic regression analysis); (ii) inverse correlation between AA and drink frequency adjusted for drink size (P = 0.007 for distilled spirits, P = 0.018 for beer); (iii) decreased frequency of AA [odds ratio (OR) = 0.46, P = 0.0004] among those who drank small amounts of distilled spirits (≤ 100 ml at a time) but frequently (≥ 1-2 times/week). A decrease of AA was also found in both cohorts of alcohol-dependent patients versus geographically matched subjects from WOBASZ yielding a pooled estimate of OR = 0.59, confidence interval (CI): 0.40-0.88, P = 0.008. Exploratory analysis showed that those with rs9939609 AA reported lower (by 1.22) mean number of cigarettes/day during a year of most intense smoking (P = 0.003) and were older at start of smoking by 0.44 years (P = 0.016). The FTO AA genotype, independently from its effect on BMI, is associated with measures of ethanol consumption and possibly tobacco smoking. © 2010 The Authors, Addiction © 2010 Society for the Study of Addiction.

  13. Combining ability, heritability and genotypic relations of different physiological traits in cacao hybrids

    PubMed Central

    de Almeida, Alex-Alan Furtado; Branco, Márcia Christina da Silva; Costa, Marcio Gilberto Cardoso; Ahnert, Dario

    2017-01-01

    Selecting parents and evaluating progenies is a very important step in breeding programs and involves approaches such as understanding the initial stages of growth and characterizing the variability among genotypes for different parameters, such as physiological, growth, biomass partitioning and nutrient translocation to the aerial part. In these cases, facilitating tools can be used to understand the involved gene dynamics, such as diallel crosses and genetic and phenotypic correlations. Our main hypothesis is that the contrasting phenotypes of these parental genotypes of cocoa used are due to genetic factors, and progenies derived from crosses of these parental genotypes are useful for breeding programs related to plant architecture, physiological parameters and translocation of mineral nutrients. We aimed to evaluate the combining abilities in progenies of cacao (Theobroma cacao L) originating from contrasting parents for canopy vigor. Emphasis was given to the evaluation of morphological and physiological parameters and the phenotypic and genotypic correlations to understand the dynamics of the action of the genes involved, as well as in expression profile from genes of gibberellins biosynthesis pathway in the parents. Fifteen F1 progenies were obtained from crosses of six clones (IMC 67, P4B, PUCALA, SCA 6, SCA 24 and SJ 02) that were evaluated in a randomized complete block design with four replicates of 12 plants per progeny, in a balanced half table diallel scheme. It is possible to identify and select plants and progenies of low, medium and high height, as there is expressive genetic variability for the evaluated parameters, some of these on higher additive effects, others on larger nonadditive effects and others under a balance of these effects. Most physiological parameters evaluated show that for selection of plants with the desired performance, no complex breeding methods would be necessary due to the high and medium heritability observed. Strong

  14. Combining ability, heritability and genotypic relations of different physiological traits in cacao hybrids.

    PubMed

    Pereira, Allan Silva; de Almeida, Alex-Alan Furtado; Branco, Márcia Christina da Silva; Costa, Marcio Gilberto Cardoso; Ahnert, Dario

    2017-01-01

    Selecting parents and evaluating progenies is a very important step in breeding programs and involves approaches such as understanding the initial stages of growth and characterizing the variability among genotypes for different parameters, such as physiological, growth, biomass partitioning and nutrient translocation to the aerial part. In these cases, facilitating tools can be used to understand the involved gene dynamics, such as diallel crosses and genetic and phenotypic correlations. Our main hypothesis is that the contrasting phenotypes of these parental genotypes of cocoa used are due to genetic factors, and progenies derived from crosses of these parental genotypes are useful for breeding programs related to plant architecture, physiological parameters and translocation of mineral nutrients. We aimed to evaluate the combining abilities in progenies of cacao (Theobroma cacao L) originating from contrasting parents for canopy vigor. Emphasis was given to the evaluation of morphological and physiological parameters and the phenotypic and genotypic correlations to understand the dynamics of the action of the genes involved, as well as in expression profile from genes of gibberellins biosynthesis pathway in the parents. Fifteen F1 progenies were obtained from crosses of six clones (IMC 67, P4B, PUCALA, SCA 6, SCA 24 and SJ 02) that were evaluated in a randomized complete block design with four replicates of 12 plants per progeny, in a balanced half table diallel scheme. It is possible to identify and select plants and progenies of low, medium and high height, as there is expressive genetic variability for the evaluated parameters, some of these on higher additive effects, others on larger nonadditive effects and others under a balance of these effects. Most physiological parameters evaluated show that for selection of plants with the desired performance, no complex breeding methods would be necessary due to the high and medium heritability observed. Strong

  15. Severity of chest disease in cystic fibrosis patients in relation to their genotypes.

    PubMed

    al-Jader, L N; Meredith, A L; Ryley, H C; Cheadle, J P; Maguire, S; Owen, G; Goodchild, M C; Harper, P S

    1992-12-01

    A detailed comparison of the severity of chest disease with mutational status was carried out by cross sectional study of 127 cystic fibrosis patients, aged 1 to 31 years, living in Wales. Lung disease was classified according to severity, depending on pulmonary function tests (carried out on 76 patients) and chest radiograph status; information was obtained also on age at diagnosis in relation to severity of chest disease and colonisation with Pseudomonas species. Genotypes were determined by analysis for the mutations delta F508, delta I507, G551D, R553X, G542X, R117H, R560T, 1717--IG > A, and 621 + 1G > T. CF patients homozygous positive and heterozygous for the delta F508 deletion showed a significant decline of lung function with age. Unlike other studies, we did not find patients homozygous positive for the delta F508 deletion to have poorer lung function compared with heterozygous patients. Patients with the genotype 621 + IG > T/delta F508 tended to have more severe chest disease than the delta F508 homozygous patients in the same age group. There was some evidence that four patients heterozygous for R117H have mild chest disease.

  16. Severity of chest disease in cystic fibrosis patients in relation to their genotypes.

    PubMed Central

    al-Jader, L N; Meredith, A L; Ryley, H C; Cheadle, J P; Maguire, S; Owen, G; Goodchild, M C; Harper, P S

    1992-01-01

    A detailed comparison of the severity of chest disease with mutational status was carried out by cross sectional study of 127 cystic fibrosis patients, aged 1 to 31 years, living in Wales. Lung disease was classified according to severity, depending on pulmonary function tests (carried out on 76 patients) and chest radiograph status; information was obtained also on age at diagnosis in relation to severity of chest disease and colonisation with Pseudomonas species. Genotypes were determined by analysis for the mutations delta F508, delta I507, G551D, R553X, G542X, R117H, R560T, 1717--IG > A, and 621 + 1G > T. CF patients homozygous positive and heterozygous for the delta F508 deletion showed a significant decline of lung function with age. Unlike other studies, we did not find patients homozygous positive for the delta F508 deletion to have poorer lung function compared with heterozygous patients. Patients with the genotype 621 + IG > T/delta F508 tended to have more severe chest disease than the delta F508 homozygous patients in the same age group. There was some evidence that four patients heterozygous for R117H have mild chest disease. PMID:1479603

  17. ABCA7 Genotypes Confer Alzheimer's Disease Risk by Modulating Amyloid-β Pathology.

    PubMed

    Zhao, Qing-Fei; Wan, Yu; Wang, Hui-Fu; Sun, Fu-Rong; Hao, Xiao-Ke; Tan, Meng-Shan; Tan, Chen-Chen; Zhang, Dao-Qiang; Tan, Lan; Yu, Jin-Tai

    2016-03-21

    ABCA7 gene has been identified as a strong genetic locus for Alzheimer's disease (AD) susceptibility in genome wide association studies (GWAS). However, the possible roles of ABCA7 variants in AD pathology were not specifically assessed. Using tagger methods, we extracted 15 targeted ABCA7 loci to investigate their associations with cerebrospinal fluid (CSF) and neuroimaging markers in Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. Finally, although we did not detect any significant associations of previously published GWAS SNPs (rs3764650 and rs78117248) with all the CSF (Aβ1 - 42, T-tau, and P-tau) and neuroimaging markers, three other variants (rs3752242, rs3752240, and rs4147912) at ABCA7 loci were detected to show significant associations with amyloid deposition on AV-45 PET in brain. Moreover, haplotype and subgroup analysis confirmed these significant findings. Furthermore, there were no remarkable correlations between ABCA7 variants and neuronal degeneration biomarkers (elevated CSF tau, brain structure atrophy, and hypometabolism on imaging) in this study. Thus, our study suggested that ABCA7 genotypes contribute to the AD risk through involvement in amyloid-β deposition on in vivo imaging, but not in tau pathology, brain atrophy, or decreased glucose metabolism.

  18. Genome-wide interaction of genotype by erythrocyte n-3 PUFAs contributes to phenotypic variance of diabetes-related traits

    USDA-ARS?s Scientific Manuscript database

    While genome-wide association studies (GWAS) and candidate gene approach have identified many genetic variants that contribute to disease risk as main effects, the impact of genotype by environment (GxE) interactions remains rather under-surveyed. The present study aimed to examine variance contribu...

  19. Comparing triage algorithms using HPV DNA genotyping, HPV E7 mRNA detection and cytology in high-risk HPV DNA-positive women.

    PubMed

    Luttmer, Roosmarijn; Berkhof, Johannes; Dijkstra, Maaike G; van Kemenade, Folkert J; Snijders, Peter J F; Heideman, Daniëlle A M; Meijer, Chris J L M

    2015-06-01

    High-risk human papillomavirus (hrHPV) DNA positive women require triage testing to identify those with high-grade cervical intraepithelial neoplasia or cancer (≥CIN2). Comparing three triage algorithms (1) E7 mRNA testing following HPV16/18/31/33/45/52/58 genotyping (E7 mRNA test), (2) HPV16/18 DNA genotyping and (3) cytology, for ≥CIN2 detection in hrHPV DNA-positive women. hrHPV DNA-positive women aged 18-63 years visiting gynecology outpatient clinics were included in a prospective observational cohort study. From these women a cervical scrape and colposcopy-directed biopsies were obtained. Cervical scrapes were evaluated by cytology, HPV DNA genotyping by bead-based multiplex genotyping of GP5+6+-PCR-products, and presence of HPV16/18/31/33/45/52/58 E7 mRNA using nucleic acid sequence-based amplification (NASBA) in DNA positive women for respective HPV types. Sensitivities and specificities for ≥CIN2 were compared between E7 mRNA test and HPV16/18 DNA genotyping in the total group (n=348), and E7 mRNA test and cytology in a subgroup of women referred for non-cervix-related gynecological complaints (n=133). Sensitivity for ≥CIN2 of the E7 mRNA test was slightly higher than that of HPV16/18 DNA genotyping (66.9% versus 60.9%; ratio 1.10, 95% CI: 1.0002-1.21), at similar specificity (54.8% versus 52.3%; ratio 1.05, 95% CI: 0.93-1.18). Neither sensitivity nor specificity of the E7 mRNA test differed significantly from that of cytology (sensitivity: 68.8% versus 75.0%; ratio 0.92, 95% CI: 0.72-1.17; specificity: 59.4% versus 65.3%; ratio 0.91, 95% CI: 0.75-1.10). For detection of ≥CIN2 in hrHPV DNA-positive women, an algorithm including E7 mRNA testing following HPV16/18/31/33/45/52/58 DNA genotyping performs similar to HPV16/18 DNA genotyping or cytology. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Prediction of sepsis-related outcomes in neonates through systematic genotyping of polymorphisms in genes for innate immunity and inflammation: a narrative review and critical perspective.

    PubMed

    Carvalho, Juliana Kilesse; Moore, Daniella Batalha; Luz, Ricardo Alves; Xavier-Elsas, Pedro Paulo; Gaspar-Elsas, Maria Ignez Capella

    2013-01-01

    Neonatal sepsis is associated with premature birth and maternal infection. Large-scale studies seek to define markers that identify neonates at risk of developing sepsis. Here, we examine whether the scientific evidence supports systematic use of polymorphism genotyping in cytokine and innate immunity genes, to identify neonates at increased risk of sepsis. Narrative literature review conducted at Fernandes Figueira Institute, Brazil. The literature was searched in PubMed, Embase (Excerpta Medica Database), Lilacs (Literatura Latino-Americana e do Caribe em Ciências da Saúde), SciELO (Scientific Electronic Library Online) and Cochrane Library. From > 400,000 references, 548 were retrieved based on inclusion/exclusion criteria; 22 were selected for detailed analysis after quality assessment. The studies retrieved addressed the impact of gene polymorphisms relating to immune mechanisms (most often TNF-a, LT-a, IL-6, IL-1β, IL-1ra, L-selectin, CD14 and MBL) or inflammatory mechanisms (ACE and angiotensin II receptors; secretory PLA2; and hemostatic factors). Despite initial reports suggesting positive associations between specific polymorphisms and increased risk of sepsis, the accumulated evidence has not confirmed that any of them have predictive power to justify systematic genotyping. Sepsis prediction through systematic genotyping needs to be reevaluated, based on studies that demonstrate the functional impact of gene polymorphisms and epidemiological differences among ethnically distinct populations.

  1. Apolipoprotein E3/E3 genotype decreases the risk of pituitary dysfunction after traumatic brain injury due to various causes: preliminary data.

    PubMed

    Tanriverdi, Fatih; Taheri, Serpil; Ulutabanca, Halil; Caglayan, Ahmet Okay; Ozkul, Yusuf; Dundar, Munis; Selcuklu, Ahmet; Unluhizarci, Kursad; Casanueva, Felipe F; Kelestimur, Fahrettin

    2008-09-01

    Traumatic brain injury (TBI) is a devastating public health problem which may result in hypopituitarism. However, the mechanisms and the risk factors responsible for hypothalamo-pituitary dysfunction due to TBI are still unclear. Although APO E is one of the most abundant protein in hypothalamo-pituitary region, there is no study investigating the relation between APO E polymorphism and TBI-induced hypopituitarism. This study was undertaken to determine whether APO E genotypes modulate the pituitary dysfunction risk after TBI due to various causes, including traffic accident, boxing, and kickboxing. Ninety-three patients with TBI (mean age, 30.61 +/- 1.25 years) and 27 healthy controls (mean age, 29.03 +/- 1.70 years) were included in the study. Pituitary functions were evaluated, and APO E genotypes (E2/E2; E3/E3; E4/E4; E2/E3; E2/E4; E3/E4) were screened. Twenty-four of 93 subjects (25.8%) had pituitary dysfunction after TBI. The ratio of pituitary dysfunction was significantly lower in subjects with APO E3/E3 (17.7%) than the subjects without APO E3/E3 genotype (41.9%; p = 0.01), and the corresponding odds ratio was 0.29 (95% confidence interval [CI], 0.11-0.78). In conclusion, this study provides strong evidence for the first time that APO E polymorphism is associated with the development of TBI-induced pituitary dysfunction. Present data demonstrated that APO E3/E3 genotype decreases the risk of hypopituitarism after TBI. The demonstration of the association between the APO E polymorphism and TBI may provide a new point of view in this field and promote further studies.

  2. The methylenetetrahydrofolate reductase C677T genotype and the risk of obesity in three large population-based cohorts.

    PubMed

    Lewis, Sarah J; Lawlor, Debbie A; Nordestgaard, Børge G; Tybjaerg-Hansen, Anne; Ebrahim, Shah; Zacho, Jeppe; Ness, Andy; Leary, Sam; Smith, George Davey

    2008-07-01

    Epidemiological studies have shown that low folate levels are associated with a high body mass index (BMI). These findings have potentially important health implications and warrant further investigation to determine whether a causal relationship exists and the direction of this relationship. The methylenetetrahydrofolate reductase (MTHFR) C677T TT genotype is associated with reduced folate availability and may be a surrogate for measuring folate levels. We sought to determine whether MTHFR C677T genotype was associated with obesity. We carried out our study on four populations from three longitudinal studies based in the UK and Denmark in which DNA for genotyping was obtained along with measures of obesity. Our subjects were taken from the British Women's Heart and Health Study (BWHHS), the Avon Longitudinal Study of Parents and Children (two populations: mothers and children) and the Copenhagen City Heart Study. We performed analyses separately by population, and then carried out a meta-analysis, combining similar populations. Initial findings in the BWHHS suggested that the TT genotype may be associated with an increased risk of obesity BMI > or =30, however, no association was found with BMI or central adiposity in this cohort. This genotype was not associated with obesity in our other cohorts. Our results suggest that the initial positive finding with obesity in the BWHHS was a chance finding. Our findings do not support a causal effect of low folate on obesity.

  3. Using genotype probabilities in survival analysis: a scrapie case

    PubMed Central

    Vitezica, Zulma G; Elsen, Jean-Michel; Rupp, Rachel; Díaz, Clara

    2005-01-01

    The objective was to evaluate the potential use of genotype probabilities to handle records of non-genotyped animals in the context of survival analysis. To do so, the risks associated with the PrP genotype and other transmission factors in relation to clinical scrapie were estimated. Data from 4049 Romanov sheep affected by natural scrapie were analyzed using survival analysis techniques. The original data set included 1310 animals with missing genotypes; five of those had uncensored records. Different missing genotype-information patterns were simulated for uncensored and censored records. Three strategies differing in the way genotype information was handled were tested. Firstly, records with unknown genotypes were discarded (P1); secondly, those records were grouped in an unknown class (P2). Finally the probabilities of genotypes were assigned (P3). Whatever the strategy, the ranking of relative risks for the most susceptible genotypes (VRQ-VRQ, ARQ-VRQ and ARQ-ARQ) was similar even when the non-genotyped animals were not a negligible part of uncensored records. However, P3 had a more efficient way of handling missing genotype information. As compared to P1, either P2 or P3 avoided discarding the records of non-genotyped animals; however, P3 eliminated the unknown class and the risk associated with this group. Genotype probabilities were shown to be a useful technique to handle records of individuals with unknown genotype. PMID:15943919

  4. Ancestry of the Timorese: age-related macular degeneration associated genotype and allele sharing among human populations from throughout the world

    PubMed Central

    Morrison, Margaux A.; Magalhaes, Tiago R.; Ramke, Jacqueline; Smith, Silvia E.; Ennis, Sean; Simpson, Claire L.; Portas, Laura; Murgia, Federico; Ahn, Jeeyun; Dardenne, Caitlin; Mayne, Katie; Robinson, Rosann; Morgan, Denise J.; Brian, Garry; Lee, Lucy; Woo, Se J.; Zacharaki, Fani; Tsironi, Evangelia E.; Miller, Joan W.; Kim, Ivana K.; Park, Kyu H.; Bailey-Wilson, Joan E.; Farrer, Lindsay A.; Stambolian, Dwight; DeAngelis, Margaret M.

    2015-01-01

    We observed that the third leading cause of blindness in the world, age-related macular degeneration (AMD), occurs at a very low documented frequency in a population-based cohort from Timor-Leste. Thus, we determined a complete catalog of the ancestry of the Timorese by analysis of whole exome chip data and haplogroup analysis of SNP genotypes determined by sequencing the Hypervariable I and II regions of the mitochondrial genome and 17 genotyped YSTR markers obtained from 535 individuals. We genotyped 20 previously reported AMD-associated SNPs in the Timorese to examine their allele frequencies compared to and between previously documented AMD cohorts of varying ethnicities. For those without AMD (average age > 55 years), genotype and allele frequencies were similar for most SNPs with a few exceptions. The major risk allele of HTRA1 rs11200638 (10q26) was at a significantly higher frequency in the Timorese, as well as 3 of the 5 protective CFH (1q32) SNPs (rs800292, rs2284664, and rs12066959). Additionally, the most commonly associated AMD-risk SNP, CFH rs1061170 (Y402H), was also seen at a much lower frequency in the Korean and Timorese populations than in the assessed Caucasian populations (C ~7 vs. ~40%, respectively). The difference in allele frequencies between the Timorese population and the other genotyped populations, along with the haplogroup analysis, also highlight the genetic diversity of the Timorese. Specifically, the most common ancestry groupings were Oceanic (Melanesian and Papuan) and Eastern Asian (specifically Han Chinese). The low prevalence of AMD in the Timorese population (2 of 535 randomly selected participants) may be due to the enrichment of protective alleles in this population at the 1q32 locus. PMID:26217379

  5. Relative Hazard and Risk Measure Calculation Methodology

    SciTech Connect

    Stenner, Robert D.; Strenge, Dennis L.; Elder, Matthew S.

    2004-03-20

    The relative hazard (RH) and risk measure (RM) methodology and computer code is a health risk-based tool designed to allow managers and environmental decision makers the opportunity to readily consider human health risks (i.e., public and worker risks) in their screening-level analysis of alternative cleanup strategies. Environmental management decisions involve consideration of costs, schedules, regulatory requirements, health hazards, and risks. The RH-RM tool is a risk-based environmental management decision tool that allows managers the ability to predict and track health hazards and risks over time as they change in relation to mitigation and cleanup actions. Analysis of the hazards and risks associated with planned mitigation and cleanup actions provides a baseline against which alternative strategies can be compared. This new tool allows managers to explore “what if scenarios,” to better understand the impact of alternative mitigation and cleanup actions (i.e., alternatives to the planned actions) on health hazards and risks. This new tool allows managers to screen alternatives on the basis of human health risk and compare the results with cost and other factors pertinent to the decision. Once an alternative or a narrow set of alternatives are selected, it will then be more cost-effective to perform the detailed risk analysis necessary for programmatic and regulatory acceptance of the selected alternative. The RH-RM code has been integrated into the PNNL developed Framework for Risk Analysis In Multimedia Environmental Systems (FRAMES) to allow the input and output data of the RH-RM code to be readily shared with the more comprehensive risk analysis models, such as the PNNL developed Multimedia Environmental Pollutant Assessment System (MEPAS) model.

  6. Fetal and maternal MTHFR C677T genotype, maternal folate intake and the risk of nonsyndromic oral clefts.

    PubMed

    Chevrier, Cécile; Perret, Claire; Bahuau, Michel; Zhu, Huiping; Nelva, Agnès; Herman, Christine; Francannet, Christine; Robert-Gnansia, Elisabeth; Finnell, Richard H; Cordier, Sylvaine

    2007-02-01

    The association between maternal folate intake and risk of nonsyndromic oral clefts has been studied among many populations with conflicting results. The methylenetetrahydrofolate reductase gene (MTHFR) plays a major role in folate metabolism, and several polymorphisms, including C677T, are common in European populations. Data from a French study (1998-2001) let us investigate the roles of maternal dietary folate intake and the MTHFR polymorphism and their interaction on the risk of cleft lip with/without cleft palate (CL/P) and cleft palate only (CP). We used both case-control (164 CL/P, 76 CP, 236 controls; 148, 59, 168 of whom, respectively, had an available genotype) and case-parent (143 CL/P and 56 CP families) study designs and distinguished the role of the child's genotype and maternally mediated effects on risks. This study observed a beneficial effect of mothers' dietary folate intake on their offspring's risk (odds ratio (OR)(< or = 230 microg/day) = ref; for CL/P, OR([230-314 microg/day]) = 0.56, 95% confidence interval = 0.3-0.9, OR(>314 microg/day) = 0.64, 0.4-1.1; for CP, OR([230-314 microg/day]) = 1.15, 0.6-2.2, OR(>314 microg/day) = 0.70, 0.3-1.4). We observed a reduced risk associated with the TT genotype of the child in the case-control analysis (OR(CC) = ref; for CL/P, OR(TT) = 0.54, 0.3-1.1; for CP, OR(TT) = 0.33, 0.1-1.0); this genotype, either fetal or maternal, was not statistically significant in the case-parent analysis. A frequency of TT genotype higher in our control group than previously reported in France can partly explain the risk reduction observed in case-control comparison. Interactions were not statistically significant. Stratified case-parent analysis showed, however, slight heterogeneity in the role of TT genotype according to folate intake. The modest sample size limits this study, which nonetheless provides new estimate of the possible impact of dietary folate intake and MTHFR polymorphism on oral clefts.

  7. Relating space radiation environments to risk estimates

    SciTech Connect

    Curtis, S.B.

    1991-10-01

    This lecture will provide a bridge from the physical energy or LET spectra as might be calculated in an organ to the risk of carcinogenesis, a particular concern for extended missions to the moon or beyond to Mars. Topics covered will include (1) LET spectra expected from galactic cosmic rays, (2) probabilities that individual cell nuclei in the body will be hit by heavy galactic cosmic ray particles, (3) the conventional methods of calculating risks from a mixed environment of high and low LET radiation, (4) an alternate method which provides certain advantages using fluence-related risk coefficients (risk cross sections), and (5) directions for future research and development of these ideas.

  8. Relating space radiation environments to risk estimates

    SciTech Connect

    Curtis, S.B.

    1991-10-01

    This lecture will provide a bridge from the physical energy or LET spectra as might be calculated in an organ to the risk of carcinogenesis, a particular concern for extended missions to the moon or beyond to Mars. Topics covered will include (1) LET spectra expected from galactic cosmic rays, (2) probabilities that individual cell nuclei in the body will be hit by heavy galactic cosmic ray particles, (3) the conventional methods of calculating risks from a mixed environment of high and low LET radiation, (4) an alternate method which provides certain advantages using fluence-related risk coefficients (risk cross sections), and (5) directions for future research and development of these ideas.

  9. Anal and perianal squamous carcinomas and high-grade intraepithelial lesions exclusively associated with "low-risk" HPV genotypes 6 and 11.

    PubMed

    Cornall, Alyssa M; Roberts, Jennifer M; Garland, Suzanne M; Hillman, Richard J; Grulich, Andrew E; Tabrizi, Sepehr N

    2013-11-01

    Anal squamous cell carcinomas are predominantly associated with high-risk human papillomaviruses (HPVs), particularly HPV 16, similar to cervical, vaginal and vulvar cancers. Although the presence of "low-risk" HPVs, in particular genotypes 6 and 11, have occasionally been reported in various HPV-related anogenital cancers, the overall distribution of these genotypes in the anal canal and perianal tissue may differ to that in the cervix. In addition, although the majority of anal and perianal cancers are associated with HPV, some are not; hence, confirmation of direct association of the virus within a lesion is important. Using laser capture microdissection, anal and perianal invasive carcinomas and high-grade squamous intraepithelial lesions (HSILs) in biopsies previously associated with HPV 6 or 11 alone were isolated from tissue sections and HPV genotype tested. Of seven cases tested, four invasive carcinomas were positive for HPV 6 only, one invasive carcinoma was negative for HPV and two HSILs were positive for HPV 11 only. All samples were confirmed as HPV 16/18 negative using two different DNA targets (E6 and L1). From these results, we confirm that HPV 6 and 11 can occasionally be associated with high-grade lesion and anal cancer.

  10. Relative risk regression models with inverse polynomials.

    PubMed

    Ning, Yang; Woodward, Mark

    2013-08-30

    The proportional hazards model assumes that the log hazard ratio is a linear function of parameters. In the current paper, we model the log relative risk as an inverse polynomial, which is particularly suitable for modeling bounded and asymmetric functions. The parameters estimated by maximizing the partial likelihood are consistent and asymptotically normal. The advantages of the inverse polynomial model over the ordinary polynomial model and the fractional polynomial model for fitting various asymmetric log relative risk functions are shown by simulation. The utility of the method is further supported by analyzing two real data sets, addressing the specific question of the location of the minimum risk threshold.

  11. Assessing the Relative Risk of Aerocapture Using Probabalistic Risk Assessment

    NASA Technical Reports Server (NTRS)

    Percy, Thomas K.; Bright, Ellanee; Torres, Abel O.

    2005-01-01

    A recent study performed for the Aerocapture Technology Area in the In-Space Propulsion Technology Projects Office at the Marshall Space Flight Center investigated the relative risk of various capture techniques for Mars missions. Aerocapture has been proposed as a possible capture technique for future Mars missions but has been perceived by many in the community as a higher risk option as compared to aerobraking and propulsive capture. By performing a probabilistic risk assessment on aerocapture, aerobraking and propulsive capture, a comparison was made to uncover the projected relative risks of these three maneuvers. For mission planners, this knowledge will allow them to decide if the mass savings provided by aerocapture warrant any incremental risk exposure. The study focuses on a Mars Sample Return mission currently under investigation at the Jet Propulsion Laboratory (JPL). In each case (propulsive, aerobraking and aerocapture), the Earth return vehicle is inserted into Martian orbit by one of the three techniques being investigated. A baseline spacecraft was established through initial sizing exercises performed by JPL's Team X. While Team X design results provided the baseline and common thread between the spacecraft, in each case the Team X results were supplemented by historical data as needed. Propulsion, thermal protection, guidance, navigation and control, software, solar arrays, navigation and targeting and atmospheric prediction were investigated. A qualitative assessment of human reliability was also included. Results show that different risk drivers contribute significantly to each capture technique. For aerocapture, the significant drivers include propulsion system failures and atmospheric prediction errors. Software and guidance hardware contribute the most to aerobraking risk. Propulsive capture risk is mainly driven by anomalous solar array degradation and propulsion system failures. While each subsystem contributes differently to the risk of

  12. Responder Interferon λ Genotypes Are Associated With Higher Risk of Liver Fibrosis in HIV-Hepatitis C Virus Coinfection.

    PubMed

    Moqueet, Nasheed; Cooper, Curtis; Gill, John; Hull, Mark; Platt, Robert W; Klein, Marina B

    2016-07-01

    Liver fibrosis progresses faster in individuals coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Interferon λ3 (IFN-λ3) has both antiviral and proinflammatory properties. Genotypes at IFNL single-nucleotide proteins (SNPs; rs12979860CC and rs8099917TT) are linked to higher HCV clearance, potentially via rs8103142. We examined the relationship between IFN-λ genotypes and significant liver fibrosis in HIV-HCV coinfection. From the prospective Canadian Co-infection Cohort (n = 1423), HCV RNA-positive participants in whom IFN-λ genotypes were detected and who were free of fibrosis, end-stage liver disease, and chronic hepatitis B at baseline (n = 485) were included. Time to significant fibrosis (defined as an aspartate transaminase level to platelet count ratio index [APRI] of ≥1.5) by IFN-λ genotypes was analyzed using Cox proportional hazards, with adjustment for age, sex, ethnicity, alcohol use, CD4(+) T-cell count, HCV genotype, γ-glutamyl transferase level, and baseline APRI. Haplotype analysis was performed, with adjustment for ethnicity. A total of 125 participants developed fibrosis over 1595 person-years (7.84 cases/100 person-years; 95% confidence interval [CI], 6.58-9.34 cases/100 person-years). Each genotype was associated with an increased fibrosis risk, with adjusted hazard ratios of 1.37 (95% CI, .94-2.02) for rs12979860CC, 1.34 (95% CI, .91-1.97) for rs8103142TT, and 1.79 (95% CI, 1.24-2.57) for rs8099917TT. Haplotype TCT was also linked with a higher risk (hazard ratio, 1.14 [95% CI, .73-1.77]). IFN-λ SNPs rs12979860, rs8099917, and rs81013142 were individually linked to higher rates of fibrosis in individuals with HIV-HCV coinfection. IFN-λ genotypes may be useful to target HCV treatments to people who are at higher risk of liver disease. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

  13. Responder Interferon λ Genotypes Are Associated With Higher Risk of Liver Fibrosis in HIV–Hepatitis C Virus Coinfection

    PubMed Central

    Moqueet, Nasheed; Cooper, Curtis; Gill, John; Hull, Mark; Platt, Robert W.; Klein, Marina B.

    2016-01-01

    Background. Liver fibrosis progresses faster in individuals coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Interferon λ3 (IFN-λ3) has both antiviral and proinflammatory properties. Genotypes at IFNL single-nucleotide proteins (SNPs; rs12979860CC and rs8099917TT) are linked to higher HCV clearance, potentially via rs8103142. We examined the relationship between IFN-λ genotypes and significant liver fibrosis in HIV-HCV coinfection. Methods. From the prospective Canadian Co-infection Cohort (n = 1423), HCV RNA–positive participants in whom IFN-λ genotypes were detected and who were free of fibrosis, end-stage liver disease, and chronic hepatitis B at baseline (n = 485) were included. Time to significant fibrosis (defined as an aspartate transaminase level to platelet count ratio index [APRI] of ≥1.5) by IFN-λ genotypes was analyzed using Cox proportional hazards, with adjustment for age, sex, ethnicity, alcohol use, CD4+ T-cell count, HCV genotype, γ-glutamyl transferase level, and baseline APRI. Haplotype analysis was performed, with adjustment for ethnicity. Results. A total of 125 participants developed fibrosis over 1595 person-years (7.84 cases/100 person-years; 95% confidence interval [CI], 6.58–9.34 cases/100 person-years). Each genotype was associated with an increased fibrosis risk, with adjusted hazard ratios of 1.37 (95% CI, .94–2.02) for rs12979860CC, 1.34 (95% CI, .91–1.97) for rs8103142TT, and 1.79 (95% CI, 1.24–2.57) for rs8099917TT. Haplotype TCT was also linked with a higher risk (hazard ratio, 1.14 [95% CI, .73–1.77]). Conclusions. IFN-λ SNPs rs12979860, rs8099917, and rs81013142 were individually linked to higher rates of fibrosis in individuals with HIV-HCV coinfection. IFN-λ genotypes may be useful to target HCV treatments to people who are at higher risk of liver disease. PMID:26984148

  14. Associations of GSTM1*0 and GSTA1*A genotypes with the risk of cardiovascular death among hemodialyses patients.

    PubMed

    Suvakov, Sonja; Damjanovic, Tatjana; Pekmezovic, Tatjana; Jakovljevic, Jovana; Savic-Radojevic, Ana; Pljesa-Ercegovac, Marija; Radovanovic, Slavica; Simic, Dragan V; Pljesa, Steva; Zarkovic, Milos; Mimic-Oka, Jasmina; Dimkovic, Nada; Simic, Tatjana

    2014-01-14

    The presence of glutathione transferase (GST) M1 null genotype (GSTM1-null) in end-stage renal disease (ESRD) patients is associated with lower overall survival rate in comparison to those with GSTM1-active variants. We examined association between GSTM1 and GSTT1 deletion polymorphisms as well as SNPs in GSTA1/rs3957357 and GSTP1/rs1695 genes with overall and cause-specific cardiovascular mortality in ESRD patients. Total of 199 patients undergoing hemodialysis were included in the study. Median value of time elapsed from dialysis initiation until the death, or the end of follow-up was 8 ± 5 years. The effect of GSTM1, GSTT1, GSTP1 and GSTA1 gene polymorphisms on predicting overall and specific cardiovascular outcomes (myocardial infarction, MI or stroke) was analyzed using Cox regression model, and differences in survival were determined by Kaplan-Meier. GSTM1-null genotype in ESRD patients was found to be independent predictor of overall and cardiovascular mortality. However, after false discovery rate and Bonferroni corrections this effect was lost. The borderline effect modification by wild-type GSTA1*A/*A genotype on associations between GSTM1-null and analyzed outcomes was found only for death from stroke. Homozygous carriers of combined GSTM1*0/GSTA1*A genotype exhibited significantly shorter time to death of stroke or MI in comparison with carriers of either GSTM1-active or at least one GSTA1*B gene variant. The best survival rate regarding cardiovascular outcome was found for ESRD patients with combined GSTM1-active and mutant GSTA1*B/*B genotype. Combined GSTM1*0/GSTA1*A genotypes might be considered as genetic markers for cardiovascular death risk in ESRD patients, which may permit targeting of preventive and early intervention.

  15. Genotypes of cancer stem cells characterized by epithelial-to-mesenchymal transition and proliferation related functions.

    PubMed

    Hsu, Chueh-Lin; Chung, Feng-Hsiang; Chen, Chih-Hao; Hsu, Tzu-Ting; Liu, Szu-Mam; Chung, Dao-Sheng; Hsu, Ya-Fen; Chen, Chien-Lung; Ma, Nianhan; Lee, Hoong-Chien

    2016-09-06

    Cancer stem cells (CSCs), or cancer cells with stem cell-like properties, generally exhibit drug resistance and have highly potent cancer inducing capabilities. Genome-wide expression data collected at public repositories over the last few years provide excellent material for studies that can lead to insights concerning the molecular and functional characteristics of CSCs. Here, we conducted functional genomic studies of CSC based on fourteen PCA-screened high quality public CSC whole genome gene expression datasets and, as control, four high quality non-stem-like cancer cell and non-cancerous stem cell datasets from the Gene Expression Omnibus database. A total of 6,002 molecular signatures were taken from the Molecular Signatures Database and used to characterize the datasets, which, under two-way hierarchical clustering, formed three genotypes. Type 1, consisting of mainly glia CSCs, had significantly enhanced proliferation, and significantly suppressed epithelial-mesenchymal transition (EMT), related functions. Type 2, mainly breast CSCs, had significantly enhanced EMT, but not proliferation, related functions. Type 3, composed of ovarian, prostate, and colon CSCs, had significantly suppressed proliferation related functions and mixed expressions on EMT related functions.

  16. Temporal changes in HCV genotype distribution in three different high risk populations in San Francisco, California

    PubMed Central

    2011-01-01

    Background Hepatitis C virus (HCV) genotype (GT) has become an important measure in the diagnosis and monitoring of HCV infection treatment. In the United States (U.S.) HCV GT 1 is reported as the most common infecting GT among chronically infected patients. In Europe, however, recent studies have suggested that the epidemiology of HCV GTs is changing. Methods We assessed HCV GT distribution in 460 patients from three HCV-infected high risk populations in San Francisco, and examined patterns by birth cohort to assess temporal trends. Multiple logistic regression was used to assess factors independently associated with GT 1 infection compared to other GTs (2, 3, and 4). Results Overall, GT 1 was predominant (72.4%), however younger injection drug users (IDU) had a lower proportion of GT 1 infections (54.7%) compared to older IDU and HIV-infected patients (80.5% and 76.6%, respectively). Analysis by birth cohort showed increasing proportions of non-GT 1 infections associated with year of birth: birth before 1970 was independently associated with higher adjusted odds of GT 1: AOR 2.03 (95% CI: 1.23, 3.34). African-Americans as compared to whites also had higher adjusted odds of GT 1 infection (AOR: 3.37; 95% CI: 1.89, 5.99). Conclusions Although, HCV GT 1 remains the most prevalent GT, especially among older groups, changes in GT distribution could have significant implications for how HCV might be controlled on a population level and treated on an individual level. PMID:21810243

  17. The risk for depression conferred by stressful life events is modified by variation at the serotonin transporter 5HTTLPR genotype: evidence from the Spanish PREDICT-Gene cohort.

    PubMed

    Cervilla, J A; Molina, E; Rivera, M; Torres-González, F; Bellón, J A; Moreno, B; Luna, J D; Lorente, J A; Mayoral, F; King, M; Nazareth, I; Gutiérrez, B

    2007-08-01

    We report results from the PREDICT-Gene case-control study nested in a prospective cohort designed to identify predictors of the onset of depression among adult primary-care attendees. We tested the potential gene-by-environment interaction between 5HTTLPR genotype at the serotonin transporter gene and previous exposure to threatening life events (TLEs) in depression. A total of 737 consecutively recruited participants were genotyped. Additional information was gathered on exposure to TLEs over a 6-month period, socio-demographic data and family history of psychological problems among first-degree relatives. Diagnoses of depression were ascertained using the Composite International Diagnostic Interview (CIDI) by trained interviewers. Two different depressive outcomes were used (ICD-10 depressive episode and ICD-10 severe depressive episode). Both the s/s genotype and exposure to increasing number of TLEs were significantly associated with depression. Moreover, the 5HTTLPR s/s genotype significantly modified the risk conferred by TLEs for both depressive outcomes. Thus, s/s homozygous participants required minimal exposure to TLE (1 TLE) to acquire a level of risk for depression that was only found among l/s or l/l individuals after significantly higher exposure to TLEs (two or more TLEs). The interaction was more apparent when applied to the diagnosis of ICD-10 severe depressive episode and after adjusting for gender, age and family history of psychological problems. Likelihood ratios tests for the interaction were statistically significant for both depressive outcomes (ICD-10 depressive episode: LR X(2)=4.7, P=0.09 (crude), LR-X(2)=6.4, P=0.04 (adjusted); ICD-10 severe depressive episode: LR X(2)=6.9, P=0.032 (crude), LR-X(2)=8.1, P=0.017 (adjusted)).

  18. Glutathione-S-transferase (GST) M1 null genotype and combined GSTM1 and GSTT1 null genotypes are risk factors for increased serum gamma-glutamyltransferase in valproic acid-treated patients.

    PubMed

    Fukushima, Yumi; Seo, Takayuki; Hashimoto, Nami; Higa, Yoko; Ishitsu, Takateru; Nakagawa, Kazuko

    2008-03-01

    This study was designed to verify whether the glutathione S-transferase (GST) genotypes affect mild hepatotoxicity in valproic acid (VPA)-treated patients. The association between the GSTM1 and GSTT1 genotypes, and the levels of aminotransferases and total bilirubin was retrospectively investigated in 149 Japanese epileptic patients treated with VPA. The adjusted odds ratio (OR) of the GSTM1- vs. GSTM1+ genotype and the GSTM1-/GSTT1-vs. GSTM1+/GSTT1+ genotypes for gamma-glutamyltransferase (GGT) increase over the upper limit of normal were 2.8 [95% confidence interval (CI): 1.1-7.2] and 6.5 (95% CI: 1.5-28.0), respectively. The GSTT1 genotypes alone did not significantly affect the liver function tests. The alanine aminotransferase, aspartate aminotransferase and (gamma-glutamyltransferase) GGT levels in patients treated with VPA >6 months were significantly higher in the GSTM1- than GSTM1+ genotype. The GGT levels were significantly higher in the older subjects receiving polytherapy, and the effects of the polytherapy and age were greater in the GSTM1- genotype. The GSTM1- and GSTM1-/GSTT1- genotypes may be a genetic risk factor for the increase of GGT in VPA-treated patients. However, it was not possible to clarify whether the GGT increase was caused by VPA-induced hepatotoxicity or not.

  19. Interactions between C-Reactive Protein Genotypes with Markers of Nutritional Status in Relation to Inflammation

    PubMed Central

    Nienaber-Rousseau, Cornelie; Swanepoel, Bianca; Dolman, Robin C.; Pieters, Marlien; Conradie, Karin R.; Towers, G. Wayne

    2014-01-01

    Inflammation, as indicated by C-reactive protein concentrations (CRP), is a risk factor for chronic diseases. Both genetic and environmental factors affect susceptibility to inflammation. As dietary interventions can influence inflammatory status, we hypothesized that dietary effects could be influenced by interactions with single nucleotide polymorphisms (SNPs) in the CRP gene. We determined 12 CRP SNPs, as well as various nutrition status markers in 2010 black South Africans and analyzed their effect on CRP. Interactions were observed for several genotypes with obesity in determining CRP. Lipid intake modulated the pro-inflammatory effects of some SNPs, i.e., an increase in both saturated fatty acid and monounsaturated fatty acid intake in those homozygous for the polymorphic allele at rs2808630 was associated with a larger increase in CRP. Those harboring the minor alleles at rs3093058 and rs3093062 presented with significantly higher CRP in the presence of increased triglyceride or cholesterol intake. When harboring the minor allele of these SNPs, a high omega-6 to -3 ratio was, however, found to be anti-inflammatory. Carbohydrate intake also modulated CRP SNPs, as HbA1C and fasting glucose levels interacted with some SNPs to influence the CRP. This investigation highlights the impact that nutritional status can have on reducing the inherent genetic susceptibility to a heightened systemic inflammatory state. PMID:25393688

  20. Interactions between C-reactive protein genotypes with markers of nutritional status in relation to inflammation.

    PubMed

    Nienaber-Rousseau, Cornelie; Swanepoel, Bianca; Dolman, Robin C; Pieters, Marlien; Conradie, Karin R; Towers, G Wayne

    2014-11-11

    Inflammation, as indicated by C-reactive protein concentrations (CRP), is a risk factor for chronic diseases. Both genetic and environmental factors affect susceptibility to inflammation. As dietary interventions can influence inflammatory status, we hypothesized that dietary effects could be influenced by interactions with single nucleotide polymorphisms (SNPs) in the CRP gene. We determined 12 CRP SNPs, as well as various nutrition status markers in 2010 black South Africans and analyzed their effect on CRP. Interactions were observed for several genotypes with obesity in determining CRP. Lipid intake modulated the pro-inflammatory effects of some SNPs, i.e., an increase in both saturated fatty acid and monounsaturated fatty acid intake in those homozygous for the polymorphic allele at rs2808630 was associated with a larger increase in CRP. Those harboring the minor alleles at rs3093058 and rs3093062 presented with significantly higher CRP in the presence of increased triglyceride or cholesterol intake. When harboring the minor allele of these SNPs, a high omega-6 to -3 ratio was, however, found to be anti-inflammatory. Carbohydrate intake also modulated CRP SNPs, as HbA1C and fasting glucose levels interacted with some SNPs to influence the CRP. This investigation highlights the impact that nutritional status can have on reducing the inherent genetic susceptibility to a heightened systemic inflammatory state.

  1. Far East Scarlet-Like Fever Caused by a Few Related Genotypes of Yersinia pseudotuberculosis, Russia.

    PubMed

    Timchenko, Nelly F; Adgamov, Ruslan R; Popov, Alexander F; Psareva, Ekaterina K; Sobyanin, Konstantin A; Gintsburg, Alexander L; Ermolaeva, Svetlana A

    2016-03-01

    We used multivirulence locus sequence typing to analyze 68 Yersinia pseudotuberculosis isolates from patients in Russia during 1973-2014, including 41 isolates from patients with Far East scarlet-like fever. Four genotypes were found responsible, with 1 being especially prevalent. Evolutionary analysis suggests that epidemiologic advantages could cause this genotype's dominance.

  2. Validated context-dependent associations of coronary heart disease risk with genotype variation in the chromosome 9p21 region: the Atherosclerosis Risk in Communities study

    PubMed Central

    Lusk, Christine M.; Dyson, Greg; Clark, Andrew G.; Ballantyne, Christie M.; Frikke-Schmidt, Ruth; Tybjærg-Hansen, Anne; Boerwinkle, Eric

    2014-01-01

    Markers of the chromosome 9p21 region are regarded as the strongest and most reliably significant genome-wide association study (GWAS) signals for Coronary heart disease (CHD) risk; this was recently confirmed by the CARDIoGRAMplusC4D Consortium meta-analysis. However, while these associations are significant at the population level, they may not be clinically relevant predictors of risk for all individuals. We describe here the results of a study designed to address the question: What is the contribution of context defined by traditional risk factors in determining the utility of DNA sequence variations marking the 9p21 region for explaining variation in CHD risk? We analyzed a sample of 7,589 (3,869 females and 3,720 males) European American participants of the Atherosclerosis Risk in Communities study. We confirmed CHD-SNP genotype associations for two 9p21 region marker SNPs previously identified by the CARDIoGRAMplusC4D Consortium study, of which ARIC was a part. We then tested each marker SNP genotype effect on prediction of CHD within sub-groups of the ARIC sample defined by traditional CHD risk factors by applying a novel multi-model strategy, PRIM. We observed that the effects of SNP genotypes in the 9p21 region were strongest in a subgroup of hypertensives. We subsequently validated the effect of the region in an independent sample from the Copenhagen City Heart Study. Our study suggests that marker SNPs identified as predictors of CHD risk in large population based GWAS may have their greatest utility in explaining risk of disease in particular sub-groups characterized by biological and environmental effects measured by the traditional CHD risk factors. PMID:24889828

  3. Cancer risks related to electricity production.

    PubMed

    Boffetta, P; Cardis, E; Vainio, H; Coleman, M P; Kogevinas, M; Nordberg, G; Parkin, D M; Partensky, C; Shuker, D; Tomatis, L

    1991-01-01

    The International Agency for Research on Cancer has previously evaluated the cancer risks associated with fossil fuel-based industrial processes such as coal gastification and coke production, substances and mixtures such as coal tars, coal tar pitch and mineral oils, and a number of substances emitted from fossil-fuelled plants such as benzo[a]pyrene and other polycyclic aromatic hydrocarbons, arsenic, beryllium, cadmium, chromium, nickel, lead and formaldehyde. Based on these evaluations and other evidence from the literature, the carcinogenic risks to the general population and occupational groups from the fossil fuel cycle, the nuclear fuel cycle and renewable cycles are reviewed. Cancer risks from waste disposal, accidents and misuses, and electricity distribution are also considered. No cycle appears to be totally free from cancer risk, but the quantification of the effects of such exposures (in particular of those involving potential exposure to large amounts of carcinogens, such as coal, oil and nuclear) requires the application of methods which are subject to considerable margins of error. Uncertainties due to inadequate data and unconfirmed assumptions are discussed. Cancer risks related to the operation of renewable energy sources are negligible, although there may be some risks from construction of such installations. The elements of knowledge at our disposal do not encourage any attempt toward a quantitative comparative risk assessment. However, even in the absence of an accurate quantification of risk, qualitative indication of carcinogenic hazards should lead to preventive measures.

  4. GSTT1 Null Genotype Is a Risk Factor for Diabetic Retinopathy in Caucasians with Type 2 Diabetes, whereas GSTM1 Null Genotype Might Confer Protection against Retinopathy

    PubMed Central

    Cilenšek, Ines; Mankoč, Sara; Petrovič, Mojca Globočnik; Petrovič, Daniel

    2012-01-01

    Aim: Substantial data indicate that oxidative stress is involved in the development of diabetic retinopathy (DR). The aim of the present study was to investigate whether the genetic polymorphisms: polymorphic deletions of glutathione S-transferases M1 (GSTM1) and T1 (GSTT1) and Ile105Val of the GSTP1 are associated with DR in Slovenian patients with type 2 diabetes. Methods: In this cross sectional case-control study 604 unrelated Slovene subjects (Caucasians) with type 2 diabetes mellitus were enrolled: 284 patients with DR (cases) and the control group of 320 subjects with type 2 diabetes of more than 10 years’ duration who had no clinical signs of DR. Genotypes were determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Results: In our study, the deletion of the GSTM1 was found less frequent in cases with DR than in the controls (27.5% versus 44.4%; P < 0.001), whereas the deletion of GSTT1 was found significantly more often in cases than in the controls (49.3% versus 29.7%;P < 0.001). We did not find statistically significant differences in the genotype distribution in GSTP1 (Ile105Val) polymorphism between cases and controls (40.5% versus 46.0%). Conclusions: We may conclude that individuals homozygous for the deletion of GSTT1 are at an ≈ 2-fold-greater risk of DR, whereas the GSTM1 deficiency is associated with lower frequency of DR in type 2 diabetics. PMID:22377702

  5. Temporal trends of HLA genotype frequencies of type 1 diabetes patients in Sweden from 1986 to 2005 suggest altered risk.

    PubMed

    Resic-Lindehammer, Sabina; Larsson, K; Ortqvist, E; Carlsson, A; Cederwall, E; Cilio, C M; Ivarsson, S-A; Jönsson, B A; Larsson, H E; Lynch, K; Neiderud, J; Nilsson, A; Sjöblad, S; Lernmark, A; Aili, M; Bååth, L E; Carlsson, E; Edenwall, H; Forsander, G; Granstro, B W; Gustavsson, I; Hanås, R; Hellenberg, L; Hellgren, H; Holmberg, E; Hörnell, H; Ivarsson, Sten-A; Johansson, C; Jonsell, G; Kockum, K; Lindblad, B; Lindh, A; Ludvigsson, J; Myrdal, U; Neiderud, J; Segnestam, K; Sjöblad, S; Skogsberg, L; Strömberg, L; Ståhle, U; Thalme, B; Tullus, K; Tuvemo, T; Wallensteen, M; Westphal, O; Aman, J

    2008-12-01

    The aim of this study was to compare the frequency of human leukocyte antigen (HLA) genotypes in 1-18-year-old patients with type 1 diabetes newly diagnosed in 1986-1987 (n = 430), 1996-2000 (n = 342) and in 2003-2005 (n = 171). We tested the hypothesis that the HLA DQ genotype distribution changes over time. Swedish type 1 diabetes patients and controls were typed for HLA using polymerase chain reaction amplification and allele specific probes for DQ A1* and B1* alleles. The most common type 1 diabetes HLA DQA1*-B1*genotype 0501-0201/0301-0302 was 36% (153/430) in 1986-1987 and 37% (127/342) in 1996-2000, but decreased to 19% (33/171) in 2003-2005 (P \\ 0.0001). The 0501-0201/0501-0201 genotype increased from 1% in 1986-1987 to 7% in 1996-2000 (P = 0.0047) and to 5% in 2003-2005 (P > 0.05). This study in 1-18-year-old Swedish type 1 diabetes patients supports the notion that there is a temporal change in HLA risk.

  6. Features of coronary heart disease development in emergency workers of the Chornobyl accident depending on the action of radiation and non radiation risk factors and genotypes of single nucleotide polymorphism rs966221 of phosphodiesterase 4D gene.

    PubMed

    Belyi, D; Pleskach, G; Nastina, O; Sidorenko, G; Kursina, N; Bazyka, O; Kovalev, O; Chumak, A; Abramenko, I

    2016-12-01

    This study devoted to specific features of coronary heart disease (CHD) development in emergency work ers (EW) of the accident at the Chernobyl nuclear power plant (ChNPP) based on analysis the interaction between radiation and non radiation risk factors and single nucleotide polymorphism (SNP) rs966221 of phosphodiesterase (PDE) 4D gene. It was examined 397 men with CHD, including 274 EW of 1986-1987 and 123 non irradiated persons (con trol group) who were 66±10 and 69±11 years old relatively. The program studies included clinical examination, elec trocardiography (ECG), ECG daily monitoring, ECG stress testing, echo doppler cardiography, analysis of serum lipid spectrum, polymerase chain reaction with restriction of reaction products, retrospective analysis of case histories. Diagnosis of CHD or its approval was carried out in accordance with the standards of diagnosis, accepted in Ukraine. All EW before their taking part in cleaning ChNPP territory did not suffered from CHD. According to the analysis of contingency tables, carriers of the TT genotype of rs966221 increased the risk of myocardial infarction (MI) in 2.538 times compared with carriers of genotypes CC and CT. The use of Kaplan Meier method showed that a half of EW with the TT genotype developed MI before 64 years old, while with the other geno types up to 78.7 years old. In the control group statistically significant increase of cumulative proportion of patients with MI, carriers of the TT genotype, began from 60 years old. Compared to the non irradiated patients EW fell ill with CHD on 9.4 years earlier. Using proportional hazards analysis (Cox regression), it was found that EW had 3.9 times higher risk of CHD than in non irradiated individuals. Smoking and overweight brought three times less but significant risk - 1.37 and 1.33 respectively. The TT genotype unlike genotypes CC and CT gene PDE4D increased risk of MI in 1.757 times more both in EW and control group. The risk of CHD development was

  7. Combined GSTM1-Null, GSTT1-Active, GSTA1 Low-Activity and GSTP1-Variant Genotype Is Associated with Increased Risk of Clear Cell Renal Cell Carcinoma.

    PubMed

    Coric, Vesna M; Simic, Tatjana P; Pekmezovic, Tatjana D; Basta-Jovanovic, Gordana M; Savic Radojevic, Ana R; Radojevic-Skodric, Sanja M; Matic, Marija G; Dragicevic, Dejan P; Radic, Tanja M; Bogdanovic, Ljiljana M; Dzamic, Zoran M; Pljesa-Ercegovac, Marija S

    2016-01-01

    The aim of this study was to evaluate specific glutathione S-transferase (GST) gene variants as determinants of risk in patients with clear cell renal cell carcinoma (cRCC), independently or simultaneously with established RCC risk factors, as well as to discern whether phenotype changes reflect genotype-associated risk. GSTA1, GSTM1, GSTP1 and GSTT1 genotypes were determined in 199 cRCC patients and 274 matched controls. Benzo(a)pyrene diolepoxide (BPDE)-DNA adducts were determined in DNA samples obtained from cRCC patients by ELISA method. Significant association between GST genotype and risk of cRCC development was found for the GSTM1-null and GSTP1-variant genotype (p = 0.02 and p<0.001, respectively). Furthermore, 22% of all recruited cRCC patients were carriers of combined GSTM1-null, GSTT1-active, GSTA1-low activity and GSTP1-variant genotype, exhibiting 9.32-fold elevated cRCC risk compared to the reference genotype combination (p = 0.04). Significant association between GST genotype and cRCC risk in smokers was found only for the GSTP1 genotype, while GSTM1-null/GSTP1-variant/GSTA1 low-activity genotype combination was present in 94% of smokers with cRCC, increasing the risk of cRCC up to 7.57 (p = 0.02). Furthermore, cRCC smokers with GSTM1-null genotype had significantly higher concentration of BPDE-DNA adducts in comparison with GSTM1-active cRCC smokers (p = 0.05). GSTM1, GSTT1, GSTA1 and GSTP1 polymorphisms might be associated with the risk of cRCC, with special emphasis on GSTM1-null and GSTP1-variant genotypes. Combined GSTM1-null, GSTT1-active, GSTA1 low activity and GSTP1-variant genotypes might be considered as "risk-carrying genotype combination" in cRCC.

  8. Combined GSTM1-Null, GSTT1-Active, GSTA1 Low-Activity and GSTP1-Variant Genotype Is Associated with Increased Risk of Clear Cell Renal Cell Carcinoma

    PubMed Central

    Coric, Vesna M.; Simic, Tatjana P.; Pekmezovic, Tatjana D.; Basta-Jovanovic, Gordana M.; Savic Radojevic, Ana R.; Radojevic-Skodric, Sanja M.; Matic, Marija G.; Dragicevic, Dejan P.; Radic, Tanja M.; Bogdanovic, Ljiljana M.; Dzamic, Zoran M.; Pljesa-Ercegovac, Marija S.

    2016-01-01

    The aim of this study was to evaluate specific glutathione S-transferase (GST) gene variants as determinants of risk in patients with clear cell renal cell carcinoma (cRCC), independently or simultaneously with established RCC risk factors, as well as to discern whether phenotype changes reflect genotype-associated risk. GSTA1, GSTM1, GSTP1 and GSTT1 genotypes were determined in 199 cRCC patients and 274 matched controls. Benzo(a)pyrene diolepoxide (BPDE)-DNA adducts were determined in DNA samples obtained from cRCC patients by ELISA method. Significant association between GST genotype and risk of cRCC development was found for the GSTM1-null and GSTP1-variant genotype (p = 0.02 and p<0.001, respectively). Furthermore, 22% of all recruited cRCC patients were carriers of combined GSTM1-null, GSTT1-active, GSTA1-low activity and GSTP1-variant genotype, exhibiting 9.32-fold elevated cRCC risk compared to the reference genotype combination (p = 0.04). Significant association between GST genotype and cRCC risk in smokers was found only for the GSTP1 genotype, while GSTM1-null/GSTP1-variant/GSTA1 low-activity genotype combination was present in 94% of smokers with cRCC, increasing the risk of cRCC up to 7.57 (p = 0.02). Furthermore, cRCC smokers with GSTM1-null genotype had significantly higher concentration of BPDE-DNA adducts in comparison with GSTM1-active cRCC smokers (p = 0.05). GSTM1, GSTT1, GSTA1 and GSTP1 polymorphisms might be associated with the risk of cRCC, with special emphasis on GSTM1-null and GSTP1-variant genotypes. Combined GSTM1-null, GSTT1-active, GSTA1 low activity and GSTP1-variant genotypes might be considered as “risk-carrying genotype combination” in cRCC. PMID:27500405

  9. Prevalence of HBV genotypes in South American immigrants affected by HBV-related chronic active hepatitis.

    PubMed

    Palumbo, Emilio; Scotto, Gaetano; Faleo, Giuseppina; Cibelli, Donatella Concetta; Angarano, Gioacchino

    2007-06-01

    This study evaluated the prevalence of HBV infection in a population of South American immigrants in Italy and to determine in patients with detectable serum HBV-DNA the HBV genotypes. Between April 2005 and April 2006 a total of 130 South American immigrants were tested for HBsAg. In HBsAg positive patients the biochemical and virological activity of infection and the possible presence of co-infections (HCV, HDV, HIV) were evaluated. In patients with detectable serum HBV DNA, the HBV genotype was determined by INNOLiPA. Among the 130 subjects tested, 14 (10.7%) resulted HBsAg positive. All were men, with a mean age of 22 years (range 19-37) and 12 (85.7 %) came from Brazil, while 2 (14.3%) came from Ecuador. All patients infected by HBV had elevated alanine-aminotransferase serum levels (mean level was 127 IU/L, range 74-312) and serum HBV DNA detectable by PCR-Real Time (mean level 1,037,652 copies/mL, range 19,876-1,377,648). Genotype distribution was as follow: genotype D, 9 (64.2%), genotype A, 5 (35.8%). All patients infected by genotype D came from Brazil, while among the patients infected by genotype A, three came from Brazil and two from Ecuador. Our study evidences a moderate prevalence of HBV-infection in South American immigrants with the identification of two genotypes, D and A. These genotypes are not the most prevalent in the South America and this is probably the expression of a possible geographical redistribution of HBV genotypes.

  10. Genotype-Derived ABO Blood Group Alleles and the Risk of Pancreatic Cancer: Data from the Pancreatic Cancer Cohort Consortium

    PubMed Central

    Wolpin, Brian M.; Kraft, Peter; Gross, Myron; Helzlsouer, Kathy; Bueno-de-Mesquita, H. Bas; Steplowski, Emily; Stolzenberg-Solomon, Rachael Z.; Arslan, Alan A.; Jacobs, Eric J.; LaCroix, Andrea; Petersen, Gloria; Zheng, Wei; Albanes, Demetrius; Allen, Naomi E.; Amundadottir, Laufey; Anderson, Garnet; Boutron-Ruault, Marie-Christine; Buring, Julie E.; Canzian, Federico; Chanock, Stephen J.; Clipp, Sandra; Gaziano, J. Michael; Giovannucci, Edward L.; Hallmans, Göran; Hankinson, Susan E.; Hoover, Robert N.; Hunter, David J.; Hutchinson, Amy; Jacobs, Kevin; Kooperberg, Charles; Lynch, Shannon M.; Mendelsohn, Julie B.; Michaud, Dominique S.; Overvad, Kim; Patel, Alpa V.; Rajkovic, Aleksandar; Sanchéz, Maria-José; Shu, Xiao-Ou; Slimani, Nadia; Thomas, Gilles; Tobias, Geoffrey S.; Trichopoulos, Dimitrios; Vineis, Paolo; Virtamo, Jarmo; Wactawski-Wende, Jean; Yu, Kai; Zeleniuch-Jacquotte, Anne; Hartge, Patricia; Fuchs, Charles S.

    2009-01-01

    A recent genome-wide association study (PanScan) identified significant associations at the ABO gene locus with pancreatic cancer risk; however, the mechanisms underlying these associations and the influence of specific ABO genotypes remain unknown. We determined ABO genotypes (OO, AO, AA, AB, BO, BB) in 1534 cases and 1583 controls from 12 prospective cohort studies participating in PanScan. We also grouped participants by genotype-derived serologic blood type (O, A, AB, B). Adjusted odds ratios (ORs) for pancreatic cancer by ABO alleles were calculated using logistic regression. Compared to blood type O, the ORs for pancreatic cancer in subjects with types A, AB, and B were 1.38 (95% confidence interval [CI], 1.18-1.62), 1.47 (95% CI, 1.07-2.02), and 1.53 (95% CI, 1.21-1.92), respectively. The incidence rates (cases per 100,000 subjects per year) for blood types O, A, AB, and B were 28.9, 39.9, 41.8, and 44.5. An increase in risk was noted with the addition of each non-O allele. Compared to OO, subjects with AO and AA had ORs of 1.33 (95% CI, 1.13-1.58) and 1.61 (95% CI, 1.22-2.18), while subjects with BO and BB had ORs of 1.45 (95% CI, 1.14-1.85) and 2.42 (1.28-4.57). The population attributable fraction for non-O blood type was 19.5%. In a joint model with smoking, current smokers with non-O blood type had an adjusted OR of 2.68 (95% CI, 2.03-3.54), compared with non-smokers with blood type O. Among participants in a large prospective cohort consortium, ABO genotypes were significantly associated with pancreatic cancer risk. PMID:20103627

  11. GLUCOCORTICOID RECEPTOR-RELATED GENES: GENOTYPE AND BRAIN GENE EXPRESSION RELATIONSHIPS TO SUICIDE AND MAJOR DEPRESSIVE DISORDER.

    PubMed

    Yin, Honglei; Galfalvy, Hanga; Pantazatos, Spiro P; Huang, Yung-Yu; Rosoklija, Gorazd B; Dwork, Andrew J; Burke, Ainsley; Arango, Victoria; Oquendo, Maria A; Mann, J John

    2016-06-01

    We tested the relationship between genotype, gene expression and suicidal behavior and major depressive disorder (MDD) in live subjects and postmortem samples for three genes, associated with the hypothalamic-pituitary-adrenal axis, suicidal behavior, and MDD; FK506-binding protein 5 (FKBP5), Spindle and kinetochore-associated protein 2 (SKA2), and Glucocorticoid Receptor (NR3C1). Single-nucleotide polymorphisms (SNPs) and haplotypes were tested for association with suicidal behavior and MDD in a live (N = 277) and a postmortem sample (N = 209). RNA-seq was used to examine gene and isoform-level brain expression postmortem (Brodmann Area 9; N = 59). Expression quantitative trait loci (eQTL) relationships were examined using a public database (UK Brain Expression Consortium). We identified a haplotype within the FKBP5 gene, present in 47% of the live subjects, which was associated with increased risk of suicide attempt (OR = 1.58, t = 6.03, P = .014). Six SNPs on this gene, three SNPs on SKA2, and one near NR3C1 showed before-adjustment association with attempted suicide, and two SNPs of SKA2 with suicide death, but none stayed significant after adjustment for multiple testing. Only the SKA2 SNPs were related to expression in the prefrontal cortex (pFCTX). One NR3C1 transcript had lower expression in suicide relative to nonsuicide sudden death cases (b = -0.48, SE = 0.12, t = -4.02, adjusted P = .004). We have identified an association of FKBP5 haplotype with risk of suicide attempt and found an association between suicide and altered NR3C1 gene expression in the pFCTX. Our findings further implicate hypothalamic pituitary axis dysfunction in suicidal behavior. © 2016 Wiley Periodicals, Inc.

  12. Mitochondrial biogenesis related endurance genotype score and sports performance in athletes.

    PubMed

    Eynon, Nir; Ruiz, Jonatan R; Meckel, Yoav; Morán, María; Lucia, Alejandro

    2011-01-01

    We determined the probability of individuals having the 'optimal' mitochondrial biogenesis related endurance polygenic profile, and compared the endurance polygenic profile of Israeli (Caucasian) endurance athletes (n = 74), power athletes (n = 81), and non-athletes (n = 240). We computed a mitochondrial biogenesis related 'endurance genotype score' (EGS, scoring from 0 to 100) from the accumulated combination of six polymorphisms in the PPARGC1A-NRF-TFAM pathway. Some of the variant alleles of the polymorphisms studied were so infrequent, that the probability of possessing an 'optimal' EGS (= 100) was 0% in the entire study population. However, the EGS was significantly higher (P<0.001) in endurance athletes (38.9 ± 17.1) compared with controls (30.6 ± 12.4) or power athletes (29.0 ± 11.2). In summary, although the probability of an individual possessing a theoretically 'optimal' genetic background for endurance sports is very low, in general endurance athletes have a polygenic profile that is more suitable for mitochondrial biogenesis. Copyright © 2010 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

  13. Maternal apolipoprotein E genotype as a potential risk factor for poor birth outcomes: The Bogalusa Heart Study

    PubMed Central

    Jacobs, Marni B.; Harville, Emily W.; Kelly, Tanika N.; Bazzano, Lydia A.; Chen, Wei

    2016-01-01

    Objective To assess the association between apolipoprotein E (apoE) genotype and preterm birth (PTB) and small for gestational age (SGA). Study Design ApoE phenotyping was performed on 680 women linked to 1 065 births. Allele frequencies were compared and PTB and SGA risk was estimated using log-binomial regression. Results The ε2 allele was more common in SGA births (p < 0.01). SGA risk was increased among ε2 carriers compared to genotype ε3/ε3, though associations were attenuated following adjustment for maternal age, education, race, smoking, and prenatal visits. Stronger associations were observed for term SGA (first birth: aRR = 1.78, 95% CI 1.06 – 2.98; any birth: aRR = 1.52, 95% CI 0.96 – 2.40) and among whites specifically (first: aRR = 2.88, 95% CI 1.45 – 5.69; any: aRR = 2.75, 95% CI 1.46 – 5.22). Conclusions Associations between maternal apoE genotype and SGA may represent decreased fetal growth in women with lower circulating cholesterol levels. PMID:26890557

  14. Association between Manganese Superoxide Dismutase (MnSOD Val-9Ala) genotypes with the risk of generalized aggressive periodontitis disease.

    PubMed

    Kazemi, E; Moradi, M-T; Yari, K; Mousavi, S A R; Kahrizi, D

    2015-12-19

    Generalized aggressive periodontitis (GAP) is a subtype of periodontal diseases that characterized by rapid destruction of periodontal supporting tissues. The MnSOD Val-9Ala mutation of manganese superoxide dismutase gene (MnSOD Val-9Ala) and its correlation with periodontal diseases has been studied in different populations. The purpose of this study was to investigate the possible association of MnSODVal-9Ala polymorphism with periodontitis disease in sample of GAP patients in Iran for the first time. Following a GAP examination, 50 GAP patients and 100 healthy individuals were recruited. Genomic DNA was extracted from peripheral blood leukocytes and the MnSODVal-9Ala polymorphismwas detected using PCR-RFLP method. The frequency of Ala/Ala, Ala/Val and Val/Val genotypes in healthy individuals were 25, 66 and 9%, respectively. In periodontitis patients, frequencies were as Ala/Ala (12%), Ala/Val (50%) and Val/Val (38%) genotypes. There was a significant positive association between distribution of MnSOD Val-9Ala genotypes and the risk of periodontitis disease (p<0.05). Our results indicated that MnSOD Val-9Ala gene polymorphism has a positive association with the risk of periodontitis disease.

  15. High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci.

    PubMed

    Kim, Kwangwoo; Bang, So-Young; Lee, Hye-Soon; Cho, Soo-Kyung; Choi, Chan-Bum; Sung, Yoon-Kyoung; Kim, Tae-Hwan; Jun, Jae-Bum; Yoo, Dae Hyun; Kang, Young Mo; Kim, Seong-Kyu; Suh, Chang-Hee; Shim, Seung-Cheol; Lee, Shin-Seok; Lee, Jisoo; Chung, Won Tae; Choe, Jung-Yoon; Shin, Hyoung Doo; Lee, Jong-Young; Han, Bok-Ghee; Nath, Swapan K; Eyre, Steve; Bowes, John; Pappas, Dimitrios A; Kremer, Joel M; Gonzalez-Gay, Miguel A; Rodriguez-Rodriguez, Luis; Ärlestig, Lisbeth; Okada, Yukinori; Diogo, Dorothée; Liao, Katherine P; Karlson, Elizabeth W; Raychaudhuri, Soumya; Rantapää-Dahlqvist, Solbritt; Martin, Javier; Klareskog, Lars; Padyukov, Leonid; Gregersen, Peter K; Worthington, Jane; Greenberg, Jeffrey D; Plenge, Robert M; Bae, Sang-Cheol

    2015-03-01

    A highly polygenic aetiology and high degree of allele-sharing between ancestries have been well elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data. We analysed Korean rheumatoid arthritis case-control samples using the Immunochip and genome-wide association studies (GWAS) array to search for new risk alleles of rheumatoid arthritis with anticitrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data for a total sample size of 9299 Korean and 45,790 European case-control samples. We identified eight new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1-FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p<5×10(-8)), with evidence for three independent risk alleles at 1q25/TNFSF4. The risk alleles from the seven new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of single nucleotide polymorphisms (SNPs) that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs. This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  16. High-Density Genotyping of Immune Loci in Koreans and Europeans Identifies Eight New Rheumatoid Arthritis Risk Loci

    PubMed Central

    Kim, Kwangwoo; Bang, So-Young; Lee, Hye-Soon; Cho, Soo-Kyung; Choi, Chan-Bum; Sung, Yoon-Kyoung; Kim, Tae-Hwan; Jun, Jae-Bum; Yoo, Dae Hyun; Kang, Young Mo; Kim, Seong-Kyu; Suh, Chang-Hee; Shim, Seung-Cheol; Lee, Shin-Seok; Lee, Jisoo; Chung, Won Tae; Choe, Jung-Yoon; Shin, Hyoung Doo; Lee, Jong-Young; Han, Bok-Ghee; Nath, Swapan K.; Eyre, Steve; Bowes, John; Pappas, Dimitrios A.; Kremer, Joel M.; Gonzalez-Gay, Miguel A; Rodriguez-Rodriguez, Luis; Ärlestig, Lisbeth; Okada, Yukinori; Diogo, Dorothée; Liao, Katherine P.; Karlson, Elizabeth W.; Raychaudhuri, Soumya; Rantapää-Dahlqvist, Solbritt; Martin, Javier; Klareskog, Lars; Padyukov, Leonid; Gregersen, Peter K.; Worthington, Jane; Greenberg, Jeffrey D.; Plenge, Robert M.; Bae, Sang-Cheol

    2015-01-01

    Objective A highly polygenic etiology and high degree of allele-sharing between ancestries have been well-elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data. Methods We analyzed Korean rheumatoid arthritis case-control samples using the Immunochip and GWAS array to search for new risk alleles of rheumatoid arthritis with anti-citrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data, for a total sample size of 9,299 Korean and 45,790 European case-control samples. Results We identified 8 new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1–FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p<5×10−8), with evidence for three independent risk alleles at 1q25/TNFSF4. The risk alleles from the 7 new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of SNPs that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs. Conclusion This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases. PMID:24532676

  17. Association of Type 2 Diabetes Mellitus related SNP genotypes with altered serum adipokine levels and metabolic syndrome phenotypes

    PubMed Central

    Al-Daghri, Nasser M; Al-Attas, Omar S; Krishnaswamy, Soundararajan; Mohammed, Abdul Khader; Alenad, Amal M; Chrousos, George P; Alokail, Majed S

    2015-01-01

    The pathogenesis of T2DM involves secretion of several pro-inflammatory molecules by the dramatically increased adipocytes, both by number and size, and associated macrophages of adipose tissue. Since T2DM is usually preceded by obesity and chronic systemic inflammation, the objective of this study was to explore for any association between genetic variants of previously established 36 T2DM-associated SNPs and altered serum adipocytokine levels and metabolic syndrome phenotypes. Study consisted of 566 subjects (284 males and 282 females) of whom 147 were T2DM patients and 419 healthy controls. Study subjects were genotyped for 36 T2DM-linked single nucleotide polymorphisms (SNPs) using the KASPar SNP Genotyping System and grouped into different genotypes for each SNP. Various anthropometric and biochemical parameters were measured following standard procedures. The mean values of serum levels of individual adipocytokines and the presence/absence of metabolic syndrome phenotypes corresponding to various genotypes were compared by determining the odds ratios. Genotypic variants of five and seven of the 36 T2DM-related SNPs were significantly associated with altered serum levels of adiponectin and aPAI, respectively. Six variants of the 36 SNPs were associated with metabolic syndrome manifestations. This study identified positive associations between genotypic variants of five and seven of the 36 T2DM related SNPs and altered serum levels of adiponectin and aPAI, respectively. Six of 36 SNPs were also associated with metabolic syndrome in the studied population. The relation between specific SNPs and individual phenotypic traits may be useful in explaining the causal mechanisms of hereditary component of T2DM. PMID:26064370

  18. Distribution of hepatitis C virus genotypes, risk factors and liver disease in patients from Yucatán, México.

    PubMed

    García-Montalvo, Beatriz María; Galguera-Colorado, Pedro Luis

    2008-01-01

    To make a preliminary determination of hepatitis C virus (HCV) genotype prevalence and possible genotype associations with risk factors and severity of associated liver disease in patients from Yucatan, Mexico. Sera from 54 patients with positive anti-HCV and HCV RNA were genotyped using reverse transcription-polymerase chain reaction. Risk factors were evaluated using a questionnaire. The evaluations also included serum ALT levels and liver biopsies in some participants. HCV genotype 1 was detected in 37%, genotype 2 in 33.3%, genotype 3 in 16.7% and mixed genotypes in 7.4%. Subtype 2b was the most frequent (33.3%), followed by 1b (18.5%), 3a (16.7%) and 1a (14.8%). Surgeries (53.7%) and transfusion (38.9%) were the main risk factors. Liver biopsies were available in 24 (44.4%) patients. Severe liver disease was present in 6 (54.5%) of the patients with genotype 1 and in none of those with genotype 2. A statistically significant association was observed between patients with a family history of liver disease and genotype 2 (P = 0.021). Liver damage severity increased with longer duration of infection (P = 0.007). No statistically significant association was observed between severe liver damage and the different genotypes. Subtype 2b was the most prevalent. This contrasts with the studies done in different states of Mexico in that this subtype was not identified or had prevalence approximately 2 times less than reported here.

  19. Breakpoint analysis: Precise localization of genetic markers by means of nonstatistical computation using relatively few genotypes

    SciTech Connect

    Elsner, T.I.; Albertsen, H.; Gerken, S.C.; Cartwright, P.; White, R.

    1995-02-01

    Placing new markers on a previously existing genetic map by using conventional methods of multilocus linkage analysis requires that a large number of reference families be genotyped. This paper presents a methodology for placing new markers on existing genetic maps by genotyping only a few individuals in a selected subset of the reference panel. We show that by identifying meiotic breakpoint events within existing genetic maps and genotyping individuals who exhibit these events, along with one nonrecombinant sibling and their parents, we can determine precise locations for new markers even within subcentimorgan chromosomal regions. This method also improves detection of errors in genotyping and assists in the observation of chromosome behavior in specific regions. 31 refs., 9 figs.

  20. Elevated carbon dioxide alters the relative fitness of Taraxacum officinale genotypes

    USDA-ARS?s Scientific Manuscript database

    I tested whether elevated carbon dioxide concentration differentially affected which genotypes of the apomictic species dandelion produced the largest number of viable seeds in two different field experiments, and identified morphological and physiological traits associated with fitness at elevated ...

  1. Catechol-O-methyltransferase (COMT) Genotype Affects Age-Related Changes in Plasticity in Working Memory: A Pilot Study

    PubMed Central

    Riemer, Thomas G.; Schulte, Stefanie; Onken, Johanna; Heinz, Andreas; Rapp, Michael A.

    2014-01-01

    Objectives. Recent work suggests that a genetic variation associated with increased dopamine metabolism in the prefrontal cortex (catechol-O-methyltransferase Val158Met; COMT) amplifies age-related changes in working memory performance. Research on younger adults indicates that the influence of dopamine-related genetic polymorphisms on working memory performance increases when testing the cognitive limits through training. To date, this has not been studied in older adults. Method. Here we investigate the effect of COMT genotype on plasticity in working memory in a sample of 14 younger (aged 24–30 years) and 25 older (aged 60–75 years) healthy adults. Participants underwent adaptive training in the n-back working memory task over 12 sessions under increasing difficulty conditions. Results. Both younger and older adults exhibited sizeable behavioral plasticity through training (P < .001), which was larger in younger as compared to older adults (P < .001). Age-related differences were qualified by an interaction with COMT genotype (P < .001), and this interaction was due to decreased behavioral plasticity in older adults carrying the Val/Val genotype, while there was no effect of genotype in younger adults. Discussion. Our findings indicate that age-related changes in plasticity in working memory are critically affected by genetic variation in prefrontal dopamine metabolism. PMID:24772423

  2. Genotype by environment interactions in relation to growth traits in slow growing chickens

    PubMed Central

    N'Dri, Aya Lydie; Sellier, Nadine; Tixier-Boichard, Michèle; Beaumont, Catherine; Mignon-Grasteau, Sandrine

    2007-01-01

    Since feed conversion ratio (FCR) is higher in slow-growing "Label Rouge" chickens than in broiler chickens, it is important to work on its improvement in this breed. However, this involves rearing animals in cages (C), an environment very different from that used for selection (in floor pens, S) and production (outdoor, E). The aim of this study was to evaluate the importance of genotype by environment (G × E) interactions between S, C, and E environments, to find the best way to select for FCR, using 2002 related animals. Growth curve parameters were estimated and body composition measured. Individual feed conversion ratios (FCR) were recorded between 8 and 10 weeks in C. The presence of G × E interactions was assessed by the genetic correlations between the same trait recorded in different environments. Moderate but significant G × E interactions were detected for carcass traits, a significant one was observed between E and S or C for growth curve parameters but none between C and S. If G × E interactions are set aside, i.e. selecting on traits recorded in C, abdominal fatness is the best indirect selection criterion for FCR but if they are taken in account then leg yield or growth curve parameters in S and growth curve parameters in E are better. PMID:17897594

  3. Novel TMEM67 Mutations and Genotype-phenotype Correlates in Meckelin-related Ciliopathies

    PubMed Central

    Iannicelli, Miriam; Brancati, Francesco; Mougou-Zerelli, Soumaya; Mazzotta, Annalisa; Thomas, Sophie; Elkhartoufi, Nadia; Travaglini, Lorena; Gomes, Céline; Ardissino, Gian Luigi; Bertini, Enrico; Boltshauser, Eugen; Castorina, Pierangela; D'Arrigo, Stefano; Fischetto, Rita; Leroy, Brigitte; Loget, Philippe; Bonnière, Maryse; Starck, Lena; Tantau, Julia; Gentilin, Barbara; Majore, Silvia; Swistun, Dominika; Flori, Elizabeth; Lalatta, Faustina; Pantaleoni, Chiara; Johannes.Penzien; Grammatico, Paola; Dallapiccola, Bruno; Gleeson, Joseph G.; Attie-Bitach, Tania; Valente, Enza Maria

    2010-01-01

    Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin. PMID:20232449

  4. 5-HTTLPR Genotype and Anxiety-Related Personality Traits: A meta-analysis and new data

    PubMed Central

    Munafò, Marcus R.; Freimer, Nelson B.; Ng, Whitney; Ophoff, Roel; Veijola, Juha; Miettunen, Jouko; Järvelin, Marjo-Riitta; Taanila, Anja; Flint, Jonathan

    2008-01-01

    We investigated the strength of evidence for association of the 5-HTTLPR polymorphism and the personality trait of Harm Avoidance. We used new primary data from a large sample of adults drawn from the Finnish population. We also applied meta-analytic techniques to synthesize existing published data. The large number studies of the 5-HTTLPR polymorphism allowed us to apply a formal test of publication bias, as well as formally investigate the impact of potential moderating factors such as measurement instrument. Univariate ANOVA of primary data (n = 3,872), with 5-HTTLPR genotype as a between-groups factor, indicated no evidence of association with Harm Avoidance (p = 0.99). Meta-analysis indicated no evidence of significant association of 5-HTTLPR with Harm Avoidance (d = 0.02, p = 0.37), or EPQ Neuroticism (d = 0.01, p = 0.71), although there was evidence of association with NEO Neuroticism (d = 0.18, p < 0.001). Our analyses indicate that the 5-HTTLPR variant is not associated with Harm Avoidance. Together with our previous analyses of a large sample of participants with extreme Neuroticism scores (defined by the EPQ), we have data that excludes a meaningful genetic effect of the 5-HTTLPR on two measures of anxiety-related personality traits. There remains the possibility that the variant influences the NEO personality questionnaire measure of Neuroticism. However, a large, well-powered primary study is required to test this hypothesis directly and adequately. PMID:18546120

  5. No Evidence for Synergy Between Human Papillomavirus Genotypes for the Risk of High-Grade Squamous Intraepithelial Lesions in a Large Population-Based Study

    PubMed Central

    Wentzensen, Nicolas; Nason, Martha; Schiffman, Mark; Dodd, Lori; Hunt, William C.; Wheeler, Cosette M.

    2014-01-01

    Background. Multiple human papillomavirus (HPV) genotypes may be independently or synergistically associated with risk of high-grade squamous intraepithelial lesions (HSILs). We evaluated the risk of HSIL in women concomitantly infected with multiple HPV genotypes. Methods. A population-based stratified sample of 59 664 cervical cytology specimens from women residing in New Mexico were evaluated for cytologic abnormalities and HPV genotypes. We calculated the risk of HSIL in women infected with a single HPV genotype and the risk in those infected with multiple HPV genotypes. Results. The highest risk of HSIL was observed for HPV-16 (0.036), followed by HPV-33 (0.028), HPV-58 (0.024), and HPV-18 (0.022). For most types, we observed a greater risk of HSIL in women infected with multiple carcinogenic HPV types. In contrast, the risk of HSIL was similar in women infected with HPV-16 and other types, compared with women infected with HPV-16 only. We observed an increased but plateauing risk of HSIL in women infected with multiple types, compared with those infected with a single type, with risk ratios of 1.5 (95% confidence interval [CI], 1.2–1.8), 1.7 (95% CI, 1.3–2.4), and 1.4 (95% CI, 0.83–2.5) for women infected with 2, 3, and ≥4 genotypes, respectively. Conclusions. In the largest population-based study of HPV genotypes and cytologic outcomes so far, we did not see more than additive effects of HPV types on the risk of HSIL in women infected with multiple types. PMID:24179110

  6. Comparative analysis of juice volatiles in selected mandarins, mandarin relatives and other citrus genotypes.

    PubMed

    Yu, Yuan; Bai, Jinhe; Chen, Chunxian; Plotto, Anne; Baldwin, Elizabeth A; Gmitter, Frederick G

    2017-07-21

    Citrus fruit flavor is an important attribute prioritized in variety improvement. The present study compared juice volatiles compositions from 13 selected citrus genotypes, including six mandarins (Citrus reticulata), three sour oranges (Citrus aurantium), one blood orange (Citrus sinensis), one lime (Citrus limonia), one Clementine (Citrus clementina) and one satsuma (Citrus unshiu). Large differences were observed with respect to volatile compositions among the citrus genotypes. 'Goutou' sour orange contained the greatest number of volatile compounds and the largest volatile production level. 'Ponkan' mandarin had the smallest number of volatiles and 'Owari' satsuma yielded the lowest volatile production level. 'Goutou' sour orange and 'Moro' blood orange were clearly distinguished from other citrus genotypes based on the analysis of volatile compositions, even though they were assigned into one single group with two other sour oranges by the molecular marker profiles. The clustering analysis based on the aroma volatile compositions was able to differentiate mandarin varieties and natural sub-groups, and was also supported by the molecular marker study. The gas chromatography-mass spectrometry analysis of citrus juice aroma volatiles can be used as a tool to distinguish citrus genotypes and assist in the assessment of future citrus breeding programs. The aroma volatile profiles of the different citrus genotypes and inter-relationships detected among volatile compounds and among citrus genotypes will provide fundamental information on the development of marker-assisted selection in citrus breeding. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

  7. The Association of ACE Genotypes on Cardiorespiratory Variables Related to Physical Fitness in Healthy Men

    PubMed Central

    Bueno, Salomão; Pasqua, Leonardo A.; de Araújo, Gustavo; Eduardo Lima-Silva, Adriano; Bertuzzi, Rômulo

    2016-01-01

    Aerobic power (VO2max), aerobic capacity (RCP), and running efficiency (RE) are important markers of aerobic fitness. However, the influence of the angiotensin converting enzyme (ACE) polymorphism on these markers has not been investigated in healthy individuals. One hundred and fifty physically active young men (age 25 ± 3 years; height 1.77 ± 0.06 m; body mass 76.6 ± 0.9 kg; VO2max 47.7 ± 5.5 ml·kg-1·min-1) visited the laboratory on two separate occasions, and performed the following tests: a) a maximal incremental treadmill test to determine VO2max and RCP, and b) two constant-speed running tests (10 km·h-1 and 12 km·h-1) to determine RE. The genotype frequency was II = 21%; ID = 52%; and DD = 27%. There was a tendency for higher VO2max with the ACE II genotype (p = 0.08) compared to DD and ID genotypes. Magnitude based inferences suggested a likely beneficial effect on VO2max with the ACE II genotype. There was no association between genotypes for other variable. These findings suggest that individuals with the ACE II genotype have a tendency towards better values in aerobic power, but not with aerobic capacity or running economy. PMID:27861507

  8. Resting-State Brain and the FTO Obesity Risk Allele: Default Mode, Sensorimotor, and Salience Network Connectivity Underlying Different Somatosensory Integration and Reward Processing between Genotypes.

    PubMed

    Olivo, Gaia; Wiemerslage, Lyle; Nilsson, Emil K; Solstrand Dahlberg, Linda; Larsen, Anna L; Olaya Búcaro, Marcela; Gustafsson, Veronica P; Titova, Olga E; Bandstein, Marcus; Larsson, Elna-Marie; Benedict, Christian; Brooks, Samantha J; Schiöth, Helgi B

    2016-01-01

    Single-nucleotide polymorphisms (SNPs) of the fat mass and obesity associated (FTO) gene are linked to obesity, but how these SNPs influence resting-state neural activation is unknown. Few brain-imaging studies have investigated the influence of obesity-related SNPs on neural activity, and no study has investigated resting-state connectivity patterns. We tested connectivity within three, main resting-state networks: default mode (DMN), sensorimotor (SMN), and salience network (SN) in 30 male participants, grouped based on genotype for the rs9939609 FTO SNP, as well as punishment and reward sensitivity measured by the Behavioral Inhibition (BIS) and Behavioral Activation System (BAS) questionnaires. Because obesity is associated with anomalies in both systems, we calculated a BIS/BAS ratio (BBr) accounting for features of both scores. A prominence of BIS over BAS (higher BBr) resulted in increased connectivity in frontal and paralimbic regions. These alterations were more evident in the obesity-associated AA genotype, where a high BBr was also associated with increased SN connectivity in dopaminergic circuitries, and in a subnetwork involved in somatosensory integration regarding food. Participants with AA genotype and high BBr, compared to corresponding participants in the TT genotype, also showed greater DMN connectivity in regions involved in the processing of food cues, and in the SMN for regions involved in visceral perception and reward-based learning. These findings suggest that neural connectivity patterns influence the sensitivity toward punishment and reward more closely in the AA carriers, predisposing them to developing obesity. Our work explains a complex interaction between genetics, neural patterns, and behavioral measures in determining the risk for obesity and may help develop individually-tailored strategies for obesity prevention.

  9. Resting-State Brain and the FTO Obesity Risk Allele: Default Mode, Sensorimotor, and Salience Network Connectivity Underlying Different Somatosensory Integration and Reward Processing between Genotypes

    PubMed Central

    Olivo, Gaia; Wiemerslage, Lyle; Nilsson, Emil K.; Solstrand Dahlberg, Linda; Larsen, Anna L.; Olaya Búcaro, Marcela; Gustafsson, Veronica P.; Titova, Olga E.; Bandstein, Marcus; Larsson, Elna-Marie; Benedict, Christian; Brooks, Samantha J.; Schiöth, Helgi B.

    2016-01-01

    Single-nucleotide polymorphisms (SNPs) of the fat mass and obesity associated (FTO) gene are linked to obesity, but how these SNPs influence resting-state neural activation is unknown. Few brain-imaging studies have investigated the influence of obesity-related SNPs on neural activity, and no study has investigated resting-state connectivity patterns. We tested connectivity within three, main resting-state networks: default mode (DMN), sensorimotor (SMN), and salience network (SN) in 30 male participants, grouped based on genotype for the rs9939609 FTO SNP, as well as punishment and reward sensitivity measured by the Behavioral Inhibition (BIS) and Behavioral Activation System (BAS) questionnaires. Because obesity is associated with anomalies in both systems, we calculated a BIS/BAS ratio (BBr) accounting for features of both scores. A prominence of BIS over BAS (higher BBr) resulted in increased connectivity in frontal and paralimbic regions. These alterations were more evident in the obesity-associated AA genotype, where a high BBr was also associated with increased SN connectivity in dopaminergic circuitries, and in a subnetwork involved in somatosensory integration regarding food. Participants with AA genotype and high BBr, compared to corresponding participants in the TT genotype, also showed greater DMN connectivity in regions involved in the processing of food cues, and in the SMN for regions involved in visceral perception and reward-based learning. These findings suggest that neural connectivity patterns influence the sensitivity toward punishment and reward more closely in the AA carriers, predisposing them to developing obesity. Our work explains a complex interaction between genetics, neural patterns, and behavioral measures in determining the risk for obesity and may help develop individually-tailored strategies for obesity prevention. PMID:26924971

  10. Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet's disease susceptibility.

    PubMed

    Takeuchi, Masaki; Mizuki, Nobuhisa; Meguro, Akira; Ombrello, Michael J; Kirino, Yohei; Satorius, Colleen; Le, Julie; Blake, Mary; Erer, Burak; Kawagoe, Tatsukata; Ustek, Duran; Tugal-Tutkun, Ilknur; Seyahi, Emire; Ozyazgan, Yilmaz; Sousa, Inês; Davatchi, Fereydoun; Francisco, Vânia; Shahram, Farhad; Abdollahi, Bahar Sadeghi; Nadji, Abdolhadi; Shafiee, Niloofar Mojarad; Ghaderibarmi, Fahmida; Ohno, Shigeaki; Ueda, Atsuhisa; Ishigatsubo, Yoshiaki; Gadina, Massimo; Oliveira, Sofia A; Gül, Ahmet; Kastner, Daniel L; Remmers, Elaine F

    2017-03-01

    We analyzed 1,900 Turkish Behçet's disease cases and 1,779 controls genotyped with the Immunochip. The most significantly associated SNP was rs1050502, a tag SNP for HLA-B*51. In the Turkish discovery set, we identified three new risk loci, IL1A-IL1B, IRF8, and CEBPB-PTPN1, with genome-wide significance (P < 5 × 10(-8)) by direct genotyping and ADO-EGR2 by imputation. We replicated the ADO-EGR2, IRF8, and CEBPB-PTPN1 loci by genotyping 969 Iranian cases and 826 controls. Imputed data in 608 Japanese cases and 737 controls further replicated ADO-EGR2 and IRF8, and meta-analysis additionally identified RIPK2 and LACC1. The disease-associated allele of rs4402765, the lead marker at IL1A-IL1B, was associated with both decreased IL-1α and increased IL-1β production. ABO non-secretor genotypes for two ancestry-specific FUT2 SNPs showed strong disease association (P = 5.89 × 10(-15)). Our findings extend the list of susceptibility genes shared with Crohn's disease and leprosy and implicate mucosal factors and the innate immune response to microbial exposure in Behçet's disease susceptibility.

  11. Paraoxonase (PON)1 Q192R functional genotypes and PON1 Q192R genotype by smoking interactions are risk factors for the metabolic syndrome, but not overweight or obesity.

    PubMed

    Bortolasci, Chiara Cristina; Vargas, Heber Odebrecht; Souza-Nogueira, André; Gastaldello Moreira, Estefania; Vargas Nunes, Sandra Odebrecht; Berk, Michael; Dodd, Seetal; Barbosa, Décio Sabbatini; Maes, Michael

    2014-11-01

    Background The metabolic syndrome (MetS) is a complex of multiple risk factors that contribute to the onset of cardiovascular disorder, including lowered levels of high-density lipoprotein (HDL) and abdominal obesity. Smoking, mood disorders, and oxidative stress are associated with the MetS. Paraoxonase (PON)1 is an antioxidant bound to HDL, that is under genetic control by functional polymorphisms in the PON1 Q192R coding sequence. Aims and methods This study aimed to delineate the associations of the MetS with plasma PON1 activity, PON1 Q192R genotypes, smoking, and mood disorders (major depression and bipolar disorder), while adjusting for HDL cholesterol, body mass index, age, gender, and sociodemographic data. We measured plasma PON1 activity and serum HDL cholesterol and determined PON1 Q192R genotypes through functional analysis in 335 subjects, consisting of 97 with and 238 without MetS. The severity of nicotine dependence was measured using the Fagerström Nicotine Dependence Scale. Results PON1 Q192R functional genotypes and PON1 Q192R genotypes by smoking interactions were associated with the MetS. The QQ and QR genotypes were protective against MetS while smoking increased metabolic risk in QQ carriers only. There were no significant associations between PON1 Q192R genotypes and smoking by genotype interactions and obesity or overweight, while body mass index significantly increased MetS risk. Smoking and especially severe nicotine dependence are significantly associated with the MetS although these effects were no longer significant after considering the effects of the smoking by PON1 Q192R genotype interaction. The MetS was not associated with mood disorders, major depression or bipolar disorder. Discussion PON1 Q192R genotypes and genotypes by smoking interactions are risk factors for the MetS that together with lowered HDL and increased body mass and age contribute to the MetS.

  12. Paraoxonase 1 (PON1) Q192R genotypes and their interaction with smoking strongly increase atherogenicity and the Framingham risk score.

    PubMed

    Souza-Nogueira, Andre de; Camargo, Alissana Ester; Remondi, Felipe Assan; Paoliello, Monica Maria Bastos; Richter, Rebecca J; Furlong, Clement E; Barbosa, Decio Sabbatini; Maes, Michael; Moreira, Estefania Gastaldello

    2016-10-01

    Paraoxonase 1 (PON1) polymorphisms are associated with an increased susceptibility to cardiovascular disease. PON1 Q192R polymorphism (rs662) partially determine PON1 hydrolytic activity and protect against oxidation of LDL and HDL. This study aimed to delineate the association of PON1 status (functional 192 genotype and plasma activity levels) and atherogenicity in urbans residents aged 40 years or more. Anthropometric data, lipid profiles, the atherogenic index of the plasma (AIP) and Framingham score risk were measured. Three kinetic assays were conducted to assay PON1 status using phenylacetate and 4-(chloromethyl)phenyl acetate as substrates. Smoking per se did not significantly impact the AIP but the interaction PON1 genotype by smoking significantly increased the AIP. In subjects with the RR genotype smoking increased the AIP index from (estimated mean ± SEM) -0.038 ± 0.039 to 0.224 ± 0.094. The QR genotype increased the Framingham risk index by around 1.3 points. Smoking by RR genotype carriers significantly increased the Framingham risk score (17.23 ± 2.04) as compared to smoking (13.00 ± 1.06) and non-smoking (7.79 ± 0.70) by QQ+QR genotype carriers. The interaction RR genotype by smoking was a more important predictor (odds ratio = 7.90) of an increased Framingham risk score (> 20) than smoking per se (odds ratio = 2.73). The interaction smoking by RR genotype carriers significantly increased triglycerides and lowered HDL cholesterol. Smoking per se has no (AIP) or a mild (Framingham risk score) effect on atherogenicity, while the interaction smoking by PON1 RR genotype has a clinically highly significant impact on atherogenicity.

  13. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism

    PubMed Central

    James, S. Jill; Melnyk, Stepan; Jernigan, Stefanie; Cleves, Mario A.; Halsted, Charles H.; Wong, Donna H.; Cutler, Paul; Bock, Kenneth; Boris, Marvin; Bradstreet, J. Jeffrey; Baker, Sidney M.; Gaylor, David W.

    2008-01-01

    Autism is a behaviorally-defined neurodevelopmental disorder usually diagnosed in early childhood that is characterized by impairment in reciprocal communication and speech, repetitive behaviors, and social withdrawal. Although both genetic and environmental factors are thought to be involved, none have been reproducibly identified. The metabolic phenotype of an individual reflects the influence of endogenous and exogenous factors on genotype. As such, it provides a window through which the interactive impact of genes and environment may be viewed and relevant susceptibility factors identified. Although abnormal methionine metabolism has been associated with other neurologic disorders, these pathways and related polymorphisms have not been evaluated in autistic children. Plasma levels of metabolites in methionine transmethylation and transsulfuration pathways were measured in 80 autistic and 73 control children. In addition, common polymorphic variants known to modulate these metabolic pathways were evaluated in 360 autistic children and 205 controls. The metabolic results indicated that plasma methionine and the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), an indicator of methylation capacity, were significantly decreased in the autistic children relative to age-matched controls. In addition, plasma levels of cysteine, glutathione, and the ratio of reduced to oxidized glutathione, an indication of antioxidant capacity and redox homeostasis, were significantly decreased. Differences in allele frequency and/or significant gene-gene interactions were found for relevant genes encoding the reduced folate carrier (RFC 80G>A), transcobalamin II (TCN2 776G>C), catechol-O-methyltransferase (COMT 472G>A), methylenetetrahydrofolate reductase (MTHFR 677C>T and 1298A>C), and GST M1. We propose that an increased vulnerability to oxidative stress (endogenous or environmental) may contribute to the development and clinical manifestations of autism. PMID

  14. Does greater adiposity increase blood pressure and hypertension risk?: Mendelian randomization using the FTO/MC4R genotype.

    PubMed

    Timpson, Nicholas J; Harbord, Roger; Davey Smith, George; Zacho, Jeppe; Tybjaerg-Hansen, Anne; Nordestgaard, Børge G

    2009-07-01

    Elevated blood pressure increases the risk of experiencing cardiovascular events like myocardial infarction and stroke. Current observational data suggest that body mass index may have a causal role in the etiology of hypertension, but this may be influenced by confounding and reverse causation. Through the use of instrumental variable methods, we aim to estimate the strength of the unconfounded and unbiased association between body mass index/adiposity and blood pressure. We explore these issues in the Copenhagen General Population Study. We used instrumental variable methods to obtain estimates of the causal association between body mass index and blood pressure. This was performed using both rs9939609 (FTO) and rs17782313 (MC4R) genotypes as instruments for body mass index. Avoiding the epidemiological problems of confounding, bias, and reverse causation, we confirmed observational associations between body mass index and blood pressure. In analyses including those taking antihypertensive drugs, but for whom appropriate adjustment had been made, systolic blood pressure was seen to increase by 3.85 mm Hg (95% CI: 1.88 to 5.83 mm Hg) for each 10% increase in body mass index (P=0.0002), with diastolic blood pressure showing an increase of 1.79 mm Hg (95% CI: 0.68 to 2.90 mm Hg) for each 10% increase in body mass index (P=0.002). Observed associations are large and illustrate the considerable benefits in terms of reductions in blood pressure-related morbidity that could be achieved through a reduction in body mass index.

  15. Risk considerations related to lung modeling

    SciTech Connect

    Masse, R.; Cross, F.T. )

    1989-01-01

    Improved lung models provide a more accurate assessment of dose from inhalation exposures and, therefore, more accurate dose-response relationships for risk evaluation and exposure limitation. Epidemiological data for externally irradiated persons indicate that the numbers of excess respiratory tract carcinomas differ in the upper airways, bronchi, and distal lung. Neither their histogenesis and anatomical location nor their progenitor cells are known with sufficient accuracy for accurate assessment of the microdosimetry. The nuclei of sensitive cells generally can be assumed to be distributed at random in the epithelium, beneath the mucus and tips of the beating cilia and cells. In stratified epithelia, basal cells may be considered the only cells at risk. Upper-airway tumors have been observed in both therapeutically irradiated patients and in Hiroshima-Nagasaki survivors. The current International Commission on Radiological Protection Lung-Model Task Group proposes that the upper airways and lung have a similar relative risk coefficient for cancer induction. The partition of the risk weighting factor, therefore, will be proportional to the spontaneous death rate from tumors, and 80% of the weighting factor for the respiratory tract should be attributed to the lung. For Weibel lung-model branching generations 0 to 16 and 17 to 23, the Task Group proposes an 80/20 partition of the risk, i.e., 64% and 16%, respectively, of the total risk. Regarding risk in animals, recent data in rats indicate a significantly lower effectiveness for lung-cancer induction at low doses from insoluble long-lived alpha-emitters than from Rn daughters. These findings are due, in part, to the fact that different regions of the lung are irradiated. Tumors in the lymph nodes are rare in people and animals exposed to radiation.44 references.

  16. Risk Factors for Age-Related Maculopathy

    PubMed Central

    Connell, Paul P.; Keane, Pearse A.; O'Neill, Evelyn C.; Altaie, Rasha W.; Loane, Edward; Neelam, Kumari; Nolan, John M.; Beatty, Stephen

    2009-01-01

    Age-related maculopathy (ARM) is the leading cause of blindness in the elderly. Although beneficial therapeutic strategies have recently begun to emerge, much remains unclear regarding the etiopathogenesis of this disorder. Epidemiologic studies have enhanced our understanding of ARM, but the data, often conflicting, has led to difficulties with drawing firm conclusions with respect to risk for this condition. As a consequence, we saw a need to assimilate the published findings with respect to risk factors for ARM, through a review of the literature appraising results from published cross-sectional studies, prospective cohort studies, case series, and case control studies investigating risk for this condition. Our review shows that, to date, and across a spectrum of epidemiologic study designs, only age, cigarette smoking, and family history of ARM have been consistently demonstrated to represent risk for this condition. In addition, genetic studies have recently implicated many genes in the pathogenesis of age-related maculopathy, including Complement Factor H, PLEKHA 1, and LOC387715/HTRA1, demonstrating that environmental and genetic factors are important for the development of ARM suggesting that gene-environment interaction plays an important role in the pathogenesis of this condition. PMID:20339564

  17. Bladder cancer risk associated with genotypic polymorphism of the matrix metalloproteinase-1 and 7 in North Indian population.

    PubMed

    Srivastava, Priyanka; Gangwar, Ruchika; Kapoor, Rakesh; Mittal, Rama D

    2010-01-01

    Matrix metalloproteinases (MMPs) contribute to tumor invasion and microenvironment, hence are associated with bladder cancer risk. We therefore, tested whether polymorphisms in MMP genes modify the risk of bladder cancer (BC) and whether smoke exposure modifies this risk. Genotyping was performed in 200 BC patients and 200 controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). MMP1-1607 2G/2G and MMP7-181 GG genotype were associated with increased risk of BC (p < 0.001; OR, 3.04; 95% CI- 1.71-5.39 and p, 0.005; OR, 2.38; 95% CI- 1.30-4.34) respectively. Smokers in BC patients showed significant increased risk for the same SNPs (p, 0.006; OR, 3.20; 95% CI- 1.40-7.31 and p, 0.009; OR, 2.85; 95% CI- 1.30-6.23 respectively). Haplotype analysis too revealed significant association with G/2G of MMP1-519-1607 (p< 0.001; OR, 2.62; 95% CI- 1.68-4.09). The 2G allele carrier (1G/2G + 2G/2G) of MMP1-1607 showed a protective effect and high recurrence free survival in Bacillus Calmette-Guérin (BCG) treated non muscle invasive BC (NMIBC) patients (log rank p, 0.030). Our data suggested that MMP1-1607 2G and MMP7-181 G allele were associated with high risk of BC, which was quite evident amongst smokers too. BCG treated NMIBC patients reflected protective effect for 2G allele carrier (1G/2G + 2G/2G) of MMP1-1607. This study provided new support for the association of MMP1-1607 and MMP7-181 in bladder cancer development, the tumorigenic effect of which was observed to be more enhanced in case of tobacco exposure.

  18. The Role of Genotypes That Modify the Toxicity of Chemical Mutagens in the Risk for Myeloproliferative Neoplasms

    PubMed Central

    Gross-Davis, Carol Ann; Heavner, Karyn; Frank, Arthur L.; Newschaffer, Craig; Klotz, Judith; Santella, Regina M.; Burstyn, Igor

    2015-01-01

    Background: The etiology of myeloproliferative neoplasms (MPN) (polycythemia vera; essential thrombocythemia; primary myelofibrosis) is unknown, however they are associated with a somatic mutation—JAK2 V617F—suggesting a potential role for environmental mutagens. Methods: We conducted a population-based case-control study in three rural Pennsylvania counties of persons born 1921–1968 and residing in the area between 2000–2008. Twenty seven MPN cases and 292 controls were recruited through random digit dialing. Subjects were genotyped and odds ratios estimated for a select set of polymorphisms in environmentally sensitive genes that might implicate specific environmental mutagens if found to be associated with a disease. Results: The presence of NAT2 slow acetylator genotype, and CYP1A2, GSTA1, and GSTM3 variants were associated with an average 3–5 fold increased risk. Conclusions: Exposures, such as to aromatic compounds, whose toxicity is modified by genotypes associated with outcome in our analysis may play a role in the environmental etiology of MPNs. PMID:25719551

  19. MAOA and the "cycle of violence:" childhood abuse and neglect, MAOA genotype, and risk for violent and antisocial behavior.

    PubMed

    Widom, Cathy Spatz; Brzustowicz, Linda M

    2006-10-01

    Two recent studies with white males have shown that genotypes associated with high levels of monamine oxidase A (MAOA) protect against the impact of childhood maltreatment and adversity on the development of antisocial behavior and conduct disorder. Participants in a prospective cohort design study involving court substantiated cases of child abuse and neglect and a matched comparison group were followed up into adulthood and interviewed (N = 802). Eighty-two percent consented to provide blood and 631 gave permission for DNA extraction and analyses. A composite index of violent and antisocial behavior (VASB) was created based on arrest, self-report, and diagnostic information. No main effect was found for the relationship between MAOA genotype and VASB. Genotypes associated with high levels of MAOA activity buffered abused and neglected whites from increased risk of becoming violent and/or antisocial in later life. This protective effect was not found for non-white abused and neglected individuals. Possible explanations for this differential effect for whites and non-whites include differences in contextual factors (e.g., environmental stressors) and a question of the suitability of using the MAOA promoter VNTR polymorphism as a proxy for MAOA levels in non-white populations.

  20. Abdominal symptoms in cystic fibrosis and their relation to genotype, history, clinical and laboratory findings

    PubMed Central

    Tabori, Harold; Jaudszus, Anke; Mentzel, Hans-Joachim; Renz, Diane M.; Reinsch, Steffen; Lorenz, Michael; Michl, Ruth; Gerber, Andrea; Lehmann, Thomas

    2017-01-01

    Background & aims Abdominal symptoms (AS) are a hallmark of the multiorgan-disease cystic fibrosis (CF). However, the abdominal involvement in CF is insufficiently understood and, compared to the pulmonary manifestation, still receives little scientific attention. Aims were to assess and quantify AS and to relate them to laboratory parameters, clinical findings, and medical history. Methods A total of 131 patients with CF of all ages were assessed with a new CF-specific questionnaire (JenAbdomen-CF score 1.0) on abdominal pain and non-pain symptoms, disorders of appetite, eating, and bowel movements as well as symptom-related quality of life. Results were metrically dimensioned and related to abdominal manifestations, history of surgery, P. aeruginosa and S. aureus colonization, genotype, liver enzymes, antibiotic therapy, lung function, and nutritional status. Results AS during the preceding 3 months were reported by all of our patients. Most common were lack of appetite (130/131) and loss of taste (119/131) followed by abdominal pain (104/131), flatulence (102/131), and distention (83/131). Significantly increased AS were found in patients with history of rectal prolapse (p = 0.013), distal intestinal obstruction syndrome (p = 0.013), laparotomy (p = 0.022), meconium ileus (p = 0.037), pancreas insufficiency (p = 0.042), or small bowel resection (p = 0.048) as well as in patients who have been intermittently colonized with P. aeruginosa (p = 0.006) compared to patients without history of these events. In contrast, no statistically significant associations were found to CF-associated liver disease, chronic pathogen colonization, lung function, CF-related diabetes, and nutritional status. Conclusion As the complex abdominal involvement in CF is still not fully understood, the assessment of the common AS is of major interest. In this regard, symptom questionnaires like the herein presented are meaningful and practical tools facilitating a wider understanding of the

  1. Abdominal symptoms in cystic fibrosis and their relation to genotype, history, clinical and laboratory findings.

    PubMed

    Tabori, Harold; Arnold, Christin; Jaudszus, Anke; Mentzel, Hans-Joachim; Renz, Diane M; Reinsch, Steffen; Lorenz, Michael; Michl, Ruth; Gerber, Andrea; Lehmann, Thomas; Mainz, Jochen G

    2017-01-01

    Abdominal symptoms (AS) are a hallmark of the multiorgan-disease cystic fibrosis (CF). However, the abdominal involvement in CF is insufficiently understood and, compared to the pulmonary manifestation, still receives little scientific attention. Aims were to assess and quantify AS and to relate them to laboratory parameters, clinical findings, and medical history. A total of 131 patients with CF of all ages were assessed with a new CF-specific questionnaire (JenAbdomen-CF score 1.0) on abdominal pain and non-pain symptoms, disorders of appetite, eating, and bowel movements as well as symptom-related quality of life. Results were metrically dimensioned and related to abdominal manifestations, history of surgery, P. aeruginosa and S. aureus colonization, genotype, liver enzymes, antibiotic therapy, lung function, and nutritional status. AS during the preceding 3 months were reported by all of our patients. Most common were lack of appetite (130/131) and loss of taste (119/131) followed by abdominal pain (104/131), flatulence (102/131), and distention (83/131). Significantly increased AS were found in patients with history of rectal prolapse (p = 0.013), distal intestinal obstruction syndrome (p = 0.013), laparotomy (p = 0.022), meconium ileus (p = 0.037), pancreas insufficiency (p = 0.042), or small bowel resection (p = 0.048) as well as in patients who have been intermittently colonized with P. aeruginosa (p = 0.006) compared to patients without history of these events. In contrast, no statistically significant associations were found to CF-associated liver disease, chronic pathogen colonization, lung function, CF-related diabetes, and nutritional status. As the complex abdominal involvement in CF is still not fully understood, the assessment of the common AS is of major interest. In this regard, symptom questionnaires like the herein presented are meaningful and practical tools facilitating a wider understanding of the abdominal symptoms in CF. Furthermore, they

  2. HBV genotype F: natural history and treatment.

    PubMed

    Marciano, Sebastián; Galdame, Omar A; Gadano, Adrián C

    2013-01-01

    The analysis of the HBV genome revealed the existence of 10 genotypes, named A-J. Evidence of the influence of the different genotypes in the natural history and treatment response to nucleoside/nucleotide analogues or interferon-based regimens is scant. HBV genotype F is one of the most prevalent circulating genotypes in South America and the Arctic Circle. Since most of the available information on HBV is from Asia, the US and Europe, it reflects their predominant genotypes: A, B, C and D. To date, the evidence is not fully confirmed, but it appears that genotype F chronic hepatitis B is associated with a more aggressive course of liver disease, reflected by higher histological indexes, a higher risk of development of hepatocellular carcinoma and a higher rate of liver-related mortality. In terms of treatment response, the available data is, unfortunately, even more limited; however, what data is available suggests acceptable and similar response rates to pegylated interferon-α2a in genotype F compared to genotype A. Response rates to nucleoside/nucleotide analogues is not influenced by genotype. The review of this limited data sheds light on the necessity to conduct further studies in South America and the Arctic Circle in order to better understand the different aspects of HBV genotype F, especially in relation to treatment response.

  3. Multiple high-risk HPV genotypes are grouped by type and are associated with viral load and risk factors.

    PubMed

    Del Río-Ospina, L; Soto-DE León, S C; Camargo, M; Sánchez, R; Moreno-Pérez, D A; Pérez-Prados, A; Patarroyo, M E; Patarroyo, M A

    2017-02-10

    Investigating whether high-risk human papillomavirus (HR-HPV) types tend to become grouped in a particular way and whether factors are associated with such grouping is important for measuring the real impact of vaccination. In total, 219 women proving positive for HPV as detected by real-time PCR were included in the study. Each sample was analysed for detecting and quantifying six viral types and the hydroxymethylbilane synthase gene. Multiple correspondence analysis led to determining grouping patterns for six HR-HPV types and simultaneous association with multiple variables and whether viral load was related to the coexistence of other viral types. Two grouping profiles were identified: the first included HPV-16 and HPV-45 and the second profile was represented by HPV-31, HPV-33 and HPV-58. Variables such as origin, contraceptive method, births and pregnancies, educational level, healthcare affiliation regime, atypical squamous cells of undetermined significance and viral load were associated with these grouping profiles. Different socio-demographic characteristics were found when coinfection occurred by phylogenetically related HPV types and when coinfection was due to non-related types. Biological characteristics, the number of viral copies, temporality regarding acquiring infection and competition between viral types could influence the configuration of grouping patterns. Characteristics related to women and HPV, influence such interactions between coexisting HPV types reflecting the importance of their evaluation.

  4. High osteoporosis risk among East Africans linked to lactase persistence genotype.

    PubMed

    Hilliard, Constance B

    2016-01-01

    This ecological correlation study explores the marked differential in osteoporosis susceptibility between East and West Africans. African tsetse belt populations are lactase non-persistent (lactose intolerant) and possess none of the genetic polymorphisms carried by lactase persistent (lactose tolerant) ethnic populations. What appears paradoxical, however, is the fact that Niger-Kordofanian (NK) West African ethnicities are also at minimal risk of osteoporosis. Although East Africans share a genetic affinity with NK West Africans, they display susceptibility rates of the bone disorder closer to those found in Europe. Similar to Europeans, they also carry alleles conferring the lactase persistence genetic traits. Hip fracture rates of African populations are juxtaposed with a global model to determine whether it is the unique ecology of the tsetse-infested zone or other variables that may be at work. This project uses MINITAB 17 software for regression analyses. The research data are found on AJOL (African Journals Online), PUBMED and JSTOR (Scholarly Journal Archive). Data showing the risk of osteoporosis to be 80 times higher among East Africans with higher levels of lactase persistence than lactase non-persistence West Africans are compared with global statistics. Hip fracture rates in 40 countries exhibit a high Pearson's correlation of r=0.851, with P-value=0.000 in relation to dairy consumption. Lower correlations are seen for hip fracture incidence vis-à-vis lactase persistence, per capita income and animal protein consumption. Ethnic populations who lack lactase persistence single-nucleotide polymorphisms may be at low risk of developing osteoporosis.

  5. High osteoporosis risk among East Africans linked to lactase persistence genotype

    PubMed Central

    Hilliard, Constance B

    2016-01-01

    This ecological correlation study explores the marked differential in osteoporosis susceptibility between East and West Africans. African tsetse belt populations are lactase non-persistent (lactose intolerant) and possess none of the genetic polymorphisms carried by lactase persistent (lactose tolerant) ethnic populations. What appears paradoxical, however, is the fact that Niger-Kordofanian (NK) West African ethnicities are also at minimal risk of osteoporosis. Although East Africans share a genetic affinity with NK West Africans, they display susceptibility rates of the bone disorder closer to those found in Europe. Similar to Europeans, they also carry alleles conferring the lactase persistence genetic traits. Hip fracture rates of African populations are juxtaposed with a global model to determine whether it is the unique ecology of the tsetse-infested zone or other variables that may be at work. This project uses MINITAB 17 software for regression analyses. The research data are found on AJOL (African Journals Online), PUBMED and JSTOR (Scholarly Journal Archive). Data showing the risk of osteoporosis to be 80 times higher among East Africans with higher levels of lactase persistence than lactase non-persistence West Africans are compared with global statistics. Hip fracture rates in 40 countries exhibit a high Pearson's correlation of r=0.851, with P-value=0.000 in relation to dairy consumption. Lower correlations are seen for hip fracture incidence vis-à-vis lactase persistence, per capita income and animal protein consumption. Ethnic populations who lack lactase persistence single-nucleotide polymorphisms may be at low risk of developing osteoporosis. PMID:27408710

  6. PER1 rs3027172 Genotype Interacts with Early Life Stress to Predict Problematic Alcohol Use, but Not Reward-Related Ventral Striatum Activity

    PubMed Central

    Baranger, David A. A.; Ifrah, Chloé; Prather, Aric A.; Carey, Caitlin E.; Corral-Frías, Nadia S.; Drabant Conley, Emily; Hariri, Ahmad R.; Bogdan, Ryan

    2016-01-01

    Increasing evidence suggests that the circadian and stress regulatory systems contribute to alcohol use disorder (AUD) risk, which may partially arise through effects on reward-related neural function. The C allele of the PER1 rs3027172 single nucleotide polymorphism (SNP) reduces PER1 expression in cells incubated with cortisol and has been associated with increased risk for adult AUD and problematic drinking among adolescents exposed to high levels of familial psychosocial adversity. Using data from undergraduate students who completed the ongoing Duke Neurogenetics Study (DNS) (n = 665), we tested whether exposure to early life stress (ELS; Childhood Trauma Questionnaire) moderates the association between rs3027172 genotype and later problematic alcohol use (Alcohol Use Disorders Identification Test) as well as ventral striatum (VS) reactivity to reward (card-guessing task while functional magnetic resonance imaging data were acquired). Initial analyses found that PER1 rs3027172 genotype interacted with ELS to predict both problematic drinking and VS reactivity; minor C allele carriers, who were also exposed to elevated ELS reported greater problematic drinking and exhibited greater ventral striatum reactivity to reward-related stimuli. When gene × covariate and environment × covariate interactions were controlled for, the interaction predicting problematic alcohol use remained significant (p < 0.05, corrected) while the interaction predicting VS reactivity was no longer significant. These results extend our understanding of relationships between PER1 genotype, ELS, and problematic alcohol use, and serve as a cautionary tale on the importance of controlling for potential confounders in studies of moderation including gene × environment interactions. PMID:27065929

  7. Estrogen-related genes and postmenopausal osteoporosis risk.

    PubMed

    Mendoza, N; Quereda, F; Presa, J; Salamanca, A; Sánchez-Borrego, R; Vázquez, F; Martínez Astorquiza, T

    2012-12-01

    To date, more than 150 candidate genes related to osteoporosis have been described, but osteoporosis has increasingly been considered a polygenic disease modulated by environmental factors. It is thought that osteoporosis predisposition, pathology, and treatment response depend on the interaction between different genes or between genes and environmental factors. The aim of this study was to evaluate the relationship between the presence of single nucleotide polymorphisms (SNPs) in the estrogen metabolic pathway and the development of osteoporosis and to determine whether this relationship is monogenic or whether interactions between genes exist. A multicentric study with 1980 postmenopausal Spanish women in five Spanish communities was conducted. The women completed a specific questionnaire that inquired about risk factors for osteoporosis. Data on participants' bone mineral density were obtained with dual-energy X-ray densitometers, and genetic data were obtained from frozen peripheral blood. The digenic protection combinations indicated involvement of the wild-type genotype (WT) of the 3'UTR marker for the CYP19A1 gene, the IVS4 marker of the same gene, and the BMP15 and FSHR genes. Among patients who carried two or more of the genotypes considered 'risky', the triple combination among markers of the ESR2 and NRIP1 genes with any of the two mutations of the analyzed markers of the BMP15 gene gave a mean T-score value of -2.32±0.91 (p = 0.02). Variants of the new candidate genes (NRIP and BMP15) can predispose patients to osteoporosis.

  8. Impact of genetic risk assessment on nutrition-related lifestyle behaviours

    PubMed Central

    Vernarelli, Jacqueline A.

    2013-01-01

    Genetic susceptibility testing for common complex disease is a practice that is currently in clinical use. There are two types of gene mutations, and therefore, two varieties of genotype testing: deterministic and susceptibility. As the term suggests, deterministic genes determine whether or not a person will develop a given trait in Mendelian fashion, such as Huntington’s disease. Genotype screening for such deterministic mutations has existed for decades, and is commonly used in routine medical practice. In recent years, the sequencing of the human genome has identified several ‘susceptibility genes’ or genes with incomplete penetrance. Mutations in these genes may increase disease susceptibility, but are not causative for disease. Genetic susceptibility testing allows unaffected individuals to obtain risk information for a variety of common complex diseases and health conditions including Alzheimer’s disease (AD), CVD, cancer and diabetes. The availability of genetic susceptibility testing has increased over the past decade, and several studies are now focusing on the impact that genetic testing has on health and other lifestyle behaviours related to nutrition. The aim of this paper is to review the literature and evaluate what, if any, impact genetic risk assessment has on behaviours related to nutrition and physical activity. This paper summarises seven clinical studies that evaluated the impact of disclosing genetic risk information for disease on nutrition-related health behaviour changes. Of these seven studies, only three studies reported that health behaviour change was influenced by genotype disclosure. PMID:23095764

  9. Obesity-associated gene FTO rs9939609 polymorphism in relation to the risk of tuberculosis.

    PubMed

    Feng, Yan; Wang, Fengliang; Pan, Hongqiu; Qiu, Sangsang; Lü, Jieqiong; Wu, Liang; Wang, Jianming; Lu, Cheng

    2014-11-07

    Obesity is known to affect cell-mediated immune responses. Recent studies have revealed that genetic polymorphisms in the fat mass and obesity associated (FTO) gene are related to human obesity. We hypothesize that this gene may also play a role in the risk of immune-related infectious diseases such as tuberculosis. This case-control study included 1625 pulmonary tuberculosis cases and 1570 unaffected controls recruited from the Jiangsu province in China. Single nucleotide polymorphisms (SNPs), rs9939609 and rs8050136, in the FTO gene were genotyped using TaqMan allelic discrimination assays. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the unconditional logistic regression model. We observed a significant association between the genetic polymorphism rs9939609 and tuberculosis risk. Compared with the common genotype TT, individuals carrying AA had a significantly increased risk, with an OR of 3.77 (95% CI: 2.26-6.28). After adjusting for potential confounders, the relationship remains significant. An additive model showed that carriers of an allele A had a 26% increased risk of tuberculosis compared with the T allele (OR: 1.26, 95% CI: 1.08-1.48). Compared with the common haplotype rs9939609T-rs8050136C, the haplotype rs9939609A-rs8050136C was related to an increased risk of tuberculosis (OR = 6.09, 95% CI: 3.27-12.34). The FTO polymorphism rs9939609 is associated with a risk of pulmonary tuberculosis in the Chinese population.

  10. Correlation of cervical cytology with high-risk HPV molecular diagnosis, genotypes, and histopathology--A four year study from the UAE.

    PubMed

    Krishnan, Kavita; Thomas, Antony

    2016-02-01

    Cervical cancer is one of the most common cancers among women in the world and in the Middle East. Its prevention and screening strategies assume great importance especially in view of the ability to identify the illness at an early stage and disrupt its progression toward neoplasia. Cervical cancer screening program of our center in UAE as well as this study is oriented in this direction. Cervical cytology data encompassing 4 years (2011-2014) was compiled and analyzed for 14,950 cases to assess the abnormal smear reporting pattern, correlation with biopsy histopathology, HPV high-risk screening data, and HPV genotype prevalence among patients with abnormal smear test, as well as in relation to the respective nationalities of patients. Abnormal smear rates as well as HPV high-risk positivity correlated well with established data. Cytology-histology correlation was good. HPV high-risk type 16 was the commonest, type 18 which is the second common type worldwide was less frequently detected, several other high risk subtypes such as 51, 31 as well as rare types such as 66, 56, and 59 were detected in a significant number of patients. Assessment of cervical cytology reporting pattern, correlation of cervical cytology with HPV molecular diagnosis, and biopsy histopathology is a useful way to audit our work and a good quality control practice. Higher prevalence of HPV HR types such as type 51, 31 as well as 66, 56, and 59 found in the present as well as many similar other studies apart from the commonest subtype 16 may imply necessity for development of more targeted and multivalent anti-HPV vaccines for protection of women in our region. HPV genotypes correlation with the nationalities of patients is useful from an epidemiological standpoint to plan preventive strategies. © 2015 Wiley Periodicals, Inc.

  11. The ATHENA HPV study underrepresents "other" high-risk HPV genotypes when compared with a diverse New York City population.

    PubMed

    Ramos Rivera, G; Khader, S N; Lajara, S; Schlesinger, K; Goldstein, D Y; Naeem, R C; Suhrland, M J; Fox, A S

    2017-10-01

    Persistent infection with oncogenic high risk HPV (hrHPV) types causes virtually all cases of cervical cancer. HPV 16 and 18 have been targeted for individual genotyping and vaccination because of their presence in 71% of invasive cervical cancers worldwide. Montefiore Medical Center, Bronx, New York serves a population known for ethnic and racial diversity. Given this diversity it is possible that HPV genotypes not individually detected by current testing are causing significant disease. We conducted a retrospective analysis of liquid based cervicovaginal cytology and Cobas HPV results reported between October 5, 2015 and March 30, 2016. This included 20 483 samples from patients aged 16-95 (average age 42), with racial distribution including: African-American 32.4%, Other (includes denied, unknown, mixed, Hispanic) 52.1%, Caucasian 14.5%, Asian 0.7%, American Indian/Alaskan Native 0.3%. In all, 14 938 samples (72.9%) were submitted for clinically requested COBAS 4800 HPV testing, which separately reports HPV 16, 18 and a pool of 12 other hrHPV. A total of 3180 (21.5%) tested hrHPV positive. The percentage of patients with cytologic diagnosis of HSIL (high-grade squamous intraepithelial lesion) that were positive only for HPV 16 was 19.4% vs 1.8% for all cytologic diagnoses. However, only one of the HSIL cases was HPV 18 positive along with other hrHPV (OHR). Surprisingly, a majority (64.5%) was positive for only OHR. Further evaluation is needed to determine if this pool of other hrHPV includes individual genotypes that in our population carry a higher risk of persistence and progression to cancer. © 2017 John Wiley & Sons Ltd.

  12. A case–control study on the effect of Apolipoprotein E genotypes on gastric cancer risk and progression

    PubMed Central

    2012-01-01

    Background Apolipoprotein E (ApoE) is a multifunctional protein playing both a key role in the metabolism of cholesterol and triglycerides, and in tissue repair and inflammation. The ApoE gene (19q13.2) has three major isoforms encoded by ε2, ε3 and ε4 alleles with the ε4 allele associated with hypercholesterolemia and the ε2 allele with the opposite effect. An inverse relationship between cholesterol levels and gastric cancer (GC) has been previously reported, although the relationship between apoE genotypes and GC has not been explored so far. Methods One hundred and fifty-six gastric cancer cases and 444 hospital controls were genotyped for apoE polymorphism (ε2, ε3, ε4 alleles). The relationship between GC and putative risk factors was measured using the adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) from logistic regression analysis. A gene-environment interaction analysis was performed. The effect of the apoE genotypes on survival from GC was explored by a Kaplan–Meier analysis and Cox proportional hazard regression model. Results Subjects carrying at least one apoE ε2 allele have a significant 60% decrease of GC risk (OR=0.40, 95% CI: 0.19 – 0.84) compared with ε3 homozygotes. No significant interaction emerged between the ε4 or ε2 allele and environmental exposures, nor ε2 or ε4 alleles affected the median survival times, even after correcting for age, gender and stadium. Conclusions Our study reports for the first time a protective effect of the ε2 allele against GC, that might be partly attributed to the higher antioxidant properties of ε2 compared with the ε3 or ε4 alleles. Given the study’s sample size, further studies are required to confirm our findings. PMID:23098561

  13. Molecular marker based characterization and genetic diversity of wheat genotypes in relation to boron efficiency

    USDA-ARS?s Scientific Manuscript database

    Boron deficient soils pose a critical problem to wheat production in many areas of the world including Bangladesh and causes significant yield reduction. Therefore, in the present study, 21 diverse wheat (Triticum aestivum L.) genotypes collected from three different countries (Bangladesh, India, a...

  14. Correlation between relatives given complete genotypes: from identity by descent to identity by function.

    PubMed

    Sverdlov, Serge; Thompson, Elizabeth A

    2013-09-01

    In classical quantitative genetics, the correlation between the phenotypes of individuals with unknown genotypes and a known pedigree relationship is expressed in terms of probabilities of IBD states. In existing approaches to the inverse problem where genotypes are observed but pedigree relationships are not, dependence between phenotypes is either modeled as Bayesian uncertainty or mapped to an IBD model via inferred relatedness parameters. Neither approach yields a relationship between genotypic similarity and phenotypic similarity with a probabilistic interpretation corresponding to a generative model. We introduce a generative model for diploid allele effect based on the classic infinite allele mutation process. This approach motivates the concept of IBF (Identity by Function). The phenotypic covariance between two individuals given their diploid genotypes is expressed in terms of functional identity states. The IBF parameters define a genetic architecture for a trait without reference to specific alleles or population. Given full genome sequences, we treat a gene-scale functional region, rather than a SNP, as a QTL, modeling patterns of dominance for multiple alleles. Applications demonstrated by simulation include phenotype and effect prediction and association, and estimation of heritability and classical variance components. A simulation case study of the Missing Heritability problem illustrates a decomposition of heritability under the IBF framework into Explained and Unexplained components.

  15. Far East Scarlet-Like Fever Caused by a Few Related Genotypes of Yersinia pseudotuberculosis, Russia

    PubMed Central

    Timchenko, Nelly F.; Adgamov, Ruslan R.; Popov, Alexander F.; Psareva, Ekaterina K.; Sobyanin, Konstantin A.; Gintsburg, Alexander L.

    2016-01-01

    We used multivirulence locus sequence typing to analyze 68 Yersinia pseudotuberculosis isolated in Russia during 1973–2014, including 41 isolates from patients with Far East scarlet-like fever. Four genotypes were found responsible, with 1 being especially prevalent. Evolutionary analysis suggests that epidemiologic advantages could cause this genotype’s dominance. PMID:26889961

  16. Are large wattles related to particular MHC genotypes in the male pheasant?

    PubMed

    Baratti, Mariella; Ammannati, Martina; Magnelli, Claudia; Massolo, Alessandro; Dessì-Fulgheri, Francesco

    2010-06-01

    In sexually dimorphic species, partners can assess heritable mate quality by analyzing costly sexual ornaments in terms of their dimension and possibly of their symmetry. In vertebrates an important aspect of genetic quality is the efficiency of the immune system, and in particular the Major Histocompatibility Complex (MHC). If ornaments are honest advertisements of pathogen resistance (good genes), in line with the Hamilton-Zuk hypothesis, a correlation between ornament expression and MHC profiles should exist. We tested this hypothesis in the common pheasant Phasianus colchicus by comparing male ornament characteristics (wattle and spur size, and wattle fluctuating asymmetry) with a portion of exon 2 of the class IIB MHC genes containing 19 putative antigen recognition sites. A total of 8 new alleles was observed in the MHCPhco exon IIB. We found significant differences in the occurrence of MHC genotypes between males carrying large or small wattles. Homozygous genotypes predicted large wattle males more correctly than small wattle males. The association between the dimension of the spur and the occurrence of MHC genotypes was marginally significant, however, we did not find any significant association between MHC genotypes and asymmetry. Our results suggest that female pheasants may use the ornament size as a cue to evaluate male quality and thus choose males carrying particular MHC profiles.

  17. The Phenotypic and Genotypic Relation between Working Memory Speed and Capacity

    ERIC Educational Resources Information Center

    Polderman, Tinca J. C.; Stins, John F.; Posthuma, Danielle; Gosso, M. Florencia; Verhulst, Frank C.; Boomsma, Dorret I.

    2006-01-01

    This study examined the phenotypic and genotypic relationship between working memory speed (WMS) and working memory capacity (WMC) in 12-year-old twins and their siblings (N = 409). To asses WMS all children performed a reaction time task with three memory loads from which a basic mental speed measure and the derived slope were used. WMC was…

  18. Occupation-related risks for colorectal cancer.

    PubMed

    Spiegelman, D; Wegman, D H

    1985-11-01

    Several population data bases were used to generate hypotheses about associations between colorectal cancer and workplace exposures. The Third National Cancer Survey interview sample was used to select 343 male and 208 female cases and 626 male and 1,235 female cancer controls. Potential work exposures were assigned with the use of data from the National Institute for Occupational Safety and Health National Occupational Hazard Survey. Dietary factors were modeled from the National Health and Nutrition Examination Survey data. Work-related stress was considered with the use of a model based on the U.S. Department of Labor's Quality of Employment Survey. Other risk factors included age, race, ponderosity, and menopausal status. Logistic analysis yielded hypotheses for colon cancer risk in males with potentially high exposure to solvents, abrasives, and fuel oil and in those in jobs with high demand and low control (high "stress"). Hypotheses emerged for females with potentially high exposure to dyes, solvents, and grinding wheel dust.

  19. A population study of apoE genotype at the age of 85: relation to dementia, cerebrovascular disease, and mortality

    PubMed Central

    Skoog, I.; Hesse, C.; Aevarsson, O.; Landahl, S.; Wahlstrom, J.; Fredman, P.; Blennow, K.

    1998-01-01

    OBJECTIVES—To study the association of apoE genotypes with dementia and cerebrovascular disorders in a population based sample of 85year old people.
METHODS—A representative sample of 85 year old people (303 non-demented, 109 demented) were given a neuropsychiatric and a medical examination and head CT. The apoE isoforms were determined. Dementia was diagnosed according to DSM-III-R.
RESULTS—At the age of 85, carriers of the apoE ε4 allele had an increased odds ratio (OR) for dementia (1.9; p<0.01) and its subtypes Alzheimer's disease (1.9; p<0.05) and vascular dementia (2.0; p<0.05). Among those categorised as having vascular dementia, the apoE ε4 allele was associated with mixed Alzheimer's disease-multi-infarct dementia (OR 6.5; p<0.05), but not with pure multi-infarct dementia (OR 1.5; NS). Only carriers of the apoE ε4 allele who also had ischaemic white matter lesions on CT of the head had an increased OR for dementia (OR 6.1; p=0.00003), and its main subtypes Alzheimer's disease (OR 6.8; p=0.002) and vascular dementia (OR 5.6; p=0.0007), whereas carriers of the apoE ε4 allele without white matter lesions had an OR for dementia of 1.0 (OR for Alzheimer's disease 1.8; NS and for vascular dementia 0.6; NS) and non-carriers of the apoE ε4 allele with white matter lesions had an OR for dementia of 2.2; NS (OR for Alzheimer's disease 2.7; NS and for vascular dementia 1.6; NS). The apoE allele variants were not related to mortality or incidence of dementia between the ages of 85 and 88. The ε2 allele was related to a higher prevalence of stroke or transient ischaemic attack at the age of 85 (OR 2.1; p<0.05) and a higher incidence of multi-infarct dementia during the follow up (OR 2.9; p<0.05).
CONCLUSIONS—Neither the apoE ε4 allele nor white matter lesions are sufficient risk factors by themselves for dementia at very old ages, whereas possession of both these entities increases the risk for Alzheimer's disease and vascular dementia

  20. High risk human papillomavirus genotyping in clinical samples: evaluation of different commercial tests.

    PubMed

    Paolini, F; Rollo, F; Brandi, R; Benevolo, M; Mariani, L; Cercato, M C; Vocaturo, A; Venuti, A

    2011-01-01

    The aim of the present study is to compare the performance of several commercial human papillomavirus (HPV) tests in a cohort of 281 women. The hybrid capture II, the PreTect-HPV-Proofer, the linear array, and DR.HPVTMIVD were utilized to detect and type HPV in parallel with in-house PCR tests followed by direct automated sequencing or by sub-cloning and sequencing. The concordance levels along with other tests were evaluated with a Cohen's K value varying between 0.60 to 0.88, indicating good correlation with nearly perfect agreement between hybrid capture II, (HCII) and the linear array test. High sensitivity was recorded by the linear array and HCII with 100% (95% CI, 0.8021 to 1.0000) detection of cervical intraepithelial neoplasia (CIN) III by both methods. Conversely, the PreTect-HPV-Proofer showed high specificity with 12% (95% CI, 0.7966 to 0.9163) positivity on normal samples. The genotyping analysis showed that agreement among tests was only low to moderate with great differences between different HPV types. Multiple infections were detected with poor concordance and sub-cloning assays revealed the presence of a lower number of HPV in comparison to the other methods. In summary, the use of different HPV tests applied to the same group of cervical smears may possibly lead to incongruent results, suggesting the need to standardize type-specific sensitivity of genotyping methods and the need to evaluate their accuracy in detecting multiple HPV infections. This would be a prerequisite for the use of genotyping assays in cervical cancer screening programs.

  1. Genetic polymorphisms in the vitamin D pathway in relation to lung cancer risk and survival

    PubMed Central

    Kong, Jinyu; Xu, Fangxiu; Qu, Jinli; Wang, Yu; Gao, Ming; Yu, Herbert; Qian, Biyun

    2015-01-01

    Studies have suggested that vitamin D may have protective effects against cancer development or tumor progression. To search for additional evidence, we investigated the role of genetic polymorphisms involved in the vitamin D pathway in non-small cell lung cancer (NSCLC). We evaluated common genetic polymorphisms associated with the vitamin D pathway in relation to NSCLC in a case-control study of 603 newly diagnosed NSCLC patients and 661 matched healthy controls. Seven single nucleotide polymorphisms (SNPs) were genotyped, the expression of CYP27B1 and CYP24A1 were measured in 153 tumor samples and their associations with genotypes and patient survival were also analyzed. In the case-control comparison, we found SNP rs3782130 (CYP27B1), rs7041 (GC), rs6068816 and rs4809957 (CYP24A1) associated with NSCLC risk. The risk of NSCLC was increased with the number of risk alleles. CYP27B1 and CYP24A1 expression were significantly different between tumor and normal tissues in NSCLC. High CYP27B1 expression was associated with better overall survival, and the expression was different by the rs3782130 genotype. The study suggests that some genetic polymorphisms involved in the vitamin D pathway may associate with NSCLC risk, and one of the polymorphisms (rs3782130) may affect gene expression and patient survival. PMID:25544771

  2. Patient-related risk factors for tooth loss in aggressive periodontitis after active periodontal therapy.

    PubMed

    Bäumer, Amelie; El Sayed, Nihad; Kim, Ti-Sun; Reitmeir, Peter; Eickholz, Peter; Pretzl, Bernadette

    2011-04-01

    Evaluation of patient-related risk factors contributing to tooth loss and recurrence of periodontitis 10.5 years after initial therapy in patients with aggressive periodontitis (AgP). Eighty-four of 174 patients were included. Re-examination consisted of patient's history, clinical examination and test for interleukin (IL)-1 composite genotype. Patients' charts were searched for regularity of maintenance and initial diagnosis. Statistical analysis was performed using Poisson and logistical regression analysis. The responder rate was 48%. Thirteen of 84 patients presented a localized AgP, 68 were females and 29 smoked. One hundred and thirteen teeth out of 2154 were lost after therapy (1.34 teeth/patient). Age (p=0.0018), absence of IL-1 composite genotype (p=0.0091) and educational status (p=0.0085) were identified as statistically significant risk factors for tooth loss. Twenty patients exhibited recurrence of periodontitis at re-examination. Smoking (p=0.0034) and mean Gingival Bleeding Index (GBI) (p=0.0239) contributed significantly to recurrence of disease. No patient participating regularly in supportive periodontal therapy (SPT) showed disease recurrence. Age, absence of IL-1 composite genotype and low social status are detected as risk factors for tooth loss. Smoking and high mean GBI are associated with an increased risk for recurrence of periodontitis, whereas regular SPT acts as a protective factor. © 2011 John Wiley & Sons A/S.

  3. Combined effect of CYP1B1, COMT, GSTP1, and MnSOD genotypes and risk of postmenopausal breast cancer

    PubMed Central

    Cerne, Jasmina-Ziva; Pohar-Perme, Maja; Novakovic, Srdjan; Frkovic-Grazio, Snjezana; Stegel, Vida

    2011-01-01

    Objective Estrogen plays a key role in breast cancer development and functionally relevant genetic variants within the estrogen metabolic pathway are prime candidates for a possible association with breast cancer risk. We investigated the independent and the combined effects of commonly occurring polymorphisms in four genes encoding key proteins of estrogen metabolic pathway on their potential contribution to breast cancer risk. Methods We studied 530 breast cancer cases and 270 controls of the same age and ethnicity participating in a case-control study of postmenopausal women. Genotyping was conducted for CYP1B1 (rs1056836), COMT (rs4680), GSTP1 (rs1695), and MnSOD (rs4880) polymorphisms by polymerase chain reaction based restriction fragment length polymorphism and TaqMan allelic discrimination method. Adjusted ORs and 95% CIs were calculated using logistic regression. Results None of the 4 genetic variants examined contributed to breast cancer risk individually. When the combined effects of the risk genotypes were investigated, significant associations were observed among women with two high-risk genotypes in CYP1B1 and COMT (OR, 2.0; 95% CI, 1.1 to 3.5) and two high-risk genotypes in COMT and MnSOD (OR, 2.0; 95% CI, 1.0 to 3.8), compared to those with low-risk genotypes. Conclusion Our results suggest that individual susceptibility to breast cancer incidence may be increased by combined effects of the high-risk genotypes in CYP1B1, COMT, and MnSOD estrogen metabolic genes. PMID:21860737

  4. Enantioselective disposition of rabeprazole in relation to CYP2C19 genotypes

    PubMed Central

    Miura, Masatomo; Kagaya, Hideaki; Tada, Hitoshi; Uno, Tsukasa; Yasui-Furukori, Norio; Tateishi, Tomonori; Suzuki, Toshio

    2006-01-01

    Aim Rabeprazole is metabolized to some extent by CYP2C19. The purpose of this study was to elucidate the pharmacokinetics of each rabeprazole enantiomer in three different CYP2C19 genotype groups. Methods Twenty-four healthy subjects, of whom each each were homozygous extensive metabolizers (homEMs), heterozygous extensive metabolizers (hetEMs) and poor metabolizers (PMs) for CYP2C19, participated in our study. After a single oral dose of 20 mg of racemic rabeprazole, the plasma concentrations of the rabeprazole enantiomers were measured over the course of 24 h. Results The area under the plasma concentration–time curves (AUC) of (R)-rabeprazole in homEMs, hetEMs and PMs were 1.8-, 2.2- and 2.4-fold, respectively, greater than those of (S)-rabeprazole; the relative AUC ratios of (R)- and (S)-rabeprazole in homEMs, hetEMs and PMs were 1 : 1.1 : 2.1 and 1 : 0.9 : 1.5, respectively. The mean maximum plasma concentrations (Cmax) of (R)-rabeprazole in homEMs, hetEMs and PMs were 1.7-, 1.9- and 1.8-fold higher, respectively, than those of the corresponding (S)-enantiomer (P < 0.05). There was no difference between homEMs and PMs in the elimination half-life of (S)-rabeprazole, whereas the elimination half-life of (R)-rabeprazole was significantly longer in PMs than in homEMs [1.7 h (1.4, 2.0) (mean (95% confidence interval)]vs. 0.8 h (0.6, 1.0), respectively, P < 0.0001). Conclusions (R)-Rabeprazole disposition was influenced to a greater degree by CYP2C19 genetic polymorphisms than was that of (S)-rabeprazole. The effect of CYP2C19 polymorphisms on the stereoselective disposition of rabeprazole was less than those of lansoprazole and omeprazole. PMID:16487225

  5. Significant association of Glutathione S-transferase T1 null genotype with prostate cancer risk: a meta-analysis of 26,393 subjects.

    PubMed

    Yang, Qing; Du, Jun; Yao, Xin

    2013-01-01

    Recent studies on the association between Glutathione S-transferase T1 (GSTT1) polymorphism and risk of prostate cancer showed inconclusive results. To clarify this possible association, we conducted a meta-analysis of published studies. DATA WERE COLLECTED FROM THE FOLLOWING ELECTRONIC DATABASES: Pubmed, Embase, and Chinese Biomedical Database (CBM). The odds ratio (OR) and its 95% confidence interval (95%CI) was used to assess the strength of the association. We summarized the data on the association between GSTT1 null genotype and risk of prostate cancer in the overall population, and performed subgroup analyses by ethnicity, adjusted ORs, and types of controls. Ultimately, a total of 43 studies with a total of 26,393 subjects (9,934 cases and 16,459 controls) were eligible for meta-analysis. Overall, there was a significant association between GSTT1 null genotype and increased risk of prostate cancer (OR = 1.14, 95%CI 1.01-1.29, P = 0.034). Meta-analysis of adjusted ORs also showed a significant association between GSTT1 null genotype and increased risk of prostate cancer (OR= 1.34, 95%CI 1.09-1.64, P = 0.006). Similar results were found in the subgroup analyses by ethnicity and types of controls. This meta-analysis demonstrates that GSTT1 null genotype is associated with prostate cancer susceptibility, and GSTT1 null genotype contributes to increased risk of prostate cancer.

  6. Organellar genomes from a ∼5,000 years old archaeological maize sample are closely related to NB genotype.

    PubMed

    Pérez-Zamorano, Bernardo; Vallebueno-Estrada, Miguel; Martínez González, Javier; García Cook, Angel; Montiel, Rafael; Vielle-Calzada, Jean-Philippe; Delaye, Luis

    2017-03-17

    The story of how pre-Columbian civilizations developed goes hand-in-hand with the process of plant domestication by Mesoamerican inhabitants. Here we present the almost complete sequence of a mitochondrial genome and a partial chloroplast genome from an archaeological maize sample collected at the Valley of Tehuacán, México. Accelerator mass spectrometry dated the maize sample to be 5,040 to 5,300 years before present (95% probability). Phylogenetic analysis of the mitochondrial genome shows that the archaeological sample branches basal to the other Zea mays genomes, as expected. However, this analysis also indicates that fertile genotype NB is closely related to the archaeological maize sample and evolved before cytoplasmic male sterility genotypes (CMS-S, CMS-T and CMS-C), thus contradicting previous phylogenetic analysis of mitochondrial genomes from maize. We show that maximum-likelihood infers a tree where CMS genotypes branch at the base of the tree when including sites that have a relative fast rate of evolution thus suggesting long-branch attraction. We also show that Bayesian analysis infer a topology where NB and the archaeological maize sample are at the base of the tree even when including faster sites. We therefore suggest that previous trees suffered from long-branch attraction. We also show that the phylogenetic analysis of the ancient chloroplast is congruent with genotype NB to be more closely related to the archaeological maize sample. As shown here, the inclusion of ancient genomes on phylogenetic trees greatly improves our understanding of the domestication process of maize, one of the most important corps worldwide.

  7. Organellar Genomes from a ∼5,000-Year-Old Archaeological Maize Sample Are Closely Related to NB Genotype

    PubMed Central

    Pérez-Zamorano, Bernardo; Vallebueno-Estrada, Miguel; Martínez González, Javier; García Cook, Angel; Montiel, Rafael; Vielle-Calzada, Jean-Philippe

    2017-01-01

    The story of how preColumbian civilizations developed goes hand-in-hand with the process of plant domestication by Mesoamerican inhabitants. Here, we present the almost complete sequence of a mitochondrial genome and a partial chloroplast genome from an archaeological maize sample collected at the Valley of Tehuacán, México. Accelerator mass spectrometry dated the maize sample to be 5,040–5,300 years before present (95% probability). Phylogenetic analysis of the mitochondrial genome shows that the archaeological sample branches basal to the other Zea mays genomes, as expected. However, this analysis also indicates that fertile genotype NB is closely related to the archaeological maize sample and evolved before cytoplasmic male sterility genotypes (CMS-S, CMS-T, and CMS-C), thus contradicting previous phylogenetic analysis of mitochondrial genomes from maize. We show that maximum-likelihood infers a tree where CMS genotypes branch at the base of the tree when including sites that have a relative fast rate of evolution thus suggesting long-branch attraction. We also show that Bayesian analysis infer a topology where NB and the archaeological maize sample are at the base of the tree even when including faster sites. We therefore suggest that previous trees suffered from long-branch attraction. We also show that the phylogenetic analysis of the ancient chloroplast is congruent with genotype NB to be more closely related to the archaeological maize sample. As shown here, the inclusion of ancient genomes on phylogenetic trees greatly improves our understanding of the domestication process of maize, one of the most important crops worldwide. PMID:28338960

  8. Hippocampal Sclerosis of Aging, a Common Alzheimer's Disease 'Mimic': Risk Genotypes are Associated with Brain Atrophy Outside the Temporal Lobe.

    PubMed

    Nho, Kwangsik; Saykin, Andrew J; Nelson, Peter T

    2016-01-01

    Hippocampal sclerosis of aging (HS-Aging) is a common brain disease in older adults with a clinical course that is similar to Alzheimer's disease. Four single-nucleotide polymorphisms (SNPs) have previously shown association with HS-Aging. The present study investigated structural brain changes associated with these SNPs using surface-based analysis. Participants from the Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n = 1,239), with both MRI scans and genotype data, were used to assess the association between brain atrophy and previously identified HS-Aging risk SNPs in the following genes: GRN, TMEM106B, ABCC9, and KCNMB2 (minor allele frequency for each is >30%). A fifth SNP (near the ABCC9 gene) was evaluated in post-hoc analysis. The GRN risk SNP (rs5848_T) was associated with a pattern of atrophy in the dorsomedial frontal lobes bilaterally, remarkable since GRN is a risk factor for frontotemporal dementia. The ABCC9 risk SNP (rs704180_A) was associated with multifocal atrophy whereas a SNP (rs7488080_A) nearby (∼50 kb upstream) ABCC9 was associated with atrophy in the right entorhinal cortex. Neither TMEM106B (rs1990622_T), KCNMB2 (rs9637454_A), nor any of the non-risk alleles were associated with brain atrophy. When all four previously identified HS-Aging risk SNPs were summed into a polygenic risk score, there was a pattern of associated multifocal brain atrophy in a predominately frontal pattern. We conclude that common SNPs previously linked to HS-Aging pathology were associated with a distinct pattern of anterior cortical atrophy. Genetic variation associated with HS-Aging pathology may represent a non-Alzheimer's disease contribution to atrophy outside of the hippocampus in older adults.

  9. Estrogen metabolism genotypes, use of long-term hormone replacement therapy and risk of postmenopausal breast cancer.

    PubMed

    Cerne, Jasmina Ziva; Novakovic, Srdjan; Frkovic-Grazio, Snjezana; Pohar-Perme, Maja; Stegel, Vida; Gersak, Ksenija

    2011-08-01

    Association between long-term hormone replacement therapy (HRT) use and increased risk of breast cancer is still under debate. Functionally relevant genetic variants within the estrogen metabolic pathway may alter exposure to exogenous sex hormones and affect the risk of postmenopausal breast cancer. We investigated the associations of common polymorphisms in 4 genes encoding key proteins of the estrogen metabolic pathway, duration of HRT use and their interactions with breast cancer risk. We studied 530 breast cancer cases and 270 controls of the same age and ethnicity participating in a case-control study of postmenopausal women. Duration of HRT use was ascertained through a postal questionnaire. Genotyping was conducted for CYP1B1 (rs1056836), COMT (rs4680), GSTP1 (rs1695) and MnSOD (rs4880) polymorphisms by PCR-based RFLP and TaqMan® allelic discrimination method. Adjusted odds ratios and 95% confidence intervals were calculated using logistic regression analysis. HRT use was significantly associated with decreased breast cancer risk (p<0.001). None of the polymorphisms studied was associated with breast cancer risk. A significant interaction was observed between MnSOD 47T>C and HRT use (pinteraction=0.036); the risk of breast cancer associated with long-term vs. short-term HRT use was decreased in women homozygous for the wild-type allele and increased in women with at least one variant allele of the MnSOD 47T>C polymorphism. Our results suggest that MnSOD 47T>C polymorphism in interaction with long-term HRT use may modify the risk of breast cancer.

  10. Circadian Clock-Related Genetic Risk Scores and Risk of Placental Abruption

    PubMed Central

    Qiu, Chunfang; Gelaye, Bizu; Denis, Marie; Tadesse, Mahlet G.; Fernandez, Miguel Angel Luque; Enquobahrie, Daniel A.; Ananth, Cande V.; Sanchez, Sixto E.; Williams, Michelle A.

    2016-01-01

    Introduction The circadian clock plays an important role in several aspects of female reproductive biology. Evidence linking circadian clock-related genes to pregnancy outcomes has been inconsistent. We sought to examine whether variations in single nucleotide polymorphisms (SNPs) of circadian clock genes are associated with PA risk. Methods Maternal blood samples were collected from 470 PA case and 473 controls. Genotyping was performed using the Illumina Cardio-MetaboChip platform. We examined 119 SNPs in 13 candidate genes known to control circadian rhythms (e.g., CRY2, ARNTL, and RORA). Univariate and penalized logistic regression models were fit to estimate odds ratios (ORs); and the combined effect of multiple SNPs on PA risk was estimated using a weighted genetic risk score (wGRS). Results A common SNP in the RORA gene (rs2899663) was associated with a 21% reduced odds of PA (P<0.05). The odds of PA increased with increasing wGRS (Ptrend< 0.001). The corresponding ORs were 1.00, 1.83, 2.81 and 5.13 across wGRS quartiles. Participants in the highest wGRS quartile had a 5.13-fold (95% confidence interval: 3.21–8.21) higher odds of PA compared to those in the lowest quartile. Although the test for interaction was not significant, the odds of PA was substantially elevated for preeclamptics with the highest wGRS quartile (OR=14.44, 95%CI: 6.62–31.53) compared to normotensive women in the lowest wGRS quartile. Discussion Genetic variants in circadian rhythm genes may be associated with PA risk. Larger studies are needed to corroborate these findings and to further elucidate the pathogenesis of this important obstetrical complication. PMID:26515929

  11. Circadian clock-related genetic risk scores and risk of placental abruption.

    PubMed

    Qiu, Chunfang; Gelaye, Bizu; Denis, Marie; Tadesse, Mahlet G; Luque Fernandez, Miguel Angel; Enquobahrie, Daniel A; Ananth, Cande V; Sanchez, Sixto E; Williams, Michelle A

    2015-12-01

    The circadian clock plays an important role in several aspects of female reproductive biology. Evidence linking circadian clock-related genes to pregnancy outcomes has been inconsistent. We sought to examine whether variations in single nucleotide polymorphisms (SNPs) of circadian clock genes are associated with PA risk. Maternal blood samples were collected from 470 PA case and 473 controls. Genotyping was performed using the Illumina Cardio-MetaboChip platform. We examined 119 SNPs in 13 candidate genes known to control circadian rhythms (e.g., CRY2, ARNTL, and RORA). Univariate and penalized logistic regression models were fit to estimate odds ratios (ORs); and the combined effect of multiple SNPs on PA risk was estimated using a weighted genetic risk score (wGRS). A common SNP in the RORA gene (rs2899663) was associated with a 21% reduced odds of PA (P < 0.05). The odds of PA increased with increasing wGRS (Ptrend < 0.001). The corresponding ORs were 1.00, 1.83, 2.81 and 5.13 across wGRS quartiles. Participants in the highest wGRS quartile had a 5.13-fold (95% confidence interval: 3.21-8.21) higher odds of PA compared to those in the lowest quartile. Although the test for interaction was not significant, the odds of PA was substantially elevated for preeclamptics with the highest wGRS quartile (OR = 14.44, 95%CI: 6.62-31.53) compared to normotensive women in the lowest wGRS quartile. Genetic variants in circadian rhythm genes may be associated with PA risk. Larger studies are needed to corroborate these findings and to further elucidate the pathogenesis of this important obstetrical complication. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. No Association of ApoE Genotype with Risk of Prostate Cancer: A Nested Case-Control Study.

    PubMed

    Liu, Hui; Shui, Irene M; Platz, Elizabeth A; Mucci, Lorelei A; Giovannucci, Edward L

    2015-10-01

    Previous studies found that low total cholesterol level was associated with a lower risk of high-grade prostate cancer. Apolipoprotein E (ApoE) isoform is associated with total cholesterol level. The aim of this study was to explore associations of ApoE isoforms with prostate cancer risk. We assessed ApoE genotypes and risk of prostate cancer in a prospective case-control study nested among men who provided a blood sample in 1993-95 within the Health Professionals Follow-up Study. We identified 1,169 incident cases of prostate cancer and 1,233 controls in follow-up through 2004. Associations of ApoE isoform and prostate cancer incidence were evaluated by logistic regression models. We found no statistically significant associations of ApoE variants with overall prostate cancer or Gleason sum ≤ 7 (3+4), Gleason sum ≥ 7 (4+3), clinically localized stage, or progression to metastasis or death. There was no evidence of effect modification by circulating total cholesterol or use of cholesterol-lowering drugs prior to diagnosis. ApoE variants were not associated with the risk of prostate cancer or aggressive disease. Our findings suggest that the mechanism of circulating cholesterol level affecting prostate cancer incidence may not rely on ApoE isoforms. ©2015 American Association for Cancer Research.

  13. Increased genetic risk or protection for canine autoimmune lymphocytic thyroiditis in Giant Schnauzers depends on DLA class II genotype.

    PubMed

    Wilbe, M; Sundberg, K; Hansen, I R; Strandberg, E; Nachreiner, R F; Hedhammar, A; Kennedy, L J; Andersson, G; Björnerfeldt, S

    2010-06-01

    Dogs represent an excellent comparative model for autoimmune thyroiditis as several dog breeds develop canine lymphocytic thyroiditis (CLT), which is clinically similar to Hashimoto's thyroiditis in human. We obtained evidence that dog leukocyte antigen (DLA) class II genotype function as either genetic risk factor that predisposes for CLT or as protective factor against the disease. Genetic diversity at their DLA-DRB1, -DQA1, and -DQB1 loci were defined and potential association to major histocompatibility complex II haplotypes and alleles was analyzed. Giant Schnauzers carrying the DLA-DRB1*01201/DQA1*00101/DQB1*00201 haplotype showed an increased risk (odds ratio of 6.5) for developing CLT. The same risk haplotype has, to date, been observed in three different breeds affected by this disease, Giant Schnauzer, Dobermann, and Labrador Retriever, indicating that it is a common genetic risk factor in a variety of breeds affected by this disease. Importantly, protection for development of the disease was found in dogs carrying the DLA-DRB1*01301/DQA1*00301/DQB1*00501 haplotype (odds ratio of 0.3).

  14. Examining the relation between the serotonin transporter 5-HTTPLR genotype x trauma exposure interaction on a contemporary phenotypic model of posttraumatic stress symptomatology: A pilot study

    PubMed Central

    Pietrzak, Robert H.; Galea, Sandro; Southwick, Steven M.; Gelernter, Joel

    2012-01-01

    Background Little is known about the specificity of the interaction of serotonin transporter 5-HTTLPR genotype x trauma exposure in relation to contemporary structural models of PTSD symptomatology, which suggest that 4- or 5-factor models provide a better representation of this phenotypic expression of this disorder. Methods One hundred forty-nine respondents of a representative sample of adults affected by Hurricane Ike were interviewed 2 to 5 months after this 2008 disaster. Results After adjustment for age, sex, and ancestral proportion scores, the interaction of 5-HTTPLR genotype x trauma exposure was significantly associated with both severity (β=.40, p<.001) and probable diagnosis (Wald=4.55, p=.033; odds ratio=3.81, 95%CI=1.11–13.03) of Ike-related PTSD. Respondents with the low-expression variant of the 5-HTTPLR polymorphism (S allele) who were highly exposed to Hurricane Ike reported significantly greater severity of PTSD symptoms and were more likely to screen positive for PTSD than respondents homozygous for the L allele who were highly exposed to Hurricane Ike. Confirmatory factor analyses revealed that a 5-factor model of intercorrelated re-experiencing, avoidance, numbing, dysphoric arousal, and anxious arousal symptoms provided the best structural representation of PTSD symptomatology. The 5-HTTPLR genotype x exposure interaction was significant only for anxious arousal (β=.44, p<.001) and re-experiencing (β=.35, p<.001) symptoms, but not avoidance, numbing, or dysphoric arousal symptoms (all β’s≤.20, all p’s>.13). Limitations The small sample size and employment of self-report measures may limit generalizability of these findings. Conclusions Results of this pilot study suggest that the low-expression variant of the 5-HTTLPR polymorphism modifies risk for PTSD, but that this effect may be specific to anxious arousal and re-experiencing symptoms. PMID:23183127

  15. Dissecting the attention deficit hyperactivity disorder (ADHD) phenotype: sustained attention, response variability and spatial attentional asymmetries in relation to dopamine transporter (DAT1) genotype.

    PubMed

    Bellgrove, Mark A; Hawi, Ziarah; Kirley, Aiveen; Gill, Michael; Robertson, Ian H

    2005-01-01

    ADHD is a childhood-onset behavioural disorder with a heterogeneous profile of neuropsychological impairment. Neuropsychological heterogeneity may, in part, reflect underlying genetic differences. Here we examined sustained attention, response variability and spatial attentional asymmetries in a sample of children and adolescents with ADHD (n=22) in relation to dopamine transporter genotype (DAT1) and also controls (n=20). Participants performed the sustained attention to response task (SART) (testing sustained attention and response variability) and the greyscales task (a perceptual measure of attentional bias). The latter has previously been shown to yield a robust leftward attentional asymmetry in healthy subjects. The 10-repeat allele of the DAT1 gene has been associated with ADHD in a number of studies and appears to have biological significance. The ADHD group was sub-divided into those individuals with two copies of the "high-risk" 10-repeat allele (high-risk DAT1) versus those with one or no copies of this allele (low-risk DAT1). The high-risk DAT1 ADHD group displayed greater response variability on the SART than either the low-risk DAT1 group or healthy controls, whereas the latter two groups did not differ. Further, the high-risk DAT1 group showed an attenuated spatial asymmetry, relative to the low-risk DAT1 ADHD group, who showed the typical leftward attentional asymmetry. Our results suggest that the 10-repeat DAT1 allele may mediate neuropsychological impairment in ADHD. The application of molecular genetics may help to define neuropsychological impaired subgroups of ADHD.

  16. Major histocompatibility complex harbors widespread genotypic variability of non-additive risk of rheumatoid arthritis including epistasis

    PubMed Central

    Wei, Wen-Hua; Bowes, John; Plant, Darren; Viatte, Sebastien; Yarwood, Annie; Massey, Jonathan; Worthington, Jane; Eyre, Stephen

    2016-01-01

    Genotypic variability based genome-wide association studies (vGWASs) can identify potentially interacting loci without prior knowledge of the interacting factors. We report a two-stage approach to make vGWAS applicable to diseases: firstly using a mixed model approach to partition dichotomous phenotypes into additive risk and non-additive environmental residuals on the liability scale and secondly using the Levene’s (Brown-Forsythe) test to assess equality of the residual variances across genotype groups per marker. We found widespread significant (P < 2.5e-05) vGWAS signals within the major histocompatibility complex (MHC) across all three study cohorts of rheumatoid arthritis. We further identified 10 epistatic interactions between the vGWAS signals independent of the MHC additive effects, each with a weak effect but jointly explained 1.9% of phenotypic variance. PTPN22 was also identified in the discovery cohort but replicated in only one independent cohort. Combining the three cohorts boosted power of vGWAS and additionally identified TYK2 and ANKRD55. Both PTPN22 and TYK2 had evidence of interactions reported elsewhere. We conclude that vGWAS can help discover interacting loci for complex diseases but require large samples to find additional signals. PMID:27109064

  17. [Lifestyle-related disease and fracture risk].

    PubMed

    Fujiwara, Saeko

    2011-05-01

    Meta analysis of fracture risk in diabetes indicates that the risk of proximal femoral fracture in type-2 diabetes is increased 1.4-1.7 times. It is well known that increased fracture risk is observed in serious kidney disease. However, it has recently been reported that increased fracture risk is also observed in the early stages of chronic kidney disease (CKD) . The risk of proximal femoral fracture increases in early stages after stroke, but gradually decreases in subsequent stages. Some reports indicate decreased fracture risk in metabolic syndrome and hyperlipidemia and increased fracture risk in hypertension, arterial calcification and ischemic heart disease, while other reports indicate contradictory results.

  18. Diagnostic accuracy of high-risk HPV genotyping in women with high-grade cervical lesions: evidence for improving the cervical cancer screening strategy in China.

    PubMed

    Xu, Huihui; Lin, Aifen; Shao, Xiujuan; Shi, Weiwu; Zhang, Yang; Yan, Weihua

    2016-12-13

    Currently, clinical data for primary HPV screening alone are lacking in China. Here, we evaluate cervical cancer screening with primary HPV genotyping, as well as possible future screening strategy. Overall, high-risk HPV (hrHPV) prevalence was 18.2% among hospital-based population in Taizhou area. For cervical intraepithelial neoplasia 2 or worse (CIN2+), the sensitivity of primary hrHPV genotyping strategy and current cervical cancer screening strategy were 93.5%, and 71.1%, respectively; whereas the specificity was 17.5%, and 62.4%, respectively. Current cervical screening strategy had slightly higher positive predictive values (28.4%) for CIN2+ than hrHPV genotyping strategy (21.9%), whereas primary hrHPV genotyping strategy demonstrated higher negative predictive values (94.7%) than current cervical screening strategy (91.1%). Compared to HPV35/39/45/51/56/59/66/68 genotypes, the odds ratios (OR) for CIN2+ in HPV16/18/31/33/52/58 infection women were 3.2 (95% confidence interval [CI] 2.3-4.1). Primary hrHPV genotyping strategy provides a better predictive value than HPV16/18 genotyping alone in guiding the clinical management of the current cervical cancer screening. HPV testing without adjunctive cytology may be sufficiently sensitive for primary cervical cancer screening.

  19. Diagnostic accuracy of high-risk HPV genotyping in women with high-grade cervical lesions: evidence for improving the cervical cancer screening strategy in China

    PubMed Central

    Xu, Huihui; Lin, Aifen; Shao, Xiujuan; Shi, Weiwu; Zhang, Yang; Yan, Weihua

    2016-01-01

    Currently, clinical data for primary HPV screening alone are lacking in China. Here, we evaluate cervical cancer screening with primary HPV genotyping, as well as possible future screening strategy. Overall, high-risk HPV (hrHPV) prevalence was 18.2% among hospital-based population in Taizhou area. For cervical intraepithelial neoplasia 2 or worse (CIN2+), the sensitivity of primary hrHPV genotyping strategy and current cervical cancer screening strategy were 93.5%, and 71.1%, respectively; whereas the specificity was 17.5%, and 62.4%, respectively. Current cervical screening strategy had slightly higher positive predictive values (28.4%) for CIN2+ than hrHPV genotyping strategy (21.9%), whereas primary hrHPV genotyping strategy demonstrated higher negative predictive values (94.7%) than current cervical screening strategy (91.1%). Compared to HPV35/39/45/51/56/59/66/68 genotypes, the odds ratios (OR) for CIN2+ in HPV16/18/31/33/52/58 infection women were 3.2 (95% confidence interval [CI] 2.3-4.1). Primary hrHPV genotyping strategy provides a better predictive value than HPV16/18 genotyping alone in guiding the clinical management of the current cervical cancer screening. HPV testing without adjunctive cytology may be sufficiently sensitive for primary cervical cancer screening. PMID:27626178

  20. A toolbox for health risk related decisions

    SciTech Connect

    Easterly, C.E.; Jones, T.D.

    1996-10-01

    Development efforts since the late 1970s have resulted in a generalized method for ranking health hazards. This method provides the basis for a wide range of applications where decisions are needed for allocating resources on the basis of health risk considerations. It has been used for more than a decade to solve real problems, and it is supported by 23 publications in the open literature. The diversity of this generalized methodology allows us to provide support in a great number of problem areas. we give four examples in this manuscript: the relative toxicities of petroleum mixtures; a method to derive Emergency Response Planning Guides; an estimate of the possible carcinogenic potency of tungsten, an alternative material to depleted uranium for heavy armor penetrators; and an approach to low dose extrapolation. Our experience suggests that many more applications of the original concept and variations on it can be of utility in military situations. Some potentially fruitful areas may be in the: development of a health-risk-ranking system for alternative solutions to manufacturing, waste management, and remediation; provision of a basis for identifying levels of hazardous agents which are below health concerns, or which should be of concern; development of a framework for evaluating chemicals and radioactive materials on the same basis, and in the development of a battery of in vitro bioassays which could take the place of long-term whole animal tests.

  1. Cholesteryl ester transfer protein TaqI B2B2 genotype is associated with higher HDL cholesterol levels and lower risk of coronary heart disease end points in men with HDL deficiency: Veterans Affairs HDL Cholesterol Intervention Trial.

    PubMed

    Brousseau, Margaret E; O'Connor, John J; Ordovas, Jose M; Collins, Dorothea; Otvos, James D; Massov, Tatyana; McNamara, Judith R; Rubins, Hanna B; Robins, Sander J; Schaefer, Ernst J

    2002-07-01

    We have previously reported that genetic variation at the cholesteryl ester transfer protein (CETP) TaqIB locus is correlated with plasma lipid levels and coronary heart disease (CHD) risk in the Framingham Offspring Study (FOS). In FOS, the B2 allele was associated with increased levels of high density lipoprotein (HDL) cholesterol (HDL-C), decreased CETP activity, and reduced CHD risk for men having the B2B2 genotype. The present study was undertaken to further define the relationship between this polymorphism and CHD risk at the population level. We tested for associations between the CETP TaqIB genotype and plasma lipoprotein levels, response to gemfibrozil therapy, and CHD end points in 852 men participating in the Veterans Affairs HDL-C Intervention Trial (VA-HIT), a study designed to explore the potential benefits of raising HDL levels in men having established CHD with low HDL-C (< or =40 mg/dL) as their primary lipid abnormality. In VA-HIT, 13.9% of the men had the B2B2 genotype relative to 19.1% of the men in FOS (-27%, P<0.03), whereas more men in VA-HIT had the B1B1 genotype (15%, P<0.05). Similar to our finding in FOS, B2B2 men in VA-HIT had the highest mean level of HDL-C (32.6+/-4.8 mg/dL), followed by B1B2 men (32.0+/-5.3 mg/dL), and, last, by B1B1 men (30.9+/-4.9 mg/dL). Interestingly, B1B1 men, who had the least favorable plasma lipid profile at baseline, had the greatest triglyceride-lowering response to gemfibrozil (-34%, P=0.006). CETP TaqIB genotype was also associated with the risk of CHD end points in VA-HIT, with an adjusted risk ratio of 0.52 for B2B2 men (P=0.08). Our data demonstrate that in men with CHD and HDL deficiency, the CETP TaqI B2B2 genotype is (1) significantly reduced and (2) associated with higher levels of plasma HDL-C and lower CHD risk. Together with our earlier report, these results support the concept that increased HDL-C levels, resulting from reduced CETP activity, are associated with decreased CHD risk.

  2. Pharmacogenetic modulation of combined hormone replacement therapy by progesterone-metabolism genotypes in postmenopausal breast cancer risk.

    PubMed

    Rebbeck, T R; Troxel, A B; Norman, S; Bunin, G; DeMichele, A; Schinnar, R; Berlin, J A; Strom, B L

    2007-12-15

    Combined hormone replacement therapy (CHRT) containing estrogens and progestins is associated with breast cancer risk. The authors evaluated interactions between CHRT use and progestin metabolism genotypes at CYP3A4 and the progesterone receptor (PGR) and their effects on breast cancer risk using the population-based Women's Insights and Shared Experiences (WISE) Study (1999-2002) of postmenopausal Caucasian women (522 breast cancer cases, 708 controls). The authors observed an elevated risk of ductal tumors in women with 3 or more years of CHRT use and PGR 331A alleles compared with those who had neither factor (odds ratio = 3.35, 95% confidence interval (CI): 1.13, 9.99; two-sided p(interaction) = 0.035). They also observed an elevated risk of progesterone receptor-positive tumors in women who had had 3 or more years of CHRT use and PGR 331A alleles compared with those who had neither factor (odds ratio = 3.82, 95% CI: 1.26, 11.55; p = 0.028). Finally, they observed an increased risk of estrogen receptor-negative tumors in women without CHRT exposure and CYP3A4*1B alleles compared with those who had neither factor (odds ratio = 6.46, 95% CI: 2.02, 20.66; p = 0.024), although the biologic interpretation of this result requires further study. When stratified by recency of use, PGR effects were observed only in current CHRT users, while CYP3A4 effects were observed only in former CHRT users. Breast cancer risk in women who have used CHRT may be influenced by genetic factors involved in progestin metabolism.

  3. Disability and risk of school related injury

    PubMed Central

    Ramirez, M; Peek-Asa, C; Kraus, J

    2004-01-01

    Objective: Approximately six million children with disabilities attend school in the United States. Cognitive and physical limitations may compromise their ability to handle environmental hazards and hence increase their risk for injury. The objective of this study was to describe the epidemiology of school related injury among children enrolled in 17 special education schools in one large, urban school district. Design: Altogether 6769 schoolchildren with disabilities were followed up from 1994–98. Injury and population data were collected from pupil accident reports and existing school records. Associations were estimated through generalized estimating equations. Results: A total of 697 injuries were reported for a rate of 4.7/100 students per year. Children with multiple disabilities had a 70% increased odds of injury compared with the developmentally disabled (odds ratio (OR) 1.7, 95% confidence interval (CI) 1.3 to 2.3). The physically disabled (OR 1.4, 95% CI 1.0 to 1.9) had a modest increased odds of injury. Cuts, bruises, and abrasions composed almost three fourths of all injuries; almost half of these injuries were to the face. Falls (34%) and insults by other students (31%) were the most common external causes. More than a fourth of injuries were sports related, and 21% occurred on the playground/athletic field. Injury patterns differed across disabilities. Conclusions: Although limited to one school district, the population studied is the largest cohort thus far of schoolchildren with disabilities. With this large study base, potentially high risk groups were identified and circumstances of injury described. This information is imperative for developing and improving school based injury prevention measures. PMID:14760022

  4. Cathecol-O-methyl transferase Val158Met genotype is not a risk factor for conversion disorder.

    PubMed

    Armagan, E; Almacıoglu, M L; Yakut, T; Köse, A; Karkucak, M; Köksal, O; Görükmez, O

    2013-03-19

    Alterations in catechol-O-methyltransferase (COMT) activity are involved in various types of neurological disorders. We examined a possible association between the COMT Val158Met polymorphism and conversion disorder in a study of 48 patients with conversion disorder and 48 control patients. In the conversion disorder group, 31 patients were Val/Met heterozygotes, 15 patients were Val/Val homozygotes and 2 patients were Met/Met homozygotes. In the control group, 32 patients were Val/Met heterozygotes and 16 patients were Val/Val homozygotes. There was no significant difference between the groups. We conclude that the COMT Val158Met genotype is quite common in Turkey and that it is not a risk factor for conversion disorder in the Turkish population.

  5. Affect and Acceptability: Exploring Teachers' Technology-Related Risk Perceptions

    ERIC Educational Resources Information Center

    Howard, Sarah K.

    2011-01-01

    Educational change, such as technology integration, involves risk. Teachers are encouraged to "take risks", but what risks they are asked to take and how do they perceive these risks? Developing an understanding of teachers' technology-related risk perceptions can help explain their choices and behaviours. This paper presents a way to…

  6. Mycorrhizal responsiveness of maize (Zea mays L.) genotypes as related to releasing date and available P content in soil.

    PubMed

    Chu, Qun; Wang, Xinxin; Yang, Yang; Chen, Fanjun; Zhang, Fusuo; Feng, Gu

    2013-08-01

    The aim of this study was to compare the mycorrhizal responsiveness among old and recent Chinese maize genotypes (released from 1950s to 2008) in low- and high-Olsen-P soils and to identify parameters that would indicate the relationships between the mycorrhizal responsiveness and the functional traits related to P uptake of maize. A greenhouse factorial experiment was conducted. The factors were maize genotype [Huangmaya (HMY), Zhongdan 2 (ZD2), Nongda 108 (ND108), and NE15], inoculation with or without arbuscular mycorrhizal fungi (AMF) (Rhizophagus irregularis), and Olsen-P levels (4, 9, 18, 36, or 60 mg P kg(-1)). Old and recently released genotypes differed in their response to AMF under low- and high-P supply. Three kinds of responses (in terms of shoot growth) were observed: the response was positive if the soil P content was low, but negative if the soil Olsen-P content was high (HMY and ND108); the response was neutral regardless of soil P content (ZD2); and the response was positive regardless of soil P content (NE15). Principle component (PC) analysis showed that the first PC comprised morphological and physiological traits of maize roots, and the second PC comprised mycorrhizal traits. The opposite was the case, however, in high-P soil. It is concluded that maize breeding selection from 1950s to 2000s is not always against the AM association and that AMF play positive roles in promoting the growth of some maize genotypes in high-P soil. The root length colonization by efficient AMF might be a useful parameter for breeding varieties with increased mycorrhizal responsiveness.

  7. Variation in chilling tolerance for photosynthesis and leaf extension growth among genotypes related to the C-4 grass Miscanthus xgiganteus

    SciTech Connect

    Glowacka, K; Adhikari, S; Peng, JH; Gifford, J; Juvik, JA; Long, SP; Sacks, EJ

    2014-09-08

    The goal of this study was to identify cold-tolerant genotypes within two species of Miscanthus related to the exceptionally chilling-tolerant C-4 biomass crop accession: M. xgiganteus 'Illinois' (Mxg) as well as in other Mxg genotypes. The ratio of leaf elongation at 10 degrees C/5 degrees C to that at 25 degrees C/25 degrees C was used to identify initially the 13 most promising Miscanthus genotypes out of 51 studied. Net leaf CO2 uptake (A(sat)) and the maximum operating efficiency of photosystem II (Phi(PSII)) were measured in warm conditions (25 degrees C/20 degrees C), and then during and following a chilling treatment of 10 degrees C/5 degrees C for 11 d. Accessions of M. sacchariflorus (Msa) showed the smallest decline in leaf elongation on transfer to chilling conditions and did not differ significantly from Mxg, indicating greater chilling tolerance than diploid M. sinensis (Msi). Msa also showed the smallest reductions in A(sat) and Phi(PSII), and greater chilling-tolerant photosynthesis than Msi, and three other forms of Mxg, including new triploid accessions and a hexaploid Mxg 'Illinois'. Tetraploid Msa 'PF30153' collected in Gifu Prefecture in Honshu, Japan did not differ significantly from Mxg 'Illinois' in leaf elongation and photosynthesis at low temperature, but was significantly superior to all other forms of Mxg tested. The results suggested that the exceptional chilling tolerance of Mxg 'Illinois' cannot be explained simply by the hybrid vigour of this intraspecific allotriploid. Selection of chilling-tolerant accessions from both of Mxg's parental species, Msi and Msa, would be advisable for breeding new highly chilling-tolerant Mxg genotypes.

  8. Genotypic and environmental variation in barley limit dextrinase activity and its relation to malt quality*

    PubMed Central

    Wang, Xu-dong; Yang, Juan; Zhang, Guo-ping

    2006-01-01

    Variation in the limit dextrinase activity of barley malt, and the relationships between limit dextrinase activity and malt quality parameters were investigated using eight cultivars grown at seven diverse locations in China for two successive years. Limit dextrinase activity varied with genotype and location, with the levels ranging from 0.245 U/g to 0.980 U/g. The results showed that the variation in limit dextrinase activity was more attributable to the environment (location and year) than to the genotype. The response of limit dextrinase activity to the environment differed markedly among cultivars, and was reflected by large difference in coefficient of variation of cultivars across diverse locations. Regression analysis showed that limit dextrinase activity was negatively correlated with malt viscosity (r=−0.52, P<0.01), positively correlated with Kolbach index (r=0.38, P<0.01) and malt extract (r=0.30, P<0.05), but had no significant correlation with malt protein content and diastatic power. PMID:16615169

  9. Platelet monoamine oxidase activity is related to MAOB intron 13 genotype.

    PubMed

    Garpenstrand, H; Ekblom, J; Forslund, K; Rylander, G; Oreland, L

    2000-01-01

    Monoamine oxidases (MAO) play a critical role in the degradation of endogenous and exogenous amines throughout the body. There are two distinct MAO isoforms, MAO-A and MAO-B, which both are encoded in genes on the X chromosome. Alterations in MAO-B activity have previously been connected with several neurological disorders. Platelet MAO (trbc-MAO) is exclusively of the B-type and the catalytic activity of this enzyme is under strong, yet unknown, genetic control. Specific trbc-MAO activity has been reported to be increased in certain neurodegenerative diseases and to correlate with personality traits such as sensation seeking and impulsiveness. In the present study, we investigated if trbc-MAO activity is associated with genotype at a variable region (A/G dimorphism) in intron 13 of the human gene encoding MAO-B. The MAOB intron 13 allele status and levels of trbc-MAO were determined for 55 Caucasian non-smoking males. Individuals with the "A-allele" displayed significantly lower enzyme activity than individuals with the "G-allele", i.e. 11.4 +/- 0.6 nmol/10(10) platelets/min compared with 13.5 +/- 0.6 (mean +/- SEM, p = 0.019). The present results suggest that the MAOB genotype may be involved in determining trbc-MAO activity.

  10. Energy balance, insulin-related genes and risk of colon and rectal cancer.

    PubMed

    Slattery, Martha L; Murtaugh, Maureen; Caan, Bette; Ma, Khe Ni; Neuhausen, Susan; Samowitz, Wade

    2005-05-20

    Energy balance, or the ability to maintain body weight by balancing energy intake with energy expenditure, appears to be important in the etiology of colon cancer. One possible mechanism whereby energy balance may be associated with colorectal cancer is through its association with insulin. In our study, we evaluate the interaction between polymorphisms in 4 genes thought to be involved in insulin-related functions and components of energy balance with risk of colorectal cancer. Data from 2 population-based case-control studies of colon and rectal cancer conducted in Utah and Northern California were used to evaluate associations between body mass index (BMI), physical activity, energy intake and sucrose-to-fiber ratio and a CA repeat polymorphism of the IGF1 gene, the A/C polymorphism at nucleotide -202 of the IGFBP3, the G972R polymorphism of the IRS1 gene and the G1057D polymorphism of the IRS2 gene. A total of 1,346 incident colon cancer cases and 1,544 population-based controls and 952 incident rectal cancer cases and 1,205 controls were available for analysis. Inconsistent associations were identified between BMI, physical activity, energy intake and insulin-related genes. The 192/192 IGF1 genotype was associated with significant reduction in colon cancer risk among those with high physical activity (odds ratio [OR] 0.57; 95% confidence interval [CI] 0.39-0.83; p interaction 0.01). Although there was no significant pattern of interaction between either BMI or energy intake and polymorphisms assessed, specific sources of energy did appear to be more related to colon cancer risk in the presence of specific IRS2 and IGF1 genotypes. A high sucrose-to-fiber ratio increased risk of colon cancer in men who had the IRS2 DD genotype and among men who did not have the 192/192 IGF1 genotype. In summary, these data support the importance of components of energy balance in risk of colorectal cancer. Obesity, physical activity and energy intake appear to alter risk of

  11. Genotypes and haplotypes of matrix metalloproteinase 1, 3 and 12 genes and the risk of lung cancer.

    PubMed

    Su, Li; Zhou, Wei; Asomaning, Kofi; Lin, Xihong; Wain, John C; Lynch, Thomas J; Liu, Geoffrey; Christiani, David C

    2006-05-01

    The MMPs (matrix metalloproteinases) are a family of secreted zinc metalloproteases that degrade the collagens of the extracellular matrix important in tissue remodeling and repair during development and inflammation. We investigated the associations between polymorphisms of MMP-1 (-1607 1G/2G, rs1799750), MMP-3 (-1171 5A/6A, rs3025058), and MMP-12 (-82AG, rs2276109, and 1082A/G, rs652438) and the risk of lung cancer in 2014 Caucasian lung cancer patients and 1323 healthy controls. The results were analyzed using logistic regression models, adjusting for covariates. The four polymorphisms were in Hardy-Weinberg disequilibrium. Except for the 1G-1082A, the other linkage disequilibrium tests between the four MMP polymorphisms were statistically significant (P < 0.001). There was no overall association between individual MMP polymorphism and the risk of lung cancer. The MMP polymorphisms jointly were associated with a non-statistically significant higher risk of lung cancer, with the adjusted odds ratio (AOR) of subjects with 5+ variant alleles versus zero variant allele of 1.31 [95% confidence interval (CI), 0.92-1.88]. Stronger associations were observed in never-smokers and males, with the corresponding AORs of 2.44 (95%CI, 1.10-5.43, P(trend) = 0.04) in never smokers and 1.35 (95%CI, 0.79-2.30, P(trend) = 0.04) in men. In haplotype analysis, the 1G-6A-82A-1082G haplotype was associated with higher risk of lung cancer among never smokers, with the AOR of 3.65 (95%CI, 1.62-8.20) when compared with the most common 1G-5A-82A-1082A haplotype. In conclusion, the combined MMP genotypes and associated haplotypes may be associated with higher risk of lung cancer, particularly among never smokers and men.

  12. Relative Hazard and Risk Measure Calculation Methodology

    SciTech Connect

    Stenner, Robert D.; Strenge, Dennis L.; Elder, Matthew S.; Andrews, William B.; Walton, Terry L.

    2003-09-15

    The RHRM equations, as represented in methodology and code presented in this report, are primarily a collection of key factors normally used in risk assessment that are relevant to understanding the hazards and risks associated with projected mitigation, cleanup, and risk management activities. The RHRM code has broad application potential. For example, it can be used to compare one mitigation, cleanup, or risk management activity with another, instead of just comparing it to just the fixed baseline. If the appropriate source term data are available, it can be used in its non-ratio form to estimate absolute values of the associated controlling hazards and risks. These estimated values of controlling hazards and risks can then be examined to help understand which mitigation, cleanup, or risk management activities are addressing the higher hazard conditions and risk reduction potential at a site. Graphics can be generated from these absolute controlling hazard and risk values to graphically compare these high hazard and risk reduction potential conditions. If the RHRM code is used in this manner, care must be taken to specifically define and qualify (e.g., identify which factors were considered and which ones tended to drive the hazard and risk estimates) the resultant absolute controlling hazard and risk values.

  13. [Prevalence of non-vaccinable high risk genotypes of human papillomavirus in the Early Detection of Cervical Cancer Program in Cantabria].

    PubMed

    Paz-Zulueta, María; Fernández-Feito, Ana; Amparán Ruiz, Marina; Azofra Olave, Asunción; Martín Seco, Yolanda; Ojugas Zabala, Sonia; Otero García, Aurora; Royano Rasines, Carmen; Sarabia-Lavín, Raquel; Torres Manrique, Blanca; Santibáñez Margüello, Miguel

    2016-01-01

    To estimate the prevalence of infection with non-vaccinable high risk genotypes of human papillomavirus (HPV). Cross-sectional study. Seven randomly selected health centres in Cantabria (Northern Spain). All women with an evaluable vaginal smear (n=3,359) between 2010 and 2011. The variables collected were cytological diagnosis, PCR results, and family planning method. The vaginal smear results were classified with the Bethesda system. The classification by Muñoz et al. was used for typing as oncogenic risk HPV. Proportions and odds ratio (OR) were estimated with corresponding confidence intervals at 95% (95% CI). The prevalence of HPV infection was 2.71% (95% CI: 2.15 to 3.27). The prevalence of high oncogenic risk HPV genotypes was 2.26%; (95% CI: 1.75 to 2.78). The most frequent genotype was 16 (28.89%). More than half of the women were positive for one of the non-vaccinable high risk genotypes: 51 (18.89%) and 58 (13.33%) and 68 (12.22%) or 31 (11.11%). At least two non-vaccinable high-risk genotypes co-existed in 23.33% of women. Younger women (≤30 years) had twice the risk of any HPV infection: OR 2.01 (95% CI: 1.02 to 3.96); and were twice as likely to use condoms compared to hormonal contraceptives, OR 2.09 (95% CI: 1.64 to 2.67). According to the high percentage of non-vaccinable high oncogenic risk HPV types, there should be a re-think of the prevention strategy in the population, who may have a false sense of protection. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

  14. The effect of childhood cow's milk intake and HLA-DR genotype on risk of islet autoimmunity and type 1 diabetes: the Diabetes Autoimmunity Study in the Young.

    PubMed

    Lamb, Molly M; Miller, Melissa; Seifert, Jennifer A; Frederiksen, Brittni; Kroehl, Miranda; Rewers, Marian; Norris, Jill M

    2015-02-01

    Cow's milk intake has been inconsistently associated with islet autoimmunity (IA) and type 1 diabetes (T1D) development. Genetic and environmental factors may modify the effect of cow's milk on IA and T1D risk. The Diabetes Autoimmunity Study in the Young (DAISY) follows children at increased T1D risk of IA (presence of autoantibodies to insulin, GAD65, or IA-2 twice in succession) and T1D development. We examined 1835 DAISY children with data on cow's milk intake: 143 developed IA, 40 subsequently developed T1D. Cow's milk protein and lactose intake were calculated from prospectively collected parent- and self-reported food frequency questionnaires (FFQ). High risk HLA-DR genotype: HLA-DR3/4,DQB1*0302; low/moderate risk: all other genotypes. We examined interactions between cow's milk intake, age at cow's milk introduction, and HLA-DR genotype in IA and T1D development. Interaction models contained the base terms (e.g., cow's milk protein and HLA-DR genotype) and an interaction term (e.g., cow's milk protein*HLA-DR genotype). In survival models adjusted for total calories, FFQ type, T1D family history, and ethnicity, greater cow's milk protein intake was associated with increased IA risk in children with low/moderate risk HLA-DR genotypes [hazard ratio (HR): 1.41, 95% confidence interval (CI): 1.08-1.84], but not in children with high risk HLA-DR genotypes. Cow's milk protein intake was associated with progression to T1D (HR: 1.59, CI: 1.13-2.25) in children with IA. Greater cow's milk intake may increase risk of IA and progression to T1D. Early in the T1D disease process, cow's milk intake may be more influential in children with low/moderate genetic T1D risk. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Almost efficient estimation of relative risk regression

    PubMed Central

    Fitzmaurice, Garrett M.; Lipsitz, Stuart R.; Arriaga, Alex; Sinha, Debajyoti; Greenberg, Caprice; Gawande, Atul A.

    2014-01-01

    Relative risks (RRs) are often considered the preferred measures of association in prospective studies, especially when the binary outcome of interest is common. In particular, many researchers regard RRs to be more intuitively interpretable than odds ratios. Although RR regression is a special case of generalized linear models, specifically with a log link function for the binomial (or Bernoulli) outcome, the resulting log-binomial regression does not respect the natural parameter constraints. Because log-binomial regression does not ensure that predicted probabilities are mapped to the [0,1] range, maximum likelihood (ML) estimation is often subject to numerical instability that leads to convergence problems. To circumvent these problems, a number of alternative approaches for estimating RR regression parameters have been proposed. One approach that has been widely studied is the use of Poisson regression estimating equations. The estimating equations for Poisson regression yield consistent, albeit inefficient, estimators of the RR regression parameters. We consider the relative efficiency of the Poisson regression estimator and develop an alternative, almost efficient estimator for the RR regression parameters. The proposed method uses near-optimal weights based on a Maclaurin series (Taylor series expanded around zero) approximation to the true Bernoulli or binomial weight function. This yields an almost efficient estimator while avoiding convergence problems. We examine the asymptotic relative efficiency of the proposed estimator for an increase in the number of terms in the series. Using simulations, we demonstrate the potential for convergence problems with standard ML estimation of the log-binomial regression model and illustrate how this is overcome using the proposed estimator. We apply the proposed estimator to a study of predictors of pre-operative use of beta blockers among patients undergoing colorectal surgery after diagnosis of colon cancer. PMID

  16. Sleep Modifies the Relation of APOE to the Risk of Alzheimer Disease and Neurofibrillary Tangle Pathology

    PubMed Central

    Lim, Andrew S.P.; Yu, Lei; Kowgier, Matthew; Schneider, Julie A.; Buchman, Aron S.; Bennett, David A.

    2013-01-01

    IMPORTANCE The Apolipoprotein E (APOE) ε4 allele is a common and well-established genetic risk factor for Alzheimer Disease (AD). Sleep consolidation is also associated with AD risk and previous work suggests that APOE genotype and sleep may interact to influence cognitive function. OBJECTIVE To determine whether better sleep consolidation attenuates the relation of the APOE genotype to the risk of incident AD and the burden of AD pathology. DESIGN Prospective longitudinal cohort study with up to 6 years of follow-up. SETTING Community-based. PARTICIPANTS We studied a volunteer sample of 698 community dwelling older adults without dementia (average age 81.7 years; 77% female) in the Rush Memory and Aging Project followed for up to 6 years. EXPOSURES We used up to 10 days of actigraphic recording to quantify the degree of sleep consolidation, and ascertained APOE genotype. MAIN OUTCOME MEASURES Subjects underwent annual evaluation for AD over a follow-up period of up to 6 years. Autopsies were performed on 201 deceased participants, and Aβ and neurofibrillary tangle (NFT) pathology were identified by immunohistochemistry and quantified. RESULTS Over a follow-up period, 98 individuals developed AD. In a series of Cox proportional hazards models, better sleep consolidation attenuated the effect of the ε4 allele on the risk of incident AD (HR 0.67 95%CI 0.46–0.97 p=0.036 per allele per 1SD increase in sleep consolidation). In a series of linear mixed effect models, better sleep consolidation also attenuated the effect of the ε4 allele on the annual rate of cognitive decline (interaction estimate +0.048 SE=0.012 p<0.001). In deceased individuals, better sleep consolidation attenuated the effect of the ε4 allele on NFT density (interaction estimate −0.42 SE=0.17 p=0.016), which accounted for the effect of sleep consolidation on the association between APOE genotype and cognition proximate to death. CONCLUSIONS AND RELEVANCE Better sleep consolidation attenuates

  17. The assessment of risk factors for the Central/East African Genotype of chikungunya virus infections in the state of Kelantan: a case control study in Malaysia

    PubMed Central

    2013-01-01

    Background The aims of the study were to assess the risk factors in relation to cross border activities, exposure to mosquito bite and preventive measures taken. An outbreak of chikungunya virus (CHIKV) infection in Malaysia has been reported in Klang, Selangor (1998) and Bagan Panchor, Perak (2006). In 2009, CHIKV infection re-emerged in some states in Malaysia. It raises the possibilities that re-emergence is part of the epidemics in neighbouring countries or the disease is endemic in Malaysia. For this reason, A community-based case control study was carried out in the state of Kelantan. Methods Prospective case finding was performed from June to December 2009. Those who presented with signs and symptoms of CHIKV infection were investigated. We designed a case control study to assess the risk factors. Assessment consisted of answering questions, undergoing a medical examination, and being tested for the presence of IgM antibodies to CHIKV. Descriptive epidemiological studies were conducted by reviewing both the national surveillance and laboratory data. Multivariable logistic regression analysis was performed to determine risk factors contributing to the illness. Cases were determined by positive to RT-PCR or serological for antibodies by IgM. CHIKV specificity was confirmed by DNA sequencing. Results There were 129 suspected cases and 176 controls. Among suspected cases, 54.4% were diagnosed to have CHIKV infection. Among the controls, 30.1% were found to be positive to serology for antibodies [IgM, 14.2% and IgG, 15.9%]. For analytic study and based on laboratory case definition, 95 were considered as cases and 123 as controls. Those who were positive to IgG were excluded. CHIKV infection affected all ages and mostly between 50–59 years old. Staying together in the same house with infected patients and working as rubber tappers were at a higher risk of infection. The usage of Mosquito coil insecticide had shown to be a significant protective factor. Most

  18. The assessment of risk factors for the Central/East African Genotype of chikungunya virus infections in the state of Kelantan: a case control study in Malaysia.

    PubMed

    Yusoff, Ahmad Faudzi; Mustafa, Amal Nasir; Husaain, Hani Mat; Hamzah, Wan Mansor; Yusof, Apandi Mohd; Harun, Rozilawati; Abdullah, Faezah Noor

    2013-05-08

    The aims of the study were to assess the risk factors in relation to cross border activities, exposure to mosquito bite and preventive measures taken.An outbreak of chikungunya virus (CHIKV) infection in Malaysia has been reported in Klang, Selangor (1998) and Bagan Panchor, Perak (2006). In 2009, CHIKV infection re-emerged in some states in Malaysia. It raises the possibilities that re-emergence is part of the epidemics in neighbouring countries or the disease is endemic in Malaysia. For this reason, A community-based case control study was carried out in the state of Kelantan. Prospective case finding was performed from June to December 2009. Those who presented with signs and symptoms of CHIKV infection were investigated. We designed a case control study to assess the risk factors. Assessment consisted of answering questions, undergoing a medical examination, and being tested for the presence of IgM antibodies to CHIKV. Descriptive epidemiological studies were conducted by reviewing both the national surveillance and laboratory data. Multivariable logistic regression analysis was performed to determine risk factors contributing to the illness. Cases were determined by positive to RT-PCR or serological for antibodies by IgM. CHIKV specificity was confirmed by DNA sequencing. There were 129 suspected cases and 176 controls. Among suspected cases, 54.4% were diagnosed to have CHIKV infection. Among the controls, 30.1% were found to be positive to serology for antibodies [IgM, 14.2% and IgG, 15.9%]. For analytic study and based on laboratory case definition, 95 were considered as cases and 123 as controls. Those who were positive to IgG were excluded. CHIKV infection affected all ages and mostly between 50-59 years old. Staying together in the same house with infected patients and working as rubber tappers were at a higher risk of infection. The usage of Mosquito coil insecticide had shown to be a significant protective factor. Most cases were treated as outpatient

  19. Glycan Specificity of P[19] Rotavirus and Comparison with Those of Related P Genotypes

    PubMed Central

    Liu, Yang; Ramelot, Theresa A.; Huang, Pengwei; Liu, Yan; Li, Zhen; Feizi, Ten; Zhong, Weiming; Wu, Fang-Tzy; Tan, Ming; Kennedy, Michael A.

    2016-01-01

    ABSTRACT The P[19] genotype belongs to the P[II] genogroup of group A rotaviruses (RVs). However, unlike the other P[II] RVs, which mainly infect humans, P[19] RVs commonly infect animals (pigs), making P[19] unique for the study of RV diversity and host ranges. Through in vitro binding assays and saturation transfer difference (STD) nuclear magnetic resonance (NMR), we found that P[19] could bind mucin cores 2, 4, and 6, as well as type 1 histo-blood group antigens (HBGAs). The common sequences of these glycans serve as minimal binding units, while additional residues, such as the A, B, H, and Lewis epitopes of the type 1 HBGAs, can further define the binding outcomes and therefore likely the host ranges for P[19] RVs. This complex binding property of P[19] is shared with the other three P[II] RVs (P[4], P[6], and P[8]) in that all of them recognized the type 1 HBGA precursor, although P[4] and P[8], but not P[6], also bind to mucin cores. Moreover, while essential for P[4] and P[8] binding, the addition of the Lewis epitope blocked P[6] and P[19] binding to type 1 HBGAs. Chemical-shift NMR of P[19] VP8* identified a ligand binding interface that has shifted away from the known RV P-genotype binding sites but is conserved among all P[II] RVs and two P[I] RVs (P[10] and P[12]), suggesting an evolutionary connection among these human and animal RVs. Taken together, these data are important for hypotheses on potential mechanisms for RV diversity, host ranges, and cross-species transmission. IMPORTANCE In this study, we found that our P[19] strain and other P[II] RVs recognize mucin cores and the type 1 HBGA precursors as the minimal functional units and that additional saccharides adjacent to these units can alter binding outcomes and thereby possibly host ranges. These data may help to explain why some P[II] RVs, such as P[6] and P[19], commonly infect animals but rarely humans, while others, such as the P[4] and P[8] RVs, mainly infect humans and are predominant

  20. The presence of PAI-1 4G/5G and ACE DD genotypes increases the risk of early-stage AVF thrombosis in hemodialysis patients.

    PubMed

    Güngör, Yahya; Kayataş, Mansur; Yıldız, Gürsel; Özdemir, Öztürk; Candan, Ferhan

    2011-01-01

    In this study, we investigated the relationship between early arteriovenous fistula (AVF) thrombosis with angiotensin-converting enzyme (ACE) gene and thrombophilic factor gene polymorphisms. Thirty-five patients who suffered from three or more fistula thrombosis episodes in the early period after AVF operation and 33 control patients with no history of thrombosis for at least 3 years were enrolled in this study. Factor V G1691A Leiden, factor V H1299R (R2), prothrombin G20210A, factor XIIIV34L, β-fibrinogen-455 G-A, glycoprotein IIIa L33P human platelet antigens (HPA-1), methylenetetrahydrofolate reductase C677T, and methylenetetrahydrofolate reductase A1298C gene polymorphisms were similar in both groups (p > 0.05). Plasminogen activator inhibitor 1 (PAI-1) 4G/5G genotype in the study group and 4G/4G genotype in the control group were significantly higher (p = 0.014). No significant difference was detected in terms of the 5G/5G genotype. With regard to the ACE gene polymorphism, the control group showed more ID genotype (19/33, 57.6%), whereas the study group showed more DD genotype (17/35, 48.6%). II genotype was similar in both groups (x(2) = 7.40, p = 0.025). The rate of ACE inhibitor-angiotensin II receptor blockers use was 5/35 in the study group (14.3%) and 5/33 in the control group (15.2%). Individuals with PAI-1 4G/5G genotype showed 5.03 times more risk of thrombosis when compared with 4G/4G and 5G/5G genotypes [p = 0.008, OR = 5.03, 95% confidence interval (1.44:17.64)]. Individuals with ACE DD genotype showed 4.25 times more risk of thrombosis when compared with II and ID [p = 0.008, OR = 4.25, 95% confidence interval (1.404:12.83)]. PAI-1 4G/5G and ACE DD genotypes are associated with increased risk for early AVF thrombosis.

  1. CCL3L1-CCR5 Genotype Improves the Assessment of AIDS Risk in HIV-1-Infected Individuals

    PubMed Central

    Kulkarni, Hemant; Agan, Brian K.; Marconi, Vincent C.; O'Connell, Robert J.; Camargo, Jose F.; He, Weijing; Delmar, Judith; Phelps, Kenneth R.; Crawford, George; Clark, Robert A.; Dolan, Matthew J.; Ahuja, Sunil K.

    2008-01-01

    Background Whether vexing clinical decision-making dilemmas can be partly addressed by recent advances in genomics is unclear. For example, when to initiate highly active antiretroviral therapy (HAART) during HIV-1 infection remains a clinical dilemma. This decision relies heavily on assessing AIDS risk based on the CD4+ T cell count and plasma viral load. However, the trajectories of these two laboratory markers are influenced, in part, by polymorphisms in CCR5, the major HIV coreceptor, and the gene copy number of CCL3L1, a potent CCR5 ligand and HIV-suppressive chemokine. Therefore, we determined whether accounting for both genetic and laboratory markers provided an improved means of assessing AIDS risk. Methods and Findings In a prospective, single-site, ethnically-mixed cohort of 1,132 HIV-positive subjects, we determined the AIDS risk conveyed by the laboratory and genetic markers separately and in combination. Subjects were assigned to a low, moderate or high genetic risk group (GRG) based on variations in CCL3L1 and CCR5. The predictive value of the CCL3L1-CCR5 GRGs, as estimated by likelihood ratios, was equivalent to that of the laboratory markers. GRG status also predicted AIDS development when the laboratory markers conveyed a contrary risk. Additionally, in two separate and large groups of HIV+ subjects from a natural history cohort, the results from additive risk-scoring systems and classification and regression tree (CART) analysis revealed that the laboratory and CCL3L1-CCR5 genetic markers together provided more prognostic information than either marker alone. Furthermore, GRGs independently predicted the time interval from seroconversion to CD4+ cell count thresholds used to guide HAART initiation. Conclusions The combination of the laboratory and genetic markers captures a broader spectrum of AIDS risk than either marker alone. By tracking a unique aspect of AIDS risk distinct from that captured by the laboratory parameters, CCL3L1-CCR5 genotypes

  2. Can Non-HLA Single Nucleotide Polymorphisms Help Stratify Risk in TrialNet Relatives at Risk for Type 1 Diabetes?

    PubMed

    Steck, Andrea K; Xu, Ping; Geyer, Susan; Redondo, Maria J; Antinozzi, Peter; Wentworth, John M; Sosenko, Jay; Onengut-Gumuscu, Suna; Chen, Wei-Min; Rich, Stephen S; Pugliese, Alberto

    2017-08-01

    Genome-wide association studies identified >50 type 1 diabetes (T1D) associated non-human leukocyte antigens (non-HLA) loci. The purpose of this study was to assess the contribution of non-HLA single nucleotide polymorphisms (SNPs) to risk of disease progression. The TrialNet Pathway to Prevention Study follows relatives of T1D patients for development of autoantibodies (Abs) and T1D. Using the Immunochip, we analyzed 53 diabetes-associated, non-HLA SNPs in 1016 Ab-positive, at-risk non-Hispanic white relatives. Effect of SNPs on the development of multiple Abs and T1D. Cox proportional analyses included all substantial non-HLA SNPs, HLA genotypes, relationship to proband, sex, age at initial screening, initial Ab type, and number. Factors involved in progression from single to multiple Abs included age at screening, relationship to proband, HLA genotypes, and rs3087243 (cytotoxic T lymphocyte antigen-4). Significant factors for diabetes progression included age at screening, Ab number, HLA genotypes, rs6476839 [GLIS family zinc finger 3 (GLIS3)], and rs3184504 [SH2B adaptor protein 3 (SH2B3)]. When glucose area under the curve (AUC) was included, factors involved in disease progression included glucose AUC, age at screening, Ab number, relationship to proband, HLA genotypes, rs6476839 (GLIS3), and rs7221109 (CCR7). In stratified analyses by age, glucose AUC, age at screening, sibling, HLA genotypes, rs6476839 (GLIS3), and rs4900384 (C14orf64) were significantly associated with progression to diabetes in participants <12 years old, whereas glucose AUC, sibling, rs3184504 (SH2B3), and rs4900384 (C14orf64) were significant in those ≥12. In conclusion, we identified five non-HLA SNPs associated with increased risk of progression from Ab positivity to disease that may improve risk stratification for prevention trials.

  3. p53 codon 72 polymorphism interactions with dietary and tobacco related habits and risk of stomach cancer in Mizoram, India.

    PubMed

    Malakar, Mridul; Devi, K Rekha; Phukan, Rup Kumar; Kaur, Tanvir; Deka, Manab; Puia, Lalhriat; Sailo, Lalrinliana; Lalhmangaihi, T; Barua, Debajit; Rajguru, Sanjib Kumar; Mahanta, Jagadish; Narain, Kanwar

    2014-01-01

    This study was carried out to investigate the interaction of p53 codon 72 polymorphism, dietary and tobacco habits with reference to risk of stomach cancer in Mizoram, India. A total of 105 histologically confirmed stomach cancer cases and 210 age, sex and ethnicity matched healthy population controls were included in this study. The p53 codon 72 polymorphism was detected by PCR-RFLP and sequencing. H. pylori infection status was determined by ELISA. Information on various dietary and tobacco related habits was recorded with a standard questionnaire. This study revealed that overall, the Pro/ Pro genotype was significantly associated with a higher risk of stomach cancer (OR, 2.54; 95%CI, 1.01-6.40) as compared to the Arg/Arg genotype. In gender stratified analysis, the Pro/Pro genotype showed higher risk (OR, 7.50; 95%CI, 1.20-47.0) than the Arg/Arg genotype among females. Similarly, the Pro/Pro genotype demonstrated higher risk of stomach cancer (OR, 6.30; 95%CI, 1.41-28.2) among older people (>60 years). However, no such associations were observed in males and in individuals <60 years of age. Smoke dried fish and preserved meat (smoke dried/sun dried) consumers were at increased risk of stomach cancer (OR, 4.85; 95%CI, 1.91-12.3 and OR, 4.22; 95%CI, 1.46-12.2 respectively) as compared to non-consumers. Significant gene-environment interactions exist in terms of p53 codon 72 polymorphism and stomach cancer in Mizoram. Tobacco smokers with Pro/Pro and Arg/Pro genotypes were at higher risk of stomach cancer (OR, 16.2; 95%CI, 1.72-153.4 and OR, 9.45; 95%CI, 1.09-81.7 respectively) than the non-smokers Arg/Arg genotype carriers. The combination of tuibur user and Arg/Pro genotype also demonstrated an elevated risk association (OR, 4.76; 95%CI, 1.40-16.21). In conclusion, this study revealed that p53 codon 72 polymorphism and dietary and tobacco habit interactions influence stomach cancer development in Mizoram, India.

  4. A systematic review and meta-analysis of 130,000 individuals shows smoking does not modify the association of APOE genotype on risk of coronary heart disease.

    PubMed

    Holmes, Michael V; Frikke-Schmidt, Ruth; Melis, Daniela; Luben, Robert; Asselbergs, Folkert W; Boer, Jolanda M A; Cooper, Jackie; Palmen, Jutta; Horvat, Pia; Engmann, Jorgen; Li, Ka-Wah; Onland-Moret, N Charlotte; Hofker, Marten H; Kumari, Meena; Keating, Brendan J; Hubacek, Jaroslav A; Adamkova, Vera; Kubinova, Ruzena; Bobak, Martin; Khaw, Kay-Tee; Nordestgaard, Børge G; Wareham, Nick; Humphries, Steve E; Langenberg, Claudia; Tybjaerg-Hansen, Anne; Talmud, Philippa J

    2014-11-01

    Conflicting evidence exists on whether smoking acts as an effect modifier of the association between APOE genotype and risk of coronary heart disease (CHD). We searched PubMed and EMBASE to June 11, 2013 for published studies reporting APOE genotype, smoking status and CHD events and added unpublished data from population cohorts. We tested for presence of effect modification by smoking status in the relationship between APOE genotype and risk of CHD using likelihood ratio test. In total 13 studies (including unpublished data from eight cohorts) with 10,134 CHD events in 130,004 individuals of European descent were identified. The odds ratio (OR) for CHD risk from APOE genotype (ε4 carriers versus non-carriers) was 1.06 (95% confidence interval (CI): 1.01, 1.12) and for smoking (present vs. past/never smokers) was OR 2.05 (95%CI: 1.95, 2.14). When the association between APOE genotype and CHD was stratified by smoking status, compared to non-ε4 carriers, ε4 carriers had an OR of 1.11 (95%CI: 1.02, 1.21) in 28,789 present smokers and an OR of 1.04 (95%CI 0.98, 1.10) in 101,215 previous/never smokers, with no evidence of effect modification (P-value for heterogeneity = 0.19). Analysis of pack years in individual participant data of >60,000 with adjustment for cardiovascular traits also failed to identify evidence of effect modification. In the largest analysis to date, we identified no evidence for effect modification by smoking status in the association between APOE genotype and risk of CHD. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  5. Differential association for N-acetyltransferase 2 genotype and phenotype with bladder cancer risk in Chinese population

    PubMed Central

    Quan, Lei; Chattopadhyay, Koushik; Nelson, Heather H.; Chan, Kenneth K.; Xiang, Yong-Bing; Zhang, Wei; Wang, Renwei; Gao, Yu-Tang; Yuan, Jian-Min

    2016-01-01

    Background N-acetyltransferase 2 (NAT2) is involved in both carcinogen detoxification through hepatic N-acetylation and carcinogen activation through local O-acetylation. NAT2 slow acetylation status is significantly associated with increased bladder cancer risk among European populations, but its association in Asian populations is inconclusive. Methods NAT2 acetylation status was determined by both single nucleotide polymorphisms (SNPs) and caffeine metabolic ratio (CMR), in a population-based study of 494 bladder cancer patients and 507 control subjects in Shanghai, China. Results The CMR, a functional measure of hepatic N-acetylation, was significantly reduced in a dose-dependent manner among both cases and controls possessing the SNP-inferred NAT2 slow acetylation status (all P-values<5.0×10−10). The CMR-determined slow N-acetylation status (CMR<0.34) was significantly associated with a 50% increased risk of bladder cancer (odds ratio = 1.50, 95% confidence interval = 1.10-2.06) whereas the SNP-inferred slow acetylation statuses were significantly associated with an approximately 50% decreased risk of bladder cancer. The genotype-disease association was strengthened after the adjustment for CMR and was primarily observed among never smokers. Conclusions The apparent differential associations for phenotypic and genetic measures of acetylation statuses with bladder cancer risk may reflect dual functions of NAT2 in bladder carcinogenesis because the former only measures the capacity of carcinogen detoxification pathway while the latter represents both carcinogen activation and detoxification pathways. Future studies are warranted to ascertain the specific role of N- and O-acetylation in bladder carcinogenesis, particularly in populations exposed to different types of bladder carcinogens. PMID:27223070

  6. The Evolving Genotypic Profile of HIV-1 Mutations Related to Antiretroviral Treatment in the North Region of Brazil

    PubMed Central

    Lopes, Carmen Andréa F.; Soares, Marcelo A.; Falci, Diego R.; Sprinz, Eduardo

    2015-01-01

    HIV related mutations can be associated with decreased susceptibility to antiretrovirals and treatment failures. There is scarce information about HIV mutations in persons failing HIV treatment in North of Brazil. Our aim was to evaluate evolution of HIV subtypes and mutations patterns related to antiretroviral therapy in this region. We investigated HIV resistance profile in adults failing antiretroviral regimen in Northern Brazil from January, 2004, through December, 2013. Genotype data was evaluated through Stanford University algorithm. There were 377 genotypes from different individuals to evaluate. Resistance mutations were similar to worldwide reports and related to antiretroviral exposure. Most prevalent mutations in the reverse transcriptase gene were M184V (80.1%) and K130N (40.6%). Thymidine associated mutations were more frequent in multiexperienced patients. Most common protease mutations were M46I, V82A, I54V, L90M, I84V, M46L, and L76V. Subtype B was the most prevalent (90.7%). There were differences between subtypes B and non-B mutations. We documented for the first time subtypes and patterns of HIV associated mutations in Northern Brazil. A1 subtype was identified for the first time in this area. Depending on drug regimen and how experienced the patient is, an empirical switch of a failing antiretroviral treatment could be a reasonable option. PMID:26543866

  7. Evaluation of multiple approaches to identify genome-wide polymorphisms in closely related genotypes of sweet cherry (Prunus avium L.).

    PubMed

    Hewitt, Seanna; Kilian, Benjamin; Hari, Ramyya; Koepke, Tyson; Sharpe, Richard; Dhingra, Amit

    2017-01-01

    Identification of genetic polymorphisms and subsequent development of molecular markers is important for marker assisted breeding of superior cultivars of economically important species. Sweet cherry (Prunus avium L.) is an economically important non-climacteric tree fruit crop in the Rosaceae family and has undergone a genetic bottleneck due to breeding, resulting in limited genetic diversity in the germplasm that is utilized for breeding new cultivars. Therefore, it is critical to recognize the best platforms for identifying genome-wide polymorphisms that can help identify, and consequently preserve, the diversity in a genetically constrained species. For the identification of polymorphisms in five closely related genotypes of sweet cherry, a gel-based approach (TRAP), reduced representation sequencing (TRAPseq), a 6k cherry SNParray, and whole genome sequencing (WGS) approaches were evaluated in the identification of genome-wide polymorphisms in sweet cherry cultivars. All platforms facilitated detection of polymorphisms among the genotypes with variable efficiency. In assessing multiple SNP detection platforms, this study has demonstrated that a combination of appropriate approaches is necessary for efficient polymorphism identification, especially between closely related cultivars of a species. The information generated in this study provides a valuable resource for future genetic and genomic studies in sweet cherry, and the insights gained from the evaluation of multiple approaches can be utilized for other closely related species with limited genetic diversity in the breeding germplasm.

  8. Predicting risk of bacterial vaginosis: the role of race, smoking and corticotropin-releasing hormone-related genes

    PubMed Central

    Ryckman, K.K.; Simhan, H.N.; Krohn, M.A.; Williams, S.M.

    2009-01-01

    Bacterial vaginosis (BV) is one of the most prevalent vaginal disorders in adult women and is associated with adverse pregnancy outcomes such as pre-term birth. Genetic factors, particularly in genes involved in inflammation and infection, are associated with this condition. Additionally, environmental risk factors including stress and smoking are associated with BV. The purpose of this study was to identify genetic variants in stress-related genes such as corticotropin-releasing hormone (CRH), receptor 1, receptor 2 and binding protein (CRH-BP) that associate with BV. Also gene–environment effects with smoking are determined. BV was quantified using the Nugent score in 82 white and 65 black women in the first trimester of pregnancy. Associations between Nugent score, genotype and smoking were analyzed using Kruskal–Wallis and Wilcoxon rank sum non-parametric tests. In white women, non-smokers with the CT genotype at CRH-BP + 17487 have lower Nugent scores (median: 0, range: 0–0) than non-smokers with the TT genotype (median: 2, range: 0–8) (P = 0.002); whereas smokers with the CT genotype have higher Nugent scores (median: 6, range: 0–10) than smokers with the TT genotype (median: 1, range: 0–10) (P = 0.021). In black women, the AG genotype at CRH + 3362 or CRH − 1667 is associated with lower Nugent scores (median for both: 3, range: 0–10) compared with the homozygous genotypes (median for each homozygous genotype: 8, range: 0–10). Also, in black women, models remain significant after adjusting for smoking (P = 0.04 for both). These data indicate that susceptibility to BV is affected by patterns of genetic variation in stress-related genes and smoking plays an important role. PMID:19131402

  9. Naturally occurring mutations in large surface genes related to occult infection of hepatitis B virus genotype C.

    PubMed

    Kim, Hong; Lee, Seoung-Ae; Kim, Dong-Won; Lee, Sueng-Hyun; Kim, Bum-Joon

    2013-01-01

    Molecular mechanisms related to occult hepatitis B virus (HBV) infection, particularly those based on genotype C infection, have rarely been determined thus far in the ongoing efforts to determine infection mechanisms. Therefore, we aim to elucidate the mutation patterns in the surface open reading frame (S ORF) underlying occult infections of HBV genotype C in the present study. Nested PCRs were applied to 624 HBV surface antigen (HBsAg) negative Korean subjects. Cloning and sequencing of the S ORF gene was applied to 41 occult cases and 40 control chronic carriers. Forty-one (6.6%) of the 624 Korean adults with HBsAg-negative serostatus were found to be positive for DNA according to nested PCR tests. Mutation frequencies in the three regions labeled here as preS1, preS2, and S were significantly higher in the occult subjects compared to the carriers in all cases. A total of two types of deletions, preS1 deletions in the start codon and preS2 deletions as well as nine types of point mutations were significantly implicated in the occult infection cases. Mutations within the "a" determinant region in HBsAg were found more frequently in the occult subjects than in the carriers. Mutations leading to premature termination of S ORF were found in 16 occult subjects (39.0%) but only in one subject from among the carriers (2.5%). In conclusion, our data suggest that preS deletions, the premature termination of S ORF, and "a" determinant mutations are associated with occult infections of HBV genotype C among a HBsAg-negative population. The novel mutation patterns related to occult infection introduced in the present study can help to broaden our understanding of HBV occult infections.

  10. The Association of High Risk Human Papillomaviruses in Patients With Cervical Cancer: An Evidence Based Study on Patients With Squamous Cell Dysplasia or Carcinoma for Evaluation of 23 Human Papilloma Virus Genotypes

    PubMed Central

    Piroozmand, Ahmad; Mostafavi Zadeh, Seyed Mostafa; Madani, Azita; Soleimani, Reza; Nedaeinia, Reza; Niakan, Mohammad; Avan, Amir; Manian, Mostafa; Moradi, Mohammad; Eftekhar, Zahra

    2016-01-01

    Background Cervical cancer is one of the leading causes of cancer-related death in females. Human papilloma virus (HPV) is the major risk factor of cervical cancer. Objectives The aim of the current study was to explore the frequency and role of 23 different HPVs in patients with cervical cancer. Materials and Methods Overall, 117 formalin-fix and paraffin-embedded (FFPE) tissues from cervical cancer patients with squamous cell carcinoma (SCC) or dysplasia were collected from Mirza-Kochakkhan-Jangali hospital, Tehran, Iran during year 2013, to investigate the presence of HPV- HPV- 67, 68, 6, 11, 13, 16, 17, 30, 69, 39, 40, 42, 64, 66 and 51 to 59 genotypes. Results The Pap smear report illustrated the presence of malignancy in 71 cases, while 11 cases had no evidence of malignancy. Among the patients, 26 cases had sexually transmitted disease with relative frequency of 0.58. Infection with papilloma virus was observed in 83.6% of SCC patients and 45% of the dysplasia group. The most prevalent HPV genotypes were 18 with 31.62% and 16 with 27.35% of cases. Moreover the relative frequencies of HPV-33, -6, -58, -52, -35 and -51, genotypes were 15.38, 7.69, 5.98, 5.12 and 3.41%, respectively. Among the different genotypes of HPV, 31 had the lowest and 16 had the highest relative frequency. Conclusions Our findings demonstrate that HPV-16 and -18 have a higher prevalence in our population than 31 and 51. Further investigations are required to evaluate the role of these genotypes in a larger multicenter setting for establishing their values for early detection of patients, which is useful for screening and vaccination programs of cancerous and precancerous lesions of cervical cancer. PMID:27279992

  11. Combination of uterine natural killer cell immunoglobulin receptor haplotype and trophoblastic HLA-C ligand influences the risk of pregnancy loss: a retrospective cohort analysis of direct embryo genotyping data from euploid transfers.

    PubMed

    Morin, Scott J; Treff, Nathan R; Tao, Xin; Scott, Richard T; Franasiak, Jason M; Juneau, Caroline R; Maguire, Marcy; Scott, Richard T

    2017-03-01

    To compare maternal uterine natural killer cell immunoglobulin receptor (KIR) genotype and haplotype frequencies between patients whose euploid single-embryo transfer resulted in pregnancy loss and those that resulted in delivery and to determine if the risk of pregnancy loss was affected by the HLA-C genotype content in the embryo. Retrospective cohort. Academic research center. Autologous fresh IVF cycles resulting in positive serum β-hCG during 2009-2014. None. 1) Relative risk of pregnancy loss according to maternal KIR genotypes and haplotypes. 2) Comparison of pregnancy loss rates within each KIR haplotype according to HLA-C ligand present in trophectoderm biopsy samples. A total of 668 euploid single-embryo transfers with stored maternal DNA and available preamplification DNA from prior trophectoderm biopsy samples were studied. KIR2DS1, KIR3DS1, and KIR2DS5 were more common in patients who experienced pregnancy loss. Carriers of KIR A haplotype exhibited a decreased risk of pregnancy loss compared with KIR B haplotype carriers. However, among KIR A haplotype carriers, the risk of loss was significantly influenced by whether the transferred embryo carried a C1 allele versus no C1 alleles. KIR A haplotype carriers experienced fewer pregnancy losses than KIR B haplotype carriers after euploid single-embryo transfer. However, this risk was modified by HLA-C alleles present in the embryo. High-risk combinations (KIR A/homozygous C2 and KIR B/homozygous C1) resulted in a 51% increased risk of loss over all other combinations. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  12. Prevalence of High-Risk Human Papillomavirus (HR-HPV) Genotypes and Multiple Infections in Cervical Abnormalities from Northern Xinjiang, China.

    PubMed

    Wang, Lina; Wang, Pengyan; Ren, Yan; Du, Jingyun; Jiang, Jianjun; Jia, Xuesong; Chen, Chuangfu; Wang, Yuanzhi

    2016-01-01

    Multiple human papillomavirus (HPV) genotypes often coexist within the cervical epithelia and are frequently detected together in various grades of the cervical neoplasia. To date, only a few reports exist on multiple HPV infections of HPV in Xinjiang Uygur Autonomous Region (XUAR). In the present study, we investigated the prevalence of High-Risk HPV (HR-HPV) genotypes and multiple infections. Cervical cytology samples were collected from 428 women who presented cervical abnormalities. Genotyping of HPV was performed by polymerase chain reaction-sequencing based typing (PCR-SBT) using consensus primers and specific primers. Of them, 166 samples were positive for HPV according to PCR results using the consensus primers. These samples contained cervical abnormalities enriched with inflammation (n = 107), cervical intraepithelial neoplasia (CIN) I (n = 19), CINII-III (n = 9) and cervical cancer (n = 31). Of the 166 HPV positive samples as determined by PCR analysis, 151 were further typed by PCR-SBT using 19 pairs of genotype-specific primers. Using this method, 17 different HR-HPV genotypes were identified. The most frequently observed HPV genotypes were HPV16 (44.0%, 73/166), 53 (28.9%, 48/166), 52 (25.3%, 42/166), 58 (22.3%, 37/166) and 35 (17.5%, 29/166). The proportions of single and multiple infections in the HPV-positive specimens were 34.9% and 65.1%, respectively. Multiple HPV types were most prevalent in the inflammatory state (63.0%), followed by cervical cancer (24.1%), CINI (11.1%), and CINII-III (1.9%). The results of our data analyses suggested that i) multiple HPV infection is not necessarily correlated with the severity of cervical abnormalities; and ii) among the multiple HPV infections, double infections combined with HPV16 is the most common. In addition, L1 full-length sequences of the top five high-risk HPV genotypes were amplified and sequenced. According to the L1 sequence of the epidemic genotypes that were amplified, we found that these

  13. Prevalence of High-Risk Human Papillomavirus (HR-HPV) Genotypes and Multiple Infections in Cervical Abnormalities from Northern Xinjiang, China

    PubMed Central

    Du, Jingyun; Jiang, Jianjun; Jia, Xuesong; Chen, Chuangfu; Wang, Yuanzhi

    2016-01-01

    Multiple human papillomavirus (HPV) genotypes often coexist within the cervical epithelia and are frequently detected together in various grades of the cervical neoplasia. To date, only a few reports exist on multiple HPV infections of HPV in Xinjiang Uygur Autonomous Region (XUAR). In the present study, we investigated the prevalence of High-Risk HPV (HR-HPV) genotypes and multiple infections. Cervical cytology samples were collected from 428 women who presented cervical abnormalities. Genotyping of HPV was performed by polymerase chain reaction–sequencing based typing (PCR-SBT) using consensus primers and specific primers. Of them, 166 samples were positive for HPV according to PCR results using the consensus primers. These samples contained cervical abnormalities enriched with inflammation (n = 107), cervical intraepithelial neoplasia (CIN) I (n = 19), CINII-III (n = 9) and cervical cancer (n = 31). Of the 166 HPV positive samples as determined by PCR analysis, 151 were further typed by PCR-SBT using 19 pairs of genotype-specific primers. Using this method, 17 different HR-HPV genotypes were identified. The most frequently observed HPV genotypes were HPV16 (44.0%, 73/166), 53 (28.9%, 48/166), 52 (25.3%, 42/166), 58 (22.3%, 37/166) and 35 (17.5%, 29/166). The proportions of single and multiple infections in the HPV-positive specimens were 34.9% and 65.1%, respectively. Multiple HPV types were most prevalent in the inflammatory state (63.0%), followed by cervical cancer (24.1%), CINI (11.1%), and CINII-III (1.9%). The results of our data analyses suggested that i) multiple HPV infection is not necessarily correlated with the severity of cervical abnormalities; and ii) among the multiple HPV infections, double infections combined with HPV16 is the most common. In addition, L1 full-length sequences of the top five high-risk HPV genotypes were amplified and sequenced. According to the L1 sequence of the epidemic genotypes that were amplified, we found that these

  14. Muscle histopathology in nebulin-related nemaline myopathy: ultrastrastructural findings correlated to disease severity and genotype

    PubMed Central

    2014-01-01

    Nemaline myopathy (NM) is a rare congenital myopathy characterised by hypotonia, muscle weakness, and often skeletal muscle deformities with the presence of nemaline bodies (rods) in the muscle biopsy. The nebulin (NEB) gene is the most commonly mutated and is thought to account for approximately 50% of genetically diagnosed cases of NM. We undertook a detailed muscle morphological analysis of 14 NEB-mutated NM patients with different clinical forms to define muscle pathological patterns and correlate them with clinical course and genotype. Three groups were identified according to clinical severity. Group 1 (n = 5) comprises severe/lethal NM and biopsy in the first days of life. Group 2 (n = 4) includes intermediate NM and biopsy in infancy. Group 3 (n = 5) comprises typical/mild NM and biopsy in childhood or early adult life. Biopsies underwent histoenzymological, immunohistochemical and ultrastructural analysis. Fibre type distribution patterns, rod characteristics, distribution and localization were investigated. Contractile performance was studied in muscle fibre preparations isolated from seven muscle biopsies from each of the three groups. G1 showed significant myofibrillar dissociation and smallness with scattered globular rods in one third of fibres; there was no type 1 predominance. G2 presented milder sarcomeric dissociation, dispersed or clustered nemaline bodies, and type 1 predominance/uniformity. In contrast, G3 had well-delimited clusters of subsarcolemmal elongated rods and type 1 uniformity without sarcomeric alterations. In accordance with the clinical and morphological data, functional studies revealed markedly low forces in muscle bundles from G1 and a better contractile performance in muscle bundles from biopsies of patients from G2, and G3. In conclusion NEB-mutated NM patients present a wide spectrum of morphological features. It is difficult to establish firm genotype phenotype correlation. Interestingly, there was a correlation

  15. Muscle histopathology in nebulin-related nemaline myopathy: ultrastrastructural findings correlated to disease severity and genotype.

    PubMed

    Malfatti, Edoardo; Lehtokari, Vilma-Lotta; Böhm, Johann; De Winter, Josine M; Schäffer, Ursula; Estournet, Brigitte; Quijano-Roy, Susana; Monges, Soledad; Lubieniecki, Fabiana; Bellance, Remi; Viou, Mai Thao; Madelaine, Angéline; Wu, Bin; Taratuto, Ana Lía; Eymard, Bruno; Pelin, Katarina; Fardeau, Michel; Ottenheijm, Coen A C; Wallgren-Pettersson, Carina; Laporte, Jocelyn; Romero, Norma B

    2014-04-12

    Nemaline myopathy (NM) is a rare congenital myopathy characterised by hypotonia, muscle weakness, and often skeletal muscle deformities with the presence of nemaline bodies (rods) in the muscle biopsy. The nebulin (NEB) gene is the most commonly mutated and is thought to account for approximately 50% of genetically diagnosed cases of NM. We undertook a detailed muscle morphological analysis of 14 NEB-mutated NM patients with different clinical forms to define muscle pathological patterns and correlate them with clinical course and genotype. Three groups were identified according to clinical severity. Group 1 (n = 5) comprises severe/lethal NM and biopsy in the first days of life. Group 2 (n = 4) includes intermediate NM and biopsy in infancy. Group 3 (n = 5) comprises typical/mild NM and biopsy in childhood or early adult life. Biopsies underwent histoenzymological, immunohistochemical and ultrastructural analysis. Fibre type distribution patterns, rod characteristics, distribution and localization were investigated. Contractile performance was studied in muscle fibre preparations isolated from seven muscle biopsies from each of the three groups. G1 showed significant myofibrillar dissociation and smallness with scattered globular rods in one third of fibres; there was no type 1 predominance. G2 presented milder sarcomeric dissociation, dispersed or clustered nemaline bodies, and type 1 predominance/uniformity. In contrast, G3 had well-delimited clusters of subsarcolemmal elongated rods and type 1 uniformity without sarcomeric alterations. In accordance with the clinical and morphological data, functional studies revealed markedly low forces in muscle bundles from G1 and a better contractile performance in muscle bundles from biopsies of patients from G2, and G3.In conclusion NEB-mutated NM patients present a wide spectrum of morphological features. It is difficult to establish firm genotype phenotype correlation. Interestingly, there was a correlation

  16. The PNPLA3 rs738409 148M/M Genotype Is a Risk Factor for Liver Cancer in Alcoholic Cirrhosis but Shows No or Weak Association in Hepatitis C Cirrhosis

    PubMed Central

    Luda, Carolin; Berg, Thomas; Müller, Tobias; Grünhage, Frank; Lammert, Frank; Coenen, Martin; Krämer, Benjamin; Körner, Christian; Vidovic, Natascha; Oldenburg, Johannes; Nattermann, Jacob; Sauerbruch, Tilman; Spengler, Ulrich

    2011-01-01

    Background An isoleucine>methionine mutation at position 148 in the PNPLA3 gene (p.I148M, rs738409) has recently been identified as a susceptibility factor for liver damage in steatohepatitis. Here, we studied whether the PNPLA3 rs738409 polymorphism also affects predisposition to hepatocellular carcinoma (HCC). Methods We compared distributions of PNPLA3 genotypes in 80 and 81 Caucasian patients with alcoholic and hepatitis C virus (HCV)-associated HCC to 80 and 81 age- and sex-matched patients with alcohol-related and HCV-related cirrhosis without HCC, respectively. PNPLA3 genotypes in 190 healthy individuals from the same population served as reference. Potential confounders obesity, diabetes, HCV genotype and HBV co-infection were controlled by univariate and multivariate logistic regression with forward variable selection. Results PNPLA3 genotypes were in Hardy-Weinberg equilibrium for all study groups. The frequency of the 148M allele was significantly (p<0.001) increased in alcoholic cirrhosis with (53.7%) and without HCC (36.2%) but was not different between healthy controls (22.9%) and patients with cirrhosis (25.3%; p = 0.545) and HCC (30.2%; p = 0.071) due to hepatitis C. HCC risk was highest in 148M/M homozygous patients with alcoholic liver disease (odds ratio (OR) 16.8 versus healthy controls; 95% confidence interval (CI) 6.68–42.43, p<0.001). Finally, multivariate regression confirmed 148M/M homozygosity (OR 2.8; 95%-CI: 1.24–6.42; p = 0.013) as HCC risk factor in alcoholic cirrhosis. In HCV-related cirrhosis only HCV genotype 1 was confirmed as a HCC risk factor (OR 4.2; 95%-CI: 1.50–11.52; p = 0.006). Conclusion The PNPLA3 148M variant is a prominent risk factor for HCC in patients with alcoholic cirrhosis, while its effects are negligible in patients with cirrhosis due to HCV. This polymorphism provides an useful tool to identify individuals with particularly high HCC risk in patients with alcoholic liver disease that should

  17. Nicotine N-glucuronidation relative to N-oxidation and C-oxidation and UGT2B10 genotype in five ethnic/racial groups

    PubMed Central

    Murphy, Sharon E.; Park, Sung-Shim L.; Thompson, Elizabeth F.; Wilkens, Lynne R.; Patel, Yesha; Stram, Daniel O.; Le Marchand, Loic

    2014-01-01

    Nicotine metabolism influences smoking behavior and differences in metabolism probably contribute to ethnic variability in lung cancer risk. We report here on the proportion of nicotine metabolism by cytochrome P450 2A6-catalyzed C-oxidation, UDP-glucuronosyl transferase 2B10 (UGT2B10)-catalyzed N-glucuronidation and flavin monooxygenase 3-catalyzed N-oxidation in five ethnic/racial groups and the role of UGT2B10 genotype on the metabolic patterns observed. Nicotine and its metabolites were quantified in urine from African American (AA, n = 364), Native Hawaiian (NH, n = 311), White (n = 437), Latino (LA, n = 453) and Japanese American (JA, n = 674) smokers. Total nicotine equivalents, the sum of nicotine and six metabolites, and nicotine metabolism phenotypes were calculated. The relationship of UGT2B10 genotype to nicotine metabolic pathways was determined for each group; geometric means were computed and adjusted for age, sex, creatinine, and body mass index. Nicotine metabolism patterns were unique across the groups, C-oxidation was lowest in JA and NH (P < 0.0001), and N-glucuronidation lowest in AA (P < 0.0001). There was no difference in C-oxidation among Whites and AA and LA. Nicotine and cotinine glucuronide ratios were 2- and 3-fold lower in AA compared with Whites. Two UGT variants, a missense mutation (Asp67Tyr, rs61750900) and a splice variant (rs116294140) accounted for 33% of the variation in glucuronidation. In AA, the splice variant accounted for the majority of the reduced nicotine glucuronidation. UGT2B10 variant allele carriers had increased levels of C-oxidation (P = 0.0099). Our data indicate that the relative importance of nicotine metabolic pathways varies by ethnicity, and all pathways should be considered when characterizing the role of nicotine metabolism on smoking behavior and cancer risk. PMID:25233931

  18. Oxytocin receptor gene (OXTR) in relation to loneliness in adolescence: interactions with sex, parental support, and DRD2 and 5-HTTLPR genotypes.

    PubMed

    van Roekel, Eeske; Verhagen, Maaike; Engels, Rutger C M E; Goossens, Luc; Scholte, Ron H J

    2013-10-01

    Recent research has shown that loneliness, a common problem in adolescence, may have a genetic basis. The evidence, though, was limited mostly to serotonin-related and dopamine-related genes. In the present study, we focused on the oxytocin receptor gene (OXTR). Associations were examined in a longitudinal study spanning five annual waves (N=307). The relations between OXTR and loneliness were examined, as well as interactions between OXTR and sex, parental support, 5-HTTLPR genotype, and DRD2 genotype. Using Latent Growth Curve Modeling, the OXTR genotype was not directly related to loneliness. An OXTR×sex interaction was found. Girls showed a steeper decline in loneliness when they had an A allele compared with girls who were homozygous for the G allele. In addition, a gene-gene interaction or epistasis was observed. Both boys and girls who had at least one A1 allele for the DRD2 gene and also had the GG genotype for the OXTR gene showed stable levels of loneliness over time. The present study is the first to show that the GG genotype for the OXTR gene is linked to the development of loneliness in adolescence and that this association is moderated by participants' sex and their genotype for a dopamine-related gene.

  19. MS4A6A genotypes are associated with the atrophy rates of Alzheimer's disease related brain structures

    PubMed Central

    Tan, Lin; Wang, Hui-Fu; Wan, Yu; Sun, Fu-Rong; Tan, Chen-Chen; Yu, Jin-Tai; Tan, Lan

    2016-01-01

    Membrane-spanning 4-domains, subfamily A, member 6A (MS4A6A) has been identified as susceptibility loci of Alzheimer's disease (AD) by several recent genome-wide association studies (GWAS), whereas little is known about the potential roles of these variants in the brain structure and function of AD. In this study, we included a total of 812 individuals from the Alzheimer's disease Neuroimaging Initiative (ADNI) database. Using multiple linear regression models, we found MS4A6A genotypes were strongly related to atrophy rate of left middle temporal (rs610932: Pc = 0.017, rs7232: Pc = 0.022), precuneus (rs610932: Pc = 0.015) and entorhinal (rs610932, Pc = 0.022) on MRI in the entire group. In the subgroup analysis, MS4A6A SNPs were significantly accerlated the percentage of volume loss of middle temporal, precuneus and entorhinal, especially in the MCI subgroup. These findings reveal that MS4A6A genotypes affect AD specific brain structures which supported the possible role of MS4A6A polymorphisms in influencing AD-related neuroimaging phenotypes. PMID:27244883

  20. Myo-inositol changes precede amyloid pathology and relate to APOE genotype in Alzheimer disease

    PubMed Central

    Sundgren, Pia C.; Strandberg, Olof; Zetterberg, Henrik; Minthon, Lennart; Blennow, Kaj; Wahlund, Lars-Olof; Westman, Eric

    2016-01-01

    Objective: We aimed to test whether in vivo levels of magnetic resonance spectroscopy (MRS) metabolites myo-inositol (mI), N-acetylaspartate (NAA), and choline are abnormal already during preclinical Alzheimer disease (AD), relating these changes to amyloid or tau pathology, and functional connectivity. Methods: In this cross-sectional multicenter study (a subset of the prospective Swedish BioFINDER study), we included 4 groups, representing the different stages of predementia AD: (1) cognitively healthy elderly with normal CSF β-amyloid 42 (Aβ42), (2) cognitively healthy elderly with abnormal CSF Aβ42, (3) patients with subjective cognitive decline and abnormal CSF Aβ42, (4) patients with mild cognitive decline and abnormal CSF Aβ42 (Ntotal = 352). Spectroscopic markers measured in the posterior cingulate/precuneus were considered alongside known disease biomarkers: CSF Aβ42, phosphorylated tau, total tau, [18F]-flutemetamol PET, f-MRI, and the genetic risk factor APOE. Results: Amyloid-positive cognitively healthy participants showed a significant increase in mI/creatine and mI/NAA levels compared to amyloid-negative healthy elderly (p < 0.05). In amyloid-positive healthy elderly, mI/creatine and mI/NAA correlated with cortical retention of [18F] flutemetamol tracer ( = 0.44, p = 0.02 and = 0.51, p = 0.01, respectively). Healthy elderly APOE ε4 carriers with normal CSF Aβ42 levels had significantly higher mI/creatine levels (p < 0.001) than ε4 noncarriers. Finally, elevated mI/creatine was associated with decreased functional connectivity within the default mode network (rpearson = −0.16, p = 0.02), independently of amyloid pathology. Conclusions: mI levels are elevated already at asymptomatic stages of AD. Moreover, mI/creatine concentrations were increased in healthy APOE ε4 carriers with normal CSF Aβ42 levels, suggesting that mI levels may reveal regional brain consequences of APOE ε4 before detectable amyloid pathology. PMID:27164711

  1. Association between firearm ownership, firearm-related risk and risk reduction behaviours and alcohol-related risk behaviours.

    PubMed

    Wintemute, Garen J

    2011-12-01

    Alcohol use and firearm ownership are risk factors for violent injury and death. To determine whether firearm ownership and specific firearm-related behaviours are associated with alcohol-related risk behaviours, the author conducted a cross-sectional study using Behavioral Risk Factor Surveillance System data for eight states in the USA from 1996 to 1997 (the most recent data available). Altogether, 15 474 respondents provided information on firearm exposure. After adjustment for demographics and state of residence, firearm owners were more likely than those with no firearms at home to have ≥5 drinks on one occasion (OR 1.32; 95% CI 1.16 to 1.50), to drink and drive (OR 1.79; 95% CI 1.34 to 2.39) and to have ≥60 drinks per month (OR 1.45; 95% CI 1.14 to 1.83). Heavy alcohol use was most common among firearm owners who also engaged in behaviours such as carrying a firearm for protection against other people and keeping a firearm at home that was both loaded and not locked away. The author concludes that firearm ownership and specific firearm-related behaviours are associated with alcohol-related risk behaviours.

  2. ACE I/D genotype-related increase in ACE plasma activity is a better predictor for schizophrenia diagnosis than the genotype alone.

    PubMed

    Gadelha, Ary; Yonamine, Camila M; Ota, Vanessa K; Oliveira, Vitor; Sato, João Ricardo; Belangero, Sintia I; Bressan, Rodrigo A; Hayashi, Mirian A F

    2015-05-01

    Angiotensin-I converting enzyme (ACE) is a key component of the renin-angiotensin system (RAS). Although the several contradictory data, ACE has been associated with schizophrenia (SCZ) pathophysiology. Here the ACE activity of SCZ patients and healthy controls (HCs), and its possible correlations with the ACE polymorphism genotype and symptomatic dimensions, was investigated. ACE activity of 86 SCZ patients and 100 HCs paired by age, gender and educational level was measured, using the FRET peptide substrate and the specific inhibitor lisinopril. The ACE insertion/deletion (I/D) genotypes were assessed by the restriction fragment length polymorphism (RFLP) technique. Significantly higher ACE activity was observed in SCZ patients compared to HCs (t=-5.09; p<0.001). The area under the receiver operating characteristic (ROC) curve was 0.701. Mean ACE activity levels were higher for the D-allele carriers (F=5.570; p=0.005), but no significant difference was found among SCZ patients and HCs for genotypes frequencies (Chi-squared=2.08; df=2; p=0.35). Interestingly, we found that the difference between the measured ACE activity for each SCZ patient and the expected average mean value for each respective genotype group (for control subjects) was a better predictor of SCZ than the ACE dichotomized values (high/low) or ACE I/D. Our results suggest that higher levels of ACE activity are associated with SCZ with stronger impact when the genetic background of each individual is considered. This may explain the heterogeneity of the results on ACE previously reported. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Apolipoprotein E genotype modifies the risk of behavior problems after infant cardiac surgery.

    PubMed

    Gaynor, J William; Nord, Alex S; Wernovsky, Gil; Bernbaum, Judy; Solot, Cynthia B; Burnham, Nancy; Zackai, Elaine; Heagerty, Patrick J; Clancy, Robert R; Nicolson, Susan C; Jarvik, Gail P; Gerdes, Marsha

    2009-07-01

    The goal was to evaluate polymorphisms of the APOE gene as modifiers of neurobehavioral outcomes for preschool-aged children with congenital heart defects, after cardiac surgery. A prospective observational study with neurodevelopmental evaluation between the fourth and fifth birthdays was performed. Attention and behavioral skills were assessed through parental report. Parents of 380 children completed the neurobehavioral measures. Child Behavior Checklist scores for the pervasive developmental problem scale were in the at-risk or clinically significant range for 15% of the cohort, compared with 9% for the normative data (P < .00001). Attention problem scores were in the at-risk or clinically significant range for 12% of the cohort, compared with 7% for the normative data (P = .0002). The Attention-Deficit/Hyperactivity Disorder Rating Scale-IV, Preschool Version, was completed for 378 children; 30% scored in the clinically significant range for inattention and 22% for impulsivity. After adjustment for covariates, the APOE epsilon2 allele was significantly associated with higher scores (worse problems) for multiple Child Behavior Checklist indices, including somatic complaints (P = .009), pervasive developmental problems (P = .032), and internalizing problems (P = .009). In each case, the epsilon4 allele was associated with a better outcome. APOE epsilon2 carriers had impaired social skills, compared with epsilon4 carriers (P = .009). For preschool-aged children with congenital heart defects requiring surgery, parental rating scales showed an increased prevalence of restricted behavior patterns, inattention, and impaired social interactions. The APOE epsilon2 allele was associated with increased behavior problems, impaired social interactions, and restricted behavior patterns.

  4. Apolipoprotein E Genotype Modifies the Risk of Behavior Problems After Infant Cardiac Surgery

    PubMed Central

    Gaynor, J. William; Nord, Alex S; Wernovsky, Gil; Bernbaum, Judy; Solot, Cynthia B.; Burnham, Nancy; Zackai, Elaine; Heagerty, Patrick J.; Clancy, Robert R.; Nicolson, Susan C.; Jarvik, Gail P.; Gerdes, Marsha

    2010-01-01

    OBJECTIVE The goal was to evaluate polymorphisms of the APOE gene as modifiers of neurobehavioral outcomes for preschool-aged children with congenital heart defects, after cardiac surgery. METHODS A prospective observational study with neurodevelopmental evaluation between the fourth and fifth birthdays was performed. Attention and behavioral skills were assessed through parental report. RESULTS Parents of 380 children completed the neurobehavioral measures. Child Behavior Checklist scores for the pervasive developmental problem scale were in the at-risk or clinically significant range for 15% of the cohort, compared with 9% for the normative data (P < .00001). Attention problem scores were in the at-risk or clinically significant range for 12% of the cohort, compared with 7% for the normative data (P = .0002). The Attention-Deficit/Hyperactivity Disorder Rating Scale-IV, Preschool Version, was completed for 378 children; 30% scored in the clinically significant range for inattention and 22% for impulsivity. After adjustment for covariates, the APOE ε2 allele was significantly associated with higher scores (worse problems) for multiple Child Behavior Checklist indices, including somatic complaints (P = .009), pervasive developmental problems (P = .032), and internalizing problems (P=.009). In each case, the ε4 allele was associated with a better outcome. APOE ε2 carriers had impaired social skills, compared with ε4 carriers (P = .009). CONCLUSIONS For preschool-aged children with congenital heart defects requiring surgery, parental rating scales showed an increased prevalence of restricted behavior patterns, inattention, and impaired social interactions. The APOE ε2 allele was associated with increased behavior problems, impaired social interactions, and restricted behavior patterns. PMID:19564306

  5. Human immunodeficiency virus and tuberculosis in Argentina: prevalence, genotypes and risk factors.

    PubMed

    Pando, Maria A; De Salvo, Cristina; Bautista, Christian T; Eyzaguirre, Lindsay; Carrion, Gladys; Feola, Miguel; Lado, Isabel; Hoffman, Marta; Biglione, Mirna M; Carr, Jean K; Montano, Silvia M; Sanchez, José L; Weissenbacher, Mercedes; Avila, Maria M

    2008-02-01

    The objective of this study was to determine the prevalence and genetic variability of human immunodeficiency virus type 1 (HIV-1) and other sexually transmitted infections (STIs) among 205 patients with clinical diagnosis of tuberculosis (TB) in Buenos Aires in 2001. Infections with hepatitis B virus (HBV), HIV-1, hepatitis C virus (HCV), Treponema pallidum and human T-cell lymphotropic virus types I/II were diagnosed in 37/187 (19.8 %), 35/205 (17.1 %), 22/187 (11.8 %), 13/187 (7.0 %) and 4/181 (2.2 %) patients, respectively. Almost one in three participants (33.1 %) presented at least one infection in addition to TB. Multiresistance to TB drugs (isoniazid plus rifampicin) was detected in the isolates recovered from three patients. Injecting drug use was detected as the main risk factor for HIV, HBV and HCV infections. Of ten patients who died, eight were infected with HIV. HIV genetic characterization showed the presence of two different subtypes. Env subtype F was found in 13/24 samples (54.2 %) and subtype B in 11/24 samples (45.8 %) by heteroduplex mobility assay. Sequencing of the protease/RT region was performed in ten samples: three were characterized as subtype B and seven as B/F recombinants by bootscanning analysis. Phylogenetic analysis of four full-length sequences showed that three were the circulating recombinant form CRF12_BF. The results of this study suggest an urgent need to detect HIV infection in high-risk groups to prevent future HIV transmission as well as morbidity and mortality associated with TB by providing highly active antiretroviral therapy (HAART) and/or TB treatment. Collaboration between TB and HIV programmes seems to be the best approach to decrease the incidence of these diseases, especially in high-prevalence HIV settings.

  6. Three-year risk of cervical precancer and cancer after the detection of low-risk human papillomavirus genotypes targeted by a commercial test.

    PubMed

    Castle, Philip E; Hunt, William C; Langsfeld, Erika; Wheeler, Cosette M

    2014-01-01

    To investigate the risk of cervical precancer and cancer associated with detection of human papillomavirus (HPV) 6, 11, and 42. We used data from the New Mexico Human Papillomavirus Pap Registry. A stratified sample of 59,644 residual cervical cytology specimens from a population of 379,000 underwent HPV genotyping. We measured the 3-year cumulative incidence of cervical intraepithelial neoplasia grade 2 or more severe (CIN 2+) and grade 3 or more severe (CIN 3+) after detection of single HPV 6, 11, or 42 infections or single or multiple infections of HPV 6, 11, or 42 ("HPV 6, 11, 42, or combinations"; n=581). The overall prevalence of a single infection of HPV 6, 11, or 42 was 0.8% (95% confidence interval [CI] 0.7-0.9%). The 3-year risks of CIN 2+ and CIN 3+ after HPV 6, 11, 42, or combinations infections (n=581) were 0.4% (CI 0.1-0.7%) for CIN 2+ and 0.0% for CIN 3+ (nota bene, no CI was calculable because no events occurred), respectively. By comparison, the 3-year risks of CIN 2+ and CIN 3+ after a negative HPV result (n=27,522) were 0.2% (95% CI 0.1-0.2%) and 0.1% (95% CI 0.0-0.1%), respectively. Detection of HPV 6, 11, 42, or combinations in the absence of high-risk HPV types does not identify women at increased 3-year risk for cervical precancer. Testing for HPV 6, 11, 42, or combinations of those types should be discontinued because it has no proven benefit to patients. II.

  7. Three-Year Risk of Cervical Precancer and Cancer After the Detection of Low-Risk Human Papillomavirus Genotypes Targeted by a Commercial Test

    PubMed Central

    Castle, Philip E.; Hunt, William C.; Langsfeld, Erika; Wheeler, Cosette M.

    2014-01-01

    Objective To investigate the risk of cervical precancer and cancer associated with detection of human papillomavirus (HPV) 6, 11, and 42. Methods We used data from the New Mexico HPV Pap Registry. A stratified sample of 59,644 residual cervical cytology specimens from a population of 379,000 underwent HPV genotyping. We measured the 3-year cumulative incidence of cervical intraepithelial neoplasia grade 2 or more severe (CIN2+) and grade 3 or more severe (CIN3+) after detection of single HPV6, 11, or 42 infections or single or multiple infections by of HPV6, 11, or 42 (“HPV6, 11, 42, or combinations”)(n=581). Results The overall prevalence of a single infection of HPV6, 11, or 42 was 0.8% (95% confidence interval [95%CI]: 0.7%, 0.9%). The 3-year risks of CIN2+ and CIN3+ after HPV6, 11, 42, or combinations infections (n = 581) were 0.4% (CI: 0.1%, 0.7%) for CIN2+ and 0.0% for CIN3+ (nota bene, no confidence interval was calculable because no events occurred), respectively. By comparison, the 3-year risks of CIN2+ and CIN3+ after a negative HPV result (n = 27,522) were 0.2% (95%CI: 0.1%, 0.2%) and 0.1% (95%CI: 0.0%, 0.1%), respectively. Conclusion Detection of HPV6, 11, 42, or combinations in the absence of high risk HPV types does not identify women at increased 3-year risk for cervical precancer. Testing for HPV6, 11, 42, or combinations of those types should be discontinued as it has no proven benefit to patients. PMID:24463663

  8. Enforcement Related to Minimum Risk Pesticides

    EPA Pesticide Factsheets

    If a product does not meet all the requirements of the minimum risk exemption, it must be registered unless eligible for some other exemption. Learn about enforcement actions EPA can take where unregistered products make pesticidal claims.

  9. High-risk oncogenic HPV genotype infection associates with increased immune activation and T cell exhaustion in ART-suppressed HIV-1-infected women

    PubMed Central

    Papasavvas, Emmanouil; Surrey, Lea F.; Glencross, Deborah K.; Azzoni, Livio; Joseph, Jocelin; Omar, Tanvier; Feldman, Michael D.; Williamson, Anna-Lise; Siminya, Maureen; Swarts, Avril; Yin, Xiangfan; Liu, Qin; Firnhaber, Cynthia; Montaner, Luis J.

    2016-01-01

    ABSTRACT Persistence of human papillomavirus (HPV) and cervical disease in the context of HIV co-infection can be influenced by introduction of antiretroviral therapy (ART) and sustained immune activation despite ART. We conducted a cross-sectional study in order to evaluate immune activation/exhaustion in ART-suppressed HIV+ women with or without high-risk (HR) HPV-related cervical intraepithelial neoplasia (CIN). 55 South African women were recruited in three groups: HR (-) (n = 16) and HR (+) (n = 15) HPV with negative cervical histopathology, and HR (+) HPV with CIN grade 1/2/3 (n = 24). Sampling included endocervical brushing (HPV DNA genotyping), Pap smear (cytology), colposcopic punch biopsy (histopathology, histochemical evaluation of immune cells), and peripheral blood (clinical assessment, flow cytometry-based immune subset characterization). Statistics were done using R2.5.1. Irrespective of the presence of CIN, HR (+) HPV women had higher circulating levels of T cells expressing markers of activation/exhaustion (CD38, PD1, CTLA-4, BTLA, CD160), Tregs, and myeloid subsets expressing corresponding ligands (PDL1, PDL2, CD86, CD40, HVEM) than HR (-) HPV women. A decrease in circulating NK cells was associated with CIN grade. CD4+ T cell count associated negatively with T cell exhaustion and expression of negative regulators on myeloid cells. Women with CIN when compared to HR (-) HPV women, had higher cervical cell density in stroma and epithelium for CD4+, CD68+, and CD11c+ cells, and only in stroma for CD8+ cells. We conclude that in ART-suppressed HIV-infected women with HPV co-infection the levels of T and myeloid cell activation/exhaustion are associated with the presence of HR HPV genotypes. PMID:27467943

  10. Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young At-Risk Individuals.

    PubMed

    Fullerton, Janice M; Koller, Daniel L; Edenberg, Howard J; Foroud, Tatiana; Liu, Hai; Glowinski, Anne L; McInnis, Melvin G; Wilcox, Holly C; Frankland, Andrew; Roberts, Gloria; Schofield, Peter R; Mitchell, Philip B; Nurnberger, John I

    2015-10-01

    Recent studies have revealed the polygenic nature of bipolar disorder (BP), and identified common risk variants associated with illness. However, the role of common polygenic risk in multiplex families has not previously been examined. The present study examined 249 European-ancestry families from the NIMH Genetics Initiative sample, comparing subjects with narrowly defined BP (excluding bipolar II and recurrent unipolar depression; n = 601) and their adult relatives without BP (n = 695). Unrelated adult controls (n = 266) were from the NIMH TGEN control dataset. We also examined a prospective cohort of young (12-30 years) offspring and siblings of individuals with BPI and BPII disorder (at risk; n = 367) and psychiatrically screened controls (n = 229), ascertained from five sites in the US and Australia and assessed with standardized clinical protocols. Thirty-two disease-associated SNPs from the PGC-BP Working Group report (2011) were genotyped and additive polygenic risk scores (PRS) derived. We show increased PRS in adult cases compared to unrelated controls (P = 3.4 × 10(-5) , AUC = 0.60). In families with a high-polygenic load (PRS score ≥32 in two or more subjects), PRS distinguished cases with BPI/SAB from other relatives (P = 0.014, RR = 1.32). Secondly, a higher PRS was observed in at-risk youth, regardless of affected status, compared to unrelated controls (GEE-χ(2) = 5.15, P = 0.012). This report is the first to explore common polygenic risk in multiplex families, albeit using only a small number of robustly associated risk variants. We show that individuals with BP have a higher load of common disease-associated variants than unrelated controls and first-degree relatives, and illustrate the potential utility of PRS assessment in a family context.

  11. Determinants of sleep disturbances in Rett syndrome: Novel findings in relation to genotype.

    PubMed

    Boban, Sharolin; Wong, Kingsley; Epstein, Amy; Anderson, Barbara; Murphy, Nada; Downs, Jenny; Leonard, Helen

    2016-09-01

    Rett syndrome is a rare but severe neurological disorder associated with a mutation in the methyl CpG binding protein 2 (MECP2) gene. Sleep problems and epilepsy are two of many comorbidities associated with this disorder. This study investigated the prevalence and determinants of sleep problems in Rett syndrome using an international sample. Families with a child with a confirmed Rett syndrome diagnosis and a MECP2 mutation registered in the International Rett Syndrome Phenotype Database (InterRett) were invited to participate. Questionnaires were returned by 364/461 (78.9%) either in web-based or paper format. Families completed the Sleep Disturbance Scale for Children and provided information on the presence, nature, and frequency of their child's sleep problems. Multivariate multinomial regression was used to investigate the relationships between selected sleep problems, age group, and genotype and linear regression for the relationships between sleep disturbance scales and a range of covariates. Night waking was the most prevalent sleep problem affecting over 80% with nearly half (48.3%) currently waking often at night. Initiating and maintaining sleep was most disturbed for younger children and those with a p.Arg294* mutation. Severe seizure activity was associated with poor sleep after adjusting for age group, mutation type, and mobility. We were surprised to find associations between the p.Arg294* mutation and some sleep disturbances given that other aspects of its phenotype are milder. These findings highlight the complexities of aberrant MECP2 function in Rett syndrome and explain some of the variation in manifestation of sleep disturbances. © 2016 Wiley Periodicals, Inc.

  12. Genetic Variation in ACE-related pathways associated with Sudden Cardiac Arrest Risk

    PubMed Central

    Sotoodehnia, Nona; Li, Guo; Johnson, Catherine O.; Lemaitre, Rozenn N.; Rice, Kenneth M.; Rea, Thomas D.; Siscovick, David S.

    2009-01-01

    Background Angiotensin converting enzyme (ACE)-related pathways influence arrhythmias and sudden cardiac arrest (SCA) risk. Objective We investigated whether genetic variation in ACE-related pathways are associated with SCA risk. Because these pathways are sex-dependent and influenced by estrogen, we examined these genotype-SCA associations in the full study population, and tested for interaction with gender. Methods In a population-based case-control study set in King County WA, we genotyped 211 SCA cases (mean age 59, 80% male) and 730 age- and gender-matched controls of European descent for 47 single nucleotide polymorphisms (SNPs) in eight genes (ACE, AGT, REN, AGTR1, AGTR2, ACE2, KNG1, BDKRB2). We examined association of SNPs and haplotypes with SCA risk using logistic regression. Results AGTR1 SNP rs1492099 (allele frequency=15%) was associated with decreased SCA risk (OR=0.62, 95%CI=0.4–0.9). Haplotype variation in AGTR2 was associated with SCA risk (global haplotype test p=0.001), with haplotype 2 (allele frequency=27%) associated with increased risk (OR=1.26, 95%CI=1.1–1.5). There was interaction with gender on SCA risk for variation in KNG1 (interaction p-value range=0.0004–0.017 for 6/8 SNPs). KNG1 SNP rs710448 (allele frequency=42%) was associated with decreased risk (OR=0.44, 95%CI=0.3–0.8) among women but not men. Other SNPs and haplotypes in the eight genes examined were not associated with SCA risk after multiple testing correction. Conclusions Variation in AGTR1 and AGTR2 are associated with SCA risk in a population-based case-control study. There was evidence of interaction with gender on SCA risk for variation in KNG1. Our findings, if replicated, suggest that variation in genes in ACE-related pathways influence SCA risk. PMID:19716087

  13. GSTM1 polymorphism is related to risks of nasopharyngeal cancer and laryngeal cancer: a meta-analysis

    PubMed Central

    Zhang, Fengying; Wu, Xijiang; Niu, Jinming; Kang, Xiufeng; Cheng, Liya; Lv, Yanchun; Wu, Meimei

    2017-01-01

    Background Accumulating data have reported that GSTM1 polymorphism may be related to nasopharyngeal cancer (NPC) and laryngeal cancer (LC). This meta-analysis was performed to investigate the relationship between GSTM1 polymorphism and risks of NPC and LC. Methods Pubmed, Embase, and China National Knowledge Infrastructure (CNKI) databases were searched for potential articles. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the relationship of GSTM1 polymorphism with the risks of NPC and LC. I2>50% or P<0.05 indicates significant heterogeneity. When heterogeneity existed, the random-effects model was used to pool data, otherwise, the fixed-effects model was adopted. Publication bias was detected by Begg’s funnel plot and Egger’s regression. Quality of each study was evaluated by Newcastle-Ottawa Scale. Results Thirty-two eligible articles were included. Pooled outcome suggested the significant relationship of GSTM1 null genotype with increased risk of LC (OR =1.28, 95% CI =1.05–1.54). Compared with hospital-based (HB) population, GSTM1 null genotype was also related to increased risk of LC (OR =1.38, 95% CI =1.06–1.80). Positive relationship of GSTM1 null genotype with enhanced risk of NPC was observed (OR =1.43, 95% CI =1.26–1.63). A similar trend was also observed in the subgroup analysis by source of control (population-based [PB]: OR =1.39, 95% CI =1.18–1.63; HB: OR =1.52, 95% CI =1.22–1.89). Conclusion GSTM1 null genotype is related to increased risk of NPC and LC. PMID:28331336

  14. The CYP1A2 genotype modifies the association between coffee consumption and breast cancer risk among BRCA1 mutation carriers.

    PubMed

    Kotsopoulos, Joanne; Ghadirian, Parviz; El-Sohemy, Ahmed; Lynch, Henry T; Snyder, Carrie; Daly, Mary; Domchek, Susan; Randall, Susan; Karlan, Beth; Zhang, Phil; Zhang, Shiyu; Sun, Ping; Narod, Steven A

    2007-05-01

    We have recently reported that, among BRCA1 mutation carriers, the consumption of caffeinated coffee was associated with a significant reduction in breast cancer risk. Because the metabolism of caffeine is primarily by CYP1A2, we examined whether or not the CYP1A2 genotype modifies the association between a history of coffee consumption and the risk of breast cancer. A common A to C polymorphism in the CYP1A2 gene is associated with decreased enzyme inducibility and impaired caffeine metabolism. Information regarding coffee consumption habits and the CYP1A2 genotype was available for 411 BRCA1 mutation carriers (170 cases and 241 controls). We estimated the odds ratios (ORs) and 95% confidence intervals (95% CIs) for breast cancer associated with the CYP1A2 genotype and a history of coffee consumption before age 35, adjusting for potential confounders. The CYP1A2 genotype did not affect breast cancer risk. Among women with at least one variant C allele (AC or CC), those who consumed coffee had a 64% reduction in breast cancer risk, compared with women who never consumed coffee (OR, 0.36; 95% CI, 0.18-0.73). A significant protective effect of coffee consumption was not observed among women with the CYP1A2 AA genotype (OR, 0.93; 95% CI, 0.49-1.77). Similar results were obtained when the analysis was restricted to caffeinated coffee. This study suggests that caffeine protects against breast cancer in women with a BRCA1 mutation and illustrates the importance of integrating individual genetic variability when assessing diet-disease associations.

  15. Breast cancer risk associated with gene expression and genotype polymorphisms of the folate-metabolizing MTHFR gene: a case-control study in a high altitude Ecuadorian mestizo population.

    PubMed

    López-Cortés, Andrés; Echeverría, Carolina; Oña-Cisneros, Fabián; Sánchez, María Eugenia; Herrera, Camilo; Cabrera-Andrade, Alejandro; Rosales, Felipe; Ortiz, Malena; Paz-Y-Miño, César

    2015-08-01

    Breast cancer (BC) is the leading cause of cancer-related death among women in 2014. Methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and MTR reductase (MTRR) are enzymes that play an important role in folate metabolism. The single nucleotide polymorphisms, MTHFR C677T, A1298C, MTR A2756G, and MTRR A66G, alter plasmatic folate and homocysteine concentrations, causing problems during the repairment, synthesis, and methylation of the genetic material. Therefore, it is essential to know how BC risk is associated with histopathological and immunohistochemical characteristics, genotype polymorphisms, and gene expression in a high altitude Ecuadorian mestizo population. DNA was extracted from 195 healthy and 114 affected women. Genotypes were determined by restriction enzymes and genomic sequencing. mRNA was extracted from 26 glandular breast tissue samples, both from cancerous tissue and healthy tissue adjacent to the tumor. Relative gene expression was determined with the comparative Livak method (2(-ΔΔCT)). We found significant association between the rs1801133 (A222V) genotypes and an increased risk of BC development: C/T (odds ratio [OR] = 1.8; 95 % confidence interval [CI] = 1.1-3.2; P = 0.039), T/T (OR = 2.9; 95 % CI = 1.2-7.2; P = 0.025), and C/T + T/T (OR = 1.9; 95 % CI = 1.1-3.3; P = 0.019). Regarding relative gene expression, we found significant mRNA subexpression between the combined genotypes C/T + T/T (rs1801133) and triple negative breast cancer (TNBC) (P = 0.034). In brief, the MTHFR gene and its protein could act as potential predictive biomarkers of BC, especially TNBC among the high altitude Ecuadorian mestizo population.

  16. Transcriptional Profiles of Hybrid Eucalyptus Genotypes with Contrasting Lignin Content Reveal That Monolignol Biosynthesis-related Genes Regulate Wood Composition

    PubMed Central

    Shinya, Tomotaka; Iwata, Eiji; Nakahama, Katsuhiko; Fukuda, Yujiroh; Hayashi, Kazunori; Nanto, Kazuya; Rosa, Antonio C.; Kawaoka, Akiyoshi

    2016-01-01

    Eucalyptus species constitutes the most widely planted hardwood trees in temperate and subtropical regions. In this study, we compared the transcript levels of genes involved in lignocellulose formation such as cellulose, hemicellulose and lignin biosynthesis in two selected 3-year old hybrid Eucalyptus (Eucalyptus urophylla × Eucalyptus grandis) genotypes (AM063 and AM380) that have different lignin content. AM063 and AM380 had 20.2 and 35.5% of Klason lignin content and 59.0 and 48.2%, α-cellulose contents, respectively. We investigated the correlation between wood properties and transcript levels of wood formation-related genes using RNA-seq with total RNAs extracted from developing xylem tissues at a breast height. Transcript levels of cell wall construction genes such as cellulose synthase (CesA) and sucrose synthase (SUSY) were almost the same in both genotypes. However, AM063 exhibited higher transcript levels of UDP-glucose pyrophosphorylase and xyloglucan endotransglucoxylase than those in AM380. Most monolignol biosynthesis-related isozyme genes showed higher transcript levels in AM380. These results indicate monolignol biosynthesis-related genes may regulate wood composition in Eucalyptus. Flavonoids contents were also observed at much higher levels in AM380 as a result of the elevated transcript levels of common phenylpropanoid pathway genes, phenylalanine ammonium lyase, cinnamate-4-hydroxylase (C4H) and 4-coumarate-CoA ligase (4CL). Secondary plant cell wall formation is regulated by many transcription factors. We analyzed genes encoding NAC, WRKY, AP2/ERF, and KNOX transcription factors and found higher transcript levels of these genes in AM380. We also observed increased transcription of some MYB and LIM domain transcription factors in AM380 compared to AM063. All these results show that genes related to monolignol biosynthesis may regulate the wood composition and help maintain the ratio of cellulose and lignin contents in Eucalyptus plants. PMID

  17. eBURST: Inferring Patterns of Evolutionary Descent among Clusters of Related Bacterial Genotypes from Multilocus Sequence Typing Data

    PubMed Central

    Feil, Edward J.; Li, Bao C.; Aanensen, David M.; Hanage, William P.; Spratt, Brian G.

    2004-01-01

    The introduction of multilocus sequence typing (MLST) for the precise characterization of isolates of bacterial pathogens has had a marked impact on both routine epidemiological surveillance and microbial population biology. In both fields, a key prerequisite for exploiting this resource is the ability to discern the relatedness and patterns of evolutionary descent among isolates with similar genotypes. Traditional clustering techniques, such as dendrograms, provide a very poor representation of recent evolutionary events, as they attempt to reconstruct relationships in the absence of a realistic model of the way in which bacterial clones emerge and diversify to form clonal complexes. An increasingly popular approach, called BURST, has been used as an alternative, but present implementations are unable to cope with very large data sets and offer crude graphical outputs. Here we present a new implementation of this algorithm, eBURST, which divides an MLST data set of any size into groups of related isolates and clonal complexes, predicts the founding (ancestral) genotype of each clonal complex, and computes the bootstrap support for the assignment. The most parsimonious patterns of descent of all isolates in each clonal complex from the predicted founder(s) are then displayed. The advantages of eBURST for exploring patterns of evolutionary descent are demonstrated with a number of examples, including the simple Spain23F-1 clonal complex of Streptococcus pneumoniae, “population snapshots” of the entire S. pneumoniae and Staphylococcus aureus MLST databases, and the more complicated clonal complexes observed for Campylobacter jejuni and Neisseria meningitidis. PMID:14973027

  18. Genomic Prediction of Genotypic Effects with Epistasis and Environment Interactions for Yield-Related Traits of Rapeseed (Brassica napus L.)

    PubMed Central

    Luo, Xiang; Ding, Yi; Zhang, Linzhong; Yue, Yao; Snyder, John H.; Ma, Chaozhi; Zhu, Jun

    2017-01-01

    Oilseed rape (Brassica napus) is an economically important oil crop, yet the genetic architecture of its complex traits remain largely unknown. Here, genome-wide association study was conducted for eight yield-related traits to dissect the genetic architecture of additive, dominance, epistasis, and their environment interaction. Additionally, the optimal genotype combination and the breeding value of superior line, superior hybrid and existing best line in mapping population were predicted for each trait in two environments based on the predicted genotypic effects. As a result, 17 quantitative trait SNPs (QTSs) were identified significantly for target traits with total heritability varied from 58.47 to 87.98%, most of which were contributed by dominance, epistasis, and environment-specific effects. The results indicated that non-additive effects were large contributions to heritability and epistasis, and also noted that environment interactions were important variants for oilseed breeding. Our study facilitates the understanding of genetic basis of rapeseed yield trait, helps to accelerate rapeseed breading, and also offers a roadmap for precision plant breeding via marker-assisted selection. PMID:28270831

  19. Relative versus absolute risk of comorbidities in patients with psoriasis.

    PubMed

    Saleem, Mohammed D; Kesty, Chelsea; Feldman, Steven R

    2017-03-01

    Psoriasis is associated with numerous comorbidities, often reported in terms of relative risk. Both doctors and the general population tend to overestimate the effects of exposures when presented in relative terms, leading to anxiety and potentially poor treatment decisions. Absolute risks might provide a better basis for risk assessment. To characterize and compare relative and absolute risks of comorbidities in patients with psoriasis. A systematic review using Medline identified comorbidities associated with psoriasis, their relative risks, and information for calculating absolute risks. The comorbidities associated with psoriasis with the highest relative risk were nonmelanoma skin cancer, melanoma, and lymphoma, with relative risks of 7.5, 6.12, and 3.61, respectively; the attributable risk for these 3 conditions were 0.64, 0.05, and 0.17 per 1000 person-years, respectively. To attribute 1 event of these conditions to psoriasis would require seeing 1551; 20,135; and 5823 patients, respectively. Database studies might not fully account for confounders, resulting in overestimates of the risk impact of comorbidities. Presenting attributable risk in the form of the number needed to harm provides a clearer picture of the magnitude of risk and a basis for wiser medical decision making and patient education. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  20. Impact of the TCF7L2 genotype on risk of hypoglycaemia and glucagon secretion during hypoglycaemia

    PubMed Central

    Pedersen-Bjergaard, Ulrik; Due-Andersen, Rikke; Høi-Hansen, Thomas; Grimmeshave, Lise; Lyssenko, Valeriya; Groop, Leif; Holst, Jens J; Vaag, Allan A; Thorsteinsson, Birger

    2016-01-01

    Introduction In healthy carriers of the T allele of the transcription factor 7-like 2 (TCF7L2), fasting plasma glucagon concentrations are lower compared with those with the C allele. We hypothesised that presence of the T allele is associated with a diminished glucagon response during hypoglycaemia and a higher frequency of severe hypoglycaemia (SH) in type 1 diabetes (T1DM). Material and methods This is a post hoc study of an earlier prospective observational study of SH and four mechanistic studies of physiological responses to hypoglycaemia. 269 patients with T1DM were followed in a one-year observational study. A log-linear negative binomial model was applied with events of SH as dependent variable and TCF7L2 alleles as explanatory variable. In four experimental studies including 65 people, TCF7L2 genotyping was done and plasma glucagon concentration during experimental hypoglycaemia was determined. Results Incidences of SH were TT 0.54, TC 0.98 and CC 1.01 episodes per patient-year with no significant difference between groups. During experimental hypoglycaemia, the TCF7L2 polymorphism did not influence glucagon secretion. Discussion Patients with T1DM carrying the T allele of the TCF7L2 polymorphism do not exhibit diminished glucagon response during hypoglycaemia and are not at increased risk of severe hypoglycaemia compared with carriers of the C allele. PMID:27758844

  1. Genetic Polymorphisms in Estrogen-Related Genes and the Risk of Breast Cancer among Han Chinese Women

    PubMed Central

    Sun, Min-Ying; Du, Hong-Yan; Zhu, An-Na; Liang, Hui-Ying; de Garibay, Gorka Ruiz; Li, Fen-Xia; Li, Ming; Yang, Xue-Xi

    2015-01-01

    Exposure to high levels of estrogen is considered an important risk factor for susceptibility to breast cancer. Common polymorphisms in genes that affect estrogen levels may be associated with breast cancer risk, but no comprehensive study has been performed among Han Chinese women. In the present study, 32 single-nucleotide polymorphisms (SNPs) in estrogen-related genes were genotyped using the MassARRAY IPLEX platform in 1076 Han Chinese women. Genotypic and allelic frequencies were compared between case and control groups. Unconditional logistic regression was used to assess the effects of SNPs on breast cancer risk. Associations were also evaluated for breast cancer subtypes stratified by estrogen receptor (ER) and progesterone receptor (PR) status. Case-control analysis showed a significant relation between heterozygous genotypes of rs700519 and rs2069522 and breast cancer risk (OR = 0.723, 95% CI = 0.541–0.965, p = 0.028 and OR = 1.500, 95% CI = 1.078–2.087, p = 0.016, respectively). Subgroup comparisons revealed that rs2446405 and rs17268974 were related to ER status, and rs130021 was associated with PR status. Our findings suggest that rs700519 and rs2069522 are associated with susceptibility to breast cancer among the Han Chinese population and have a cumulative effect with three other identified SNPs. Further genetic and functional studies are needed to identify additional SNPs, and to elucidate the underlying molecular mechanisms. PMID:25689428

  2. Lyme disease risk not amplified in a species-poor vertebrate community: similar Borrelia burgdorferi tick infection prevalence and OspC genotype frequencies

    PubMed Central

    States, S.L.; Brinkerhoff, R. J.; Carpi, G.; Steeves, T.K.; Folsom-O'Keefe, C.; DeVeaux, M.; Diuk-Wasser, M.A.

    2015-01-01

    The effect of biodiversity declines on human health are currently debated, but empirical assessments are lacking. Lyme disease provides a model system to assess relationships between biodiversity and human disease because the etiologic agent, Borrelia burgdorferi, is transmitted in the United States by the generalist black-legged tick (Ixodes scapularis) among a wide range of mammalian and avian hosts. The ‘dilution effect’ hypothesis predicts that species-poor host communities dominated by white-footed mice (Peromyscus leucopus) will pose the greatest human risk because P. leucopus infects the largest numbers of ticks, resulting in higher human exposure to infected I. scapularis ticks. P. leucopus-dominated communities are also expected to maintain a higher frequency of those B. burgdorferi outer surface protein C (ospC) genotypes that this host species more efficiently transmits (‘multiple niche polymorphism’ hypothesis). Because some of these genotypes are human invasive, an additive increase in human disease risk is expected in species-poor settings. We assessed these theoretical predictions by comparing I. scapularis nymphal infection prevalence, density of infected nymphs and B. burgdorferi genotype diversity at sites on Block Island, RI, where P. leucopus dominates the mammalian host community, to species-diverse sites in northeastern Connecticut. We found no support for the dilution effect hypothesis; B. burgdorferi nymphal infection prevalence was similar between island and mainland and the density of B. burgdorferi infected nymphs was higher on the mainland, contrary to what is predicted by the dilution effect hypothesis. Evidence for the multiple niche polymorphism hypothesis was mixed: there was lower ospC genotype diversity at island than mainland sites, but no overrepresentation of genotypes with higher fitness in P. leucopus or that are more invasive in humans. We conclude that other mechanisms explain similar nymphal infection prevalence in

  3. Genotype x environment interaction as it relates to egg production in turkeys (Meleagris gallopavo).

    PubMed

    Case, L A; Kelly, M J; Miller, S P; Wood, B J

    2010-06-01

    Genotype x environment (GxE) interactions can reduce the accuracy of a model to predict the performance of an animal and have an undesirable influence if not accounted for when estimating breeding values. Consequently, identification of these GxE is necessary when considering a turkey breeding program. Reranking based on the genetic prediction of turkey egg production, fertility, and hatchability in different seasons was indicative of a potential GxE interaction. Quantification of the GxE interactions was based on the genetic correlation estimated when traits were expressed in different seasons. Egg production was expressed as the percentage of days with an egg produced; fertility represented the proportion of hatched eggs that contained a fertile embryo; and hatchability was defined as the percentage of fertile eggs that produced a live bird. Variance components and heritability for egg production, fertility, and hatchability were estimated using ASReml. The heritability (h(2)) of egg production was calculated to be 0.32 for both lines with the phenotypic and genetic variance, 141.3 and 45.58 (percent days with egg produced)(2) and 118.3 and 38.35 (percent days with egg produced)(2) for female and male lines, respectively. The h(2) estimates for fertility were 0.08 in both lines with and of 293.3%(2) and 24.03%(2), and 576.9%(2) and 48.43%(2) for female and male lines, respectively. The hatchability h(2), and estimates were 0.09, 267.1%(2), and 24.44%(2), respectively, for the female line and 0.15, 582.2%(2), and 90.01%(2) for the male line, respectively. Based on an animal model, the variance components were used to calculate estimated breeding values for each trait. The annual fluctuation in estimated breeding values resulted in the need to evaluate egg number, fertility, and hatchability as 2 traits, summer and winter lay. The correlation between the 2 traits was less than unity (female line: r(egg production) = 0.76, r(fertility) = -0.20, r(hatchability) = 0

  4. Risk Factors for Violence and Relational Aggression in Adolescence

    ERIC Educational Resources Information Center

    Herrenkohl, Todd I.; McMorris, Barbara J.; Catalano, Richard F.; Abbott, Robert D.; Hemphill, Sheryl A.; Toumbourou, John W.

    2007-01-01

    Analyses examined risk factors for seventh- and ninth-grade youth categorized as nonoffenders, physically violent, relationally aggressive, and both violent and relationally aggressive. Bivariate and multivariate results showed that relationally aggressive youth were elevated on most risks above levels for nonoffenders but lower than those for…

  5. Modification of the association between serotonin transporter genotype and risk of posttraumatic stress disorder in adults by county-level social environment.

    PubMed

    Koenen, Karestan C; Aiello, Allison E; Bakshis, Erin; Amstadter, Ananda B; Ruggiero, Kenneth J; Acierno, Ron; Kilpatrick, Dean G; Gelernter, Joel; Galea, Sandro

    2009-03-15

    Although both genetic factors and features of the social environment are important predictors of posttraumatic stress disorder (PTSD), there are few data examining gene-social environment interactions in studies of PTSD. The authors examined whether features of the social environment (county-level crime rate and unemployment) modified the association between the serotonin protein gene (SLC6A4) promoter variant (5-HTTLPR) and risk of current PTSD in a sample of 590 participants from the 2004 Florida Hurricane Study. Interviews conducted in 2005 were used to obtain individual-level risk factor measures and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, PTSD diagnoses. DNA was extracted from salivary samples. County-level crime and unemployment rates were assessed from Federal Bureau of Investigation and US Census data, respectively. There was a significant interaction between 5-HTTLPR genotype and both crime rate (odds ratio = 2.68, 95% confidence interval: 1.09, 6.57) and unemployment rate (odds ratio = 3.67, 95% confidence interval: 1.42, 9.50) in logistic regression models predicting PTSD risk, after adjustment for individual-level determinants of PTSD. Stratified analyses indicated that the "s" allele of the 5-HTTLPR polymorphism was associated with decreased risk of PTSD in low-risk environments (low crime/unemployment rates) but increased risk of PTSD in high-risk environments. These results suggest that social environment modifies the effect of 5-HTTLPR genotype on PTSD risk.

  6. Modification of the Association Between Serotonin Transporter Genotype and Risk of Posttraumatic Stress Disorder in Adults by County-Level Social Environment

    PubMed Central

    Aiello, Allison E.; Bakshis, Erin; Amstadter, Ananda B.; Ruggiero, Kenneth J.; Acierno, Ron; Kilpatrick, Dean G.; Gelernter, Joel; Galea, Sandro

    2009-01-01

    Although both genetic factors and features of the social environment are important predictors of posttraumatic stress disorder (PTSD), there are few data examining gene-social environment interactions in studies of PTSD. The authors examined whether features of the social environment (county-level crime rate and unemployment) modified the association between the serotonin protein gene (SLC6A4) promoter variant (5-HTTLPR) and risk of current PTSD in a sample of 590 participants from the 2004 Florida Hurricane Study. Interviews conducted in 2005 were used to obtain individual-level risk factor measures and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, PTSD diagnoses. DNA was extracted from salivary samples. County-level crime and unemployment rates were assessed from Federal Bureau of Investigation and US Census data, respectively. There was a significant interaction between 5-HTTLPR genotype and both crime rate (odds ratio = 2.68, 95% confidence interval: 1.09, 6.57) and unemployment rate (odds ratio = 3.67, 95% confidence interval: 1.42, 9.50) in logistic regression models predicting PTSD risk, after adjustment for individual-level determinants of PTSD. Stratified analyses indicated that the “s” allele of the 5-HTTLPR polymorphism was associated with decreased risk of PTSD in low-risk environments (low crime/unemployment rates) but increased risk of PTSD in high-risk environments. These results suggest that social environment modifies the effect of 5-HTTLPR genotype on PTSD risk. PMID:19228812

  7. Understanding relative risk, odds ratio, and related terms: as simple as it can get.

    PubMed

    Andrade, Chittaranjan

    2015-07-01

    Risk, and related measures of effect size (for categorical outcomes) such as relative risks and odds ratios, are frequently presented in research articles. Not all readers know how these statistics are derived and interpreted, nor are all readers aware of their strengths and limitations. This article examines several measures, including absolute risk, attributable risk, attributable risk percent, population attributable risk percent, relative risk, odds, odds ratio, and others. The concept and method of calculation are explained for each of these in simple terms and with the help of examples. The interpretation of each is presented in plain English rather than in technical language. Clinically useful notes are provided, wherever necessary.

  8. Additive effect of LRP8/APOER2 R952Q variant to APOE ε2/ε3/ε4 genotype in modulating apolipoprotein E concentration and the risk of myocardial infarction: a case-control study

    PubMed Central

    Martinelli, Nicola; Olivieri, Oliviero; Shen, Gong-Qing; Trabetti, Elisabetta; Pizzolo, Francesca; Busti, Fabiana; Friso, Simonetta; Bassi, Antonella; Li, Lin; Hu, Ying; Pignatti, Pier Franco; Corrocher, Roberto; Wang, Qing Kenneth; Girelli, Domenico

    2009-01-01

    Background The R952Q variant in the low density lipoprotein receptor-related protein 8 (LRP8)/apolipoprotein E receptor 2 (ApoER2) gene has been recently associated with familial and premature myocardial infarction (MI) by means of genome-wide linkage scan/association studies. We were interested in the possible interaction of the R952Q variant with another established cardiovascular genetic risk factor belonging to the same pathway, namely apolipoprotein E (APOE) ε2/ε3/ε4 genotype, in modulating apolipoprotein E (ApoE) plasma levels and risk of MI. Methods In the Italian cohort used to confirm the association of the R952Q variant with MI, we assessed lipid profile, apolipoprotein concentrations, and APOE ε2/ε3/ε4 genotype. Complete data were available for a total of 681 subjects in a case-control setting (287 controls and 394 patients with MI). Results Plasma ApoE levels decreased progressively across R952Q genotypes (mean levels ± SD = RR: 0.045 ± 0.020, RQ: 0.044 ± 0.014, QQ: 0.040 ± 0.008 g/l; P for trend = 0.047). Combination with APOE genotypes revealed an additive effect on ApoE levels, with the highest level observed in RR/non-carriers of the E4 allele (0.046 ± 0.021 g/l), and the lowest level in QQ/E4 carriers (0.035 ± 0.009 g/l; P for trend = 0.010). QQ/E4 was also the combined genotype with the most significant association with MI (OR 3.88 with 95%CI 1.08–13.9 as compared with RR/non-carriers E4). Conclusion Our data suggest that LRP8 R952Q variant may have an additive effect to APOE ε2/ε3/ε4 genotype in determining ApoE concentrations and risk of MI in an Italian population. PMID:19439088

  9. Cfh genotype interacts with dietary glycemic index to modulate age-related macular degeneration-like features in mice

    USDA-ARS?s Scientific Manuscript database

    Age-related macular degeneration (AMD) is a leading cause of visual impairment worldwide. Genetics and diet contribute to the relative risk for developing AMD, but their interactions are poorly understood. Genetic variations in Complement Factor H (CFH), and dietary glycemic index (GI) are major ris...

  10. Relating space radiation environments to risk estimates

    NASA Technical Reports Server (NTRS)

    Curtis, Stanley B.

    1993-01-01

    A number of considerations must go into the process of determining the risk of deleterious effects of space radiation to travelers. Among them are (1) determination of the components of the radiation environment (particle species, fluxes and energy spectra) which will encounter, (2) determination of the effects of shielding provided by the spacecraft and the bodies of the travelers which modify the incident particle spectra and mix of particles, and (3) determination of relevant biological effects of the radiation in the organs of interest. The latter can then lead to an estimation of risk from a given space scenario. Clearly, the process spans many scientific disciplines from solar and cosmic ray physics to radiation transport theeory to the multistage problem of the induction by radiation of initial lesions in living material and their evolution via physical, chemical, and biological processes at the molecular, cellular, and tissue levels to produce the end point of importance.

  11. Risk Taking in Late Adolescence: Relations between Sociomoral Reasoning, Risk Stance, and Behavior

    ERIC Educational Resources Information Center

    Shaw, Leigh A.; Amsel, Eric; Schillo, Joshua

    2011-01-01

    This study explored relations among late adolescents' sociomoral reasoning about risk taking, risk stance, and behavior. One-hundred and thirty-two participants (18-20-year-olds) were surveyed about their own risk stance (Avoidant, Opportunistic, Curious, Risk Seeking) and behavior in three realms (Alcohol Use, Drug Use, Reckless Driving), and…

  12. The quantitative estimation of IT-related risk probabilities.

    PubMed

    Herrmann, Andrea

    2013-08-01

    How well can people estimate IT-related risk? Although estimating risk is a fundamental activity in software management and risk is the basis for many decisions, little is known about how well IT-related risk can be estimated at all. Therefore, we executed a risk estimation experiment with 36 participants. They estimated the probabilities of IT-related risks and we investigated the effect of the following factors on the quality of the risk estimation: the estimator's age, work experience in computing, (self-reported) safety awareness and previous experience with this risk, the absolute value of the risk's probability, and the effect of knowing the estimates of the other participants (see: Delphi method). Our main findings are: risk probabilities are difficult to estimate. Younger and inexperienced estimators were not significantly worse than older and more experienced estimators, but the older and more experienced subjects better used the knowledge gained by knowing the other estimators' results. Persons with higher safety awareness tend to overestimate risk probabilities, but can better estimate ordinal ranks of risk probabilities. Previous own experience with a risk leads to an overestimation of its probability (unlike in other fields like medicine or disasters, where experience with a disease leads to more realistic probability estimates and nonexperience to an underestimation).

  13. [The different genotypes of MTHFR 1298A>C and PON1 -108C>T polymorphisms confer the increased risk of the abdominal aortic aneurysm in the smoking and nonsmoking persons].

    PubMed

    Strauss, Ewa; Waliszewski, Krzysztof; Pawlak, Andrzej L

    2005-01-01

    In abdominal aortic aneurysm (AAA) both the etiology and the pathogenesis are of the multifactorial character. The genetic component in the determination of this disease is proven by its familial occurrence. Smoking represents the best recognized risk factor of the AAA development. Increased concentrations of homocysteine (Hcy) in plasma are the common finding in these patients. It is assumed that the Hcy thiolactone, the most reactive metabolite of Hcy, may participate in the aortic wall destruction in AAA. The polymorphic variants of the methylenetetrahydrofolate reductase (MTHFR 677C>T and 1298A>C) influence tissue concentrations of the Hcy. Paraoxonase (PON1), the enzyme associated in plasma with the HDL fraction, as lactonase detoxicates the Hcy thiolactone. The promotor polymorphism of PON1 - 108C>T gene may determine the lower activity of this enzyme. In the case-control study of 106 patients with AAA and 97 healthy persons, the effects of selected genetic and nongenetic risk factors on development of AAA were assessed, considering the possibilities of interaction between them. It was found, that the arterial hypertension, cigarette smoking and the lower HDL fraction are independent risk factors of AAA. The arterial hypertension was a risk factor both in the smoking and the nonsmoking males, whereas the lower HDL fraction has been the risk factor only for the smoking men. By the multivariate analysis in the nonsmoking males the MTHFR 1298 AC and CC genotypes increased the risk of AAA development 4,8-fold in relation to the MTHFR 1298 AA nonsmoking males. In reference to the genotypes of the expected high impact on the metabolism of Hcy and of Hcy thiolactone, the genotypes of MTHFR 677TT and PON1 -108CT and TT were more frequent in smoking ones, but the difference was not significant. This observation fits with the assumption that the influence of smoking on the occurrence of AAA prevails over that of genetic variability. When the patients age was considered

  14. Risk Analysis Related to Quality Management Principles

    NASA Astrophysics Data System (ADS)

    Vykydal, David; Halfarová, Petra; Nenadál, Jaroslav; Plura, Jiří; Hekelová, Edita

    2012-12-01

    Efficient and effective implementation of quality management principles asks for a responsible approach from top managers' perspectives. A study of the current state of affairs in Czech organizations discovers a lot of shortcomings in this field that can be changed to vary managerial risks. The article identifies and analyses some of them and gives short guidance for appropriate treatment. Text of the article reflects the authors' experience as well as knowledge obtained from the systematic analysis of industrial companies' environments.

  15. Relation between smoking and risk of dementia and Alzheimer disease: the Rotterdam Study.

    PubMed

    Reitz, C; den Heijer, T; van Duijn, C; Hofman, A; Breteler, M M B

    2007-09-04

    Previous studies relating smoking with the risk of dementia have been inconsistent and limited in their validity by short follow-up times, large intervals between baseline and follow-up assessments, and unspecific determination of dementia diagnosis. We re-assessed after longer follow-up time in the large population-based cohort of the Rotterdam Study whether smoking habits and pack-years of smoking are associated with the risk of dementia, Alzheimer disease (AD), and vascular dementia (VaD). Prospective population-based cohort study in 6,868 participants, 55 years or older and free of dementia at baseline. First, Cox proportional hazard models were used to relate smoking status at baseline with the risks of incident dementia, VaD, and AD, using never smokers as the reference category in all analyses. Then Cox proportional hazard models were used to relate pack-years of smoking with the risks of incident dementia, VaD, and AD. To explore the impact of the APOEepsilon4 allele, sex, and age on the association between smoking status and dementia, we repeated all analyses stratifying, in separate models, by APOEepsilon4 genotype, sex, and median of age. After a mean follow-up time of 7.1 years, current smoking at baseline was associated with an increased risk of dementia (HR 1.47, 95% CI 1.18 to 1.86) and AD (HR 1.56, 95% CI 1.21 to 2.02). This increase in disease risk was restricted to persons without the APOEepsilon4 allele. There was no association between current smoking and risk of VaD, and there was no association between past smoking and risk of dementia, AD, or VaD. Current smoking increases the risk of dementia. This effect is more pronounced in persons without the APOEepsilon4 allele than APOEepsilon4 carriers.

  16. [Methicillin-sensitive Staphylococcus aureus isolates related to USA300 clone: Origin of community-genotype MRSA in Colombia?].

    PubMed

    Escobar-Pérez, Javier Antonio; Castro, Betsy Esperanza; Márquez-Ortiz, Ricaurte Alejandro; Gaines, Sebastián; Chavarro, Bibiana; Moreno, Jaime; Leal, Aura Lucía; Vanegas, Natasha

    2014-04-01

    USA300 is a genetic lineage found both in methicillin-resistant (MRSA) and methicillin-sensitive Staphylococcus aureus (MSSA) isolates. In Colombia, hospital and community MRSA infections are caused by a USA300-related community genotype MRSA (CG-MRSA) clone. The genetic origin of this clone is unknown yet. To identify and characterize methicillin-resistant (MRSA) and methicillin-sensitive S. aureus (MSSA) isolates in order to improve the information about the origin of the CG-MRSA isolates in Colombia. USA300-related MSSA isolates were detected and characterized from a study of 184 S. aureus isolates (90 MRSA and 94 MSSA) recovered from infections. The genetic relatedness of the isolates was established by means of pulsed field gel electrophoresis (PFGE), multilocus sequence typing (MLST) and protein A gene typification ( spa typing). Among 184 isolates, 27 (14.7%) showed molecular characteristics and genetic relationship with the USA300 clone, of which 18 were MRSA and nine were MSSA. All USA300-related MRSA harbored Staphylococcal cassette chromosome mec (SCC mec ) IVc (3.1.2). In the MSSA isolates, SCC mec remnants or att B duplicate sites were not detected. In Colombia, the CG-MRSA isolates probably originated in the dissemination of an USA300-related MSSA clone which later acquired SCC mec IVc.

  17. Marker-assisted selection for recognizing wheat mutant genotypes carrying HMW glutenin alleles related to baking quality.

    PubMed

    Zamani, Mohammad Javad; Bihamta, Mohammad Reza; Naserian Khiabani, Behnam; Tahernezhad, Zahra; Hallajian, Mohammad Taher; Shamsi, Marzieh Varasteh

    2014-01-01

    Allelic diversity of HMW glutenin loci in several studies revealed that allelic combinations affect dough quality. Dx5 + Dy10 subunits are related to good baking quality and Dx2 + Dy12 are related to undesirable baking quality. One of the most regular methods to evaluate the baking quality is SDS-PAGE which is used to improve baking quality labs. Marker-assisted selection is the method which can recognize the alleles related to baking quality and this method is based on polymerase chain reaction. 10 pairs of specific primers related to Dx2, Dx2.1, Dx5, Dy10, and Dy12 subunits were used for recognizing baking quality of some wheat varieties and some mutant genotypes. Only 5 pairs of them could show the specific bands. All subunits were recognized by the primers except Dx2.1. Some of the primers were extracted from previous studies and the others were designed based on D genome subunits of wheat. SDS-PAGE method accomplished having confidence in these marker's results. To realize the effect of mutation, seed storage proteins were measured. It showed that mutation had effect on the amount of seed storage protein on the mutant seeds (which showed polymorphism).

  18. Association between reward-related activation in the ventral striatum and trait reward sensitivity is moderated by dopamine transporter genotype.

    PubMed

    Hahn, Tim; Heinzel, Sebastian; Dresler, Thomas; Plichta, Michael M; Renner, Tobias J; Markulin, Falko; Jakob, Peter M; Lesch, Klaus-Peter; Fallgatter, Andreas J

    2011-10-01

    The impact of individual differences on human reward processing has been a focus of research in recent years, particularly, as they are associated with a variety of neuropsychiatric diseases including addiction and attention-deficit/hyperactivity disorder. Studies exploring the neural basis of individual differences in reward sensitivity have consistently implicated the ventral striatum (VS) as a core component of the human reward system. However, the mechanisms of dopaminergic neurotransmission underlying ventral striatal activation as well as trait reward sensitivity remain speculative. We addressed this issue by investigating the triadic interplay between VS reactivity during reward anticipation using functional magnetic resonance imaging, trait reward sensitivity, and dopamine (DA) transporter genotype (40-bp 3'VNTR of DAT, SLC6A3) affecting synaptic DA neurotransmission. Our results show that DAT variation moderates the association between VS-reactivity and trait reward sensitivity. Specifically, homozygote carriers of the DAT 10-repeat allele exhibit a strong positive correlation between reward sensitivity and reward-related VS activity whereas this relationship is absent in the DAT 9-repeat allele carriers. We discuss the possibility that this moderation of VS-trait relation might arise from DAT-dependent differences in DA availability affecting synaptic plasticity within the VS. Generally, studying the impact of dopaminergic gene variations on the relation between reward-related brain activity and trait reward sensitivity might facilitate the investigation of complex mechanisms underlying disorders linked to dysregulation of DA neurotransmission.

  19. Regulation of some salt defense-related genes in relation to physiological and biochemical changes in three sugarcane genotypes subjected to salt stress.

    PubMed

    Poonsawat, Wasinee; Theerawitaya, Cattarin; Suwan, Therapatt; Mongkolsiriwatana, Chareerat; Samphumphuang, Thapanee; Cha-um, Suriyan; Kirdmanee, Chalermpol

    2015-01-01

    Sugarcane (Saccharum officinale L.; Poaceae) is a sugar-producing plant widely grown in tropic. Being a glycophytic species, it is very sensitive to salt stress, and salinity severely reduces growth rate and cane yield. The studies investigating the regulation of salt defense metabolite-related genes in relation to final biochemical products in both susceptible and tolerant genotypes of sugarcane are largely lacking. We therefore investigated the expression levels of sugarcane shaggy-like kinase (SuSK), sucrose transporter (SUT), proline biosynthesis (pyrolline-5-carboxylate synthetase; P5CS), ion homeostasis (NHX1), and catalase (CAT2) mRNAs, and contents of Na(+), soluble sugar, and free proline in three sugarcane genotypes (A19 mutant, K88-92, and K92-80) when subjected to salt stress (200 mM NaCl). The relative expression levels of salt defense-related genes in salt-stressed plantlets of sugarcane cv. K88-92 were upregulated in relation to salt exposure times when compared with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as housekeeping gene. In addition, final biochemical products, i.e., low Na(+), sucrose enrichment, and free proline accumulation, were evidently demonstrated in salt-stressed plantlets. Chlorophyll b, total chlorophyll, total carotenoid concentrations, and maximum quantum yield of PSII (F v/F m) in positive check (K88-92) were maintained under salt stress, leading to high net photosynthetic rate (P n) and growth retention (root length, fresh weight, and leaf area). In contrast, photosynthetic abilities in negative check, K92-80, and A19 mutant lines grown under salt stress declined significantly in comparison to control, leading to a reduction in P n and an inhibition of overall growth characters. The study concludes that the genetic background of sugarcane cv. K88-92 may further be exploited to play a key role as parental clone for sugarcane breeding program for salt-tolerant purposes.

  20. Mutational analysis and genotype-phenotype relation in familial hypercholesterolemia: The SAFEHEART registry.

    PubMed

    Bourbon, Mafalda; Alves, Ana Catarina; Alonso, Rodrigo; Mata, Nelva; Aguiar, Pedro; Padró, Teresa; Mata, Pedro

    2017-07-01

    Familial hypercholesterolemia (FH) is an autosomal dominant disease of cholesterol metabolism that confers an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Therefore, early identification and treatment of these patients can improve prognosis and reduce the burden of cardiovascular mortality. The aim of this work was to perform the mutational analysis of the SAFEHEART (Spanish Familial Hypercholesterolaemia Cohort Study) registry. The study recruited 2938 individuals with genetic diagnosis of FH belonging to 775 families. Statistical analysis was performed using SPSS v23. A total of 194 variants have been detected in this study, 24 of them were never described before. About 88% of the patients have a pathogenic or likely pathogenic variant. Patients with null variants have a more severe phenotype than patients with defective variants, presenting with significantly higher levels of atherogenic particles (total cholesterol, LDL-cholesterol and apolipoprotein B). This study shows the molecular characteristics of the FH patients included in the SAFEHEART registry and the relationship with the phenotypic expression. The majority of the genetic variants are considered to be pathogenic or likely pathogenic, which confers a high level of confidence to the entry and follow-up data analysis performed with this registry concerning FH patients' prognosis, treatment and survival. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Color vision in an elderly patient with protanopic genotype and successfully treated unilateral age-related macular degeneration.

    PubMed

    Kitakawa, Takaaki; Hayashi, Takaaki; Tsuzuranuki, Satoshi; Kubo, Akiko; Tsuneoka, Hiroshi

    2011-12-01

    We investigated differences in color discrimination between the fellow eye and the affected eye successfully treated for unilateral age-related macular degeneration (AMD) in a 69-year-old male patient with protanopia. His best-corrected visual acuity (BCVA) was 1.2 in the right eye (RE) and 0.2 in the left eye (LE). Fundus and angiographic findings showed classic choroidal neovascularization (CNV) secondary to AMD in the LE. BCVA of the LE improved to 0.4, and CNV resolved by 15 months after initiating combined anti-vascular endothelial growth factor and photodynamic therapies. After CNV closure, the Farnsworth dichotomous was performed, showing confusion patterns of the protan axis in either eye. The Farnsworth-Munsell 100-hue test showed a total error score of 520 in the LE, much higher than the score of 348 in the RE. Complete genotypes of the long-wavelength-sensitive (L-) cone and middle-wavelength-sensitive (M-) cone opsin genes were determined by polymerase chain reaction, revealing that the patient had a single 5' L-M 3' hybrid gene (encoding an M-cone opsin), with this genotype responsible for protanopia (the L-cone opsin gene was non-functional), instead of the L-cone and M-cone opsin gene arrays. Poorer color vision discrimination in the LE than the RE remained present despite closure of CNV. The presence and type of congenital color vision defect can be confirmed using molecular genetic testing even if complications of acquired retinal diseases such as AMD are identified.

  2. Human Papillomavirus (HPV) Infection: Molecular Epidemiology, Genotyping, Seroprevalence and Associated Risk Factors among Arab Women in Qatar

    PubMed Central

    Acharya, Anushree; Skariah, Sini; Dargham, Soha R.; Abu-Raddad, Laith J.; Mohamed-Nady, Nady; Amuna, Paul; Al-Thani, Asma A. J.; Sultan, Ali A.

    2017-01-01

    Human Papillomavirus (HPV) infections are known to cause cervical cancer worldwide, however, limited information is currently available on prevalence, types distribution and risk factors for HPV infection in the Arab countries. We conducted a cross-sectional observational study exclusively of women of Arabic origin residing in Qatar (n = 406) who were selected from the Women’s Hospital at Hamad Medical Corporation (HMC) and Health Centers of the Primary Health Care Corporation in Doha, Qatar over the period March 2013 to August 2014. Socio-demographic, behavioral and clinical data were collected. Four hundred and six cervical smears and 292 blood samples were included in the study. HPV typing was done using HPV type-specific primers-based real-time PCR, and Sanger sequencing. HPV-IgG and IgM were quantified using ELISA assays. The prevalence of HPV infection amongst Qatari and non-Qatari Arab women were 9.8% and 6.1%, respectively and 7.6% and 16.7% in women with normal and abnormal cytology, respectively. HPV 81 was the most commonly found genotype in women with normal cytology (34.5%), whereas HPV 81, 16 and 59 in women with abnormal cytology (25.0% each). All the HPV DNA positive women were seronegative and HPV-IgG prevalence was higher in Qatari women than in non-Qatari Arab women. None of the studied factors had any significant association with HPV-DNA positivity or HPV-IgG seropositivity. The overall identified HPV DNA prevalence and HPV seroprevalence among Arab women in Qatar were on the low side compared to global levels. PMID:28046025

  3. GSTM1 null genotype as a risk factor for anti-BPDE-DNA adduct formation in mononuclear white blood cells of coke-oven workers.

    PubMed

    Pavanello, Sofia; Siwinska, Ewa; Mielzynska, Danuta; Clonfero, Erminio

    2004-03-14

    The influence of the genetic deletion polymorphism of glutathione S-transferase micro 1 (GSTM1 *0/*0) on levels of anti (+/-)-r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE-DNA) adduct in the peripheral blood lymphocyte plus monocyte fraction (LMF) of coke-oven workers was investigated. A total of 95 male Polish coke-oven workers (60% current smokers) from two different plants comprised the sample population. Polycyclic aromatic hydrocarbons (PAH) exposure was assessed by means of the individual post-shift urinary excretion of 1-pyrenol (mean +/- S.D.: 6.93 +/- 7.20 micromol/mol creatinine; 70% of the subjects exceeded the proposed biological exposure index (BEI) 2.28 micromol/mol creatinine). Anti-BPDE-DNA adduct levels were detected by high performance liquid chromatography (HPLC)/fluorescence analysis of the anti-BPDE tetrol I-1 released after acid hydrolysis of DNA samples. Genotypes were determined by polymerase chain reaction (PCR) on the genomic DNA of each subject. Coke-oven workers without active GSTM1 (GSTM1 *0/*0, 33%) had significantly higher adduct levels than those with active GSTM1 (GSTM1*1/*1 and *1/*0) (5.90 +/- 5.59 versus 3.25 +/- 2.01 adducts/10(8) bases, Mann-Whitney U-test, z = 2.53, P = 0.011), PAH exposure in the two subgroups being similar (7.06 +/- 6.83 versus 6.67 +/- 8.00 1-pyrenol micromol/mol creatinine). The highest number of GSTM1 null subjects (12/23, 39%) belonged to the quartile with the highest adduct levels (i.e., >4.67 adducts/10(8) nucleotides). That is, coke-oven workers with GSTM1 *0/*0 genotype had a significantly higher risk of having high adduct levels than individuals with active GSTM1 genotype (Fisher exact test P = 0.0355; odds ratio (OR) = 4.145, 95% CI 1.0-18.8). Multiple linear regression analysis showed that the increase in anti-BPDE-DNA adduct levels in LMF was significantly related to the high occupational exposure to PAHs (benzo[a]pyrene (BaP)) of coke-oven workers (t = 3.087, P < 0

  4. Association between vitamin D status and age-related macular degeneration by genetic risk

    PubMed Central

    Millen, Amy E.; Meyers, Kristin J; Liu, Zhe; Engelman, Corinne D; Wallace, Robert B; LeBlanc, Erin S; Tinker, Lesley F.; Iyengar, Sudha K; Robinson, Jennifer; Sarto, Gloria E.; Mares, Julie A

    2016-01-01

    Importance Deficient 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with increased odds of age-related macular degeneration (AMD). Objective We examined 1) whether this association is modified by genetic risk for AMD and 2) if there is an association between AMD and single nucleotide polymorphisms (SNPs) of genes involved in vitamin D transport, metabolism and genomic function. Design, Setting and Participants Women were postmenopausal and participants of the Carotenoids in Age-Related Eye Disease Study (CAREDS) (54 to <75 years) with available serum 25(OH)D concentrations (assessed from 1994–1998), genetic data, and measures of AMD (n=142) assessed at CAREDS baseline from 2001–2004 (n=913). Main Outcomes and Measures Prevalent early or late AMD was determined from graded, stereoscopic fundus photographs. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for AMD by the joint effects of 25(OH)D (<30, ≥30 to <50, ≥50 to <75, and ≥75 nmol/L) and risk genotype (noncarrier, one, or two risk alleles). The referent group was noncarriers with adequate vitamin D status (≥75 nmol/L). Joint effect ORs were adjusted for age, smoking, iris pigmentation, self-reported cardiovascular disease, self-reported diabetes status, and hormone use. Additive and multiplicative interactions were assessed using the Synergy Index (SI) and an interaction term, respectively. Results We observed a 6.7-fold increased odds of AMD (95% CI=1.6, 28.2) among women with deficient vitamin D status (25(OH)D<30 nmol/L) and two risk alleles for complement factor H (CFH) Y402H (SI for additive interaction=1.4, 95% CI=1.1, 1.7; p for multiplicative interaction=0.25,. A significant additive (SI=1.4, 95% CI=1.1, 1.7) and multiplicative interaction (p=0.02) was observed for deficient women with two high risk complement factor I (CFI) (rs10033900) alleles (OR=6.3, 95% CI=1.6, 24.2). The odds of AMD did not differ by genotype of candidate

  5. Dense genotyping of immune-related loci identifies variants associated with clearance of HPV among HIV-positive women in the HIV epidemiology research study (HERS).

    PubMed

    Sudenga, Staci L; Wiener, Howard W; King, Caroline C; Rompalo, Anne M; Cu-Uvin, Susan; Klein, Robert S; Shah, Keerti V; Sobel, Jack D; Jamieson, Denise J; Shrestha, Sadeep

    2014-01-01

    Persistent high-risk human papillomavirus (HR-HPV) is a necessary and causal factor of cervical cancer. Most women naturally clear HPV infections; however, the biological mechanisms related to HPV pathogenesis have not been clearly elucidated. Host genetic factors that specifically regulate immune response could play an important role. All HIV-positive women in the HIV Epidemiology Research Study (HERS) with a HR-HPV infection and at least one follow-up biannual visit were included in the study. Cervicovaginal lavage samples were tested for HPV using type-specific HPV hybridization assays. Type-specific HPV clearance was defined as two consecutive HPV-negative tests after a positive test. DNA from participants was genotyped for 196,524 variants within 186 known immune related loci using the custom ImmunoChip microarray. To assess the influence of each single-nucleotide polymorphism (SNP) with HR-HPV clearance, the Cox proportional hazards model with the Wei-Lin-Weissfeld approach was used, adjusting for CD4+ count, low risk HPV (LR-HPV) co-infection, and relevant confounders. Three analytical models were performed: race-specific (African Americans (n = 258), European Americans (n = 87), Hispanics (n = 55), race-adjusted combined analysis, and meta-analysis of pooled independent race-specific analyses. Women were followed for a median time of 1,617 days. Overall, three SNPs (rs1112085, rs11102637, and rs12030900) in the MAGI-3 gene and one SNP (rs8031627) in the SMAD3 gene were associated with HR-HPV clearance (p<10(-6)). A variant (rs1633038) in HLA-G were also significantly associated in African American. Results from this study support associations of immune-related genes, having potential biological mechanism, with differential cervical HR-HPV infection outcomes.

  6. Cervical human papillomavirus infection among young women engaged in sex work in Phnom Penh, Cambodia: prevalence, genotypes, risk factors and association with HIV infection

    PubMed Central

    2012-01-01

    Background Although cervical cancer is the leading cancer in Cambodia, most women receive no routine screening for cervical cancer and few treatment options exist. Moreover, nothing is known regarding the prevalence of cervical HPV or the genotypes present among women in the country. Young sexually active women, especially those with multiple sex partners are at highest risk of HPV infection. We examine the prevalence and genotypes of cervical HPV, as well as the associated risk factors among young women engaged in sex work in Phnom Penh, Cambodia. Methods We conducted a cross-sectional study among 220 young women (15–29 years) engaged in sex work in different venues including brothels or entertainment establishments, and on a freelance basis in streets, parks and private apartments. Cervical specimens were collected using standard cytobrush technique. HPV DNA was tested for by polymerase chain reaction (PCR) and genotyping using type-specific probes for 29 individual HPV types, as well as for a mixture of 10 less common HPV types. All participants were also screened for HIV status using blood samples. Multivariate logistic regression analyses were conducted to assess risk factors for any or multiple HPV infection. Results The prevalence of cervical HPV 41.1%. HPV 51 and 70 were the most common (5.0%), followed by 16 (4.6%), 71 (4.1%) and 81 (3.7%). Thirty-six women (16.4%) were infected with multiple genotypes and 23.3% were infected with at least one oncogenic HPV type. In multivariate analyses, having HIV infection and a higher number of sexual partners were associated with cervical HPV infection. Risk factors for infection with multiple genotypes included working as freelance female sex workers (FSW) or in brothels, recent binge use of drugs, high number of sexual partners, and HIV infection. Conclusions This is the first Cambodian study on cervical HPV prevalence and genotypes. We found that HPV infection was common among young FSW, especially among women

  7. Pro-Inflammatory Interleukin-1 Genotypes Potentiate the Risk of Coronary Artery Disease and Cardiovascular Events Mediated by Oxidized Phospholipids and Lipoprotein (a)

    PubMed Central

    Tsimikas, Sotirios; Duff, Gordon W.; Berger, Peter B.; Rogus, John; Huttner, Kenneth; Clopton, Paul; Brilakis, Emmanuel; Kornman, Kenneth S; Witztum, Joseph L

    2014-01-01

    Objective To assess the influence of pro-inflammatory IL-1 genotype status on the risk of CAD, defined as >50% diameter stenosis, and cardiovascular events mediated by OxPL and Lp(a). Background Oxidized phospholipids (OxPL) are pro-inflammatory, circulate on lipoprotein (a) [Lp(a)] and mediate coronary artery disease (CAD). Genetic variations in the interleukin-1 (IL-1) region are associated with increased inflammatory mediators. Methods IL-1 genotypes, OxPL on apolipoprotein B-100 (OxPL/apoB) and Lp(a) levels were measured in 499 patients undergoing coronary angiography. The composite genotype termed IL-1(+) was defined by three single nucleotide polymorphisms (SNPs) in the IL-1 gene cluster associated with higher levels of pro-inflammatory cytokines. All other IL-1 genotypes were termed IL-1(−). Results Among IL-1(+) patients, the highest quartile of OxPL/apoB was significantly associated with a higher risk of CAD compared to the lowest quartile (OR 2.84, P=0.001). This effect was accentuated in patients ≤60 years old (OR 7.03, P<0.001). In IL-1(−) patients, OxPL/apoB levels showed no association with CAD. The interaction was significant for OxPL/apoB (OR 1.99, P=0.004) and Lp(a) (OR 1.96, P<0.001) in IL-1(+) versus IL-1(−) groups for patients ≤60 years old but not for patients >60 years old. In IL-1(+) patients ≤60 years old, after adjusting for established risk factors, high sensitivity C-reactive protein and Lp(a), OxPL/apoB remained an independent predictor of CAD. IL-1(+) patients above the median OxPL/apoB presented to the cardiac catheterization laboratory a mean of 3.9 years earlier (P=0.002) and had worse 4-year event-free survival (death, MI, stroke, and revascularization) compared to other groups (P=0.006). Conclusion Our study suggests that IL-1 genotype status can stratify population risk for CAD and cardiovascular events mediated by OxPL. These data suggest a clinically-relevant biological link between pro-inflammatory IL-1 genotypes

  8. Development of a Genotyping Microarray for Studying the Role of Gene-Environment Interactions in Risk for Lung Cancer

    PubMed Central

    Baldwin, Don A.; Sarnowski, Christopher P.; Reddy, Sabrina A.; Blair, Ian A.; Clapper, Margie; Lazarus, Philip; Li, Mingyao; Muscat, Joshua E.; Penning, Trevor M.; Vachani, Anil; Whitehead, Alexander S.

    2013-01-01

    A microarray (LungCaGxE), based on Illumina BeadChip technology, was developed for high-resolution genotyping of genes that are candidates for involvement in environmentally driven aspects of lung cancer oncogenesis and/or tumor growth. The iterative array design process illustrates techniques for managing large panels of candidate genes and optimizing marker selection, aided by a new bioinformatics pipeline component, Tagger Batch Assistant. The LungCaGxE platform targets 298 genes and the proximal genetic regions in which they are located, using ∼13,000 DNA single nucleotide polymorphisms (SNPs), which include haplotype linkage markers with a minimum allele frequency of 1% and additional specifically targeted SNPs, for which published reports have indicated functional consequences or associations with lung cancer or other smoking-related diseases. The overall assay conversion rate was 98.9%; 99.0% of markers with a minimum Illumina design score of 0.6 successfully generated allele calls using genomic DNA from a study population of 1873 lung-cancer patients and controls. PMID:24294113

  9. Prevalence of High-Risk Genotypes of Human Papillomavirus: Women Diagnosed with Premalignant and Malignant Pap Smear Tests in Southern Ecuador

    PubMed Central

    Loján González, Cisne; Córdova Rodríguez, Ana; Acurio Páez, Katherine; Arévalo, Ana Paulina; Bobokova, Jana

    2017-01-01

    Human papillomavirus (HPV) is the primary infectious agent for the development of cervical cancer, although the presence of the virus alone is insufficient for viral development and proliferation; this can be attributed to the increase in potential oncogenic risk, along with other risk factors. In the present investigation, the prevalence of high-risk HPV was determined from samples of premalignant or malignant cervical cytology in women from the southern region of Ecuador. The kit we used was able to detect genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59. In addition, 64.5% of the analyzed samples were positive for HPV, with genotypes 16 and 18 being the most prevalent (16 was detected in 148 samples and 18 in 108). Genotypes 58 and 51 were the third most frequent simple and multiple infections, respectively. The data are very similar to those obtained worldwide, suggesting that the strategy of sex education, and the use of vaccines as primary prevention agents, could significantly decrease the incidence and mortality rate of cervical cancer in the southern region of Ecuador. PMID:28717342

  10. Null genotypes of glutathione S-transferase μ1 and glutathione S-transferase θ1 are associated with osteosarcoma risk: A meta-analysis

    PubMed Central

    HAN, JICHENG; DENG, WEI; WANG, LAIYING; QI, WANLI

    2015-01-01

    Glutathione S-transferase (GST) genetic polymorphisms has been reported to be associated with osteosarcoma; however, the results of previous studies are conflicting. Thus, in the present study, a meta-analysis was conducted to investigate the effects of GSTM1 and GSTT1 polymorphisms on osteosarcoma risk. A literature search was performed in the PubMed, Cochrane Library and China National Knowledge Infrastructure databases to identify case-control studies published prior to March 2014. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. In addition, Begg’s test was used to measure publication bias. Sensitivity analysis were performed to ensure the accuracy of the results. The meta-analysis results demonstrated no significant association between the null genotype of GSTM1 and osteosarcoma risk (OR=0.83; 95% CI, 0.37–1.85). By contrast, the results revealed a significant association for the comparison of null vs. non-null genotypes of GSTT1 (OR=1.54; 95% CI, 1.09–2.19). In conclusion, the GSTT1 null genotype may be associated with an increased risk of developing osteosarcoma. Further studies with larger sample sizes and well-designed methodologies are required to verify these conclusions. PMID:25789067

  11. Assessing the risk of work-related international travel.

    PubMed

    Druckman, Myles; Harber, Philip; Liu, Yihang; Quigley, Robert L

    2014-11-01

    To identify factors affecting the likelihood of requiring medical services during international business trips. Data from more than 800,000 international trips and medical assistance cases provided to 48 multinational corporations in 2009. Travel destination countries were grouped into four a prior