1513A>C polymorphism in the P2X7 receptor gene in patients with papillary thyroid cancer: correlation with histological variants and clinical parameters.

PubMed

Dardano, Angela; Falzoni, Simonetta; Caraccio, Nadia; Polini, Antonio; Tognini, Sara; Solini, Anna; Berti, Piero; Di Virgilio, Francesco; Monzani, Fabio

2009-02-01

The modulation of the purinergic receptor P2X7 may be implicated in human carcinogenesis. The 1513A>C and 489C>T polymorphisms of P2X7R gene induce loss of function and gain of function, respectively. The aim of the study was to assess the frequency of both 1513A>C and 489C>T polymorphisms in patients with papillary thyroid carcinoma (PTC) and to evaluate the possible association with clinical and histological features. P2X7R analysis was performed in lymphocytes from 121 PTC patients (100 women, 21 men; aged 43.4 +/- 13.6 yr), 100 matched healthy subjects, and 80 patients with nodular goiter. The minor allele frequency for 1513A>C polymorphism in PTC patients with the classical variant was similar to controls (0.21 and 0.20, respectively), whereas it resulted in a significant increase in patients with the follicular variant (0.36; P = 0.01 vs. classical variant, and P = 0.005 vs. controls). In detail, 13.6% of patients with PTC follicular variant were homozygous for the 1513C allele, compared to 2.6% of patients with the classical variant and 2% of controls. Moreover, a positive relationship between 1513A>C polymorphism and either cancer diameter (Rho = 0.22; P = 0.02) or TNM stage (Rho = 0.38; P < 0.001) was found. No significant difference in the genotype frequency of 489C>T polymorphism between PTC patients and healthy controls was observed (0.42 and 0.47, respectively). Our data show, for the first time, a strong association between 1513A>C polymorphism of P2X7R gene and the follicular variant of PTC. Further studies are needed to confirm the possible role of this polymorphism as a novel clinical marker of PTC follicular variant and its usefulness in selecting patients with different clinical outcome.

Analysis of Structural MtrC Models Based on Homology with the Crystal Structure of MtrF

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

Edwards, Marcus; Fredrickson, Jim K.; Zachara, John M.

2012-12-01

The outer-membrane decahaem cytochrome MtrC is part of the transmembrane MtrCAB complex required for mineral respiration by Shewanella oneidensis. MtrC has significant sequence similarity to the paralogous decahaem cytochrome MtrF, which has been structurally solved through X-ray crystallography. This now allows for homology-based models of MtrC to be generated. The structure of these MtrC homology models contain ten bis-histidine-co-ordinated c-type haems arranged in a staggered cross through a four-domain structure. This model is consistent with current spectroscopic data and shows that the areas around haem 5 and haem 10, at the termini of an octahaem chain, are likely to havemore » functions similar to those of the corresponding haems in MtrF. The electrostatic surfaces around haem 7, close to the β-barrels, are different in MtrF and MtrC, indicating that these haems may have different potentials and interact with substrates differently.« less

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

PubMed

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

2017-01-01

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

Proposal for the nomenclature of human plasminogen (PLG) polymorphism.

PubMed

Skoda, U; Bertrams, J; Dykes, D; Eiberg, H; Hobart, M; Hummel, K; Kühnl, P; Mauff, G; Nakamura, S; Nishimukai, H

1986-01-01

Since its discovery, human plasminogen (PLG) polymorphism has received widespread acceptance in population genetics and forensic haematology. Due to the large number of variant alleles described, a PLG reference typing and Plasminogen Symposium was held, at which a nomenclature proposal was inaugurated. The technology of comparing PLG variants was based on isoelectric focusing and subsequent detection by caseinolytic overlay and 'Western' blotting. Typing results permitted comparison of so far described variant designations and resulted in a new nomenclature proposal for PLG polymorphism. It is recommended that the two most common alleles found in all investigated races be called: PLG*A (previously also PLG*1) and PLG*B (previously also PLG*2), the known variants with acidic pI: PLG*A1 to *A3, intermediate variants: PLG*M1 to *M5, PLG*M5 being functionally inactive, and basic variants: PLG*B1 to *B3. For future classification of newly discovered variants, samples should be compared at any of the laboratories participating in the reference typing.

33 CFR 154.1041 - Specific response information to be maintained on mobile MTR facilities.

Code of Federal Regulations, 2010 CFR

2010-07-01

... be maintained on mobile MTR facilities. 154.1041 Section 154.1041 Navigation and Navigable Waters... maintained on mobile MTR facilities. (a) Each mobile MTR facility must carry the following information as... respond to a discharge from the mobile MTR facility. (3) List of the appropriate persons and agencies...

Effects of human SAMHD1 polymorphisms on HIV-1 susceptibility

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

White, Tommy E.; Brandariz-Nuñez, Alberto; Valle-Casuso, Jose Carlos

SAMHD1 is a human restriction factor that prevents efficient infection of macrophages, dendritic cells and resting CD4+ T cells by HIV-1. Here we explored the antiviral activity and biochemical properties of human SAMHD1 polymorphisms. Our studies focused on human SAMHD1 polymorphisms that were previously identified as evolving under positive selection for rapid amino acid replacement during primate speciation. The different human SAMHD1 polymorphisms were tested for their ability to block HIV-1, HIV-2 and equine infectious anemia virus (EIAV). All studied SAMHD1 variants block HIV-1, HIV-2 and EIAV infection when compared to wild type. We found that these variants did notmore » lose their ability to oligomerize or to bind RNA. Furthermore, all tested variants were susceptible to degradation by Vpx, and localized to the nuclear compartment. We tested the ability of human SAMHD1 polymorphisms to decrease the dNTP cellular levels. In agreement, none of the different SAMHD1 variants lost their ability to reduce cellular levels of dNTPs. Finally, we found that none of the tested human SAMHD1 polymorphisms affected the ability of the protein to block LINE-1 retrotransposition. - Highlights: • Human SAMHD1 single-nucleotide polymorphisms block HIV-1 and HIV-2 infection. • SAMHD1 polymorphisms do not affect its ability to block LINE-1 retrotransposition. • SAMHD1 polymorphisms decrease the cellular levels of dNTPs.« less

Prevalence of myofascial trigger points in fibromyalgia: the overlap of two common problems.

PubMed

Ge, Hong-You

2010-10-01

With the objective evidence of their existence, myofascial trigger points (MTrPs) contribute to an increasing number of chronic regional and widespread pain conditions. The widespread spontaneous pain pattern in fibromyalgia (FM) is a summation of multiple regional pains due to active MTrPs. A regional pain in FM is from local active MTrPs and/or referred from remote active MTrPs. Positive tender points specified in FM are MTrPs, either active or latent. Manual stimulation of active MTrPs located in the muscles in different body regions completely reproduced overall spontaneous FM pain pattern. Active MTrPs as tonic peripheral nociceptive input contribute tremendously to the initiation and maintenance of central sensitization, to the impairment of descending inhibition, to the increased excitability of motor units, and to the induction of sympathetic hyperactivity observed in FM. The considerable overlap of MTrPs and FM in pain characteristics and pathophysiology suggests that FM pain is largely due to MTrPs.

Novel Applications of Ultrasound Technology to Visualize and Characterize Myofascial Trigger Points and Surrounding Soft Tissue

PubMed Central

Sikdar, Siddhartha; Shah, Jay P.; Gebreab, Tadesse; Yen, Ru-Huey; Gilliams, Elizabeth; Danoff, Jerome; Gerber, Lynn H.

2009-01-01

Objective Apply ultrasound (US) imaging techniques to better describe the characteristics of myofascial trigger points (MTrPs) and the immediately adjacent soft tissue. Design Descriptive (exploratory) study. Setting Biomedical research center. Participants 9 subjects meeting Travell and Simons’s criteria for MTrPs in a taut band in the upper trapezius. Interventions (None) Main Outcome Measures MTrPs were evaluated by 1) physical examination, 2) pressure algometry, and 3) three types of ultrasound imaging including grayscale (2D US), vibration sonoelastography (VSE), and Doppler. Methods Four sites in each patient were labeled based on physical examination as either active MTrP (spontaneously-painful, A-MTrP), latent MTrP (non-painful, L-MTrP), or normal myofascial tissue. US examination was performed on each subject by a team blinded to the physical findings. A 12-5 MHz US transducer was used. VSE was performed by color Doppler variance imaging while simultaneously inducing vibrations (~92Hz) with a handheld massage vibrator. Each site was assigned a tissue imaging score (TIS) as follows: 0 = uniform echogenicity and stiffness; 1 = focal hypoechoic region with stiff nodule; 2 = multiple hypoechoic regions with stiff nodules. Blood flow in the neighborhood of MTrPs was assessed using Doppler imaging. Each site was assigned a blood flow waveform score (BFS) as follows: 0 = normal arterial flow in muscle; 1 = elevated diastolic flow; 2 = high-resistance flow waveform with retrograde diastolic flow. Results MTrPs appeared as focal, hypoechoic regions on 2D US, indicating local changes in tissue echogenicity, and as focal regions of reduced vibration amplitude on VSE, indicating a localized stiff nodule. MTrPs were elliptical in shape, with a size of 0.16 ± 0.11 cm2. There were no significant differences in size between A-MTrPs and L-MTrPs. Sites containing MTrPs were more likely to have higher TIS compared to normal myofascial tissue (p<0.002). Small arteries (or enlarged arterioles) near A-MTrPs showed retrograde flow in diastole indicating a highly resistive vascular bed. A-MTrP sites were more likely to have higher BFS compared to L-MTrPs (p<0.021). Conclusions Preliminary findings show that, under the conditions of this investigation, US imaging techniques can be used to distinguish myofascial tissue containing MTrPs from normal myofascial tissue (lacking trigger points). Ultrasound enables visualization and some characterization of MTrPs and adjacent soft tissue. PMID:19887205

DNA repair genes polymorphisms and genetic susceptibility to Philadelphia-negative myeloproliferative neoplasms in a Portuguese population: The role of base excision repair genes polymorphisms.

PubMed

Azevedo, Ana P; Silva, Susana N; De Lima, João P; Reichert, Alice; Lima, Fernando; Júnior, Esmeraldina; Rueff, José

2017-06-01

The role of base excision repair (BER) genes in Philadelphia-negative (PN)-myeloproliferative neoplasms (MPNs) susceptibility was evaluated by genotyping eight polymorphisms [apurinic/apyrimidinic endodeoxyribonuclease 1, mutY DNA glycosylase, earlier mutY homolog ( E. coli ) (MUTYH), 8-oxoguanine DNA glycosylase 1, poly (ADP-ribose) polymerase (PARP) 1, PARP4 and X-ray repair cross-complementing 1 (XRCC1)] in a case-control study involving 133 Caucasian Portuguese patients. The results did not reveal a correlation between individual BER polymorphisms and PN-MPNs when considered as a whole. However, stratification for essential thrombocythaemia revealed i) borderline effect/tendency to increased risk when carrying at least one variant allele for XRCC1_399 single-nucleotide polymorphism (SNP); ii) decreased risk for Janus kinase 2-positive patients carrying at least one variant allele for XRCC1_399 SNP; and iii) decreased risk in females carrying at least one variant allele for MUTYH SNP. Combination of alleles demonstrated an increased risk to PN-MPNs for one specific haplogroup. These findings may provide evidence for gene variants in susceptibility to MPNs. Indeed, common variants in DNA repair genes may hamper the capacity to repair DNA, thus increasing cancer susceptibility.

DNA repair genes polymorphisms and genetic susceptibility to Philadelphia-negative myeloproliferative neoplasms in a Portuguese population: The role of base excision repair genes polymorphisms

PubMed Central

Azevedo, Ana P.; Silva, Susana N.; De Lima, João P.; Reichert, Alice; Lima, Fernando; Júnior, Esmeraldina; Rueff, José

2017-01-01

The role of base excision repair (BER) genes in Philadelphia-negative (PN)-myeloproliferative neoplasms (MPNs) susceptibility was evaluated by genotyping eight polymorphisms [apurinic/apyrimidinic endodeoxyribonuclease 1, mutY DNA glycosylase, earlier mutY homolog (E. coli) (MUTYH), 8-oxoguanine DNA glycosylase 1, poly (ADP-ribose) polymerase (PARP) 1, PARP4 and X-ray repair cross-complementing 1 (XRCC1)] in a case-control study involving 133 Caucasian Portuguese patients. The results did not reveal a correlation between individual BER polymorphisms and PN-MPNs when considered as a whole. However, stratification for essential thrombocythaemia revealed i) borderline effect/tendency to increased risk when carrying at least one variant allele for XRCC1_399 single-nucleotide polymorphism (SNP); ii) decreased risk for Janus kinase 2-positive patients carrying at least one variant allele for XRCC1_399 SNP; and iii) decreased risk in females carrying at least one variant allele for MUTYH SNP. Combination of alleles demonstrated an increased risk to PN-MPNs for one specific haplogroup. These findings may provide evidence for gene variants in susceptibility to MPNs. Indeed, common variants in DNA repair genes may hamper the capacity to repair DNA, thus increasing cancer susceptibility. PMID:28599464

The Role of the Transcription Factors MtrR and MtrA in the Fitness of the Pathogen Neisseria gonorrhoeae

DTIC Science & Technology

2007-10-19

MacA -MacB efflux pump is expressed at very low levels in N. gonorrhoeae; however, experimental alteration of the promoter sequence showed that the...specificity (132). The gonococcus expresses four efflux pump systems, namely MtrC-Mtr-D-MtrE (64), FarA-FarB-MtrE (97), NorM (158), and MacA -MacB (161...2005. Characterization of the MacA -MacB efflux system in Neisseria gonorrhoeae. The Journal of antimicrobial chemotherapy 56:856-860. 162. Rouquette, C

ETR AND MTR COMPLEXES IN CONTEXT. CAMERA FACING NORTHERLY. FROM ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

ETR AND MTR COMPLEXES IN CONTEXT. CAMERA FACING NORTHERLY. FROM BOTTOM TO TOP: ETR COOLING TOWER, ELECTRICAL BUILDING AND LOW-BAY SECTION OF ETR BUILDING, HEAT EXCHANGER BUILDING (WITH U SHAPED YARD), COMPRESSOR BUILDING. MTR REACTOR SERVICES BUILDING IS ATTACHED TO SOUTH WALL OF MTR. WING A IS ATTACHED TO BALCONY FLOOR OF MTR. NEAR UPPER RIGHT CORNER OF VIEW IS MTR PROCESS WATER BUILDING. WING B IS AT FAR WEST END OF COMPLEX. NEAR MAIN GATE IS GAMMA FACILITY, WITH "COLD" BUILDINGS BEYOND: RAW WATER STORAGE TANKS, STEAM PLANT, MTR COOLING TOWER PUMP HOUSE AND COOLING TOWER. INL NEGATIVE NO. 56-4101. - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

Rapid electron exchange between surface-exposed bacterial cytochromes and Fe(III) minerals

PubMed Central

White, Gaye F.; Shi, Zhi; Shi, Liang; Wang, Zheming; Dohnalkova, Alice C.; Marshall, Matthew J.; Fredrickson, James K.; Zachara, John M.; Butt, Julea N.; Richardson, David J.; Clarke, Thomas A.

2013-01-01

The mineral-respiring bacterium Shewanella oneidensis uses a protein complex, MtrCAB, composed of two decaheme cytochromes, MtrC and MtrA, brought together inside a transmembrane porin, MtrB, to transport electrons across the outer membrane to a variety of mineral-based electron acceptors. A proteoliposome system containing a pool of internalized electron carriers was used to investigate how the topology of the MtrCAB complex relates to its ability to transport electrons across a lipid bilayer to externally located Fe(III) oxides. With MtrA facing the interior and MtrC exposed on the outer surface of the phospholipid bilayer, the established in vivo orientation, electron transfer from the interior electron carrier pool through MtrCAB to solid-phase Fe(III) oxides was demonstrated. The rates were 103 times higher than those reported for reduction of goethite, hematite, and lepidocrocite by S. oneidensis, and the order of the reaction rates was consistent with those observed in S. oneidensis cultures. In contrast, established rates for single turnover reactions between purified MtrC and Fe(III) oxides were 103 times lower. By providing a continuous flow of electrons, the proteoliposome experiments demonstrate that conduction through MtrCAB directly to Fe(III) oxides is sufficient to support in vivo, anaerobic, solid-phase iron respiration. PMID:23538304

Genetic variants of apolipoprotein A5 T-1131C and apolipoprotein E common polymorphisms and their relationship to features of metabolic syndrome in adult dyslipidemic patients.

PubMed

Novotny, Dalibor; Vaverkova, Helena; Karasek, David; Malina, Pavel

2014-08-01

The aim was to evaluate the relationships of the T-1131C (rs662799) polymorphism variants of apolipoprotein A5 (Apo A5) gene and variants of apolipoprotein E (Apo E) gene common polymorphism (rs429358, rs7412) to signs of metabolic syndrome (MetS). We examined 590 asymptomatic dyslipidemic patients divided into MetS+ (n=146) and MetS- (n=444) groups according to criteria of NCEP ATPIII Panel. We evaluated genotype frequencies and differences in MetS features between individual groups. Logistic regression analysis was used for the evaluation of Apo A5/Apo E variants as possible risk factors for MetS. We found no statistical differences between genotype and allele frequencies for both Apo A5 and Apo E polymorphisms between MetS+ and MetS- groups. In all subjects and MetS- group, we confirmed well-known association of the -1131C Apo A5 minor allele with elevated triglycerides (TG, p<0.001). The Apo E gene E2 and E4 variants were associated with higher levels of TG (p<0.01) in comparison to E33 common variant. However, no statistical differences were observed in MetS+ subjects, regardless of significantly higher TG levels in this group. Apo A5/Apo E variant analysis in all dyslipidemic patients revealed significant increase of TG levels in all subgroups in comparison to common -1131T/E3 variant carriers, the most in -1131C/E4 variant subgroup. Logistic regression analysis models showed no association of Apo A5, Apo E and all Apo A5/Apo E variants with metabolic syndrome, even after adjustment for age and sex. Our study refined the role of Apo A5 and Apo E genetic variants in the group of adult dyslipidemic patients. We demonstrate that except of TG, Apo A5 T-1131C (rs662799) and Apo E (rs429358, rs7412) polymorphisms have no remarkable effect on MetS characteristics. Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Polymorphism of antibiotic-inactivating enzyme driven by ecology expands the environmental resistome.

PubMed

Kim, Dae-Wi; Thawng, Cung Nawl; Choi, Jung-Hye; Lee, Kihyun; Cha, Chang-Jun

2018-01-01

The environmental resistome has been recognized as the origin and reservoir of antibiotic resistance genes and considered to be dynamic and ever expanding. In this study, a targeted gene sequencing approach revealed that the polymorphic diversity of the aminoglycoside-inactivating enzyme AAC(6')-Ib was ecological niche-specific. AAC(6')-Ib-cr, previously known as a clinical variant, was prevalent in various soils and the intestines of chickens and humans, suggesting that this variant might not have arisen from adaptive mutations in the clinic but instead originated from the environment. Furthermore, ecologically dominant polymorphic variants of AAC(6')-Ib were characterized and found to display different substrate specificities for quinolones and aminoglycosides, conferring the altered resistance spectra. Interestingly, a novel variant with the D179Y substitution showed an extended resistance spectrum to the recently developed fluoroquinolone gemifloxacin. Our results suggest that soil and animal microbiomes could be major reservoirs of antibiotic resistance; polymorphic diversity expands the antibiotic resistome in the environment, resulting in the potential emergence of novel resistance.

Additive effects of LPL, APOA5 and APOE variant combinations on triglyceride levels and hypertriglyceridemia: results of the ICARIA genetic sub-study

PubMed Central

2010-01-01

Background Hypertriglyceridemia (HTG) is a well-established independent risk factor for cardiovascular disease and the influence of several genetic variants in genes related with triglyceride (TG) metabolism has been described, including LPL, APOA5 and APOE. The combined analysis of these polymorphisms could produce clinically meaningful complementary information. Methods A subgroup of the ICARIA study comprising 1825 Spanish subjects (80% men, mean age 36 years) was genotyped for the LPL-HindIII (rs320), S447X (rs328), D9N (rs1801177) and N291S (rs268) polymorphisms, the APOA5-S19W (rs3135506) and -1131T/C (rs662799) variants, and the APOE polymorphism (rs429358; rs7412) using PCR and restriction analysis and TaqMan assays. We used regression analyses to examine their combined effects on TG levels (with the log-transformed variable) and the association of variant combinations with TG levels and hypertriglyceridemia (TG ≥ 1.69 mmol/L), including the covariates: gender, age, waist circumference, blood glucose, blood pressure, smoking and alcohol consumption. Results We found a significant lowering effect of the LPL-HindIII and S447X polymorphisms (p < 0.0001). In addition, the D9N, N291S, S19W and -1131T/C variants and the APOE-ε4 allele were significantly associated with an independent additive TG-raising effect (p < 0.05, p < 0.01, p < 0.001, p < 0.0001 and p < 0.001, respectively). Grouping individuals according to the presence of TG-lowering or TG-raising polymorphisms showed significant differences in TG levels (p < 0.0001), with the lowest levels exhibited by carriers of two lowering variants (10.2% reduction in TG geometric mean with respect to individuals who were homozygous for the frequent alleles of all the variants), and the highest levels in carriers of raising combinations (25.1% mean TG increase). Thus, carrying two lowering variants was protective against HTG (OR = 0.62; 95% CI, 0.39-0.98; p = 0.042) and having one single raising polymorphism (OR = 1.20; 95% CI, 1.39-2.87; p < 0.001) or more (2 or 3 raising variants; OR = 2.90; 95% CI, 1.56-5.41; p < 0.001) were associated with HTG. Conclusion Our results showed a significant independent additive effect on TG levels of the LPL polymorphisms HindIII, S447X, D9N and N291S; the S19W and -1131T/C variants of APOA5, and the ε4 allele of APOE in our study population. Moreover, some of the variant combinations studied were significantly associated with the absence or the presence of hypertriglyceridemia. PMID:20429872

High prevalence of shoulder girdle muscles with myofascial trigger points in patients with shoulder pain

PubMed Central

2011-01-01

Background Shoulder pain is reported to be highly prevalent and tends to be recurrent or persistent despite medical treatment. The pathophysiological mechanisms of shoulder pain are poorly understood. Furthermore, there is little evidence supporting the effectiveness of current treatment protocols. Although myofascial trigger points (MTrPs) are rarely mentioned in relation to shoulder pain, they may present an alternative underlying mechanism, which would provide new treatment targets through MTrP inactivation. While previous research has demonstrated that trained physiotherapists can reliably identify MTrPs in patients with shoulder pain, the percentage of patients who actually have MTrPs remains unclear. The aim of this observational study was to assess the prevalence of muscles with MTrPs and the association between MTrPs and the severity of pain and functioning in patients with chronic non-traumatic unilateral shoulder pain. Methods An observational study was conducted. Subjects were recruited from patients participating in a controlled trial studying the effectiveness of physical therapy on patients with unilateral non-traumatic shoulder pain. Sociodemographic and patient-reported symptom scores, including the Disabilities of the Arm, Shoulder, and Hand (DASH) Questionnaire, and Visual Analogue Scales for Pain were compared with other studies. To test for differences in age, gender distribution, and education level between the current study population and the populations from Dutch shoulder studies, the one sample T-test was used. One observer examined all subjects (n = 72) for the presence of MTrPs. Frequency distributions, means, medians, standard deviations, and 95% confidence intervals were calculated for descriptive purposes. The Spearman's rank-order correlation (ρ) was used to test for association between variables. Results MTrPs were identified in all subjects. The median number of muscles with MTrPs per subject was 6 (active MTrPs) and 4 (latent MTrPs). Active MTrPs were most prevalent in the infraspinatus (77%) and the upper trapezius muscles (58%), whereas latent MTrPs were most prevalent in the teres major (49%) and anterior deltoid muscles (38%). The number of muscles with active MTrPs was only moderately correlated with the DASH score. Conclusion The prevalence of muscles containing active and latent MTrPs in a sample of patients with chronic non-traumatic shoulder pain was high. PMID:21711512

The MAOA, COMT, MTHFR and ESR1 gene polymorphisms are associated with the risk of depression in menopausal women.

PubMed

Różycka, Agata; Słopień, Radosław; Słopień, Agnieszka; Dorszewska, Jolanta; Seremak-Mrozikiewicz, Agnieszka; Lianeri, Margarita; Maciukiewicz, Małgorzata; Warenik-Szymankiewicz, Alina; Grzelak, Teresa; Kurzawińska, Grażyna; Drews, Krzysztof; Klejewski, Andrzej; Jagodziński, Paweł P

2016-02-01

The aim of the study was assessment of a possible relationship between the polymorphisms of the candidate genes participating in the etiology of some neurological and psychiatric disorders and the risk of depression in perimenopausal and postmenopausal women. A total of 167 (54 perimenopausal and 113 postmenopausal) Caucasian women from western Poland, aged 42-67, were recruited as the patient group in the study because of depressive symptoms, and another 321 healthy women (102 perimenopausal and 219 postmenopausal) served as the controls. All study participants were evaluated for climacteric and depressive disorders according to the Kupperman index and Hamilton rating scale for depression (HRSD), respectively. The following candidate genes were selected for the study: 5HTR2A, 5HTR1B, 5HTR2C, TPH1, TPH2, MAOA, COMT, NET, GABRB1, ESR1, MTHFR, MTR and MTHFD1. In each group the frequencies of the polymorphisms were determined using PCR-RFLP analysis. After correcting for Bonferroni multiple tests, we found associations between the MAOA c.1460C>T (SNP 1137070), COMT c.472G>A (SNP 4680), MTHFR c.677C>T (SNP 1801133) and ESR1 454(-351) A>G (SNP 9340799) polymorphisms to mild and moderate depressive symptoms in menopausal women. In the perimenopausal and postmenopausal women, genotype association of the MAOA c.1460 CT and c.1460 CT+TT (OR=1.83; pcorr=0.009 and OR=1.85; pcorr=0.003, resp.), and of the MTHFR c.677 TT and c.677 CT+TT (OR=3.52; pcorr=0.00009 and OR=2.06; pcorr=0.0006, resp.), as well as of the COMT c.472 GA and COMT c.472 GA+AA genotypes (OR=2.23; pcorr=0.03 and OR=2.17; pcorr=0.027, resp.) in the postmenopausal women revealed significantly higher frequencies of these variants in depressed female patients than in controls, whereas the ESR1 454(-351) AG and 454(-351) AG+GG genotypes were associated with lower risk of depression in postmenopausal women (OR=0.48; pcorr=0.012, and OR=0.52; pcorr=0.015, resp.). Our study substantiates the involvement of the MAOA and MTHFR polymorphisms in climacteric depression and offers evidence that the COMT and ESR1 genes may also play a role in the susceptibility to depressive mood in postmenopausal women. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Detection of a single nucleotide polymorphism in the human alpha-lactalbumin gene: implications for human milk proteins.

PubMed

Chowanadisai, Winyoo; Kelleher, Shannon L; Nemeth, Jennifer F; Yachetti, Stephen; Kuhlman, Charles F; Jackson, Joan G; Davis, Anne M; Lien, Eric L; Lönnerdal, Bo

2005-05-01

Variability in the protein composition of breast milk has been observed in many women and is believed to be due to natural variation of the human population. Single nucleotide polymorphisms (SNPs) are present throughout the entire human genome, but the impact of this variation on human milk composition and biological activity and infant nutrition and health is unclear. The goals of this study were to characterize a variant of human alpha-lactalbumin observed in milk from a Filipino population by determining the location of the polymorphism in the amino acid and genomic sequences of alpha-lactalbumin. Milk and blood samples were collected from 20 Filipino women, and milk samples were collected from an additional 450 women from nine different countries. alpha-Lactalbumin concentration was measured by high-performance liquid chromatography (HPLC), and milk samples containing the variant form of the protein were identified with both HPLC and mass spectrometry (MS). The molecular weight of the variant form was measured by MS, and the location of the polymorphism was narrowed down by protein reduction, alkylation and trypsin digestion. Genomic DNA was isolated from whole blood, and the polymorphism location and subject genotype were determined by amplifying the entire coding sequence of human alpha-lactalbumin by PCR, followed by DNA sequencing. A variant form of alpha-lactalbumin was observed in HPLC chromatograms, and the difference in molecular weight was determined by MS (wild type=14,070 Da, variant=14,056 Da). Protein reduction and digestion narrowed the polymorphism between the 33rd and 77th amino acid of the protein. The genetic polymorphism was identified as adenine to guanine, which translates to a substitution from isoleucine to valine at amino acid 46. The frequency of variation was higher in milk from China, Japan and Philippines, which suggests that this polymorphism is most prevalent in Asia. There are SNPs in the genome for human milk proteins and their implications for protein bioactivity and infant nutrition need to be considered.

Lack of association between sigma receptor gene variants and schizophrenia.

PubMed

Satoh, Fumiaki; Miyatake, Ryosuke; Furukawa, Aizo; Suwaki, Hiroshi

2004-08-01

Several pharmacological studies suggest the possible involvement of sigma(1) receptors in the pathogenesis of schizophrenia. An association has been reported between schizophrenia and two variants (GC-241-240TT and Gln2Pro) in the sigma(1) receptor gene (SIGMAR1). We also previously reported that, along with T-485 A, these two variants alter SIGMAR1 function. To investigate the role of SIGMAR1 in conveying susceptibility to schizophrenia, we performed a case-control study. We initially screened for polymorphisms in the SIGMAR1 coding region using PCR-single strand conformation polymorphism analysis. The distribution of SIGMAR1 polymorphisms was analyzed in 100 schizophrenic and 104 control subjects. A novel G620A variant was detected in exon4. G620A was predicted to alter the amino acid represented by codon 211 from arginine to glutamine. Our case-control study showed no significant association between the T-485 A, GC-241-240TT, Gln2Pro, and G620A (Arg211Gln) variants and schizophrenia and clinical characteristics. These findings suggest that these SIGMAR1 variants may not affect susceptibility to schizophrenia.

MTR, SOUTH FACE OF REACTOR. SPECIAL SUPPLEMENTAL SHIELDING WAS REQUIRED ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

MTR, SOUTH FACE OF REACTOR. SPECIAL SUPPLEMENTAL SHIELDING WAS REQUIRED OUTSIDE OF MTR FOR EXPERIMENTS. THE AIRCRAFT NUCLEAR PROPULSION PROJECT DOMINATED THE USE OF THIS PART OF THE MTR. INL NEGATIVE NO. 7225. Unknown Photographer, 11/28/1952 - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

Test-retest reliability of myofascial trigger point detection in hip and thigh areas.

PubMed

Rozenfeld, E; Finestone, A S; Moran, U; Damri, E; Kalichman, L

2017-10-01

Myofascial trigger points (MTrP's) are a primary source of pain in patients with musculoskeletal disorders. Nevertheless, they are frequently underdiagnosed. Reliable MTrP palpation is the necessary for their diagnosis and treatment. The few studies that have looked for intra-tester reliability of MTrPs detection in upper body, provide preliminary evidence that MTrP palpation is reliable. Reliability tests for MTrP palpation on the lower limb have not yet been performed. To evaluate inter- and intra-tester reliability of MTrP recognition in hip and thigh muscles. Reliability study. 21 patients (15 males and 6 females, mean age 21.1 years) referred to the physical therapy clinic, 10 with knee or hip pain and 11 with pain in an upper limb, low back, shin or ankle. Two experienced physical therapists performed the examinations, blinded to the subjects' identity, medical condition and results of the previous MTrP evaluation. Each subject was evaluated four times, twice by each examiner in a random order. Dichotomous findings included a palpable taut band, tenderness, referred pain, and relevance of referred pain to patient's complaint. Based on these, diagnosis of latent MTrP's or active MTrP's was established. The evaluation was performed on both legs and included a total of 16 locations in the following muscles: rectus femoris (proximal), vastus medialis (middle and distal), vastus lateralis (middle and distal) and gluteus medius (anterior, posterior and distal). Inter- and intra-tester reliability (Cohen's kappa (κ)) values for single sites ranged from -0.25 to 0.77. Median intra-tester reliability was 0.45 and 0.46 for latent and active MTrP's, and median inter-tester reliability was 0.51 and 0.64 for latent and active MTrPs, respectively. The examination of the distal vastus medialis was most reliable for latent and active MTrP's (intra-tester k = 0.27-0.77, inter-tester k = 0.77 and intra-tester k = 0.53-0.72, inter-tester k = 0.72, correspondingly). Inter- and intra-tester reliability of active and latent MTrP evaluation was moderate to substantial. Palpation evaluation can be used for clinical diagnosis of MTrP's in the hip and thigh muscles. This study provides evidence that MTrP palpation is a moderately reliable diagnostic tool in the hip and thigh muscles and can be used in clinical practice and research. Copyright © 2017 Elsevier Ltd. All rights reserved.

Targeted Protein Degradation of Outer Membrane Decaheme Cytochrome MtrC Metal Reductase in Shewanella oneidensis MR-1 Measured Using Biarsenical Probe CrAsH-EDT2

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

Xiong, Yijia; Chen, Baowei; Shi, Liang

2011-10-14

Development of efficient microbial biofuel cells requires an ability to exploit interfacial electron transfer reactions to external electron acceptors, such as metal oxides; such reactions occur in the facultative anaerobic gram-negative bacterium Shewanella oneidensis MR-1 through the catalytic activity of the outer membrane decaheme c-type cytochrome MtrC. Central to the utility of this pathway to synthetic biology is an understanding of cellular mechanisms that maintain optimal MtrC function, cellular localization, and renewal by degradation and resynthesis. In order to monitor trafficking to the outer membrane, and the environmental sensitivity of MtrC, we have engineered a tetracysteine tag (i.e., CCPGCC) atmore » its C-terminus that permits labeling by the cell impermeable biarsenical fluorophore, carboxy-FlAsH (CrAsH) of MtrC at the surface of living Shewanella oneidensis MR-1 cells. In comparison, the cell permeable reagent FlAsH permits labeling of the entire population of MtrC, including proteolytic fragments resulting from incorrect maturation. We demonstrate specific labeling by CrAsH of engineered MtrC which is dependent on the presence of a functional type-2 secretion system (T2S), as evidenced by T2S system gspD or gspG deletion mutants which are incapable of CrAsH labeling. Under these latter conditions, MtrC undergoes proteolytic degradation to form a large 35-38 kDa fragment; this degradation product is also resolved during normal turnover of the CrAsH-labeled MtrC protein. No MtrC protein is released into the medium during turnover, suggesting the presence of cellular turnover systems involving MtrC reuptake and degradation. The mature MtrC localized on the outer membrane is a long-lived protein, with a turnover rate of 0.043 hr-1 that is insensitive to O2 concentration. Maturation of MtrC is relatively inefficient, with substantial rates of turnover of the immature protein prior to export to the outer membrane (i.e., 0.028 hr-1) that are consistent with the inherent complexity associated with correct heme insertion and acylation of MtrC that occurs in the periplasm prior to its targeting to the outer membrane. These latter results suggest that MtrC protein trafficking to the outer membrane and its subsequent degradation are tightly regulated, which is consistent with cellular processing pathways that target MtrC to extracellular structures and their possible role in promoting electron transfer from Shewanella to extracellular acceptors.« less

TPC2 polymorphisms associated with a hair pigmentation phenotype in humans result in gain of channel function by independent mechanisms.

PubMed

Chao, Yu-Kai; Schludi, Verena; Chen, Cheng-Chang; Butz, Elisabeth; Nguyen, O N Phuong; Müller, Martin; Krüger, Jens; Kammerbauer, Claudia; Ben-Johny, Manu; Vollmar, Angelika M; Berking, Carola; Biel, Martin; Wahl-Schott, Christian A; Grimm, Christian

2017-10-10

Two-pore channels (TPCs) are endolysosomal cation channels. Two members exist in humans, TPC1 and TPC2. Functional roles associated with the ubiquitously expressed TPCs include VEGF-induced neoangiogenesis, LDL-cholesterol trafficking and degradation, physical endurance under fasting conditions, autophagy regulation, the acrosome reaction in sperm, cancer cell migration, and intracellular trafficking of pathogens such as Ebola virus or bacterial toxins (e.g., cholera toxin). In a genome-wide association study for variants associated with human pigmentation characteristics two coding variants of TPC2, rs35264875 (encoding M484L) and rs3829241 (encoding G734E), have been found to be associated with a shift from brown to blond hair color. In two recent follow-up studies a role for TPC2 in pigmentation has been further confirmed. However, these human polymorphic variants have not been functionally characterized until now. The development of endolysosomal patch-clamp techniques has made it possible to investigate directly ion channel activities and characteristics in isolated endolysosomal organelles. We applied this technique here to scrutinize channel characteristics of the polymorphic TPC2 variants in direct comparison with WT. We found that both polymorphisms lead to a gain of channel function by independent mechanisms. We next conducted a clinical study with more than 100 blond- and brown/black-haired individuals. We performed a genotype/phenotype analysis and subsequently isolated fibroblasts from WT and polymorphic variant carriers for endolysosomal patch-clamp experimentation to confirm key in vitro findings.

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

PubMed

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

2016-11-01

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

The first step in using a robot in brain injury rehabilitation: patients' and health-care professionals' perspective.

PubMed

Boman, Inga-Lill; Bartfai, Aniko

2015-01-01

To evaluate the usability of a mobile telepresence robot (MTR) in a hospital training apartment (HTA). The MTR was manoeuvred remotely and was used for communication when assessing independent living skills, and for security monitoring of cognitively impaired patients. Occupational therapists (OTs) and nurses received training in how to use the MTR. The nurses completed a questionnaire regarding their expectations of using the MTR. OTs and patients staying in the HTA were interviewed about their experiences of the MTR. Interviews and questionnaires were analysed qualitatively. The HTA patients were very satisfied with the MTR. The OTs and nurses reported generally positive experiences. The OT's found that assessment via the MTR was more neutral than being physically present. However, the use of the MTR implied considerable difficulties for health-care professionals. The main obstacle for the nurses was the need for fast and easy access in emergency situations while protecting the patients' integrity. The results indicate that the MTR could be a useful tool to support daily living skills and safety monitoring of HTA patients. However, when designing technology for multiple users, such as health-care professionals, the needs of all users, their routines and support services involved, should also be considered. Implications for Rehabilitation A mobile telepresence robot (MTR) can be a useful tool for assessments and communication in rehabilitation. The design of the robot has to allow easy use by remote users, particularly in emergency situations. When designing MTRs the needs of ALL users have to be taken into consideration.

Hospital-based epidemiological and clinical characterisation of the malignant transformation of oral leukoplakia in a Chinese population.

PubMed

Lyu, Ming-Yue; Guo, Yu-Si; Li, Shuo; Yang, Di; Hua, Hong

2017-08-01

The aim of this review was to analyse, systematically, hospital-based epidemiological information concerning the malignant transformation rate (MTR) of oral leukoplakia (OL) in a Chinese population, as well as the associated risk factors. Four electronic databases were searched for studies dealing with OL and related risk factors, including age, gender, type of lesion, site, and smoking and drinking habits. The MTR of OL in the hospital-based Chinese population ranged from 4% to 13%, based on the studies analysed. Regarding risk factors, we found that female patients had a higher MTR than male patients, and that patients older than 50 years of age also had a higher MTR. Patients who smoked had a lower MTR, while alcohol consumption seemed to have no association with MTR. Malignant transformation occurred most commonly on the tongue. Regarding lesion type, non-homogeneous OL had a higher MTR, with the granular type having the highest MTR. Our results regarding the epidemiology of OL showed a similar trend to those reported in western populations and provided preliminary epidemiological information on the Chinese population. Our findings show that female gender, age >50 years and non-homogeneous OL are risk factors for malignant transformation. It is important to develop clinical strategies to educate, diagnose and treat patients with OL and to minimise the MTR of OL. © 2017 FDI World Dental Federation.

Helicase-Dependent RNA Decay Illuminated by a Cryo-EM Structure of a Human Nuclear RNA Exosome-MTR4 Complex.

PubMed

Weick, Eva-Maria; Puno, M Rhyan; Januszyk, Kurt; Zinder, John C; DiMattia, Michael A; Lima, Christopher D

2018-06-14

The ribonucleolytic RNA exosome interacts with RNA helicases to degrade RNA. To understand how the 3' to 5' Mtr4 helicase engages RNA and the nuclear exosome, we reconstituted 14-subunit Mtr4-containing RNA exosomes from Saccharomyces cerevisiae, Schizosaccharomyces pombe, and human and show that they unwind structured substrates to promote degradation. We loaded a human exosome with an optimized DNA-RNA chimera that stalls MTR4 during unwinding and determined its structure to an overall resolution of 3.45 Å by cryoelectron microscopy (cryo-EM). The structure reveals an RNA-engaged helicase atop the non-catalytic core, with RNA captured within the central channel and DIS3 exoribonuclease active site. MPP6 tethers MTR4 to the exosome through contacts to the RecA domains of MTR4. EXOSC10 remains bound to the core, but its catalytic module and cofactor C1D are displaced by RNA-engaged MTR4. Competition for the exosome core may ensure that RNA is committed to degradation by DIS3 when engaged by MTR4. Copyright © 2018 Elsevier Inc. All rights reserved.

Association between MTHFR 1298A>C polymorphism and spontaneous abortion with fetal chromosomal aneuploidy.

PubMed

Kim, Shin Young; Park, So Yeon; Choi, Ji Won; Kim, Do Jin; Lee, Shin Yeong; Lim, Ji Hyae; Han, Jung Yeol; Ryu, Hyun Mee; Kim, Min Hyoung

2011-10-01

PROBLEM  Polymorphisms in genes involved in folate metabolism are commonly associated with defects in folate-dependent homocysteine metabolism, which can result in DNA hypomethylation and chromosome nondisjunction. This prospective study aimed to investigate the associations between MTHFR 677C>T, MTHFR 1298A>C, MTR 2756A>G, MTRR 66A>G, and CBS 844ins68 polymorphisms and spontaneous abortion (SA) with fetal chromosomal aneuploidy. METHOD OF STUDY  Subjects included 33 SA with normal fetal karyotype, 24 SA with fetal chromosomal aneuploidy and 155 normal controls. Polymorphisms were genotyped by PCR-RFLP and QF-PCR analysis. RESULTS  The frequencies of MTHFR 1298AC and combined 1298AC/CC genotypes were higher in SA with fetal chromosomal aneuploidy than in controls. The 1298C allele frequency was also significantly higher in SA with fetal chromosomal aneuploidy than in controls. Moreover, the 1298C allele frequency was higher in SA with fetal chromosomal aneuploidy than in SA with normal fetal karyotype. The combined 1298AC/CC genotype was significantly associated with the risk of SA with fetal chromosomal aneuploidy compared with that of the 1298AA genotype (adjusted OR = 2.93, 95% CI: 1.11-7.69). There was no association between SA with fetal chromosomal aneuploidy and other polymorphisms. CONCLUSIONS  Our findings indicate that MTHFR 1298A>C polymorphism may be an independent risk factor for SA with fetal chromosomal aneuploidy. © 2011 John Wiley & Sons A/S.

Yield of the RYR2 Genetic Test in Suspected Catecholaminergic Polymorphic Ventricular Tachycardia and Implications for Test Interpretation.

PubMed

Kapplinger, Jamie D; Pundi, Krishna N; Larson, Nicholas B; Callis, Thomas E; Tester, David J; Bikker, Hennie; Wilde, Arthur A M; Ackerman, Michael J

2018-02-01

Pathogenic RYR2 variants account for ≈60% of clinically definite cases of catecholaminergic polymorphic ventricular tachycardia. However, the rate of rare benign RYR2 variants identified in the general population remains a challenge for genetic test interpretation. Therefore, we examined the results of the RYR2 genetic test among patients referred for commercial genetic testing and examined factors impacting variant interpretability. Frequency and location comparisons were made for RYR2 variants identified among 1355 total patients of varying clinical certainty and 60 706 Exome Aggregation Consortium controls. The impact of the clinical phenotype on the yield of RYR2 variants was examined. Six in silico tools were assessed using patient- and control-derived variants. A total of 18.2% (218/1200) of patients referred for commercial testing hosted rare RYR2 variants, statistically less than the 59% (46/78) yield among clinically definite cases, resulting in a much higher potential genetic false discovery rate among referrals considering the 3.2% background rate of rare, benign RYR2 variants. Exclusion of clearly putative pathogenic variants further complicates the interpretation of the next novel RYR2 variant. Exonic/topologic analyses revealed overrepresentation of patient variants in exons covering only one third of the protein. In silico tools largely failed to show evidence toward enhancement of variant interpretation. Current expert recommendations have resulted in increased use of RYR2 genetic testing in patients with questionable clinical phenotypes. Using the largest to date catecholaminergic polymorphic ventricular tachycardia patient versus control comparison, this study highlights important variables in the interpretation of variants to overcome the 3.2% background rate that confounds RYR2 variant interpretation. © 2018 American Heart Association, Inc.

An ATP2B4 polymorphism protects against malaria in pregnancy.

PubMed

Bedu-Addo, George; Meese, Stefanie; Mockenhaupt, Frank P

2013-05-15

Polymorphisms of ATP2B4 encoding an ubiquitous Ca(2+) pump protect against severe childhood malaria. We assessed the influence of a main polymorphism (rs10900585) on malaria among 834 delivering Ghanaian women. In homozygous primiparae, the odds of placental Plasmodium falciparum infection were reduced by 64%. No influence of the polymorphism on parasite density, low birth weight, or preterm delivery was discernible. However, malarial anemia was greatly reduced in primiparous carriers of the variant allele, paralleling the reduced impact of malaria on hemoglobin levels in this group. A common ATP2B4 polymorphism protects against malaria in pregnancy and related maternal anemia, suggesting ATP2B4 variant associated protection not to be limited to severe childhood malaria.

Modification of the association between early adversity and obsessive-compulsive disorder by polymorphisms in the MAOA, MAOB and COMT genes.

PubMed

McGregor, N W; Hemmings, S M J; Erdman, L; Calmarza-Font, I; Stein, D J; Lochner, C

2016-12-30

The monoamine oxidases (MAOA/B) and catechol-O-methyltransferase (COMT) enzymes break down regulatory components within serotonin and dopamine pathways, and polymorphisms within these genes are candidates for OCD susceptibility. Childhood trauma has been linked OCD psychopathology, but little attention has been paid to the interactions between genes and environment in OCD aetiology. This pilot study investigated gene-by-environment interactions between childhood trauma and polymorphisms in the MAOA, MAOB and COMT genes in OCD. Ten polymorphisms (MAOA: 3 variants, MAOB: 4 variants, COMT: 3 variants) were genotyped in a cohort of OCD patients and controls. Early-life trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Gene-by-gene (GxG) and gene-by-environment interactions (GxE) of the variants and childhood trauma were assessed using logistic regression models. Significant GxG interactions were found between rs362204 (COMT) and two independent polymorphisms in the MAOB gene (rs1799836 and rs6651806). Haplotype associations for OCD susceptibility were found for MAOB. Investigation of GxE interactions indicated that the sexual abuse sub-category was significantly associated with all three genes in haplotype x environment interaction analyses. Preliminary findings indicate that polymorphisms within the MAOB and COMT genes interact resulting in risk for OCD. Childhood trauma interacts with haplotypes in COMT, MAOA and MAOB, increasing risk for OCD. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A promoter variant of the APOA5 gene increases atherogenic LDL levels and arterial stiffness in hypertriglyceridemic patients.

PubMed

Kim, Minjoo; Kim, Minkyung; Yoo, Hye Jin; Lee, Eunji; Chae, Jey Sook; Lee, Sang-Hyun; Lee, Jong Ho

2017-01-01

Hypertriglyceridemia is recognized as an independent risk factor for coronary artery disease. The apolipoprotein A5 gene (APOA5) is a key regulator of triglyceride levels. We aimed to evaluate the associations of single nucleotide polymorphisms (SNPs) in APOA5, including -1131T>C and c.553G>T, with hypertriglyceridemia, apoA5 concentrations, atherogenic LDL cholesterol levels, and arterial stiffness in hypertriglyceridemic patients. The study population included 599 hypertriglyceridemic patients (case) and 1,549 untreated normotriglyceridemic subjects (control). We genotyped two APOA5 variants, -1131T>C (rs662799) and c.553G>T (rs2075291). The frequencies of the CC genotype of -1131T>C (0.165) and the T allele of c.553G>T (0.119) were significantly higher in hypertriglyceridemic patients than in normotriglyceridemic subjects (0.061 and 0.070, respectively; all p<0.001). In the control and case groups, both the -1131T>C and c.553G>T variants were associated with higher triglyceride and lower HDL cholesterol levels. Controls with the -1131CC variant had lower apoA5 concentrations than controls with the -1131TT variant. Similar effects of the -1131T>C variant on apoA5 were observed in the cases. In the hypertriglyceridemic group, the -1131T>C variant was associated with a smaller LDL particle size, higher levels of oxidized LDL and malondialdehyde, and higher brachial-ankle pulse wave velocity. The -1131T>C and c.553G>T polymorphisms were associated with hypertriglyceridemia in the study population, but only the -1131T>C polymorphism directly affected apoA5 concentrations. Hypertriglyceridemic patients carrying the APOA5 -1131T>C polymorphism exhibited increased atherogenic LDL levels and arterial stiffness, probably due to an effect of the -1131T>C polymorphism on apoA5 concentrations.

MTR BUILDING, TRA603. DETAILED VIEW OF NORTHWEST CORNERS OF MTR ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

MTR BUILDING, TRA-603. DETAILED VIEW OF NORTHWEST CORNERS OF MTR HIGH-BAY AND SECOND/THIRD STORY SECTIONS. NOTE SHAPE OF PANEL ABOVE WINDOW OVER "TRA-603" BUILDING NUMBERS. THIS IS A "STANDARD PANEL." INL NEGATIVE NUMBER HD46-42-2. Mike Crane, Photographer, 4/2005 - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

MTR BASEMENT. WORKERS (DON ALVORD AND CYRIL VAN ORDEN OF ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

MTR BASEMENT. WORKERS (DON ALVORD AND CYRIL VAN ORDEN OF PHILLIPS PETROLEUM CO.) POSE FOR GAMMA IRRADIATION EXPERIMENT IN MTR CANAL. CANS OF FOOD WILL BE LOWERED TO CANAL BOTTOM, WHERE SPENT MTR FUEL ELEMENTS EMIT GAMMA RADIATION. INL NEGATIVE NO. 11746. Unknown Photographer, 8/20/1954 - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

A High Proportion of Chromosome 21 Promoter Polymorphisms Influence Transcriptional Activity

PubMed Central

Buckland, Paul R.; Coleman, Sharol L.; Hoogendoorn, Bastiaan; Guy, Carol; Smith, S. Kaye; O’Donovan, Michael C.

2004-01-01

We have sought to obtain an unbiased estimate of the proportion of polymorphisms in promoters of human genes that have functional effects. We carried out polymorphism discovery on a randomly selected group of 51 gene promoters mapping to human chromosome 21 and successfully analyzed the effect on transcription of 38 of the sequence variants. To achieve this, a total of 53 different haplotypes from 20 promoters were cloned into a modified pGL3 luciferase reporter gene vector and were tested for their abilities to promote transcription in HEK293t and JEG-3 cells. Up to seven (18%) of the 38 tested variants altered transcription by 1.5-fold, confirming that a surprisingly high proportion of promoter region polymorphisms are likely to be functionally important. The functional variants were distributed across the promoters of CRYAA, IFNAR1, KCNJ15, NCAM2, IGSF5, and B3GALT5. Three of the genes (NCAM2, IFNAR1, and CRYAA) have been previously associated with human phenotypes and the polymorphisms we describe here may therefore play a role in those phenotypes. PMID:15200235

Association between MTHFR variant and diabetic neuropathy.

PubMed

Kakavand Hamidi, Armita; Radfar, Mania; Amoli, Mahsa M

2018-02-01

Methylene-tetrahydrofolate reductase (MTHFR) gene variant may play an important role in the pathophysiology of diabetes and its complications due to its influence on plasma homocysteine levels and also its effect on scavenging peroxynitrite radicals. Diabetic peripheral neuropathy (DPN) is one of the most common diabetic chronic complications. The aim of this study was to investigate the relationship between diabetic neuropathy and MTHFR gene C677T and 1298A ⁄C polymorphisms. Patients with type 2 diabetes N=248 were enrolled in the study, consisting of patients with neuropathy (N=141) and patients without neuropathy (N=107). MTHFR C677T polymorphism was analyzed using polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP) of genomic DNA for genotyping of samples. 1298A/C polymorphism was evaluated using ARMS-PCR. There was a significant difference in MTHFR polymorphism between the groups with and without neuropathy. Our results suggest that MTHFR 677 variant confer risk for diabetic neuropathy among Iranian patients with type 2 diabetes. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.

Localized grey matter damage in early primary progressive multiple sclerosis contributes to disability.

PubMed

Khaleeli, Z; Cercignani, M; Audoin, B; Ciccarelli, O; Miller, D H; Thompson, A J

2007-08-01

Disability in primary progressive multiple sclerosis (PPMS) has been correlated with damage to the normal appearing brain tissues. Magnetization transfer ratio (MTR) and volume changes indicate that much of this damage occurs in the normal appearing grey matter, but the clinical significance of this remains uncertain. We aimed to localize these changes to distinct grey matter regions, and investigate the clinical impact of the MTR changes. 46 patients with early PPMS and 23 controls underwent MT and high-resolution T1-weighted imaging. Patients were scored on the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite and subtests (Nine-Hole Peg Test, Timed Walk Test, Paced Auditory Serial Addition Test [PASAT]). Grey matter volume and MTR were compared between patients and controls, adjusting for age. Mean MTR for significant regions within the motor network and in areas relevant to PASAT performance were correlated with appropriate clinical scores, adjusting for grey matter volume. Patients showed reduced MTR and atrophy in the right pre- and left post-central gyri, right middle frontal gyrus, left insula, and thalamus bilaterally. Reduced MTR without significant atrophy occurred in the left pre-central gyrus, left superior frontal gyri, bilateral superior temporal gyri, right insula and visual cortex. Higher EDSS correlated with lower MTR in the right primary motor cortex (BA 4). In conclusion, localized grey matter damage occurs in early PPMS, and MTR change is more widespread than atrophy. Damage demonstrated by reduced MTR is clinically eloquent.

A Decaheme Cytochrome as a Molecular Electron Conduit in Dye-Sensitized Photoanodes

PubMed Central

Hwang, Ee Taek; Sheikh, Khizar; Orchard, Katherine L; Hojo, Daisuke; Radu, Valentin; Lee, Chong-Yong; Ainsworth, Emma; Lockwood, Colin; Gross, Manuela A; Adschiri, Tadafumi; Reisner, Erwin; Butt, Julea N; Jeuken, Lars J C

2015-01-01

In nature, charge recombination in light-harvesting reaction centers is minimized by efficient charge separation. Here, it is aimed to mimic this by coupling dye-sensitized TiO2 nanocrystals to a decaheme protein, MtrC from Shewanella oneidensis MR-1, where the 10 hemes of MtrC form a ≈7-nm-long molecular wire between the TiO2 and the underlying electrode. The system is assembled by forming a densely packed MtrC film on an ultra-flat gold electrode, followed by the adsorption of approximately 7 nm TiO2 nanocrystals that are modified with a phosphonated bipyridine Ru(II) dye (RuP). The step-by-step construction of the MtrC/TiO2 system is monitored with (photo)electrochemistry, quartz-crystal microbalance with dissipation (QCM-D), and atomic force microscopy (AFM). Photocurrents are dependent on the redox state of the MtrC, confirming that electrons are transferred from the TiO2 nanocrystals to the surface via the MtrC conduit. In other words, in these TiO2/MtrC hybrid photodiodes, MtrC traps the conduction-band electrons from TiO2 before transferring them to the electrode, creating a photobioelectrochemical system in which a redox protein is used to mimic the efficient charge separation found in biological photosystems. PMID:26180522

267 Spanish Exomes Reveal Population-Specific Differences in Disease-Related Genetic Variation

PubMed Central

Dopazo, Joaquín; Amadoz, Alicia; Bleda, Marta; Garcia-Alonso, Luz; Alemán, Alejandro; García-García, Francisco; Rodriguez, Juan A.; Daub, Josephine T.; Muntané, Gerard; Rueda, Antonio; Vela-Boza, Alicia; López-Domingo, Francisco J.; Florido, Javier P.; Arce, Pablo; Ruiz-Ferrer, Macarena; Méndez-Vidal, Cristina; Arnold, Todd E.; Spleiss, Olivia; Alvarez-Tejado, Miguel; Navarro, Arcadi; Bhattacharya, Shomi S.; Borrego, Salud; Santoyo-López, Javier; Antiñolo, Guillermo

2016-01-01

Recent results from large-scale genomic projects suggest that allele frequencies, which are highly relevant for medical purposes, differ considerably across different populations. The need for a detailed catalog of local variability motivated the whole-exome sequencing of 267 unrelated individuals, representative of the healthy Spanish population. Like in other studies, a considerable number of rare variants were found (almost one-third of the described variants). There were also relevant differences in allelic frequencies in polymorphic variants, including ∼10,000 polymorphisms private to the Spanish population. The allelic frequencies of variants conferring susceptibility to complex diseases (including cancer, schizophrenia, Alzheimer disease, type 2 diabetes, and other pathologies) were overall similar to those of other populations. However, the trend is the opposite for variants linked to Mendelian and rare diseases (including several retinal degenerative dystrophies and cardiomyopathies) that show marked frequency differences between populations. Interestingly, a correspondence between differences in allelic frequencies and disease prevalence was found, highlighting the relevance of frequency differences in disease risk. These differences are also observed in variants that disrupt known drug binding sites, suggesting an important role for local variability in population-specific drug resistances or adverse effects. We have made the Spanish population variant server web page that contains population frequency information for the complete list of 170,888 variant positions we found publicly available (http://spv.babelomics.org/), We show that it if fundamental to determine population-specific variant frequencies to distinguish real disease associations from population-specific polymorphisms. PMID:26764160

Structure and reconstitution of yeast Mpp6-nuclear exosome complexes reveals that Mpp6 stimulates RNA decay and recruits the Mtr4 helicase.

PubMed

Wasmuth, Elizabeth V; Zinder, John C; Zattas, Dimitrios; Das, Mom; Lima, Christopher D

2017-07-25

Nuclear RNA exosomes catalyze a range of RNA processing and decay activities that are coordinated in part by cofactors, including Mpp6, Rrp47, and the Mtr4 RNA helicase. Mpp6 interacts with the nine-subunit exosome core, while Rrp47 stabilizes the exoribonuclease Rrp6 and recruits Mtr4, but it is less clear if these cofactors work together. Using biochemistry with Saccharomyces cerevisiae proteins, we show that Rrp47 and Mpp6 stimulate exosome-mediated RNA decay, albeit with unique dependencies on elements within the nuclear exosome. Mpp6-exosomes can recruit Mtr4, while Mpp6 and Rrp47 each contribute to Mtr4-dependent RNA decay, with maximal Mtr4-dependent decay observed with both cofactors. The 3.3 Å structure of a twelve-subunit nuclear Mpp6 exosome bound to RNA shows the central region of Mpp6 bound to the exosome core, positioning its Mtr4 recruitment domain next to Rrp6 and the exosome central channel. Genetic analysis reveals interactions that are largely consistent with our model.

Photoreduction of Shewanella oneidensis Extracellular Cytochromes by Organic Chromophores and Dye‐Sensitized TiO2

PubMed Central

Ainsworth, Emma V.; Lockwood, Colin W. J.; White, Gaye F.; Hwang, Ee Taek; Sakai, Tsubasa; Gross, Manuela A.; Richardson, David J.; Clarke, Thomas A.

2016-01-01

Abstract The transfer of photoenergized electrons from extracellular photosensitizers across a bacterial cell envelope to drive intracellular chemical transformations represents an attractive way to harness nature's catalytic machinery for solar‐assisted chemical synthesis. In Shewanella oneidensis MR‐1 (MR‐1), trans‐outer‐membrane electron transfer is performed by the extracellular cytochromes MtrC and OmcA acting together with the outer‐membrane‐spanning porin⋅cytochrome complex (MtrAB). Here we demonstrate photoreduction of solutions of MtrC, OmcA, and the MtrCAB complex by soluble photosensitizers: namely, eosin Y, fluorescein, proflavine, flavin, and adenine dinucleotide, as well as by riboflavin and flavin mononucleotide, two compounds secreted by MR‐1. We show photoreduction of MtrC and OmcA adsorbed on RuII‐dye‐sensitized TiO2 nanoparticles and that these protein‐coated particles perform photocatalytic reduction of solutions of MtrC, OmcA, and MtrCAB. These findings provide a framework for informed development of strategies for using the outer‐membrane‐associated cytochromes of MR‐1 for solar‐driven microbial synthesis in natural and engineered bacteria. PMID:27685371

Metabolism of 5-methylthioribose to methionine

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

Miyazaki, J.H.; Yang, S.F.

1987-06-01

During ethylene biosynthesis, the H/sub 3/CS-group of S-adenosylmethionine is released as 5'-methylthioadenosine, which is recycled to methionine via 5-methylthioribose (MTR). In mungbean hypocotyls and cell-free extracts of avocado, (/sup 14/C)MTR was converted into labeled methionine via 2-keto-4-methylthiobutyric acid (KMB) and 2-hydroxy-4-methylthiobutyric acid (HMB), as intermediates. Incubation of (ribose-U-/sup 14/C)MTR with avocado extract resulted in the production of (/sup 14/C)formate, indicating the conversion of MTR to KMB involves a loss of formate, presumably from C-1 of MTR. Tracer studies showed that KMB was converted readily in vivo and in vitro to methionine, while HMB was converted much more slowly. The conversionmore » of KMB to methionine by dialyzed avocado extract requires an amino donor. Among several potential donors examined, L-glutamine was the most efficient. Anaerobiosis inhibited only partially the oxidation of MTR to formate, KMB/HMB, and methionine by avocado extract. The role of O/sub 2/ in the conversion of MTR to methionine is discussed.« less

Mismatch repair polymorphisms and the risk of colorectal cancer.

PubMed

Berndt, Sonja I; Platz, Elizabeth A; Fallin, M Daniele; Thuita, Lucy W; Hoffman, Sandra C; Helzlsouer, Kathy J

2007-04-01

Rare germline variants in mismatch repair genes have been linked to hereditary nonpolyposis colorectal cancer; however, it is unknown whether common polymorphisms in these genes alter the risk of colorectal cancer. To examine the association between common variants in mismatch repair genes and colorectal cancer, we conducted a case-cohort study within the CLUE II cohort. Four single nucleotide polymorphisms in 3 mismatch repair genes (MSH3 R940Q, MSH3 T1036A, MSH6 G39E and MLH1 I219V) were genotyped in 237 colorectal cancer cases and a subcohort of 2,189 participants. Incidence rate ratios (RRs) and 95% confidence intervals (95% CIs) for each polymorphism were estimated. The MSH3 1036A variant was found to be associated with an increased risk of colorectal cancer (RR=1.28, 95% CI: 0.94-1.74 and RR=1.65, 95% CI: 1.01-2.70 for the AT and TT genotypes, respectively, with p(trend)=0.02), particularly proximal colon cancer. Although the MSH3 940Q variant was only weakly associated with colorectal cancer overall (p(trend)=0.07), it was associated with a significant increased risk of proximal colon cancer (RR=1.69, 95% CI: 1.10-2.61 and RR=2.68, 95% CI: 0.96-7.47 for the RQ and QQ genotypes, respectively with p(trend)=0.005). Processed meat intake appeared to modify the association between the MSH3 polymorphisms and colorectal cancer (p(interaction) < 0.10 for both). No association was observed with the MSH6 and MLH1 polymorphisms overall. This study suggests that common polymorphisms in the mismatch repair gene, MSH3, may increase the risk of colorectal cancer, especially proximal colon cancer. (c) 2006 Wiley-Liss, Inc.

Effective utilization of genetic information for athletes and coaches: focus on ACTN3 R577X polymorphism

PubMed Central

Kikuchi, Naoki; Nakazato, Koichi

2015-01-01

Training variants (type, intensity, and duration of exercise) can be selected according to individual aims and fitness assessment. Recently, various methods of resistance and endurance training have been used for muscle hypertrophy and VO2max improvement. Although several genetic variants are associated with elite athletic performance and muscle phenotypes, genetic background has not been used as variant for physical training. ACTN3 R577X is a well-studied genetic polymorphism. It is the only genotype associated with elite athletic performance in multiple cohorts. This association is strongly supported by mechanistic data from an Actn3-knockout mouse model. In this review, possible guidelines are discussed for effective utilization of ACTN3 R577X polymorphism for physical training. PMID:26526670

Combined effects of the PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738 variants on NAFLD severity: a multicenter biopsy-based study1[S

PubMed Central

Krawczyk, Marcin; Rau, Monika; Schattenberg, Jörn M.; Bantel, Heike; Pathil, Anita; Demir, Münevver; Kluwe, Johannes; Boettler, Tobias; Lammert, Frank; Geier, Andreas

2017-01-01

The PNPLA3 p.I148M, TM6SF2 p.E167K, and MBOAT7 rs641738 variants represent genetic risk factors for nonalcoholic fatty liver disease (NAFLD). Here we investigate if these polymorphisms modulate both steatosis and fibrosis in patients with NAFLD. We recruited 515 patients with NAFLD (age 16–88 years, 280 female patients). Liver biopsies were performed in 320 patients. PCR-based assays were used to genotype the PNPLA3, TM6SF2, and MBOAT7 variants. Carriers of the PNPLA3 and TM6SF2 risk alleles showed increased serum aspartate aminotransferase and alanine transaminase activities (P < 0.05). The PNPLA3 genotype was associated with steatosis grades S2–S3 (P < 0.001) and fibrosis stages F2–F4 (P < 0.001). The TM6SF2 genotype was associated with steatosis (P = 0.003) but not with fibrosis (P > 0.05). The MBOAT7 variant was solely associated with increased fibrosis (P = 0.046). In the multivariate model, variants PNPLA3 (P = 0.004) and TM6SF2 (P = 0.038) were associated with steatosis. Fibrosis stages were affected by the PNPLA3 (P = 0.042) and MBOAT7 (P = 0.021) but not by the TM6SF2 polymorphism (P > 0.05). The PNPLA3, TM6SF2, and MBOAT7 variants are associated with increased liver injury. The TM6SF2 variant seems to modulate predominantly hepatic fat accumulation, whereas the MBOAT7 polymorphism is linked to fibrosis. The PNPLA3 polymorphism confers risk of both increased steatosis and fibrosis. PMID:27836992

Combined effects of the PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738 variants on NAFLD severity: a multicenter biopsy-based study.

PubMed

Krawczyk, Marcin; Rau, Monika; Schattenberg, Jörn M; Bantel, Heike; Pathil, Anita; Demir, Münevver; Kluwe, Johannes; Boettler, Tobias; Lammert, Frank; Geier, Andreas

2017-01-01

The PNPLA3 p.I148M, TM6SF2 p.E167K, and MBOAT7 rs641738 variants represent genetic risk factors for nonalcoholic fatty liver disease (NAFLD). Here we investigate if these polymorphisms modulate both steatosis and fibrosis in patients with NAFLD. We recruited 515 patients with NAFLD (age 16-88 years, 280 female patients). Liver biopsies were performed in 320 patients. PCR-based assays were used to genotype the PNPLA3, TM6SF2, and MBOAT7 variants. Carriers of the PNPLA3 and TM6SF2 risk alleles showed increased serum aspartate aminotransferase and alanine transaminase activities (P < 0.05). The PNPLA3 genotype was associated with steatosis grades S2-S3 (P < 0.001) and fibrosis stages F2-F4 (P < 0.001). The TM6SF2 genotype was associated with steatosis (P = 0.003) but not with fibrosis (P > 0.05). The MBOAT7 variant was solely associated with increased fibrosis (P = 0.046). In the multivariate model, variants PNPLA3 (P = 0.004) and TM6SF2 (P = 0.038) were associated with steatosis. Fibrosis stages were affected by the PNPLA3 (P = 0.042) and MBOAT7 (P = 0.021) but not by the TM6SF2 polymorphism (P > 0.05). The PNPLA3, TM6SF2, and MBOAT7 variants are associated with increased liver injury. The TM6SF2 variant seems to modulate predominantly hepatic fat accumulation, whereas the MBOAT7 polymorphism is linked to fibrosis. The PNPLA3 polymorphism confers risk of both increased steatosis and fibrosis. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

Association of ghrelin polymorphisms with metabolic syndrome in Han Nationality Chinese.

PubMed

Xu, Ling-Ling; Xiang, Hong-Ding; Qiu, Chang-Chun; Xu, Qun

2008-06-01

To investigate the association of ghrelin gene polymorphisms with metabolic syndrome in Han Nationality Chinese. A total of 240 patients with metabolic syndrome and 427 adults aged above forty years were recruited. Genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism analysis. The allelic frequency of the Leu72Met polymorphism was 17.3% in the patient group and 11.9% in the control group (chi2 = 7.36, P = 0.007). Metabolic syndrome was more prevalent among carriers of the Met72 variant (43.8 vs 33.1%, age- and sex-adjusted odds ratio = 1.57, P = 0.01). No Arg51Gln variants were found in our study subjects. Rather than being associated with its individual components, Leu72Met polymorphism is associated with metabolic syndrome in the Han Nationality Chinese. Arg51Gln polymorphism is rare in the Han Nationality Chinese.

A new-generation 5-nitroimidazole can induce highly metronidazole-resistant Giardia lamblia in vitro

PubMed Central

Dunn, Linda A.; Burgess, Anita G.; Krauer, Kenia G.; Eckmann, Lars; Vanelle, Patrice; Crozet, Maxime D.; Gillin, Frances D.; Upcroft, Peter; Upcroft, Jacqueline A.

2010-01-01

The 5-nitroimidazole (NI) compound C17, with a side chain carrying a remote phenyl group in the 2-position of the imidazole ring, is at least 14-fold more active against the gut protozoan parasite Giardia lamblia than the 5-NI drug metronidazole (MTR), with a side chain in the 1-position of the imidazole ring, which is the primary drug for the treatment of giardiasis. Over 10 months, lines resistant to C17 were induced in vitro and were at least 12-fold more resistant to C17 than the parent strains. However, these lines had ID90 values (concentration of drug at which 10% of control parasite ATP levels are detected) for MTR of >200 μM, whilst lines induced to be highly resistant to MTR in vitro have maximum ID90 values around 100 μM (MTR-susceptible isolates typically have an ID90 of 5–12.8 μM). The mechanism of MTR activation in Giardia apparently involves reduction to toxic radicals by the activity of pyruvate:ferredoxin oxidoreductase (PFOR) and the electron acceptor ferredoxin. MTR-resistant Giardia have decreased PFOR activity, which is consistent with decreased activation of MTR in these lines, but C17-resistant lines have normal levels of PFOR. Therefore, an alternative mechanism of resistance in Giardia must account for these super-MTR-resistant cells. PMID:20456926

Gender-related association of AGT gene variants (M235T and T174M) with essential hypertension--a case-control study.

PubMed

Mohana, Vamsi U; Swapna, N; Surender, Reddy S; Vishnupriya, S; Padma, Tirunilai

2012-01-01

The human angiotensinogen (AGT) is a promising candidate gene for evaluating susceptibility to essential hypertension (EH). We aimed to assess the association of the variants of AGT gene and the extent of risk involved in developing EH. A case-control study was designed to compare 279 hypertensive patients with 200 normotensive subjects. The frequency distribution of M235T and T174M polymorphisms of AGT gene was assessed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method. A haplotype analysis was done to determine the risk conferred by the combination of alleles of the two polymorphisms for EH. The genotype distribution of the T174M variant differed significantly between hypertensives and normotensives, whereas genotypes of M235T variant did not show such difference. For M235T, MM genotype conferred an increase in risk for hypertension in women (odds ratios (OR) = 2.82; 95% confidence interval (CI) = 1.22-6.49). For the variant T174M, the TM genotype frequency was elevated in hypertensive females (36.5%) as compared to controls (18.8 %; P = .034). The 174M allele was more prevalent among female hypertensives than among female controls (0.20 vs. 0.12; P = .059). The haplotype analysis showed a significant association for the haplotypes of paired markers (M235 and 174M) with a χ(2) value of 8.037 (P = .045). Our findings suggest that the polymorphic variants of AGT gene-M235T and T174M-show association with hypertension.

Influence of Folate-Related Gene Polymorphisms on High-Dose Methotrexate-Related Toxicity and Prognosis in Turkish Children with Acute Lymphoblastic Leukemia.

PubMed

Yazıcıoğlu, Burcu; Kaya, Zühre; Güntekin Ergun, Sezen; Perçin, Ferda; Koçak, Ülker; Yenicesu, İdil; Gürsel, Türkiz

2017-06-05

High-dose methotrexate (HD-MTX) is widely used in the consolidation phase of childhood acute lymphoblastic leukemia (ALL), but the roles that polymorphisms in folate-related genes (FRGs) play in HD-MTX toxicity and prognosis in children with ALL are not understood. The aims of this study were to investigate the frequencies of polymorphisms in the genes for thymidylate synthase (TS), methionine synthase reductase (MTRR), and methylene tetrahydrofolate reductase (MTHFR) in Turkish children with ALL and to assess associations between these polymorphisms and HD-MTX-related toxicity and leukemia prognosis in this patient group. FRG polymorphisms were assessed by real-time polymerase chain reaction. Survival status, MTX levels, and toxicity data were retrieved from 106 patients' charts. The allele frequencies for the FRG polymorphisms were as follows: TS 2R 41.0%, 3R 57.0%, and 4R 2.0%; MTRR 66A 42.4% and 66G 57.6%; MTHFR 677C 59.3% and 677T 40.7%; and MTHFR 1298A 58.1% and 1298C 41.9%. At the 48th hour of HD-MTX infusion, serum MTX was significantly higher in patients who had TS 2R/3R/4R variants as compared to those with wild-type TS (p<0.05). No significant differences were detected with respect to event-free survival or toxicity between wild-type and other FRG variants. The frequencies of FRG polymorphisms in Turkish children with ALL are similar to those reported in other Caucasian populations. This is the first published finding of the TS 3R/4R variant in the Turkish population. The results indicate that HD-MTX can be tolerated by leukemic children with some polymorphic variants of FRG; thus, it may prevent future risk of leukemic relapse.

Angiotensin-converting enzyme activity in Cavalier King Charles Spaniels with an ACE gene polymorphism and myxomatous mitral valve disease.

PubMed

Meurs, Kathryn M; Olsen, Lisbeth H; Reimann, Maria J; Keene, Bruce W; Atkins, Clarke E; Adin, Darcy; Aona, Brent; Condit, Julia; DeFrancesco, Teresa; Reina-Doreste, Yamir; Stern, Joshua A; Tou, Sandra; Ward, Jessica; Woodruff, Kathleen

2018-02-01

Myxomatous mitral valve disease (MMVD) is the most common heart disease in the dog. It is particularly common in the Cavalier King Charles Spaniel (CKCS) breed and affected dogs are frequently managed with angiotensin-converting enzyme inhibitors (ACE-I). We have previously identified a canine ACE gene polymorphism associated with a decrease in angiotensin-converting enzyme (ACE) activity. The aim of this study was to evaluate for the prevalence of the ACE polymorphism in CKCS with mitral valve disease and to determine whether the presence of the polymorphism is associated with alterations in ACE activity at different stages of cardiac disease. Seventy-three dogs with a diagnosis of mitral valve disease were evaluated and a blood sample was drawn for ACE polymorphism genotyping and ACE activity measurement. Forty-three dogs were homozygous for the ACE polymorphism; five were heterozygous and 25 were homozygous wild type. The mean age and the median severity of disease were not different for dogs with the polymorphism and dogs with the wild-type sequence. The median baseline ACE activity was significantly lower for the ACE polymorphism (27.0 U/l) than the wild-type sequence dogs (31.0 U/l) (P=0.02). Dogs with more severe disease and the ACE polymorphism had significantly lower levels of ACE activity than dogs with the wild-type sequence (P=0.03). The CKCS appears to have a high prevalence of the ACE variant. Dogs with the ACE variant had lower levels of ACE activity even in more advanced mitral valve disease than dogs without the variant. The clinical significance of this finding and its impact on the need for ACE-I in dogs with the polymorphism and heart disease deserves further study.

Epidermal growth factor receptor gene polymorphisms are associated with prognostic features of breast cancer

PubMed Central

2014-01-01

Background The epidermal growth factor receptor (EGFR) is differently expressed in breast cancer, and its presence may favor cancer progression. We hypothesized that two EGFR functional polymorphisms, a (CA)n repeat in intron 1, and a single nucleotide polymorphism, R497K, may affect EGFR expression and breast cancer clinical profile. Methods The study population consisted of 508 Brazilian women with unilateral breast cancer, and no distant metastases. Patients were genotyped for the (CA)n and R497K polymorphisms, and the associations between (CA)n polymorphism and EGFR transcript levels (n = 129), or between either polymorphism and histopathological features (n = 505) were evaluated. The REMARK criteria of tumor marker evaluation were followed. Results (CA)n lengths ranged from 14 to 24 repeats, comprehending 11 alleles and 37 genotypes. The most frequent allele was (CA)16 (0.43; 95% CI = 0.40–0.46), which was set as the cut-off length to define the Short allele. Variant (CA)n genotypes had no significant effect in tumoral EGFR mRNA levels, but patients with two (CA)n Long alleles showed lower chances of being negative for progesterone receptor (ORadjusted = 0.42; 95% CI = 0.19–0.91). The evaluation of R497K polymorphism indicated a frequency of 0.21 (95% CI = 0.19 – 0.24) for the variant (Lys) allele. Patients with variant R497K genotypes presented lower proportion of worse lymph node status (pN2 or pN3) when compared to the reference genotype Arg/Arg (ORadjusted = 0.32; 95% CI = 0.17–0.59), which resulted in lower tumor staging (ORadjusted = 0.34; 95% CI = 0.19-0.63), and lower estimated recurrence risk (OR = 0.50; 95% CI = 0.30-0.81). The combined presence of both EGFR polymorphisms (Lys allele of R497K and Long/Long (CA)n) resulted in lower TNM status (ORadjusted = 0.22; 95% CI = 0.07-0.75) and lower ERR (OR = 0.25; 95% CI = 0.09-0.71). When tumors were stratified according to biological classification, the favorable effects of variant EGFR polymorphisms were preserved for luminal A tumors, but not for other subtypes. Conclusions The data suggest that the presence of the variant forms of EGFR polymorphisms may lead to better prognosis in breast cancer, especially in patients with luminal A tumors. PMID:24629097

Structure and reconstitution of yeast Mpp6-nuclear exosome complexes reveals that Mpp6 stimulates RNA decay and recruits the Mtr4 helicase

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

Wasmuth, Elizabeth V.; Zinder, John C.; Zattas, Dimitrios

Nuclear RNA exosomes catalyze a range of RNA processing and decay activities that are coordinated in part by cofactors, including Mpp6, Rrp47, and the Mtr4 RNA helicase. Mpp6 interacts with the nine-subunit exosome core, while Rrp47 stabilizes the exoribonuclease Rrp6 and recruits Mtr4, but it is less clear if these cofactors work together. Using biochemistry with Saccharomyces cerevisiae proteins, we show that Rrp47 and Mpp6 stimulate exosome-mediated RNA decay, albeit with unique dependencies on elements within the nuclear exosome. Mpp6-exosomes can recruit Mtr4, while Mpp6 and Rrp47 each contribute to Mtr4-dependent RNA decay, with maximal Mtr4-dependent decay observed with bothmore » cofactors. The 3.3 Å structure of a twelve-subunit nuclear Mpp6 exosome bound to RNA shows the central region of Mpp6 bound to the exosome core, positioning its Mtr4 recruitment domain next to Rrp6 and the exosome central channel. Genetic analysis reveals interactions that are largely consistent with our model.« less

MTR AND ETR COMPLEXES. CAMERA FACING EASTERLY TOWARD CHEMICAL PROCESSING ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

MTR AND ETR COMPLEXES. CAMERA FACING EASTERLY TOWARD CHEMICAL PROCESSING PLANT. MTR AND ITS ATTACHMENTS IN FOREGROUND. ETR BEYOND TO RIGHT. INL NEGATIVE NO. 56-4100. - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

Association of ITPA polymorphisms rs6051702/rs1127354 instead of rs7270101/rs1127354 as predictor of ribavirin-associated anemia in chronic hepatitis C treated patients.

PubMed

D'Avolio, Antonio; De Nicolò, Amedeo; Cusato, Jessica; Ciancio, Alessia; Boglione, Lucio; Strona, Silvia; Cariti, Giuseppe; Troshina, Giulia; Caviglia, Gian Paolo; Smedile, Antonina; Rizzetto, Mario; Di Perri, Giovanni

2013-10-01

Functional variants rs7270101 and rs1127354 of inosine triphosphatase (ITPA) were recently found to protect against ribavirin (RBV)-induced hemolytic anemia. However, no definitive data are yet available on the role of no functional rs6051702 polymorphism. Since a simultaneous evaluation of the three ITPA SNPs for hemolytic anemia has not yet been investigated, we aimed to understand the contribution of each SNPs and its potential clinical use to predict anemia in HCV treated patients. A retrospective analysis included 379 HCV treated patients. The ITPA variants rs6051702, rs7270101 and rs1127354 were genotyped and tested for association with achieving anemia at week 4. We also investigated, using multivariate logistic regression, the impact of each single and paired associated polymorphism on anemia onset. All SNPs were associated with Hb decrease. The carrier of at least one variant allele in the functional ITPA SNPs was associated with a lower decrement of Hb, as compared to patients without a variant allele. In multivariate logistic regression analyses the carrier of a variant allele in the rs6051702/rs1127354 association (OR=0.11, p=1.75×10(-5)) and Hb at baseline (OR=1.51, p=1.21×10(-4)) were independently associated with protection against clinically significant anemia at week 4. All ITPA polymorphisms considered were shown to be significantly associated with anemia onset. A multivariate regression model based on ITPA genetic polymorphisms was developed for predicting the risk of anemia. Considering the characterization of pre-therapy anemia predictors, rs6051702 SNP in association to rs1127354 is more informative in order to avoid this relevant adverse event. Copyright © 2013 Elsevier B.V. All rights reserved.

267 Spanish Exomes Reveal Population-Specific Differences in Disease-Related Genetic Variation.

PubMed

Dopazo, Joaquín; Amadoz, Alicia; Bleda, Marta; Garcia-Alonso, Luz; Alemán, Alejandro; García-García, Francisco; Rodriguez, Juan A; Daub, Josephine T; Muntané, Gerard; Rueda, Antonio; Vela-Boza, Alicia; López-Domingo, Francisco J; Florido, Javier P; Arce, Pablo; Ruiz-Ferrer, Macarena; Méndez-Vidal, Cristina; Arnold, Todd E; Spleiss, Olivia; Alvarez-Tejado, Miguel; Navarro, Arcadi; Bhattacharya, Shomi S; Borrego, Salud; Santoyo-López, Javier; Antiñolo, Guillermo

2016-05-01

Recent results from large-scale genomic projects suggest that allele frequencies, which are highly relevant for medical purposes, differ considerably across different populations. The need for a detailed catalog of local variability motivated the whole-exome sequencing of 267 unrelated individuals, representative of the healthy Spanish population. Like in other studies, a considerable number of rare variants were found (almost one-third of the described variants). There were also relevant differences in allelic frequencies in polymorphic variants, including ∼10,000 polymorphisms private to the Spanish population. The allelic frequencies of variants conferring susceptibility to complex diseases (including cancer, schizophrenia, Alzheimer disease, type 2 diabetes, and other pathologies) were overall similar to those of other populations. However, the trend is the opposite for variants linked to Mendelian and rare diseases (including several retinal degenerative dystrophies and cardiomyopathies) that show marked frequency differences between populations. Interestingly, a correspondence between differences in allelic frequencies and disease prevalence was found, highlighting the relevance of frequency differences in disease risk. These differences are also observed in variants that disrupt known drug binding sites, suggesting an important role for local variability in population-specific drug resistances or adverse effects. We have made the Spanish population variant server web page that contains population frequency information for the complete list of 170,888 variant positions we found publicly available (http://spv.babelomics.org/), We show that it if fundamental to determine population-specific variant frequencies to distinguish real disease associations from population-specific polymorphisms. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Distinctive Epstein-Barr virus variants associated with benign and malignant pediatric pathologies: LMP1 sequence characterization and linkage with other viral gene polymorphisms.

PubMed

Lorenzetti, Mario Alejandro; Gantuz, Magdalena; Altcheh, Jaime; De Matteo, Elena; Chabay, Paola Andrea; Preciado, María Victoria

2012-03-01

The ubiquitous Epstein-Barr virus (EBV) is related to the development of lymphoma and is also the etiological agent for infectious mononucleosis (IM). Sequence variations in the gene encoding LMP1 have been deeply studied in different pathologies and geographic regions. Controversial results propose the existence of tumor-related variants, while others argued in favor of a geographical distribution of these variants. Reports assessing EBV variants in IM were performed in adult patients who displayed multiple variant infections. In the present study, LMP1 variants in 15 pediatric patients with IM and 20 pediatric patients with EBV-associated lymphomas from Argentina were analyzed as representatives of benign and malignant infections in children, respectively. A 3-month follow-up study of LMP1 variants in peripheral blood cells and in oral secretions of patients with IM was performed. Moreover, an integrated linkage analysis was performed with variants of EBNA1 and the promoter region of BZLF1. Similar sequence polymorphisms were detected in both pathological conditions, IM and lymphoma, but these differ from those previously described in healthy donors from Argentina and Brazil. The results suggest that certain LMP1 polymorphisms, namely, the 30-bp deletion and high copy number of the 33-bp repeats, are associated with EBV-related pathologies, either benign or malignant, instead of just being tumor related. Additionally, this is the first study to describe the Alaskan variant in EBV-related lymphomas that previously was restricted to nasopharyngeal carcinomas from North America.

Distinctive Epstein-Barr Virus Variants Associated with Benign and Malignant Pediatric Pathologies: LMP1 Sequence Characterization and Linkage with Other Viral Gene Polymorphisms

PubMed Central

Gantuz, Magdalena; Altcheh, Jaime; De Matteo, Elena; Chabay, Paola Andrea; Preciado, María Victoria

2012-01-01

The ubiquitous Epstein-Barr virus (EBV) is related to the development of lymphoma and is also the etiological agent for infectious mononucleosis (IM). Sequence variations in the gene encoding LMP1 have been deeply studied in different pathologies and geographic regions. Controversial results propose the existence of tumor-related variants, while others argued in favor of a geographical distribution of these variants. Reports assessing EBV variants in IM were performed in adult patients who displayed multiple variant infections. In the present study, LMP1 variants in 15 pediatric patients with IM and 20 pediatric patients with EBV-associated lymphomas from Argentina were analyzed as representatives of benign and malignant infections in children, respectively. A 3-month follow-up study of LMP1 variants in peripheral blood cells and in oral secretions of patients with IM was performed. Moreover, an integrated linkage analysis was performed with variants of EBNA1 and the promoter region of BZLF1. Similar sequence polymorphisms were detected in both pathological conditions, IM and lymphoma, but these differ from those previously described in healthy donors from Argentina and Brazil. The results suggest that certain LMP1 polymorphisms, namely, the 30-bp deletion and high copy number of the 33-bp repeats, are associated with EBV-related pathologies, either benign or malignant, instead of just being tumor related. Additionally, this is the first study to describe the Alaskan variant in EBV-related lymphomas that previously was restricted to nasopharyngeal carcinomas from North America. PMID:22205789

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

Fahrenkrog, Annette M.; Neves, Leandro G.; Resende, Jr., Marcio F. R.

Genome-wide association studies (GWAS) have been used extensively to dissect the genetic regulation of complex traits in plants. These studies have focused largely on the analysis of common genetic variants despite the abundance of rare polymorphisms in several species, and their potential role in trait variation. Here, we conducted the first GWAS in Populus deltoides, a genetically diverse keystone forest species in North America and an important short rotation woody crop for the bioenergy industry. We searched for associations between eight growth and wood composition traits, and common and low-frequency single-nucleotide polymorphisms detected by targeted resequencing of 18 153 genesmore » in a population of 391 unrelated individuals. To increase power to detect associations with low-frequency variants, multiple-marker association tests were used in combination with single-marker association tests. Significant associations were discovered for all phenotypes and are indicative that low-frequency polymorphisms contribute to phenotypic variance of several bioenergy traits. Our results suggest that both common and low-frequency variants need to be considered for a comprehensive understanding of the genetic regulation of complex traits, particularly in species that carry large numbers of rare polymorphisms. Lastly, these polymorphisms may be critical for the development of specialized plant feedstocks for bioenergy.« less

Frequency of genetic polymorphisms of PXR gene in the Brazilian population.

PubMed

Moreira, Ricardo P P; Jorge, Alexander A L; Mendonca, Berenice B; Bachega, Tânia A S S

2011-01-01

PXR polymorphisms have been implicated in modulating CYP3A4 and PXR expression, potentially accounting for interindividual differences in drug metabolism. The prevalence of PXR polymorphisms varies among ethnic groups and data on the allelic distribution in the highly mixed Brazilian population is lacking. The aim of this study was to analyze genetic variations in the PXR gene in Brazilians and to compare the results to other ethnic groups. DNA samples from 117 healthy Brazilians underwent PCR amplification and sequencing. Eleven polymorphisms were identified, 3 of which are highly associated with differences in CYP3A4 expression. We also identified 1 new synonymous variant in 1.3% of the alleles. Among the functional polymorphisms, -25913 C>T and -6994T>C occurred at a higher frequency comparedtothe Africanalleles (p < 0.05) but at a lower frequency compared to Caucasian alleles. The 8055 C>T allele was found at a similar frequency to those described in Caucasians and Africans (p > 0.05). We observed that functional variants of the PXR were frequent in our sample of the Brazilian population. Our results suggest that PXR gene variants may be of interest in pharmacogenetic studies involving Brazilians.

Differences in the efficiency of reductive activation of methionine synthase and exogenous electron acceptors between the common polymorphic variants of human methionine synthase reductase.

PubMed

Olteanu, Horatiu; Munson, Troy; Banerjee, Ruma

2002-11-12

Methionine synthase reductase (MSR) catalyzes the conversion of the inactive form of human methionine synthase to the active state of the enzyme. This reaction is of paramount physiological importance since methionine synthase is an essential enzyme that plays a key role in the methionine and folate cycles. A common polymorphism in human MSR has been identified (66A --> G) that leads to replacement of isoleucine with methionine at residue 22 and has an allele frequency of 0.5. Another polymorphism is 524C --> T, which leads to the substitution of serine 175 with leucine, but its allele frequency is not known. The I22M polymorphism is a genetic determinant for mild hyperhomocysteinemia, a risk factor for cardiovascular disease. In this study, we have examined the kinetic properties of the M22/S175 and I22/S175 and the I22/L175 and I22/S175 pairs of variants. EPR spectra of the semiquinone forms of variants I22/S175 and M22/S175 are indistinguishable and exhibit an isotropic signal at g = 2.00. In addition, the electronic absorption and reduction stoichiometries with NADPH are identical in these variants. Significantly, the variants activate methionine synthase with the same V(max); however, a 3-4-fold higher ratio of MSR to methionine synthase is required to elicit maximal activity with the M22/S175 and I22/L175 variant versus the I22/S175 enzyme. Differences are also observed between the variants in the efficacies of reduction of the artificial electron acceptors: ferricyanide, 2,6-dichloroindophenol, 3-acetylpyridine adenine dinucleotide phosphate, menadione, and the anticancer drug doxorubicin. These results reveal differences in the interactions between the natural and artificial electron acceptors and MSR variants in vitro, which are predicted to result in less efficient reductive repair of methionine synthase in vivo.

ENGINEERING TEST REACTOR, TRA642. CONTEXTUAL VIEW ORIENTATING ETR TO MTR. ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

ENGINEERING TEST REACTOR, TRA-642. CONTEXTUAL VIEW ORIENTATING ETR TO MTR. CAMERA IS ON ROOF OF MTR BUILDING AND FACES DUE SOUTH. MTR SERVICE BUILDING, TRA-635, IN LOWER RIGHT CORNER. STEEL FRAMES SHOW BUILDINGS TO BE ATTACHED TO ETR BUILDING. HIGH-BAY SECTION IN CENTER IS REACTOR BUILDING. TWO-STORY CONTROL ROOM AND OFFICE BUILDING, TRA-647, IS BETWEEN IT AND MTR SERVICE BUILDING. STRUCTURE TO THE LEFT (WITH NO FRAMING YET) IS COMPRESSOR BUILDING, TRA-643, AND BEYOND IT WILL BE HEAT EXCHANGER BUILDING, TRA-644, GREAT SOUTHERN BUTTE ON HORIZON. INL NEGATIVE NO. 56-2382. Jack L. Anderson, Photographer, 6/10/1956 - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

Protein variants in Hiroshima and Nagasaki: tales of two cities.

PubMed Central

Neel, J V; Satoh, C; Smouse, P; Asakawa, J; Takahashi, N; Goriki, K; Fujita, M; Kageoka, T; Hazama, R

1988-01-01

The results of 1,465,423 allele product determinations based on blood samples from Hiroshima and Nagasaki, involving 30 different proteins representing 32 different gene products, are analyzed in a variety of ways, with the following conclusions: (1) Sibships and their parents are included in the sample. Our analysis reveals that statistical procedures designed to reduce the sample to equivalent independent genomes do not in population comparisons compensate for the familial cluster effect of rare variants. Accordingly, the data set was reduced to one representative of each sibship (937,427 allele products). (2) Both chi 2-type contrasts and a genetic distance measure (delta) reveal that rare variants (P less than .01) are collectively as effective as polymorphisms in establishing genetic differences between the two cities. (3) We suggest that rare variants that individually exhibit significant intercity differences are probably the legacy of tribal private polymorphisms that occurred during prehistoric times. (4) Despite the great differences in the known histories of the two cities, both the overall frequency of rare variants and the number of different rare variants are essentially identical in the two cities. (5) The well-known differences in locus variability are confirmed, now after adjustment for sample size differences for the various locus products; in this large series we failed to detect variants at only three of 29 loci for which sample size exceeded 23,000. (6) The number of alleles identified per locus correlates positively with subunit molecular weight. (7) Loci supporting genetic polymorphisms are characterized by more rare variants than are loci at which polymorphisms were not encountered. (8) Loci whose products do not appear to be essential for health support more variants than do loci the absence of whose product is detrimental to health. (9) There is a striking excess of rare variants over the expectation under the neutral mutation/drift/equilibrium theory. We suggest that this finding is primarily due to the relatively recent (in genetic time) agglomeration of previously separated tribal populations; efforts to test for agreement with the expectations of this theory by using data from modern cosmopolitan populations are exercises in futility. (10) All of these findings should characterize DNA variants in exons as more data become available, since the finding are the protein expression of such variants. PMID:3195587

Protein variants in Hiroshima and Nagasaki: tales of two cities.

PubMed

Neel, J V; Satoh, C; Smouse, P; Asakawa, J; Takahashi, N; Goriki, K; Fujita, M; Kageoka, T; Hazama, R

1988-12-01

The results of 1,465,423 allele product determinations based on blood samples from Hiroshima and Nagasaki, involving 30 different proteins representing 32 different gene products, are analyzed in a variety of ways, with the following conclusions: (1) Sibships and their parents are included in the sample. Our analysis reveals that statistical procedures designed to reduce the sample to equivalent independent genomes do not in population comparisons compensate for the familial cluster effect of rare variants. Accordingly, the data set was reduced to one representative of each sibship (937,427 allele products). (2) Both chi 2-type contrasts and a genetic distance measure (delta) reveal that rare variants (P less than .01) are collectively as effective as polymorphisms in establishing genetic differences between the two cities. (3) We suggest that rare variants that individually exhibit significant intercity differences are probably the legacy of tribal private polymorphisms that occurred during prehistoric times. (4) Despite the great differences in the known histories of the two cities, both the overall frequency of rare variants and the number of different rare variants are essentially identical in the two cities. (5) The well-known differences in locus variability are confirmed, now after adjustment for sample size differences for the various locus products; in this large series we failed to detect variants at only three of 29 loci for which sample size exceeded 23,000. (6) The number of alleles identified per locus correlates positively with subunit molecular weight. (7) Loci supporting genetic polymorphisms are characterized by more rare variants than are loci at which polymorphisms were not encountered. (8) Loci whose products do not appear to be essential for health support more variants than do loci the absence of whose product is detrimental to health. (9) There is a striking excess of rare variants over the expectation under the neutral mutation/drift/equilibrium theory. We suggest that this finding is primarily due to the relatively recent (in genetic time) agglomeration of previously separated tribal populations; efforts to test for agreement with the expectations of this theory by using data from modern cosmopolitan populations are exercises in futility. (10) All of these findings should characterize DNA variants in exons as more data become available, since the finding are the protein expression of such variants.

Mutation in a locus linked to penB-nmp causes suppression of the Mtr phenotype of Neisseria gonorrhoeae.

PubMed Central

Shinners, E N; Catlin, B W

1988-01-01

The chromosomal locus mtr, which encodes low-level resistance to multiple antibacterial agents in Neisseria gonorrhoeae, is subject to phenotypic suppression by env mutations that increase the permeability of the envelope. We have identified a new locus, mom (for modifier of Mtr), which is located on the chromosome very close to penB and nmp, loci known to be linked to each other and to spc. Phenotypic suppression of Mtr was recognized by reductions of resistance to benzylpenicillin and also to oxacillin and the hydrophobic agents novobiocin and erythromycin. The resistance to each of these antibiotics returned to the Mtr levels in mom+ transformants isolated by selection for increased resistance to either novobiocin or erythromycin; the accompanying change of the outer membrane protein I seroreactions confirmed the proximity of nmp and mom. Thus, some mutant gonococci display wild-type antibiotic susceptibilities but can express multiple resistance following a mom+ mutation that releases the suppressed Mtr phenotype. PMID:3142343

The MATROSHKA experiment: results and comparison from extravehicular activity (MTR-1) and intravehicular activity (MTR-2A/2B) exposure.

PubMed

Berger, Thomas; Bilski, Paweł; Hajek, Michael; Puchalska, Monika; Reitz, Günther

2013-12-01

Astronauts working and living in space are exposed to considerably higher doses and different qualities of ionizing radiation than people on Earth. The multilateral MATROSHKA (MTR) experiment, coordinated by the German Aerospace Center, represents the most comprehensive effort to date in radiation protection dosimetry in space using an anthropomorphic upper-torso phantom used for radiotherapy treatment planning. The anthropomorphic upper-torso phantom maps the radiation distribution as a simulated human body installed outside (MTR-1) and inside different compartments (MTR-2A: Pirs; MTR-2B: Zvezda) of the Russian Segment of the International Space Station. Thermoluminescence dosimeters arranged in a 2.54 cm orthogonal grid, at the site of vital organs and on the surface of the phantom allow for visualization of the absorbed dose distribution with superior spatial resolution. These results should help improve the estimation of radiation risks for long-term human space exploration and support benchmarking of radiation transport codes.

Influence of cytarabine metabolic pathway polymorphisms in acute myeloid leukemia induction treatment.

PubMed

Megías-Vericat, Juan Eduardo; Montesinos, Pau; Herrero, María José; Moscardó, Federico; Bosó, Virginia; Martínez-Cuadrón, David; Rojas, Luis; Rodríguez-Veiga, Rebeca; Boluda, Blanca; Sendra, Luis; Cervera, José; Poveda, José Luis; Sanz, Miguel Ángel; Aliño, Salvador F

2017-12-01

Cytarabine is considered the most effective chemotherapeutic option in acute myeloid leukemia (AML). The impact of 10 polymorphisms in cytarabine metabolic pathway genes were evaluated in 225 adult de novo AML patients. Variant alleles of DCK rs2306744 and CDA rs602950 showed higher complete remission (p = .024, p = .045), with lower survival rates for variant alleles of CDA rs2072671 (p = .015, p = .045, p = .032), rs3215400 (p = .033) and wild-type genotype of rs602950 (p = .039, .014). Induction death (p = .033) and lower survival rates (p = .021, p = .047) were correlated to RRM1 rs9937 variant allele. In addition, variant alleles of CDA rs532545 and rs602950 were related to skin toxicity (p = .031, p = .049) and mucositis to DCK rs2306744 minor allele (p = .046). Other toxicities associated to variant alleles were hepatotoxicity to NT5C2 rs11598702 (p = .032), lung toxicity (p = .031) and thrombocytopenia to DCK rs4694362 (p = .046). This study supports the interest of cytarabine pathway polymorphisms regarding efficacy and toxicity of AML therapy in a coherent integrated manner.

[Study of genetic variants in the BDNF, COMT, DAT1 and SERT genes in Colombian children with attention deficit disorder].

PubMed

Ortega-Rojas, Jenny; Arboleda-Bustos, Carlos E; Morales, Luis; Benítez, Bruno A; Beltrán, Diana; Izquierdo, Álvaro; Arboleda, Humberto; Vásquez, Rafael

Attention deficit and hyperactive disorder (ADHD) is highly prevalent among children in Bogota City. Both genetic and environmental factors play a very important role in the etiology of ADHD. However, to date few studies have addressed the association of genetic variants and ADHD in the Colombian population. To test the genetic association between polymorphisms in the DAT1, HTTLPR, COMT and BDNF genes and ADHD in a sample from Bogota City. We genotyped the most common polymorphisms in DAT1, SERT, COMT and BDNF genes associated with ADHD using conventional PCR followed by restriction fragment length polymorphism (RFLP) in 97 trios recruited in a medical center in Bogota. The transmission disequilibrium test (TDT) was used to determine the association between such genetic variants and ADHD. The TDT analysis showed that no individual allele of any variant studied has a preferential transmission. Our results suggest that the etiology of the ADHD may be complex and involves several genetic factors. Further studies in other candidate polymorphisms in a larger sample size will improve our knowledge of the ADHD in Colombian population. Copyright © 2016 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

Molecular epidemiology of HFE gene polymorphic variants (C282Y, H63D and S65C) in the population of Espírito Santo, Brazil.

PubMed

Alves, L N R; Santos, E V W; Stur, E; Silva Conforti, A M A; Louro, I D

2016-04-27

Hereditary hemochromatosis (HH) is an autosomal recessive disorder that leads to progressive iron accumulation and may cause cirrhosis, hepatocellular carcinoma, diabetes, and heart failure. Most cases of HH have been linked to mutations in genes associated with iron homeostasis. There have been three major variants in the high Fe (HFE) gene associated with the disease: C282Y, H63D and S65C. In this context, we aimed to evaluate the prevalence of the polymorphic variants (C282Y, H63D and S65C) of the HFE gene in the population of the Espírito Santo State (ES), Brazil by analyzing three different groups: general population (N = 120), Pomeranian descendants (N = 59), and patients with HH (N = 20). Using genomic DNA extracted from peripheral blood, polymorphic variant identification was performed by polymerase chain reaction-restriction fragment length polymorphism. Statistically significant differences were observed for genotype distribution of C282Y (P < 0.001) and H63D (P = 0.013) between the general population and the patients diagnosed with HH. This is the first study to analyze HFE gene allele frequencies for the general population, Pomeranian subpopulation, and patients with HH of ES, Brazil.

Genetic variants on apolipoprotein gene cluster influence triglycerides with a risk of coronary artery disease among Indians.

PubMed

AshokKumar, Manickaraj; Subhashini, Navaneethan Gnana Veera; SaiBabu, Ramineni; Ramesh, Arabandi; Cherian, Kotturathu Mammen; Emmanuel, Cyril

2010-01-01

Apolipoprotein C3 and apolipoprotien A5 are proteins coded from the APOA1/C3/A4/A5 gene cluster. Sst I polymorphism on apolipoprotein C3 and -1131C polymorphism of apolipoprotien A5 are key variants involved in triglyceride metabolism and cause a significant cardio-metabolic risk. Here, we have evaluated these two variants for their roles in coronary artery disease in patients of the Indian population. The apolipoprotein gene cluster variants were analysed in 416 angiographically determined coronary artery disease patients and matched 416 controls using polymerase chain reaction-restriction fragment length polymorphism. The characteristics of the study subjects were analyzed statistically for their association with the polymorphisms. The alleles were combined as haplotypes and their combined risks were evaluated. The minor allele genotypes of both apolipoprotein C3 (S2) and apolipoprotien A5 (C) had a significant risk for coronary artery disease. The S2 allele genotyped patients had a significantly increased triglyceride level (P < 0.001) and increased triglycerides were observed among both patient and control CC genotype carriers. We identified the haplotype S2/C with a significant increased risk (P < 0.001) to coronary artery disease with increased levels of circulating triglycerides compared to other haplotypes in patients. We conclude that the variants on apolipoprotein C3 and apolipoprotien A5 modulate serum triglyceride levels and increase the risk of coronary artery disease.

MTR BUILDING AND BALCONY FLOORS. CAMERA FACING EASTERLY. PHOTOGRAPHER DID ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

MTR BUILDING AND BALCONY FLOORS. CAMERA FACING EASTERLY. PHOTOGRAPHER DID NOT EXPLAIN DARK CLOUD. MTR WING WILL ATTACH TO GROUND FLOOR. INL NEGATIVE NO. 1567. Unknown Photographer, 2/28/1951 - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

Integrating 400 million variants from 80,000 human samples with extensive annotations: towards a knowledge base to analyze disease cohorts.

PubMed

Hakenberg, Jörg; Cheng, Wei-Yi; Thomas, Philippe; Wang, Ying-Chih; Uzilov, Andrew V; Chen, Rong

2016-01-08

Data from a plethora of high-throughput sequencing studies is readily available to researchers, providing genetic variants detected in a variety of healthy and disease populations. While each individual cohort helps gain insights into polymorphic and disease-associated variants, a joint perspective can be more powerful in identifying polymorphisms, rare variants, disease-associations, genetic burden, somatic variants, and disease mechanisms. We have set up a Reference Variant Store (RVS) containing variants observed in a number of large-scale sequencing efforts, such as 1000 Genomes, ExAC, Scripps Wellderly, UK10K; various genotyping studies; and disease association databases. RVS holds extensive annotations pertaining to affected genes, functional impacts, disease associations, and population frequencies. RVS currently stores 400 million distinct variants observed in more than 80,000 human samples. RVS facilitates cross-study analysis to discover novel genetic risk factors, gene-disease associations, potential disease mechanisms, and actionable variants. Due to its large reference populations, RVS can also be employed for variant filtration and gene prioritization. A web interface to public datasets and annotations in RVS is available at https://rvs.u.hpc.mssm.edu/.

Polymorphic variants of neurotransmitter receptor genes may affect sexual function in aging males: data from the HALS study.

PubMed

Jóźków, Paweł; Słowińska-Lisowska, Małgorzata; Łaczmański, Łukasz; Mędraś, Marek

2013-01-01

Human behavior is influenced by a number of brain neurotransmitters. Central dopamine, serotonin and melanocortin systems have special importance for male sexual function. We searched for associations between male aging symptoms and polymorphic sites of serotonin (5-HTR1B), melanocortin (MC4R) and dopamine (DRD2, DRD4) receptors. In a population-based sample, genotyping of 5-HTR1B (polymorphism: G861C), MC4R (polymorphisms: C-2745T, Val103Ile), DRD2 (polymorphism: C313T) and DRD4 (polymorphism: 48-bp VNTR) was performed in 387 healthy men. The Aging Males' Symptoms (AMS) scale was used to evaluate specific ailments of aging men. We analyzed answers to questions from the AMS scale. Five points of the questionnaire addressed sexual symptoms of the aging male: feeling of passing one's peak, decrease in beard growth, decrease in ability/frequency to perform sexually, decrease in the number of morning erections, and decrease in sexual desire/libido (lacking pleasure in sex, lacking desire for sexual intercourse). Relations between reported symptoms and variants of the polymorphic sites of the studied genes were assessed. After adjusting for confounding factors (education, arterial hypertension, physical activity, weight, waist circumference) an association between the sexual dimension of AMS and genetic variants of 5-HTR1B G861C (p = 0.04) was observed. Variability of neurotransmitter receptor genes may be associated with sexual symptoms of aging in men. Copyright © 2013 S. Karger AG, Basel.

Genetic alterations within TLR genes in development of Toxoplasma gondii infection among Polish pregnant women.

PubMed

Wujcicka, Wioletta; Wilczyński, Jan; Nowakowska, Dorota

2017-09-01

The research was conducted to evaluate the role of genotypes, haplotypes and multiple-SNP variants in the range of TLR2, TLR4 and TLR9 single nucleotide polymorphisms (SNPs) in the development of Toxoplasma gondii infection among Polish pregnant women. The study was performed for 116 Polish pregnant women, including 51 patients infected with T. gondii, and 65 age-matched control pregnant individuals. Genotypes in TLR2 2258 G>A, TLR4 896 A>G, TLR4 1196 C>T and TLR9 2848 G>A SNPs were estimated by self-designed, nested PCR-RFLP assays. Randomly selected PCR products, representative for distinct genotypes in the studied polymorphisms, were confirmed by sequencing. All the genotypes were calculated for Hardy-Weinberg (H-W) equilibrium and TLR4 variants were tested for linkage disequilibrium. Relationships were assessed between alleles, genotypes, haplotypes or multiple-SNP variants in TLR polymorphisms and the occurrence of T. gondii infection in pregnant women, using a logistic regression model. All the analyzed genotypes preserved the H-W equilibrium among the studied groups of patients (P>0.050). Similar distribution of distinct alleles and individual genotypes in TLR SNPs, as well as of haplotypes in TLR4 polymorphisms, were observed in T. gondii infected and control uninfected pregnant women. However, the GACG multiple-SNP variant, within the range of all the four studied polymorphisms, was correlated with a decreased risk of the parasitic infection (OR 0.52, 95% CI 0.28-0.97; P≤0.050). The polymorphisms, located within TLR2, TLR4 and TLR9 genes, may be involved together in occurrence of T. gondii infection among Polish pregnant women. Copyright © 2017 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.

Gender-related survival differences associated with EGFR polymorphisms in metastatic colon cancer.

PubMed

Press, Oliver A; Zhang, Wu; Gordon, Michael A; Yang, Dongyun; Lurje, Georg; Iqbal, Syma; El-Khoueiry, Anthony; Lenz, Heinz-Josef

2008-04-15

Evidence is accumulating supporting gender-related differences in the development of colonic carcinomas. Sex steroid hormone receptors are expressed in the colon and interact with epidermal growth factor receptor (EGFR), a gene widely expressed in colonic tissue. Increased EGFR expression is linked with poor prognosis in colon cancer. Within the EGFR gene there are two functional polymorphisms of interest: a polymorphism located at codon 497 (HER-1 R497K) and a dinucleotide (CA)(n) repeat polymorphism located within intron 1. These germ-line polymorphisms of EGFR were analyzed in genomic DNA from 318 metastatic colon cancer patients, 177 males and 141 females, collected from 1992 to 2003. Gender-related survival differences were associated with the HER-1 R497K polymorphism (P(interaction) = 0.003). Females with the HER-1 497 Arg/Arg variant had better overall survival (OS) when compared with the Lys/Lys and/or Lys/Arg variants. In males the opposite was true. The EGFR dinucleotide (CA)(n) repeat also trended with a gender-related OS difference (P(interaction) = 0.11). Females with both short <20 (CA)(n) repeat alleles had better OS than those with any long >or=20 (CA)(n) repeats. In males the opposite was true. Combination analysis of the two polymorphisms taken together also revealed the same gender-related survival difference (P(interaction) = 0.002). These associations were observed using multivariable analysis. The two polymorphisms were not in linkage disequilibrium and are independent of one another. This study supports the role of functional EGFR polymorphisms as independent prognostic markers in metastatic colon cancer. As a prognostic factor, these variants had opposite prognostic implications based on gender.

REACTIVITY MEASUREMENT FACILITY, UNDER CONSTRUCTION OVER MTR CANAL IN BASEMENT ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

REACTIVITY MEASUREMENT FACILITY, UNDER CONSTRUCTION OVER MTR CANAL IN BASEMENT OF MTR BUILDING, TRA-603. WOOD PLANKS REST ON CANAL WALL OBSERVABLE IN FOREGROUND. INL NEGATIVE NO. 11745. Unknown Photographer, 8/20/1954 - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

MATERIALS TESTING REACTOR (MTR) BUILDING, TRA603. CONTEXTUAL VIEW OF MTR ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

MATERIALS TESTING REACTOR (MTR) BUILDING, TRA-603. CONTEXTUAL VIEW OF MTR BUILDING SHOWING NORTH SIDES OF THE HIGH-BAY REACTOR BUILDING, ITS SECOND/THIRD FLOOR BALCONY LEVEL, AND THE ATTACHED ONE-STORY OFFICE/LABORATORY BUILDING, TRA-604. CAMERA FACING SOUTHEAST. VERTICAL CONCRETE-SHROUDED BEAMS SUPPORT PRECAST CONCRETE PANELS. CONCRETE PROJECTION FORMED AS A BUNKER AT LEFT OF VIEW IS TRA-657, PLUG STORAGE BUILDING. INL NEGATIVE NO. HD46-42-1. Mike Crane, Photographer, 4/2005 - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

MtrA of the sodium ion pumping methyltransferase binds cobalamin in a unique mode

PubMed Central

Wagner, Tristan; Ermler, Ulrich; Shima, Seigo

2016-01-01

In the three domains of life, vitamin B12 (cobalamin) is primarily used in methyltransferase and isomerase reactions. The methyltransferase complex MtrA–H of methanogenic archaea has a key function in energy conservation by catalysing the methyl transfer from methyl-tetrahydromethanopterin to coenzyme M and its coupling with sodium-ion translocation. The cobalamin-binding subunit MtrA is not homologous to any known B12-binding proteins and is proposed as the motor of the sodium-ion pump. Here, we present crystal structures of the soluble domain of the membrane-associated MtrA from Methanocaldococcus jannaschii and the cytoplasmic MtrA homologue/cobalamin complex from Methanothermus fervidus. The MtrA fold corresponds to the Rossmann-type α/β fold, which is also found in many cobalamin-containing proteins. Surprisingly, the cobalamin-binding site of MtrA differed greatly from all the other cobalamin-binding sites. Nevertheless, the hydrogen-bond linkage at the lower axial-ligand site of cobalt was equivalently constructed to that found in other methyltransferases and mutases. A distinct polypeptide segment fixed through the hydrogen-bond linkage in the relaxed Co(III) state might be involved in propagating the energy released upon corrinoid demethylation to the sodium-translocation site by a conformational change. PMID:27324530

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

PubMed

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

2016-09-01

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

Preproghrelin Leu72Met polymorphism in Chinese subjects with coronary artery disease and controls.

PubMed

Tang, Na-Ping; Wang, Lian-Sheng; Yang, Li; Gu, Hai-Juan; Zhu, Huai-Jun; Zhou, Bo; Sun, Qing-Min; Cong, Ri-Hong; Wang, Bin

2008-01-01

Ghrelin, a novel endogenous ligand for the growth hormone secretagogue receptor, is considered to exert a protective effect against atherosclerosis. The Leu72Met (+408C>A) polymorphic variant of the preproghrelin, the gene for the ghrelin precursor, has been linked to obesity, diabetes and metabolic syndrome. However, it is unclear whether this polymorphism is associated with coronary artery disease (CAD). We conducted a case-control study with 317 CAD patients and 323 controls to investigate the potential association of the Leu72Met polymorphism with the occurrence of CAD and CAD-related phenotypes in Chinese population. No significant difference in the Leu72Met genotype frequency was observed between CAD patients and controls (P=NS). The Leu72Met polymorphism was not associated with hypertension, diabetes, dyslipidemia, the number of diseased vessels, plasma total cholesterol, triglyceride, high density lipoprotein cholesterol, low density lipoprotein cholesterol or fasting glucose levels in CAD patients. However, among CAD patients, those with variant genotypes (Leu72Met and Met72Met) had lower BMI (24.4+/-0.3 kg/m(2)) than Leu72Leu carriers (25.4+/-0.2 kg/m(2), adjusted P=0.033). Our data indicate that the preproghrelin Leu72Met polymorphism is not associated with CAD in Chinese population. However, the Leu72Met variant is associated with BMI among CAD patients.

Association of TNF, MBL, and VDR Polymorphisms with Leprosy Phenotypes

PubMed Central

Sapkota, Bishwa R.; Macdonald, Murdo; Berrington, William R.; Misch, E. Ann; Ranjit, Chaman; Siddiqui, M. Ruby; Kaplan, Gilla; Hawn, Thomas R.

2010-01-01

Background Although genetic variants in tumor necrosis factor (TNF), mannose binding lectin (MBL), and the vitamin D receptor (VDR) have been associated with leprosy clinical outcomes these findings have not been extensively validated. Methods We used a case-control study design with 933 patients in Nepal, which included 240 patients with type I reversal reaction (RR), and 124 patients with erythema nodosum leprosum (ENL) reactions. We compared genotype frequencies in 933 cases and 101 controls of 7 polymorphisms, including a promoter region variant in TNF (G−308A), three polymorphisms in MBL (C154T, G161A and G170A), and three variants in VDR (FokI, BsmI, and TaqI). Results We observed an association between TNF −308A and protection from leprosy with an odds ratio (OR) of 0.52 (95% confidence interval (CI) of 0.29 to 0.95, P = 0.016). MBL polymorphism G161A was associated with protection from lepromatous leprosy (OR (95% CI) = 0.33 (0.12–0.85), P = 0.010). VDR polymorphisms were not associated with leprosy phenotypes. Conclusion These results confirm previous findings of an association of TNF −308A with protection from leprosy and MBL polymorphisms with protection from lepromatous leprosy. The statistical significance was modest and will require further study for conclusive validation. PMID:20650301

Allelic polymorphism in the T cell receptor and its impact on immune responses.

PubMed

Gras, Stephanie; Chen, Zhenjun; Miles, John J; Liu, Yu Chih; Bell, Melissa J; Sullivan, Lucy C; Kjer-Nielsen, Lars; Brennan, Rebekah M; Burrows, Jacqueline M; Neller, Michelle A; Khanna, Rajiv; Purcell, Anthony W; Brooks, Andrew G; McCluskey, James; Rossjohn, Jamie; Burrows, Scott R

2010-07-05

In comparison to human leukocyte antigen (HLA) polymorphism, the impact of allelic sequence variation within T cell receptor (TCR) loci is much less understood. Particular TCR loci have been associated with autoimmunity, but the molecular basis for this phenomenon is undefined. We examined the T cell response to an HLA-B*3501-restricted epitope (HPVGEADYFEY) from Epstein-Barr virus (EBV), which is frequently dominated by a TRBV9*01(+) public TCR (TK3). However, the common allelic variant TRBV9*02, which differs by a single amino acid near the CDR2beta loop (Gln55-->His55), was never used in this response. The structure of the TK3 TCR, its allelic variant, and a nonnaturally occurring mutant (Gln55-->Ala55) in complex with HLA-B*3501(HPVGEADYFEY) revealed that the Gln55-->His55 polymorphism affected the charge complementarity at the TCR-peptide-MHC interface, resulting in reduced functional recognition of the cognate and naturally occurring variants of this EBV peptide. Thus, polymorphism in the TCR loci may contribute toward variability in immune responses and the outcome of infection.

Genetic association analysis of inositol polyphosphate phosphatase‐like 1 (INPPL1, SHIP2) variants with essential hypertension

PubMed Central

Marçano, Ana Carolina Braga; Burke, Beverley; Gungadoo, Johannie; Wallace, Chris; Kaisaki, Pamela J; Woon, Peng Y; Farrall, Martin; Clayton, David; Brown, Morris; Dominiczak, Anna; Connell, John M; Webster, John; Lathrop, Mark; Caulfield, Mark; Samani, Nilesh; Gauguier, Dominique; Munroe, Patricia B

2007-01-01

Background Inositol polyphosphate phosphatase‐like 1 (INPPL1, SHIP2) is a negative regulator of insulin signalling and has previously been found to be associated with hypertension, obesity and type 2 diabetes in a cohort of families with diabetes in the UK presenting features of metabolic syndrome. In particular, a haplotype of three genetic polymorphisms (rs2276047, rs9886 and an insertion/deletion polymorphism in intron 1) was found to be strongly associated with increased susceptibility to hypertension. Objective and methods To assess if INPPL1 variants play a direct role in the development of essential hypertension, we genotyped the three previously associated INPPL1 polymorphisms in a cohort of 712 families with severe hypertension from the BRIGHT study transmission disequilibrium test cohort. Results We found no evidence of significant association between hypertension and any of the three INPPL1 polymorphisms or haplotypes (p>0.1). Conclusion These results suggest that INPPL1 variants may be involved in mechanisms causing hypertension in metabolic syndrome patients specifically. PMID:17557929

The Membrane-bound O-Acyltransferase7 rs641738 Variant in Pediatric Nonalcoholic Fatty Liver Disease.

PubMed

Di Sessa, Anna; Umano, Giuseppina Rosaria; Cirillo, Grazia; Del Prete, Angela; Iacomino, Roberta; Marzuillo, Pierluigi; Giudice, Emanuele Miraglia Del

2018-03-29

The rs641738 polymorphism in the membrane-bound O-acyltransferase domain containing protein 7 (MBOAT7) gene has been associated with increased risk of nonalcoholic fatty liver disease (NAFLD). To investigate the association between the MBOAT7 rs641738 polymorphism and both hepatic steatosis and biochemical markers of liver damage and to evaluate the potential additive effect of this variant and the I148M patatin-like phospholipase domain-containing 3 (PNPLA3) and the rs58542926 transmembrane 6 superfamily member 2 (TM6SF2) polymorphisms. One thousand and 2 obese children were genotyped for MBOAT7, PNPLA3, and TM6SF2 polymorphisms and underwent anthropometrical, ultrasonographic, and biochemical evaluation. Indirect measurement of liver fibrosis (Pediatric NAFLD Fibrosis Index [PNFI]) and a genetic risk score from these polymorphisms were calculated. Carriers of the MBOAT7 T allele showed both higher alanine transaminase (ALT) (P = 0.004) and PNFI values (P = 0.04) than noncarriers. These findings were confirmed also for the carriers of the MBOAT7 T allele polymorphism with hepatic steatosis compared with noncarriers. A higher genetic risk score was associated with higher ALT (P = 0.011) and with an odds ratio (OR) to show elevated ALT of 3.4 (95% CI 1.3-5.5, P = 0.003). Patients belonging to genetic risk score 3 group had an OR to present steatosis of 2.6 (95% CI 1.43-4.83, P = 0.0018) compared with those belonging to lower genetic risk score group. We first demonstrated in childhood obesity the role of the MBOAT7 rs641738 variant on serum ALT and the combined effect of the MBOAT7, PNPLA3, and TM6SF2 variants on NAFLD risk. We also provided the first pediatric association of the MBOAT7 polymorphism with indirect markers of liver fibrosis.

Comparison of adherence to generic multi-tablet regimens vs. brand multi-tablet and brand single-tablet regimens likely to incorporate generic antiretroviral drugs by breaking or not fixed-dose combinations in HIV-infected patients.

PubMed

Rwagitinywa, Joseph; Lapeyre-Mestre, Maryse; Bourrel, Robert; Montastruc, Jean-Louis; Sommet, Agnès

2018-03-05

Adherence to antiretroviral (ARV) is crucial to achieve viral load suppression in HIV-infected patients. This study aimed to compare adherence to generic multi-tablet regimens (MTR) vs. brand MTR likely to incorporate ARV drugs without breaking fixed-dose combinations (FDC) and brand single-tablet regimens (STR) likely to incorporate generics by breaking the FDC. Patients aged of 18 years or over exposed to one of the generic or the brand of lamivudine (3TC), zidovudine/lamivudine (AZT/TC), nevirapine (NVP), or efavirenz (EFV), or the brand STR of efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF). Adherence was measured by medication possession ratio (MPR) using both defined daily dose (DDD) and daily number of tablet recommended for adults (DNT). Adherence to generic MTR vs. brand MTR and brand STR was compared using Kruskal-Wallis. The overall median adherence was 0.97 (IQR 0.13) by DNT method and 0.97 (0.14) by DDD method. Adherence in patients exposed to generic MTR (n = 165) vs. brand MTR (n = 481) and brand STR (n = 470) was comparable by DNT and DDD methods. In conclusion, adherence to generic MTR was high and comparable with adherence to brand MTR and to STR. Utilization of DDD instead DNT to measure the MPR led to small but nonsignificant difference that has no clinical impact. © 2018 Société Française de Pharmacologie et de Thérapeutique.

Chemical exchange rotation transfer (CERT) on human brain at 3 Tesla.

PubMed

Lin, Eugene C; Li, Hua; Zu, Zhongliang; Louie, Elizabeth A; Lankford, Christopher L; Dortch, Richard D; Does, Mark D; Gore, John C; Gochberg, Daniel F

2018-05-25

To test the ability of a novel pulse sequence applied in vivo at 3 Tesla to separate the contributions to the water signal from amide proton transfer (APT) and relayed nuclear Overhauser enhancement (rNOE) from background direct water saturation and semisolid magnetization transfer (MT). The lack of such signal source isolation has confounded conventional chemical exchange saturation transfer (CEST) imaging. We quantified APT and rNOE signals using a chemical exchange rotation transfer (CERT) metric, MTR double . A range of duty cycles and average irradiation powers were applied, and results were compared with conventional CEST analyses using asymmetry (MTR asym ) and extrapolated magnetization transfer (EMR). Our results indicate that MTR double is more specific than MTR asym and, because it requires as few as 3 data points, is more rapid than methods requiring a complete Z-spectrum, such as EMR. In white matter, APT (1.5 ± 0.5%) and rNOE (2.1 ± 0.7%) were quantified by using MTR double with a 30% duty cycle and a 0.5-µT average power. In addition, our results suggest that MTR double is insensitive to B 0 inhomogeneity, further magnifying its speed advantage over CEST metrics that require a separate B 0 measurement. However, MTR double still has nontrivial sensitivity to B 1 inhomogeneities. We demonstrated that MTR double is an alternative metric to evaluate APT and rNOE, which is fast, robust to B 0 inhomogeneity, and easy to process. © 2018 International Society for Magnetic Resonance in Medicine.

Use of Mixer Torque Rheometer to Clarify the Relationship between the Kneading States of Wet Mass and the Dissolution of Final Product in High Shear Granulation.

PubMed

Otsuka, Tomoko; Kuroiwa, Yosuke; Sato, Kazunari; Yamashita, Kazunari; Hakomori, Tadashi; Kimura, Shin-Ichiro; Iwao, Yasunori; Itai, Shigeru

2018-01-01

The properties of wet mass, which indicate the progress of high shear granulation processes, usually have an effect on final product properties, such as tablet dissolution. The mixer torque rheometer (MTR) is a useful tool for quantitatively measuring the 'kneading state' of wet mass and detecting differences in granules. However, there have been no studies of the relationship between the MTR torque and the final product properties to date. In this study, we measured the MTR torque of wet granules at different kneading states, which were prepared by changing the granulation conditions. We then evaluated the relationship between the MTR torque and the dissolution rate of the final product properties. The amperage of the high shear granulator is usually monitored during granulation, but we could not detect a difference in the kneading state through the amperage. However, using MTR torque we were able to quantify the difference of the wet mass. Moreover, MTR torque showed a high correlation with dissolution, compared with the correlations with other intermediate properties, such as granules particle size and tablet hardness. These other properties are affected by following processes and are not properties that directly relate to the kneading state. Thus, MTR torque is a property of wet mass after granulation, and it can be used to directly evaluate differences of the kneading state, and as a result, dissolution. These results indicate the importance of controlling the kneading state, i.e., the progress of granulation, and the utility of MTR for detecting differences in wet mass.

Polygenic influences on dyslipidemias.

PubMed

Dron, Jacqueline S; Hegele, Robert A

2018-04-01

Rare large-effect genetic variants underlie monogenic dyslipidemias, whereas common small-effect genetic variants - single nucleotide polymorphisms (SNPs) - have modest influences on lipid traits. Over the past decade, these small-effect SNPs have been shown to cumulatively exert consistent effects on lipid phenotypes under a polygenic framework, which is the focus of this review. Several groups have reported polygenic risk scores assembled from lipid-associated SNPs, and have applied them to their respective phenotypes. For lipid traits in the normal population distribution, polygenic effects quantified by a score that integrates several common polymorphisms account for about 20-30% of genetic variation. Among individuals at the extremes of the distribution, that is, those with clinical dyslipidemia, the polygenic component includes both rare variants with large effects and common polymorphisms: depending on the trait, 20-50% of susceptibility can be accounted for by this assortment of genetic variants. Accounting for polygenic effects increases the numbers of dyslipidemic individuals who can be explained genetically, but a substantial proportion of susceptibility remains unexplained. Whether documenting the polygenic basis of dyslipidemia will affect outcomes in clinical trials or prospective observational studies remains to be determined.

HFE p.C282Y gene variant is associated with varicose veins in Russian population.

PubMed

Sokolova, Ekaterina A; Shadrina, Alexandra S; Sevost'ianova, Kseniya S; Shevela, Andrey I; Soldatsky, Evgenii Yu; Seliverstov, Evgenii I; Demekhova, Marina Yu; Shonov, Oleg A; Ilyukhin, Evgenii A; Smetanina, Mariya A; Voronina, Elena N; Zolotukhin, Igor A; Filipenko, Maxim L

2016-08-01

Recently, the association of polymorphism rs1800562 (p.C282Y) in the hemochromatosis (HFE) gene with the increased risk of venous ulceration was shown. We hypothesized that HFE gene polymorphism might be involved not only in ulceration process, but also in susceptibility to primary varicose veins. We genotyped HFE p.C282Y (rs1800562) and p.H63D (rs1799945) variants in patients with primary varicose veins (n = 463) and in the control group (n = 754). In our study, p.282Y variant (rs1800562 A allele) was significantly associated with the risk of varicose veins (OR 1.79, 95 % CI = 1.11-2.89, P = 0.02). A borderline significant reverse association of p.63D variant (rs1799945 G allele) with venous leg ulcer development was revealed in Russians (OR 0.25, 95 % CI = 0.06-1.00, P = 0.05), but not in the meta-analysis (P = 0.56). We conclude that the HFE gene polymorphism can affect the risk of developing primary varicose veins.

Genetic variants involved in gallstone formation and capsaicin metabolism, and the risk of gallbladder cancer in Chilean women

PubMed Central

Báez, Sergio; Tsuchiya, Yasuo; Calvo, Alfonso; Pruyas, Martha; Nakamura, Kazutoshi; Kiyohara, Chikako; Oyama, Mari; Yamamoto, Masaharu

2010-01-01

AIM: To determine the effects of genetic variants associated with gallstone formation and capsaicin (a pungent component of chili pepper) metabolism on the risk of gallbladder cancer (GBC). METHODS: A total of 57 patients with GBC, 119 patients with gallstones, and 70 controls were enrolled in this study. DNA was extracted from their blood or paraffin block sample using standard commercial kits. The statuses of the genetic variants were assayed using Taqman® SNP Genotyping Assays or Custom Taqman® SNP Genotyping Assays. RESULTS: The non-ancestral T/T genotype of apolipoprotein B rs693 polymorphism was associated with a decreased risk of GBC (OR: 0.14, 95% CI: 0.03-0.63). The T/T genotype of cholesteryl ester transfer protein (CETP) rs708272 polymorphism was associated with an increased risk of GBC (OR: 5.04, 95% CI: 1.43-17.8). CONCLUSION: Genetic variants involved in gallstone formation such as the apolipoprotein B rs693 and CETP rs708272 polymorphisms may be related to the risk of developing GBC in Chilean women. PMID:20082485

Functional genetic variant in the Kozak sequence of WW domain-containing oxidoreductase (WWOX) gene is associated with oral cancer risk.

PubMed

Cheng, Hsin-Lin; Liu, Yu-Fan; Su, Chun-Wen; Su, Shih-Chi; Chen, Mu-Kuan; Yang, Shun-Fa; Lin, Chiao-Wen

2016-10-25

In Taiwan, oral cancer is the fourth leading cancer in males and is associated with exposure to environmental carcinogens. WW domain-containing oxidoreductase (WWOX), a tumor suppressor gene, is associated with the development of various cancers. We hypothesized that genetic variants of WWOX influence the susceptibility to oral cancer. Five polymorphisms of WWOX gene from 761 male patients with oral cancer and 1199 male cancer-free individuals were genotyped. We observed that individuals carrying the polymorphic allele of WWOX rs11545028 are more susceptible to oral cancer. Furthermore, patients with advanced-stage oral cancer were associated with a higher frequency of WWOX rs11545028 polymorphisms with the variant genotype TT than did patients with the wild-type gene. An additional integrated in silico analysis confirmed that rs11545028 affects WWOX expression, which significantly correlates with tumor expression and subsequently with tumor development and aggressiveness. In conclusion, genetic variants of WWOX contribute to the occurrence of oral cancer, and the findings regarding these biomarkers provided a prediction model for risk assessment.

Association of monoamine oxidase A gene polymorphism with Alzheimer's disease and Lewy body variant.

PubMed

Takehashi, Masanori; Tanaka, Seigo; Masliah, Eliezer; Ueda, Kunihiro

2002-07-19

The association between (GT)n dinucleotide repeats in monoamine oxidase gene loci, monoamine oxidase A (MAOA) and B (MAOB), and Parkinson's disease (PD), Alzheimer's disease (AD), and Lewy body variant (LBV) of AD were determined. MAOA-GT polymorphisms were significantly associated with pure AD and LBV. MAOA-GT allele 113 was excessively represented in pure AD and LBV compared with controls. Furthermore, the frequency of females homozygous for MAOA-GT allele 113 was higher in pure AD and LBV than controls by 2.79- and 2.77-fold, respectively. In contrast, there was no association between MAOA-GT or MAOB-GT polymorphisms and PD. These results suggest that polymorphisms within the MAOA gene may have implication in AD pathology shared by pure AD and LBV.

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

PubMed

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

2014-01-01

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

Genome-wide association study reveals putative regulators of bioenergy traits in Populus deltoides

DOE PAGES

Fahrenkrog, Annette M.; Neves, Leandro G.; Resende, Jr., Marcio F. R.; ...

2016-09-06

Genome-wide association studies (GWAS) have been used extensively to dissect the genetic regulation of complex traits in plants. These studies have focused largely on the analysis of common genetic variants despite the abundance of rare polymorphisms in several species, and their potential role in trait variation. Here, we conducted the first GWAS in Populus deltoides, a genetically diverse keystone forest species in North America and an important short rotation woody crop for the bioenergy industry. We searched for associations between eight growth and wood composition traits, and common and low-frequency single-nucleotide polymorphisms detected by targeted resequencing of 18 153 genesmore » in a population of 391 unrelated individuals. To increase power to detect associations with low-frequency variants, multiple-marker association tests were used in combination with single-marker association tests. Significant associations were discovered for all phenotypes and are indicative that low-frequency polymorphisms contribute to phenotypic variance of several bioenergy traits. Our results suggest that both common and low-frequency variants need to be considered for a comprehensive understanding of the genetic regulation of complex traits, particularly in species that carry large numbers of rare polymorphisms. Lastly, these polymorphisms may be critical for the development of specialized plant feedstocks for bioenergy.« less

CONTEXTUAL AERIAL VIEW OF "EXCLUSION" MTR AREA WITH IDAHO CHEMICAL ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

CONTEXTUAL AERIAL VIEW OF "EXCLUSION" MTR AREA WITH IDAHO CHEMICAL PROCESSING PLANT IN BACKGROUND AT CENTER TOP OF VIEW. CAMERA FACING EAST. EXCLUSION GATE HOUSE AT LEFT OF VIEW. BEYOND MTR BUILDING AND ITS WING, THE PROCESS WATER BUILDING AND WORKING RESERVOIR ARE LEFT-MOST. FAN HOUSE AND STACK ARE TO ITS RIGHT. PLUG STORAGE BUILDING IS RIGHT-MOST STRUCTURE. NOTE FAN LOFT ABOVE MTR BUILDING'S ONE-STORY WING. THIS WAS LATER CONVERTED FOR OFFICES. INL NEGATIVE NO. 3610. Unknown Photographer, 10/30/1951 - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

The NASA modern technology rotors program

NASA Technical Reports Server (NTRS)

Watts, M. E.; Cross, J. L.

1986-01-01

Existing data bases regarding helicopters are based on work conducted on 'old-technology' rotor systems. The Modern Technology Rotors (MTR) Program is to provide extensive data bases on rotor systems using present and emerging technology. The MTR is concerned with modern, four-bladed, rotor systems presently being manufactured or under development. Aspects of MTR philosophy are considered along with instrumentation, the MTR test program, the BV 360 Rotor, and the UH-60 Black Hawk. The program phases include computer modelling, shake test, model-scale test, minimally instrumented flight test, extensively pressure-instrumented-blade flight test, and full-scale wind tunnel test.

Associations between homocysteine metabolism related SNPs and carotid intima-media thickness: a Chinese sib pair study.

PubMed

Sun, Kexin; Song, Jing; Liu, Kuo; Fang, Kai; Wang, Ling; Wang, Xueyin; Li, Jing; Tang, Xun; Wu, Yiqun; Qin, Xueying; Wu, Tao; Gao, Pei; Chen, Dafang; Hu, Yonghua

2017-04-01

Carotid intima-media thickness (CIMT) is a good surrogate for atherosclerosis. Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases. We aim to investigate the relationships between homocysteine (Hcy) related biochemical indexes and CIMT, the associations between Hcy related SNPs and CIMT, as well as the potential gene-gene interactions. The present study recruited full siblings (186 eligible families with 424 individuals) with no history of cardiovascular events from a rural area of Beijing. We examined CIMT, intima-media thickness for common carotid artery (CCA-IMT) and carotid bifurcation, tested plasma levels for Hcy, vitamin B6 (VB6), vitamin B12 (VB12) and folic acid (FA), and genotyped 9 SNPs on MTHFR, MTR, MTRR, BHMT, SHMT1, CBS genes. Associations between SNPs and biochemical indexes and CIMT indexes were analyzed using family-based association test analysis. We used multi-level mixed-effects regression model to verify SNP-CIMT associations and to explore the potential gene-gene interactions. VB6, VB12 and FA were negatively correlated with CIMT indexes (p < 0.05). rs2851391 T allele was associated with decreased plasma VB12 levels (p = 0.036). In FABT, CBS rs2851391 was significantly associated with CCA-IMT (p = 0.021) and CIMT (p = 0.019). In multi-level mixed-effects regression model, CBS rs2851391 was positively significantly associated with CCA-IMT (Coef = 0.032, se = 0.009, raw p < 0.001) after Bonferoni correction (corrected α = 0.0056). Gene-gene interactions were found between CBS rs2851391 and BHMT rs10037045 for CCA-IMT (p = 0.011), as well as between CBS rs2851391 and MTR rs1805087 for CCA-IMT (p = 0.007) and CIMT (p = 0.022). Significant associations are found between Hcy metabolism related genetic polymorphisms, biochemical indexes and CIMT indexes. There are complex interactions between genetic polymorphisms for CCA-IMT and CIMT.

Structural basis for MTR4-ZCCHC8 interactions that stimulate the MTR4 helicase in the nuclear exosome-targeting complex.

PubMed

Puno, M Rhyan; Lima, Christopher D

2018-06-12

The nuclear exosome-targeting (NEXT) complex functions as an RNA exosome cofactor and is involved in surveillance and turnover of aberrant transcripts and noncoding RNAs. NEXT is a ternary complex composed of the RNA-binding protein RBM7, the scaffold zinc-knuckle protein ZCCHC8, and the helicase MTR4. While RNA interactions with RBM7 are known, it remains unclear how NEXT subunits collaborate to recognize and prepare substrates for degradation. Here, we show that MTR4 helicase activity is enhanced when associated with RBM7 and ZCCHC8. While uridine-rich substrates interact with RBM7 and are preferred, optimal activity is observed when substrates include a polyadenylated 3' end. We identify a bipartite interaction of ZCCHC8 with MTR4 and uncover a role for the conserved C-terminal domain of ZCCHC8 in stimulating MTR4 helicase and ATPase activities. A crystal structure reveals that the ZCCHC8 C-terminal domain binds the helicase core in a manner that is distinct from that observed for Saccharomyces cerevisiae exosome cofactors Trf4p and Air2p. Our results are consistent with a model whereby effective targeting of substrates by NEXT entails recognition of elements within the substrate and activation of MTR4 helicase activity. Copyright © 2018 the Author(s). Published by PNAS.

Regional patterns of grey matter atrophy and magnetisation transfer ratio abnormalities in multiple sclerosis clinical subgroups: a voxel-based analysis study.

PubMed

Mallik, Shahrukh; Muhlert, Nils; Samson, Rebecca S; Sethi, Varun; Wheeler-Kingshott, Claudia A M; Miller, David H; Chard, Declan T

2015-04-01

In multiple sclerosis (MS), demyelination and neuro-axonal loss occur in the brain grey matter (GM). We used magnetic resonance imaging (MRI) measures of GM magnetisation transfer ratio (MTR) and volume to assess the regional localisation of reduced MTR (reflecting demyelination) and atrophy (reflecting neuro-axonal loss) in relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS). A total of 98 people with MS (51 RRMS, 28 SPMS, 19 PPMS) and 29 controls had T1-weighted volumetric and magnetisation transfer scans. SPM8 was used to undertake voxel-based analysis (VBA) of GM tissue volumes and MTR. MS subgroups were compared with controls, adjusting for age and gender. A voxel-by-voxel basis correlation analysis between MTR and volume within each subject group was performed, using biological parametric mapping. MTR reduction was more extensive than atrophy. RRMS and SPMS patients showed proportionately more atrophy in the deep GM. SPMS and PPMS patients showed proportionately greater cortical MTR reduction. RRMS patients demonstrated the most correlation of MTR reduction and atrophy in deep GM. In SPMS and PPMS patients, there was less extensive correlation. These results suggest that in the deep GM of RRMS patients, demyelination and neuro-axonal loss may be linked, while in SPMS and PPMS patients, neuro-axonal loss and demyelination may occur mostly independently. © The Author(s), 2014.

A few nucleotide polymorphisms are sufficient to recruit nuclear factors differentially to the intron 1 of HPV-16 intratypic variants.

PubMed

López-Urrutia, Eduardo; Valdés, Jesús; Bonilla-Moreno, Raúl; Martínez-Salazar, Martha; Martínez-Garcia, Martha; Berumen, Jaime; Villegas-Sepúlveda, Nicolás

2012-06-01

The HPV-16 E6/E7 genes, which contain intron 1, are processed by alternative splicing and its transcripts are detected with a heterogeneous profile in tumours cells. Frequently, the HPV-16 positive carcinoma cells bear viral variants that contain single nucleotide polymorphisms into its DNA sequence. We were interested in analysing the contribution of this polymorphism to the heterogeneity in the pattern of the E6/E7 spliced transcripts. Using the E6/E7 sequences from three closely related HPV-16 variants, we have shown that a few nucleotide changes are sufficient to produce heterogeneity in the splicing profile. Furthermore, using mutants that contained a single SNP, we also showed that one nucleotide change was sufficient to reproduce the heterogeneous splicing profile. Additionally, a difference of two or three SNPs among these viral sequences was sufficient to recruit differentially several splicing factors to the polymorphic E6/E7 transcripts. Moreover, only one SNP was sufficient to alter the binding site of at least one splicing factor, changing the ability of splicing factors to bind the transcript. Finally, the factors that were differentially bound to the short form of intron 1 of one of these E6/E7 variants were identified as TIA1 and/or TIAR and U1-70k, while U2AF65, U5-52k and PTB were preferentially bound to the transcript of the other variants. Copyright © 2012 Elsevier B.V. All rights reserved.

The association of DLG5 polymorphisms with inflammatory bowel disease: a meta-analysis of 25 studies.

PubMed

Dai, Y-E; Guan, R; Song, Y-T

2016-06-01

The aim of this study was to explore the association of polymorphisms in DLG5 gene (G113A, C4136A and e26) with inflammatory bowel disease (IBD) risk. A total of 25 studies involved 26583 subjects were pooled for analysis. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to pool the effect size. For G113A variant, a significant association was observed with CD risk in children (A vs. G: OR = 0.745, 95% CI = 0.569-0.977) and high quality studies (A vs. G: OR = 0.913, 95% CI = 0.850-0.981). Additionally, the results of genotype-phenotype analysis suggested G113A variant was associated with colonic involvement in CD. However, in overall population, the results indicated G113A variant was not associated with CD or UC. We also provided evidence that C4136A polymorphism had different effects on CD risk between Europeans (AA vs. CC: OR = 3.239, 95% CI = 1.149-9.136) and Asians (AA vs. CC: OR = 0.511, 95% CI = 0.299-0.873). For UC, patients with AA genotype of C4136A variant had a significantly increased UC risk (AA vs. CC: OR = 3.877, 95% CI = 1.168-12.867). Finally, no association was detected with G113A or e26 polymorphism in CD or UC patients. This meta-analysis indicated G113A variant may be significantly associated with CD risk in children and colonic involvement.

Relationship between polymorphisms of nucleotide excision repair genes and oral cancer risk in Taiwan: evidence for modification of smoking habit.

PubMed

Bau, Da-Tian; Tsai, Ming-Hsui; Huang, Chih-Yang; Lee, Cheng-Chun; Tseng, Hsien-Chang; Lo, Yen-Li; Tsai, Yuhsin; Tsai, Fuu-Jen

2007-12-31

Inherited polymorphisms in DNA repair genes may be associated with differences in the repair capacity and contribute to individual's susceptibility to smoking-related cancers. Both XPA and XPD encode proteins that are part of the nucleotide excision repair (NER) pathway. In a hospital-based case-control study, we have investigated the influence of XPA A-23G and XPD Lys751Gln polymorphisms on oral cancer risk in a Taiwanese population. In total, 154 patients with oral cancer, and 105 age-matched controls recruited from the Chinese Medical Hospital in Central Taiwan were genotyped. No significant association was found between the heterozygous variant allele (AG), the homozygous variant allele (AA) at XPA A-23G, the heterozygous variant allele (AC), the homozygous variant allele (CC) at XPD Lys751Gln, and oral cancer risk. There was no significant joint effect of XPA A-23G and XPD Lys751Gln on oral cancer risk either. Since XPA and XPD are both NER genes, which are very important in removing tobacco-induced DNA adducts, further stratified analyses of both genotype and smoking habit were performed. We found a synergistic effect of variant genotypes of both XPA and XPD, and smoking status on oral cancer risk. Our results suggest that the genetic polymorphisms are modified by environmental carcinogen exposure status, and combined analyses of both genotype and personal habit record are a better access to know the development of oral cancer and useful for primary prevention and early intervention.

UGT1A1*6 and UGT1A1*28 polymorphisms are correlated with irinotecan-induced toxicity: A meta-analysis.

PubMed

Yang, Yuwei; Zhou, MengMeng; Hu, Mingjun; Cui, Yanjie; Zhong, Qi; Liang, Ling; Huang, Fen

2018-06-22

Previous articles explored the role of UGT1A1 polymorphism on predicting irinotecan-induced toxicity, but the conclusions were still inconsistent and not comprehensive. We performed this meta-analysis to investigate the association between UGT1A1 polymorphism and irinotecan-induced toxicity. PubMed and Web of Science were searched for articles before July 2017. Inclusion and exclusion criteria were set to select eligible articles, and corresponding data were extracted from those articles. Subgroup analyses based on different cancer categories, doses and races were carried out to achieve comprehensive results. Statistical analyses were conducted using STATA 11.0. A total of 38 studies with 6742 cases were included after reading full text. Both UGT1A1*6 and UGT1A1*28 polymorphism are significantly associated with severe irinotecan-induced toxicity. Both Asian and Caucasian cancer patients with UGT1A1*28 variant had an increased risk. Compared with heterozygous variant, patients with homozygous variant suffered from a higher risk of toxicity. The effect of UGT1A1*28 polymorphism on diarrhea was less than on neutropenia. Subgroup analysis exhibited that for UGT1A1*6 polymorphism, patients treated with low-dose irinotecan were at a notable risk of toxicity. Moreover, the association between UGT1A1*6 polymorphism and irinotecan-induced toxicity was found in patients suffering from respiratory system cancers. Both UGT1A1*6 and UGT1A1*28 polymorphisms can be considered as predictors of irinotecan-induced toxicity, with effect varying by race, cancer type and irinotecan dose. © 2018 John Wiley & Sons Australia, Ltd.

Effect of polymorphic variants of GH, Pit-1, and beta-LG genes on milk production of Holstein cows.

PubMed

Heidari, M; Azari, M A; Hasani, S; Khanahmadi, A; Zerehdaran, S

2012-04-01

Effect of polymorphic variants of growth hormone (GH), beta-lactoglobulin (beta-LG), and Pit-1 genes on milk yield was analyzed in a Holstein herd. Genotypes of the cows for these genes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Allele frequencies were 0.884 and 0.116 for L and V variants of GH, 0.170 and 0.830 for A and B variants of Pit-1, and 0.529 and 0.471 for A and B variants of beta-LG, respectively. GLM procedure of SAS software was used to test the effects of these genes on milk yield. Results indicated significant effects of these genes on milk yield (P < 0.05). Cows with LL genotype of GH produced more milk than cows with LVgenotype (P < 0.05). Also, for Pit-1 gene, animals with AB genotype produced more milk than BB genotype (P < 0.05). In the case of beta-LG gene, milk yield of animals with AA genotype was more than BB genotype (P < 0.01). Therefore, it might be concluded that homozygote genotypes of GH (LL) and beta-LG (AA) were superior compared to heterozygote genotypes, whereas, the heterozygote genotype of Pit-1 gene (AB) was desirable.

Genetic Variants of TPCN2 Associated with Type 2 Diabetes Risk in the Chinese Population

PubMed Central

Zhang, Yu; Fan, Xiaofang; Zhang, Ning; Zheng, Hui; Song, Yuping; Shen, Chunfang; Shen, Jiayi; Ren, Fengdong; Yang, Jialin

2016-01-01

Objective The aim of this study was to determine whether TPCN2 genetic variants are associated with type 2 diabetes and to elucidate which variants in TPCN2 confer diabetes susceptibility in the Chinese population. Research Design and Methods The sample population included 384 patients with type 2 diabetes and 1468 controls. Anthropometric parameters, glycemic and lipid profiles and insulin resistance were measured. We selected 6 TPCN2 tag single nucleotide polymorphisms (rs35264875, rs267603153, rs267603154, rs3829241, rs1551305, and rs3750965). Genotypes were determined using a Sequenom MassARRAY SNP genotyping system. Results Ultimately, we genotyped 3 single nucleotide polymorphisms (rs3750965, rs3829241, and rs1551305) in all individuals. There was a 5.1% higher prevalence of the rs1551305 variant allele in type 2 diabetes individuals (A) compared with wild-type homozygous individuals (G). The AA genotype of rs1551305 was associated with a higher diabetes risk (p<0.05). The distributions of rs3829241 and rs3750965 polymorphisms were not significantly different between the two groups. HOMA-%B of subjects harboring the AA genotype of rs1551305 decreased by 14.87% relative to the GG genotype. Conclusions TPCN2 plays a role in metabolic regulation, and the rs1551305 single nucleotide polymorphism is associated with type 2 diabetes risk. Future work will begin to unravel the underlying mechanisms. PMID:26918892

Genomic variant representation in a Chlamydia population is dynamic and adaptive with dependence on in vitro and in vivo passage.

PubMed

Jasper, Deana K; Sigar, Ira M; Schripsema, Justin H; Sainvil, Carlyn K; Smith, Christopher L; Yeruva, Laxmi; Rank, Roger G; Murthy, Ashlesh K; Widder, Jared R; Ramsey, Kyle H

2015-02-01

We have previously shown that Chlamydia muridarum has multiple genomic variants that concomitantly vary in their in vitro and in vivo phenotype. Herein, we used real-time polymerase chain reaction-based genotyping assays to query plaque-cloned isolates of C. muridarum for the frequency of eight selected polymorphisms. These strains had no history of passage in vivo since their original isolation from laboratory mice. There was significant variance in the frequency of two of the eight polymorphisms assessed with the remaining exhibiting a low rate of variance. To determine if any of these polymorphisms were more favorable for in vivo conditions, we blindly passaged non-clonal C. muridarum three times at 7-day intervals through the urogenital tract of mice. Seven of the eight polymorphisms varied in frequency following in vivo passage and four of these varied between C. muridarum strains. Selected isolates displayed variable growth rates and cytopathic effect in vitro. We conclude that multiple genotypic variants are present within the existing known C. muridarum strains and that the frequency of these variants changes upon introduction into the mouse host. These findings lend support to the concept that genotypic proportional representation in a chlamydial population is dynamic and adaptive. © The Author 2015. Published by Oxford University Press on behalf of on behalf of Federation of European Microbiological Society.

Genetic polymorphisms in one-carbon metabolism: associations with CpG island methylator phenotype (CIMP) in colon cancer and the modifying effects of diet

PubMed Central

Curtin, Karen; Slattery, Martha L.; Ulrich, Cornelia M.; Bigler, Jeannette; Levin, Theodore R.; Wolff, Roger K.; Albertsen, Hans; Potter, John D.; Samowitz, Wade S.

2008-01-01

This study investigated associations between CpG island methylator phenotype (CIMP) colon cancer and genetic polymorphisms relevant to one-carbon metabolism and thus, potentially the provision of methyl groups and risk of colon cancer. Data from a large, population-based case–control study (916 incident colon cancer cases and 1972 matched controls) were used. Candidate polymorphisms in methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS), transcobalamin II (TCNII), methionine synthase (MTR), reduced folate carrier (RFC), methylene-tetrahydrofolate dehydrogenase 1 (MTHFD1), dihydrofolate reductase (DHFR) and alcohol dehydrogenase 3 (ADH3) were evaluated. CIMP− or CIMP+ phenotype was based on five CpG island markers: MINT1, MINT2, MINT31, p16 and MLH1. The influence of specific dietary factors (folate, methionine, vitamin B12 and alcohol) on these associations was also analyzed. We hypothesized that polymorphisms involved in the provision of methyl groups would be associated with CIMP+ tumors (two or more of five markers methylated), potentially modified by diet. Few associations specific to CIMP+ tumors were observed overall, which does not support the hypothesis that the provision of methyl groups is important in defining a methylator phenotype. However, our data suggest that genetic polymorphisms in MTHFR 1298A > C, interacting with diet, may be involved in the development of highly CpG-methylated colon cancers. AC and CC genotypes in conjunction with a high-risk dietary pattern (low folate and methionine intake and high alcohol use) were associated with CIMP+ (OR = 2.1, 95% CI = 1.3–3.4 versus AA/high risk; P-interaction = 0.03). These results provide only limited support for a role of polymorphisms in one-carbon metabolism in the etiology of CIMP colon cancer. PMID:17449906

Genetic polymorphisms in one-carbon metabolism: associations with CpG island methylator phenotype (CIMP) in colon cancer and the modifying effects of diet.

PubMed

Curtin, Karen; Slattery, Martha L; Ulrich, Cornelia M; Bigler, Jeannette; Levin, Theodore R; Wolff, Roger K; Albertsen, Hans; Potter, John D; Samowitz, Wade S

2007-08-01

This study investigated associations between CpG island methylator phenotype (CIMP) colon cancer and genetic polymorphisms relevant to one-carbon metabolism and thus, potentially the provision of methyl groups and risk of colon cancer. Data from a large, population-based case-control study (916 incident colon cancer cases and 1,972 matched controls) were used. Candidate polymorphisms in methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS), transcobalamin II (TCNII), methionine synthase (MTR), reduced folate carrier (RFC), methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), dihydrofolate reductase (DHFR) and alcohol dehydrogenase 3 (ADH3) were evaluated. CIMP- or CIMP+ phenotype was based on five CpG island markers: MINT1, MINT2, MINT31, p16 and MLH1. The influence of specific dietary factors (folate, methionine, vitamin B(12) and alcohol) on these associations was also analyzed. We hypothesized that polymorphisms involved in the provision of methyl groups would be associated with CIMP+ tumors (two or more of five markers methylated), potentially modified by diet. Few associations specific to CIMP+ tumors were observed overall, which does not support the hypothesis that the provision of methyl groups is important in defining a methylator phenotype. However, our data suggest that genetic polymorphisms in MTHFR 1,298A > C, interacting with diet, may be involved in the development of highly CpG-methylated colon cancers. AC and CC genotypes in conjunction with a high-risk dietary pattern (low folate and methionine intake and high alcohol use) were associated with CIMP+ (OR = 2.1, 95% CI = 1.3-3.4 versus AA/high risk; P-interaction = 0.03). These results provide only limited support for a role of polymorphisms in one-carbon metabolism in the etiology of CIMP colon cancer.

Systematic review of community health impacts of mountaintop removal mining.

PubMed

Boyles, Abee L; Blain, Robyn B; Rochester, Johanna R; Avanasi, Raghavendhran; Goldhaber, Susan B; McComb, Sofie; Holmgren, Stephanie D; Masten, Scott A; Thayer, Kristina A

2017-10-01

The objective of this evaluation is to understand the human health impacts of mountaintop removal (MTR) mining, the major method of coal mining in and around Central Appalachia. MTR mining impacts the air, water, and soil and raises concerns about potential adverse health effects in neighboring communities; exposures associated with MTR mining include particulate matter (PM), polycyclic aromatic hydrocarbons (PAHs), metals, hydrogen sulfide, and other recognized harmful substances. A systematic review was conducted of published studies of MTR mining and community health, occupational studies of MTR mining, and any available animal and in vitro experimental studies investigating the effects of exposures to MTR-mining-related chemical mixtures. Six databases (Embase, PsycINFO, PubMed, Scopus, Toxline, and Web of Science) were searched with customized terms, and no restrictions on publication year or language, through October 27, 2016. The eligibility criteria included all human population studies and animal models of human health, direct and indirect measures of MTR-mining exposure, any health-related effect or change in physiological response, and any study design type. Risk of bias was assessed for observational and experimental studies using an approach developed by the National Toxicology Program (NTP) Office of Health Assessment and Translation (OHAT). To provide context for these health effects, a summary of the exposure literature is included that focuses on describing findings for outdoor air, indoor air, and drinking water. From a literature search capturing 3088 studies, 33 human studies (29 community, four occupational), four experimental studies (two in rat, one in vitro and in mice, one in C. elegans), and 58 MTR mining exposure studies were identified. A number of health findings were reported in observational human studies, including cardiopulmonary effects, mortality, and birth defects. However, concerns for risk of bias were identified, especially with respect to exposure characterization, accounting for confounding variables (such as socioeconomic status), and methods used to assess health outcomes. Typically, exposure was assessed by proximity of residence or hospital to coal mining or production level at the county level. In addition, assessing the consistency of findings was challenging because separate publications likely included overlapping case and comparison groups. For example, 11 studies of mortality were conducted with most reporting higher rates associated with coal mining, but many of these relied on the same national datasets and were unable to consider individual-level contributors to mortality such as poor socioeconomic status or smoking. Two studies of adult rats reported impaired microvascular and cardiac mitochondrial function after intratracheal exposure to PM from MTR-mining sites. Exposures associated with MTR mining included reports of PM levels that sometimes exceeded Environmental Protection Agency (EPA) standards; higher levels of dust, trace metals, hydrogen sulfide gas; and a report of increased public drinking water violations. This systematic review could not reach conclusions on community health effects of MTR mining because of the strong potential for bias in the current body of human literature. Improved characterization of exposures by future community health studies and further study of the effects of MTR mining chemical mixtures in experimental models will be critical to determining health risks of MTR mining to communities. Without such work, uncertainty will remain regarding the impact of these practices on the health of the people who breathe the air and drink the water affected by MTR mining. Published by Elsevier Ltd.

Mechanical tissue resuscitation (MTR): a nonpharmacological approach to treatment of acute myocardial infarction.

PubMed

Jordan, James E; Pereira, Beatriz D; Lane, Magan R; Morykwas, Michael J; McGee, Maria; Argenta, Louis C

2015-08-01

Myocardial ischemia-reperfusion injury is known to trigger an inflammatory response involving edema, apoptosis, and neutrophil activation/accumulation. Recently, mechanical tissue resuscitation (MTR) was described as a potent cardioprotective strategy for reduction of myocardial ischemia-reperfusion injury. Here, we further describe the protective actions of MTR and begin to define its therapeutic window. A left ventricular, free-wall ischemic area was created in anesthetized swine for 85 minutes and then reperfused for three hours. Animals were randomized to two groups: (1) untreated controls (Control) and (2) application of MTR that was delayed 90 minutes after the initiation of reperfusion (D90). Hemodynamics and regional myocardial blood flow were assessed at multiple time points. Infarct size and neutrophil accumulation were assessed following the reperfusion period. In separate cohorts, the effect of MTR on myocardial interstitial water (MRI imaging) and blood flow was examined. Both groups had similar areas at risk (AAR), hemodynamics, and arterial blood gas values. MTR, even when delayed 90 minutes into reperfusion (D90, 29.2 ± 5.0% of AAR), reduced infarct size significantly compared to Controls (51.9 ± 2.7%, p = 0.006). This protection was associated with a 33% decrease in neutrophil accumulation (p = 0.047). Improvements in blood flow and interstitial water were also observed. Moreover, we demonstrated that the therapeutic window for MTR lasts for at least 90 minutes following reperfusion. This study confirms our previous observations that MTR is an effective therapeutic approach to reducing reperfusion injury with a clinically useful treatment window. © 2015 Wiley Periodicals, Inc.

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

Jackson, R.N.; Robinson, H.; Klauer, A. A.

The essential RNA helicase, Mtr4, performs a critical role in RNA processing and degradation as an activator of the nuclear exosome. The molecular basis for this vital function is not understood and detailed analysis is significantly limited by the lack of structural data. In this study, we present the crystal structure of Mtr4. The structure reveals a new arch-like domain that is specific to Mtr4 and Ski2 (the cytosolic homologue of Mtr4). In vivo and in vitro analyses demonstrate that the Mtr4 arch domain is required for proper 5.8S rRNA processing, and suggest that the arch functions independently of canonicalmore » helicase activity. In addition, extensive conservation along the face of the putative RNA exit site highlights a potential interface with the exosome. These studies provide a molecular framework for understanding fundamental aspects of helicase function in exosome activation, and more broadly define the molecular architecture of Ski2-like helicases.« less

Evaluation of Effect CAT -262C/T, SOD + 35A/C, GPx1 Pro197Leu Polymorphisms in Patients with IBD in the Polish Population.

PubMed

Mrowicki, Jerzy; Mrowicka, Małgorzata; Majsterek, Ireneusz; Mik, Michał; Dziki, Adam; Dziki, Łukasz

2016-12-01

Inflammatory bowel disease (IBD) are a heterogeneous group of disorders in the course dominated by chronic, recurrent gastrointestinal inflammation. It is believed that the activation of IBD occurs in patients with a genetic predisposition to their development. Chronic inflammation develops as a result of an excessive reaction of the immune system principally under the influence of environmental risk factors. Among them, it has been shown that the mechanism of oxidative stress is associated with the pathophysiology of inflammatory bowel disease, responsible for the commencement and progress of these diseases. The aim of the study was the relationship between single nucleotide polymorphisms (SNPs) of individual antioxidant enzymes, and the prevalence of inflammatory bowel disease that may be associated with increased levels of oxidative stress. A total of 111 IBD patients, including 65 patients with ulcerative colitis (UC) and 46 with Crohn's disease (CD) and 125 healthy controls recruited from the Polish population, were genotyped for CAT -262C / T (rs1001179), SOD + 35A / C (rs2234694), GPx Pro 197 Leu polymorphisms. Genotyping of CAT, SOD, GPx gene polymorphism was performed by a RFLP-PCR. The performed analysis of genetic polymorphisms of antioxidant enzymes showed that polymorphic variant of the CAT -262 C / T may have protective effects in patients with ulcerative colitis in the range of genotype C / T; OR = 0.49 (0.25-0.99), p = 0.044. Trend protective, but statistically unrelated, it was also observed for genotype T / T and T allele of the same polymorphism and genotypes and alleles + 35A / C SOD1 in UC as well as polymorphic variants CAT -262 C / T, Pro197Leu of GPx1, + 35A / C SOD1 in CD. The results were compared with a control group of potentially healthy individuals without such diseases. It has been shown that the polymorphism of antioxidant enzymes CAT gene -262 C / T may have protective effects in patients who are carriers of a genotype C / T at the UC. The potential protective effect without statistical relationships were also observed for other genotypes and alleles studied polymorphic variants of antioxidant enzymes in CD and CAT- 262C / T and + 35 A / C SOD1 in UC. Conducted our audit should be extended to more group of patients in order to assess whether or not to confirm the observed during analysis, the protective effect of CAT-262 C / T in ulcerative colitis and other trends observed for other polymorphic variants tested genes.

Identification of a null allele of cytochrome P450 3A7: CYP3A7 polymorphism in a Korean population.

PubMed

Lee, Sang Seop; Jung, Hyun-Ju; Park, Jung Soon; Cha, In-June; Cho, Doo-Yeoun; Shin, Jae-Gook

2010-01-01

Cytochrome P450 3A7 (CYP3A7) is expressed in the human fetal liver and plays a role in the metabolism of hormones, drugs, and toxic compounds. Genetic variants of CYP3A7 are associated with serum estrone level, bone density, and hepatic CYP3A activity in adults. We analyzed the genetic variations of CYP3A7 in a Korean population. From direct sequencing of all exons and flanking regions of the CYP3A7 gene in 48 Koreans, we found five genetic variants, including three novel variants. One variant, a thymidine insertion in exon 2 (4011insT), causes premature termination of CYP3A7 translation, which may result in a null phenotype. The novel variant was assigned to the CYP3A7*3 allele by the CYP allele nomenclature committee. For further screen of this novel variant in other ethnic populations, we used pyrosequencing to analyze an additional 185 Koreans, 100 African Americans, 100 Caucasians, and 159 Vietnamese for the presence of this variant. The variant was not found in any other individuals, except for one Korean subject. The frequencies of two known functional alleles, CYP3A7*2 and CYP3A7*1C, were 26 and 0%, respectively, in Koreans. The frequencies of the functional CYP3A7 polymorphisms in Koreans were significantly different from those in Caucasians and African Americans. This is the first report of a null-type allele of the CYP3A7 gene. It also provides population-level genetic data on CYP3A7 in Koreans to reveal the wide ethnic variation in CYP3A7 polymorphism.

Association of GSTM1, GSTT1 and GSTP1 Ile105Val polymorphisms with clinical response to imatinib mesylate treatment among Malaysian chronic myeloid leukaemia patients.

PubMed

Makhtar, Siti Maziras; Husin, Azlan; Baba, Abdul Aziz; Ankathil, Ravindran

2017-09-01

The detoxifying activity of glutathione S-transferases (GST) enzymes not only protect cells from the adverse effects of xenobiotics, but also alters the effectiveness of drugs in cancer cells, resulting in toxicity or drug resistance. In this study, we aimed to evaluate the association of GSTM1, GSTT1 and GSTP1 Ile105Val polymorphisms with treatment response among Malaysian chronic myeloid leukaemia (CML) patients who everyday undergo 400 mg of imatinib mesylate (IM) therapy. Multiplex polymerase chain reaction (multiplex-PCR) was performed to detect GSTM1 and GSTT1 polymorphisms simultaneously and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was conducted to detect the GSTP1 Ile195Val polymorphism. On evaluating the association of the variant genotype with treatment outcome, heterozygous variant (AG) and homozygous variant (GG) of GSTP1 Ile105Val showed significantly a higher risk for the development of resistance to IM with OR: 1.951 (95% CI: 1.186-3.209, P = 0.009) and OR: 3.540 (95% CI: 1.305-9.606, P = 0.013), respectively. Likewise, GSTT1 null genotype was also associated with a significantly higher risk for the development of resistance to IM with OR = 1.664 (95% CI: 1.011-2.739, P = 0.045). Our results indicate the potential usefulness of GST polymorphism genotyping in predicting the IM treatment response among CML patients.

Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to pediatric acute lymphoblastic leukemia in a German study population.

PubMed

Schnakenberg, Eckart; Mehles, Andrea; Cario, Gunnar; Rehe, Klaus; Seidemann, Kathrin; Schlegelberger, Brigitte; Elsner, Holger A; Welte, Karl H; Schrappe, Martin; Stanulla, Martin

2005-05-27

Methylenetetrahydrofolate reductase (MTHFR) has a major impact on the regulation of the folic acid pathway due to conversion of 5,10-methylenetetrahydrofolate (methylene-THF) to 5-methyl-THF. Two common polymorphisms (677C>T and 1298A>C) in the gene coding for MTHFR have been shown to reduce MTHFR enzyme activity and were associated with the susceptibility to different disorders, including vascular disease, neural tube defects and lymphoid malignancies. Studies on the role of these polymorphisms in the susceptibility to acute lymphoblastic leukemia (ALL) led to discrepant results. We retrospectively evaluated the association of the MTHFR 677C>T and 1298A>C polymorphisms with pediatric ALL by genotyping a study sample of 443 ALL patients consecutively enrolled onto the German multicenter trial ALL-BFM 2000 and 379 healthy controls. We calculated odds ratios of MTHFR genotypes based on the MTHFR 677C>T and 1298A>C polymorphisms to examine if one or both of these polymorphisms are associated with pediatric ALL. No significant associations between specific MTHFR variants or combinations of variants and risk of ALL were observed neither in the total patient group nor in analyses stratified by gender, age at diagnosis, DNA index, immunophenotype, or TEL/AML1 rearrangement. Our findings suggest that the MTHFR 677C>T and 1298A>C gene variants do not have a major influence on the susceptibility to pediatric ALL in the German population.

Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to pediatric acute lymphoblastic leukemia in a German study population

PubMed Central

Schnakenberg, Eckart; Mehles, Andrea; Cario, Gunnar; Rehe, Klaus; Seidemann, Kathrin; Schlegelberger, Brigitte; Elsner, Holger A; Welte, Karl H; Schrappe, Martin; Stanulla, Martin

2005-01-01

Background Methylenetetrahydrofolate reductase (MTHFR) has a major impact on the regulation of the folic acid pathway due to conversion of 5,10-methylenetetrahydrofolate (methylene-THF) to 5-methyl-THF. Two common polymorphisms (677C>T and 1298A>C) in the gene coding for MTHFR have been shown to reduce MTHFR enzyme activity and were associated with the susceptibility to different disorders, including vascular disease, neural tube defects and lymphoid malignancies. Studies on the role of these polymorphisms in the susceptibility to acute lymphoblastic leukemia (ALL) led to discrepant results. Methods We retrospectively evaluated the association of the MTHFR 677C>T and 1298A>C polymorphisms with pediatric ALL by genotyping a study sample of 443 ALL patients consecutively enrolled onto the German multicenter trial ALL-BFM 2000 and 379 healthy controls. We calculated odds ratios of MTHFR genotypes based on the MTHFR 677C>T and 1298A>C polymorphisms to examine if one or both of these polymorphisms are associated with pediatric ALL. Results No significant associations between specific MTHFR variants or combinations of variants and risk of ALL were observed neither in the total patient group nor in analyses stratified by gender, age at diagnosis, DNA index, immunophenotype, or TEL/AML1 rearrangement. Conclusion Our findings suggest that the MTHFR 677C>T and 1298A>C gene variants do not have a major influence on the susceptibility to pediatric ALL in the German population. PMID:15921520

APOC3 Promoter Polymorphisms C-482T and T-455C Are Associated with the Metabolic Syndrome1

PubMed Central

Miller, Michael; Rhyne, Jeffrey; Chen, Hegang; Beach, Valerie; Ericson, Richard; Luthra, Kalpana; Dwivedi, Manjari; Misra, Anoop

2007-01-01

Background Despite the growing epidemic of the metabolic syndrome (MetS), few studies have evaluated genetic polymorphisms associated with the MetS phenotype. One candidate, APOC3, modulates lipid and lipoprotein metabolism and the promoter polymorphisms C-482T/T-455C are associated with loss of insulin downregulation. Methods One hundred twenty two consecutive MetS cases were matched by age, sex and race in a 1:1 case-control design to evaluate the prevalence of common polymorphisms in the following candidate genes: APOC3, APOE, B3AR, FABP2, GNB3, LPL, and PPARα and PPARγ. Results Compared to controls, MetS subjects exhibited a greater prevalence of APOC3 promoter polymorphisms. Specifically, the frequency of the variant C-482T and T-455C alleles was 70.5 and 81.9% of cases compared to 43.4 and 54.1% in controls, respectively ( p <0.0001). Overall, APOC3 promoter variants were associated with a greater likelihood of MetS compared to wild type [C-482T (OR: 4.3; 95% CI: 2.2, 8.6 [p <0.0001]), T-455C (OR: 3.6; 95% CI: 2.0, 6.7 [p <0.0001])]. No material differences were identified between the other genetic variants tested and prevalence of MetS. Conclusions These data, therefore, suggest that the APOC3 promoter polymorphisms C-482T and T-455C are associated with the MetS. PMID:17416293

APOC3 promoter polymorphisms C-482T and T-455C are associated with the metabolic syndrome.

PubMed

Miller, Michael; Rhyne, Jeffrey; Chen, Hegang; Beach, Valerie; Ericson, Richard; Luthra, Kalpana; Dwivedi, Manjari; Misra, Anoop

2007-05-01

Despite the growing epidemic of the metabolic syndrome (MetS), few studies have evaluated genetic polymorphisms associated with the MetS phenotype. One candidate, APOC3, modulates lipid and lipoprotein metabolism and the promoter polymorphisms C-482T/T-455C are associated with loss of insulin downregulation. One hundred twenty two consecutive MetS cases were matched by age, sex and race in a 1:1 case-control design to evaluate the prevalence of common polymorphisms in the following candidate genes: APOC3, APOE, B3AR, FABP2, GNB3, LPL, and PPARalpha and PPARgamma. Compared to controls, MetS subjects exhibited a greater prevalence of APOC3 promoter polymorphisms. Specifically, the frequency of the variant C-482T and T-455C alleles was 70.5 and 81.9% of cases compared to 43.4 and 54.1% in controls, respectively (p <0.0001). Overall, APOC3 promoter variants were associated with a greater likelihood of MetS compared to wild type [C-482T (OR: 4.3; 95% CI: 2.2, 8.6 [p <0.0001]), T-455C (OR: 3.6; 95% CI: 2.0, 6.7 [p <0.0001])]. No material differences were identified between the other genetic variants tested and prevalence of MetS. These data, therefore, suggest that the APOC3 promoter polymorphisms C-482T and T-455C are associated with the MetS.

Neanderthal and Denisova tooth protein variants in present-day humans

PubMed Central

Zanolli, Clément; Hourset, Mathilde; Esclassan, Rémi

2017-01-01

Environment parameters, diet and genetic factors interact to shape tooth morphostructure. In the human lineage, archaic and modern hominins show differences in dental traits, including enamel thickness, but variability also exists among living populations. Several polymorphisms, in particular in the non-collagenous extracellular matrix proteins of the tooth hard tissues, like enamelin, are involved in dental structure variation and defects and may be associated with dental disorders or susceptibility to caries. To gain insights into the relationships between tooth protein polymorphisms and dental structural morphology and defects, we searched for non-synonymous polymorphisms in tooth proteins from Neanderthal and Denisova hominins. The objective was to identify archaic-specific missense variants that may explain the dental morphostructural variability between extinct and modern humans, and to explore their putative impact on present-day dental phenotypes. Thirteen non-collagenous extracellular matrix proteins specific to hard dental tissues have been selected, searched in the publicly available sequence databases of Neanderthal and Denisova individuals and compared with modern human genome data. A total of 16 non-synonymous polymorphisms were identified in 6 proteins (ameloblastin, amelotin, cementum protein 1, dentin matrix acidic phosphoprotein 1, enamelin and matrix Gla protein). Most of them are encoded by dentin and enamel genes located on chromosome 4, previously reported to show signs of archaic introgression within Africa. Among the variants shared with modern humans, two are ancestral (common with apes) and one is the derived enamelin major variant, T648I (rs7671281), associated with a thinner enamel and specific to the Homo lineage. All the others are specific to Neanderthals and Denisova, and are found at a very low frequency in modern Africans or East and South Asians, suggesting that they may be related to particular dental traits or disease susceptibility in these populations. This modern regional distribution of archaic dental polymorphisms may reflect persistence of archaic variants in some populations and may contribute in part to the geographic dental variations described in modern humans. PMID:28902892

Inosine triphosphatase polymorphisms and ribavirin pharmacokinetics as determinants of ribavirin-associate anemia in patients receiving standard anti-HCV treatment.

PubMed

DʼAvolio, Antonio; Ciancio, Alessia; Siccardi, Marco; Smedile, Antonina; Baietto, Lorena; Simiele, Marco; Marucco, Diego Aguilar; Cariti, Giuseppe; Calcagno, Andrea; de Requena, Daniel Gonzalez; Sciandra, Mauro; Cusato, Jessica; Troshina, Giulia; Bonora, Stefano; Rizzetto, Mario; Di Perri, Giovanni

2012-04-01

Functional variants of inosine triphosphatase (ITPA) were recently found to protect against ribavirin (RBV)-induced hemolytic anemia. However, no definitive data are yet available on the role of plasma RBV concentrations on hemoglobin (Hb) decrement. Moreover, no data have been published on the possible interplay between these 2 factors. A retrospective analysis included 167 patients. The ITPA variants rs7270101 and rs1127354 were genotyped and tested using the χ test for association with Hb reduction at week 4. We also investigated, using multivariate logistic regression, the impact of RBV plasma exposure on Hb concentrations. Both single nucleotide polymorphisms were associated with Hb decrease. The carrier of at least 1 variant allele in the functional ITPA single nucleotide polymorphisms was associated with a lower decrement of Hb (-1.1 g/dL), as compared with patients without a variant allele (-2.75 g/dL; P = 4.09 × 10). RBV concentrations were not influenced by ITPA genotypes. A cut-off of 2.3 μg/mL of RBV was found to be associated with anemia (area-under-receiver operating characteristic = 0.630, sensitivity = 50.0%, and specificity = 69.5%, P = 0.008). In multivariate logistic regression analyses, the carrier of a variant allele (P = 0.005) and plasma RBV concentrations <2.3 μg/mL (P = 0.016) were independently associated with protection against clinically significant anemia at week 4. Although no direct relationship was found between ITPA polymorphisms and plasma RBV concentrations, both factors were shown to be significantly associated with anemia. A multivariate regression model based on ITPA genetic polymorphisms and RBV trough concentration was developed for predicting the risk of anemia. By relying upon these 2 variables, an individualized management of anemia seems to be feasible in recipients of pegylated interferon-RBV therapy.

Evaluation of targeted exome sequencing for 28 protein-based blood group systems, including the homologous gene systems, for blood group genotyping.

PubMed

Schoeman, Elizna M; Lopez, Genghis H; McGowan, Eunike C; Millard, Glenda M; O'Brien, Helen; Roulis, Eileen V; Liew, Yew-Wah; Martin, Jacqueline R; McGrath, Kelli A; Powley, Tanya; Flower, Robert L; Hyland, Catherine A

2017-04-01

Blood group single nucleotide polymorphism genotyping probes for a limited range of polymorphisms. This study investigated whether massively parallel sequencing (also known as next-generation sequencing), with a targeted exome strategy, provides an extended blood group genotype and the extent to which massively parallel sequencing correctly genotypes in homologous gene systems, such as RH and MNS. Donor samples (n = 28) that were extensively phenotyped and genotyped using single nucleotide polymorphism typing, were analyzed using the TruSight One Sequencing Panel and MiSeq platform. Genes for 28 protein-based blood group systems, GATA1, and KLF1 were analyzed. Copy number variation analysis was used to characterize complex structural variants in the GYPC and RH systems. The average sequencing depth per target region was 66.2 ± 39.8. Each sample harbored on average 43 ± 9 variants, of which 10 ± 3 were used for genotyping. For the 28 samples, massively parallel sequencing variant sequences correctly matched expected sequences based on single nucleotide polymorphism genotyping data. Copy number variation analysis defined the Rh C/c alleles and complex RHD hybrids. Hybrid RHD*D-CE-D variants were correctly identified, but copy number variation analysis did not confidently distinguish between D and CE exon deletion versus rearrangement. The targeted exome sequencing strategy employed extended the range of blood group genotypes detected compared with single nucleotide polymorphism typing. This single-test format included detection of complex MNS hybrid cases and, with copy number variation analysis, defined RH hybrid genes along with the RHCE*C allele hitherto difficult to resolve by variant detection. The approach is economical compared with whole-genome sequencing and is suitable for a red blood cell reference laboratory setting. © 2017 AABB.

Genetic variation in the folate metabolic pathway and risk of childhood leukemia

PubMed Central

Johnston, W. Thomas; Painter, Dan; Simpson, Jill; Roman, Eve; Skibola, Chris F.; Smith, Martyn T.; Allan, James M.; Taylor, G. Malcolm

2010-01-01

Studies of childhood leukemia and the potential etiologic role of genetic variation in folate metabolism have produced conflicting findings and have often been based on small numbers. We investigated the association between polymorphisms in key folate metabolism enzymes (MTHFR 677 C>T, MTHFR 1298 A>C, SHMT1 1420 C>T, MTR 2756 A>G, TS 1494del6, and TS 28bp repeat) in 939 cases of childhood acute lymphoblastic leukemia (ALL) and 89 cases of acute myeloid leukemia (AML) recruited into the United Kingdom Childhood Cancer Study. We also examined the maternal genotypes of 752 of these cases. Data from 824 noncancer controls recruited were used for comparison. No evidence of an association with MTHFR 677 was observed for ALL or AML, either in children or their mothers. However, in children an increased risk of ALL (odds ratio [OR] = 1.88; 95% confidence interval [CI], 1.16-3.07; P = .010) and AML (OR = 2.74; 95% CI, 1.07-7.01; P = .036) was observed with the MTR 2756 GG genotype; the association was most pronounced for cases with the MLL translocation (OR = 4.90; 95% CI, 1.30-18.45; P = .019). These data suggest that genetic variation in methionine synthase could mediate risk of childhood leukemia, either via effects on DNA methylation or via effects on fetal growth and development. PMID:20101025

BDNF Variants May Modulate Long-Term Visual Memory Performance in a Healthy Cohort

PubMed Central

Avgan, Nesli; Sutherland, Heidi G.; Spriggens, Lauren K.; Yu, Chieh; Ibrahim, Omar; Bellis, Claire; Haupt, Larisa M.; Shum, David H. K.; Griffiths, Lyn R.

2017-01-01

Brain-derived neurotrophic factor (BDNF) is involved in numerous cognitive functions including learning and memory. BDNF plays an important role in synaptic plasticity in humans and rats with BDNF shown to be essential for the formation of long-term memories. We previously identified a significant association between the BDNF Val66Met polymorphism (rs6265) and long-term visual memory (p-value = 0.003) in a small cohort (n = 181) comprised of healthy individuals who had been phenotyped for various aspects of memory function. In this study, we have extended the cohort to 597 individuals and examined multiple genetic variants across both the BDNF and BDNF-AS genes for association with visual memory performance as assessed by the Wechsler Memory Scale—Fourth Edition subtests Visual Reproduction I and II (VR I and II). VR I assesses immediate visual memory, whereas VR II assesses long-term visual memory. Genetic association analyses were performed for 34 single nucleotide polymorphisms genotyped on Illumina OmniExpress BeadChip arrays with the immediate and long-term visual memory phenotypes. While none of the BDNF and BDNF-AS variants were shown to be significant for immediate visual memory, we found 10 variants (including the Val66Met polymorphism (p-value = 0.006)) that were nominally associated, and three variants (two variants in BDNF and one variant in the BDNF-AS locus) that were significantly associated with long-term visual memory. Our data therefore suggests a potential role for BDNF, and its anti-sense transcript BDNF-AS, in long-term visual memory performance. PMID:28304362

BDNF Variants May Modulate Long-Term Visual Memory Performance in a Healthy Cohort.

PubMed

Avgan, Nesli; Sutherland, Heidi G; Spriggens, Lauren K; Yu, Chieh; Ibrahim, Omar; Bellis, Claire; Haupt, Larisa M; Shum, David H K; Griffiths, Lyn R

2017-03-17

Brain-derived neurotrophic factor (BDNF) is involved in numerous cognitive functions including learning and memory. BDNF plays an important role in synaptic plasticity in humans and rats with BDNF shown to be essential for the formation of long-term memories. We previously identified a significant association between the BDNF Val66Met polymorphism (rs6265) and long-term visual memory ( p -value = 0.003) in a small cohort ( n = 181) comprised of healthy individuals who had been phenotyped for various aspects of memory function. In this study, we have extended the cohort to 597 individuals and examined multiple genetic variants across both the BDNF and BDNF-AS genes for association with visual memory performance as assessed by the Wechsler Memory Scale-Fourth Edition subtests Visual Reproduction I and II (VR I and II). VR I assesses immediate visual memory, whereas VR II assesses long-term visual memory. Genetic association analyses were performed for 34 single nucleotide polymorphisms genotyped on Illumina OmniExpress BeadChip arrays with the immediate and long-term visual memory phenotypes. While none of the BDNF and BDNF-AS variants were shown to be significant for immediate visual memory, we found 10 variants (including the Val66Met polymorphism ( p -value = 0.006)) that were nominally associated, and three variants (two variants in BDNF and one variant in the BDNF-AS locus) that were significantly associated with long-term visual memory. Our data therefore suggests a potential role for BDNF , and its anti-sense transcript BDNF-AS , in long-term visual memory performance.

PRECONSTRUCTION IMAGE OF THE MTR SITE. ABANDONED IRRIGATION CANAL (FROM ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

PRE-CONSTRUCTION IMAGE OF THE MTR SITE. ABANDONED IRRIGATION CANAL (FROM EARLY 1900s) ILLUSTRATES FLATNESS OF MTR/TRA TERRAIN. FEATURE ON HORIZON IN LEFT OF VIEW IS EXPLORATORY WATER DRILLING EQUIPMENT. CAMERA LOOKS SOUTHEAST. INL NEGATIVE NO. 136. Unknown Photographer, 12/5/1949 - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

Modified pectic polysaccharide from turmeric (Curcuma longa): A potent dietary component against gastric ulcer.

PubMed

Harsha, Mysore R; Chandra Prakash, Serkad V; Dharmesh, Shylaja M

2016-03-15

Native, intact (TrPP) and modified, low-molecular-weight (MTrPP) forms of pectic polysaccharides isolated from turmeric were evaluated for ulcer-preventive potentials in in vitro and in vivo models. Data indicated that MTrPP possessed significantly better ulcer-preventive property than TrPP; inhibiting ulcer scores up to 85%. Results were substantiated by effective muco-protection, H(+),K(+)-ATPase down-regulation, inhibition of H. pylori growth/adherence, higher antioxidant/cytoprotective mechanisms. Structural data indicated TrPP and MTrPP differ in their molecular weights and structural characteristics with different sugar compositions and side chain ratios. MTrPP was rich in galacturonic acid (687mg/g; TrPP-544mg/g) and galactose (52.9%; TrPP-21.7%). Results were substantiated by NMR/FTIR data indicating the presence of homogalacturonan and rhamnogalacturonam-I containing galactans. By virtue of binding to inflammatory marker (galectin-3), galactans may reduce inflammation induced ulcerations. The low molecular weight of MTrPP (155kDa; TrPP-13kDa) may increase its bioavailability than TrPP, thus MTrPP may possess higher antiulcer potential. Copyright © 2015 Elsevier Ltd. All rights reserved.

Moderate treadmill running exercise prior to tendon injury enhances wound healing in aging rats

PubMed Central

Zhang, Jianying; Yuan, Ting; Wang, James H-C.

2016-01-01

The effect of exercise on wound healing in aging tendon was tested using a rat moderate treadmill running (MTR) model. The rats were divided into an MTR group that ran on a treadmill for 4 weeks and a control group that remained in cages. After MTR, a window defect was created in the patellar tendons of all rats and wound healing was analyzed. We found that MTR accelerated wound healing by promoting quicker closure of wounds, improving the organization of collagen fibers, and decreasing senescent cells in the wounded tendons when compared to the cage control. MTR also lowered vascularization, increased the numbers of tendon stem/progenitor cells (TSCs) and TSC proliferation than the control. Besides, MTR significantly increased the expression of stem cell markers, OCT-4 and Nanog, and tenocyte genes, Collagen I, Collagen III and tenomodulin, and down-regulated PPAR-γ, Collagen II and Runx-2 (non-tenocyte genes). These findings indicated that moderate exercise enhances healing of injuries in aging tendons through TSC based mechanisms, through which exercise regulates beneficial effects in tendons. This study reveals that appropriate exercise may be used in clinics to enhance tendon healing in aging patients. PMID:26885754

Moderate treadmill running exercise prior to tendon injury enhances wound healing in aging rats.

PubMed

Zhang, Jianying; Yuan, Ting; Wang, James H-C

2016-02-23

The effect of exercise on wound healing in aging tendon was tested using a rat moderate treadmill running (MTR) model. The rats were divided into an MTR group that ran on a treadmill for 4 weeks and a control group that remained in cages. After MTR, a window defect was created in the patellar tendons of all rats and wound healing was analyzed. We found that MTR accelerated wound healing by promoting quicker closure of wounds, improving the organization of collagen fibers, and decreasing senescent cells in the wounded tendons when compared to the cage control. MTR also lowered vascularization, increased the numbers of tendon stem/progenitor cells (TSCs) and TSC proliferation than the control. Besides, MTR significantly increased the expression of stem cell markers, OCT-4 and Nanog, and tenocyte genes, Collagen I, Collagen III and tenomodulin, and down-regulated PPAR-γ, Collagen II and Runx-2 (non-tenocyte genes). These findings indicated that moderate exercise enhances healing of injuries in aging tendons through TSC based mechanisms, through which exercise regulates beneficial effects in tendons. This study reveals that appropriate exercise may be used in clinics to enhance tendon healing in aging patients.

Polymorphism of the transcription factor 7-like 2 Gene (TCF7L2) interacts with obesity on type-2 diabetes in the PREDIMED Study emphasizing the heterogeneity of genetic variants in type-2 diabetes risk prediction: time for...

USDA-ARS?s Scientific Manuscript database

Nutrigenetic studies analyzing gene-diet interactions of the TCF7L2-rs7903146 C > T polymorphism on type-2 diabetes (T2D) have shown controversial results. A reason contributing to this may be the additional modulation by obesity. Moreover, TCF7L2-rs7903146 is one of the most influential variants in...

Emerging role of NUDT15 polymorphisms in 6-mercaptopurine metabolism and dose related toxicity in acute lymphoblastic leukaemia.

PubMed

Singh, Minu; Bhatia, Prateek; Khera, Sanjeev; Trehan, Amita

2017-11-01

Despite more than 80% long term survival in ALL, morbidity due to drug related myelotoxicity remains high. Germline variants of thiopurine metabolizing enzymes (TPMT and ITPA) have been described which are associated with increased drug toxicity during maintenance phase, but their prevalence in different ethnic groups is variable to account for relatively high myelotoxicity incidence. NUDT15 variant (rs116855232) has been recently identified as a novel polymorphism related with thiopurine-induced leucopenia in inflammatory bowel disease and ALL. Current review highlights the scientific data on NUDT15 enzyme variant and its relation to 6-MP toxicity in various ethnic populations. Copyright © 2017 Elsevier Ltd. All rights reserved.

Margin to tumor thickness ratio - A predictor of local recurrence and survival in oral squamous cell carcinoma.

PubMed

Heiduschka, Gregor; Virk, Sohaib A; Palme, Carsten E; Ch'ng, Sydney; Elliot, Michael; Gupta, Ruta; Clark, Jonathan

2016-04-01

To assess whether small oral squamous cell carcinomas (OSCC) require the same margin clearance as large tumors. We evaluated the association between the ratio of the closest margin to tumor size (MSR) and tumor thickness (MTR) with local control and survival. The clinicopathologic and follow up data were obtained for 501 OSCC patients who had surgical resection with curative intent at our institution. MTR and MSR were computed and their associations with local control and survival were assessed using multivariable Cox-regression model. Survival curves were generated using the Kaplan-Meier method. MTR was a better predictor of disease control than MSR. MTR was a predictor of local failure (p=0.033) and disease specific death (p=0.038) after adjusting for perineural invasion, lymphovascular involvement, nodal status, and radiotherapy. A threshold MTR value of 0.3 was identified, above which the risk of local recurrence was low. The ratio of margin to tumor thickness was an independent predictor for local recurrence and disease specific death in this cohort. A MTR>0.3 can serve as a useful tool for adjuvant therapy planning as it combines tumor thickness and margin clearance, two well established prognostic factors. The minimum safe margin can be calculated by multiplying the tumor thickness by 0.3. Further prospective studies in other institutions are warranted to confirm the prognostic utility of MTR and assess the generalizability of our threshold values. Copyright © 2016 Elsevier Ltd. All rights reserved.

Regional patterns of grey matter atrophy and magnetisation transfer ratio abnormalities in multiple sclerosis clinical subgroups: A voxel-based analysis study

PubMed Central

Muhlert, Nils; Samson, Rebecca S; Sethi, Varun; Wheeler-Kingshott, Claudia AM; Miller, David H; Chard, Declan T

2015-01-01

Background: In multiple sclerosis (MS), demyelination and neuro-axonal loss occur in the brain grey matter (GM). We used magnetic resonance imaging (MRI) measures of GM magnetisation transfer ratio (MTR) and volume to assess the regional localisation of reduced MTR (reflecting demyelination) and atrophy (reflecting neuro-axonal loss) in relapsing–remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS). Methods: A total of 98 people with MS (51 RRMS, 28 SPMS, 19 PPMS) and 29 controls had T1-weighted volumetric and magnetisation transfer scans. SPM8 was used to undertake voxel-based analysis (VBA) of GM tissue volumes and MTR. MS subgroups were compared with controls, adjusting for age and gender. A voxel-by-voxel basis correlation analysis between MTR and volume within each subject group was performed, using biological parametric mapping. Results: MTR reduction was more extensive than atrophy. RRMS and SPMS patients showed proportionately more atrophy in the deep GM. SPMS and PPMS patients showed proportionately greater cortical MTR reduction. RRMS patients demonstrated the most correlation of MTR reduction and atrophy in deep GM. In SPMS and PPMS patients, there was less extensive correlation. Conclusions: These results suggest that in the deep GM of RRMS patients, demyelination and neuro-axonal loss may be linked, while in SPMS and PPMS patients, neuro-axonal loss and demyelination may occur mostly independently. PMID:25145689

Serotonin-related FEV gene variant in the sudden infant death syndrome is a common polymorphism in the African-American population.

PubMed

Broadbelt, Kevin G; Barger, Melissa A; Paterson, David S; Holm, Ingrid A; Haas, Elisabeth A; Krous, Henry F; Kinney, Hannah C; Markianos, Kyriacos; Beggs, Alan H

2009-12-01

An important subset of the sudden infant death syndrome (SIDS) is associated with multiple serotonergic (5-HT) abnormalities in regions of the medulla oblongata. The mouse ortholog of the fifth Ewing variant gene (FEV) is critical for 5-HT neuronal development. A putatively rare intronic variant [IVS2-191_190insA, here referred to as c.128-(191_192)dupA] has been reported as a SIDS-associated mutation in an African-American population. We tested this association in an independent dataset: 137 autopsied cases (78 SIDS, 59 controls) and an additional 296 control DNA samples from Coriell Cell Repositories. In addition to the c.128-(191_192)dupA variant, we observed an associated single-base deletion [c.128-(301-306)delG] in a subset of the samples. Neither of the two FEV variants showed significant association with SIDS in either the African-American subgroup or the overall cohort. Although we found a significant association of c.128-(191_192)dupA with SIDS when San Diego Hispanic SIDS cases were compared with San Diego Hispanic controls plus Mexican controls (p = 0.04), this became nonsignificant after multiple testing correction. Among Coriell controls, 33 of 99 (33%) African-American and 0 of 197 (0%) of the remaining controls carry the polymorphism (c.128-(191_192)dupA). The polymorphism seems to be a common, likely nonpathogenic, variant in the African-American population.

Search for methylation-sensitive amplification polymorphisms associated with the mantled variant phenotype in oil palm (Elaeis guineensis Jacq).

PubMed

Jaligot, E; Beulé, T; Baurens, F-C; Billotte, N; Rival, A

2004-02-01

The methylation-sensitive amplification polymorphism (MSAP) technique has been employed on somatic embryo-derived oil palms (Elaeis guineensis Jacq.) to identify methylation polymorphisms correlated with the "mantled" somaclonal variation. The variant phenotype displays an unstable feminization of male organs in both male and female flowers. Using MSAP, the methylation status of CCGG sites was compared in three normal versus three mantled regenerants sampled in clonal populations obtained through somatic embryogenesis from four genotypically distinct mother palms. Overall, 64 selective primer combinations were used and they have amplified 23 markers exhibiting a differential methylation pattern between the two phenotypes. Our results indicate that CCGG sites are poorly affected by the considerable decrease in global DNA methylation that has been previously associated with the mantled phenotype. Each of the 23 markers isolated in the present study could discriminate between the two phenotypes only when they were from the same genetic origin. This result hampers at the moment the direct use of MSAP markers for the early detection of variants, even though valuable information on putative target sequences will be obtained from a further characterization of these polymorphic markers.

Functional analysis of regulatory single-nucleotide polymorphisms.

PubMed

Pampín, Sandra; Rodríguez-Rey, José C

2007-04-01

The identification of regulatory polymorphisms has become a key problem in human genetics. In the past few years there has been a conceptual change in the way in which regulatory single-nucleotide polymorphisms are studied. We revise the new approaches and discuss how gene expression studies can contribute to a better knowledge of the genetics of common diseases. New techniques for the association of single-nucleotide polymorphisms with changes in gene expression have been recently developed. This, together with a more comprehensive use of the old in-vitro methods, has produced a great amount of genetic information. When added to current databases, it will help to design better tools for the detection of regulatory single-nucleotide polymorphisms. The identification of functional regulatory single-nucleotide polymorphisms cannot be done by the simple inspection of DNA sequence. In-vivo techniques, based on primer-extension, and the more recently developed 'haploChIP' allow the association of gene variants to changes in gene expression. Gene expression analysis by conventional in-vitro techniques is the only way to identify the functional consequences of regulatory single-nucleotide polymorphisms. The amount of information produced in the last few years will help to refine the tools for the future analysis of regulatory gene variants.

MTR BUILDING INTERIOR, TRA603. BASEMENT. CAMERA IN WEST CORRIDOR FACING ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

MTR BUILDING INTERIOR, TRA-603. BASEMENT. CAMERA IN WEST CORRIDOR FACING SOUTH. FREIGHT ELEVATOR IS AT RIGHT OF VIEW. AT CENTER VIEW IS MTR VAULT NO. 1, USED TO STORE SPECIAL OR FISSIONABLE MATERIALS. INL NEGATIVE NO. HD46-6-3. Mike Crane, Photographer, 2/2005 - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

GDNF Gene Is Associated With Tourette Syndrome in a Family Study

PubMed Central

Huertas-Fernández, Ismael; Gómez-Garre, Pilar; Madruga-Garrido, Marcos; Bernal-Bernal, Inmaculada; Bonilla-Toribio, Marta; Martín-Rodríguez, Juan Francisco; Cáceres-Redondo, María Teresa; Vargas-González, Laura; Carrillo, Fátima; Pascual, Alberto; Tischfield, Jay A.; King, Robert A.; Heiman, Gary A.; Mir, Pablo

2016-01-01

Background Tourette syndrome is a disorder characterized by persistent motor and vocal tics, and frequently accompanied by the comorbidities attention deficit hyperactivity disorder and obsessive-compulsive disorder. Impaired synaptic neurotransmission has been implicated in its pathogenesis. Our aim was to investigate the association of 28 candidate genes, including genes related to synaptic neurotransmission and neurotrophic factors, with Tourette syndrome. Methods We genotyped 506 polymorphisms in a discovery cohort from the United States composed of 112 families and 47 unrelated singletons with Tourette syndrome (201 cases and 253 controls). Genes containing significant polymorphisms were imputed to fine-map the signal(s) to potential causal variants. Allelic analyses in Tourette syndrome cases were performed to check the role in attention deficit hyperactivity disorder and obsessive-compulsive disorder comorbidities. Target polymorphisms were further studied in a replication cohort from southern Spain composed of 37 families and three unrelated singletons (44 cases and 73 controls). Results The polymorphism rs3096140 in glial cell line–derived neurotrophic factor gene (GDNF) was significant in the discovery cohort after correction (P = 1.5 × 10−4). No linkage disequilibrium was found between rs3096140 and other functional variants in the gene. We selected rs3096140 as target polymorphism, and the association was confirmed in the replication cohort (P = 0.01). No association with any comorbidity was found. Conclusions As a conclusion, a common genetic variant in GDNF is associated with Tourette syndrome. A defect in the production of GDNF could compromise the survival of parvalbumin interneurons, thus altering the excitatory/inhibitory balance in the corticostriatal circuitry. Validation of this variant in other family cohorts is necessary. PMID:26096985

GDNF gene is associated with tourette syndrome in a family study.

PubMed

Huertas-Fernández, Ismael; Gómez-Garre, Pilar; Madruga-Garrido, Marcos; Bernal-Bernal, Inmaculada; Bonilla-Toribio, Marta; Martín-Rodríguez, Juan Francisco; Cáceres-Redondo, María Teresa; Vargas-González, Laura; Carrillo, Fátima; Pascual, Alberto; Tischfield, Jay A; King, Robert A; Heiman, Gary A; Mir, Pablo

2015-07-01

Tourette syndrome is a disorder characterized by persistent motor and vocal tics, and frequently accompanied by the comorbidities attention deficit hyperactivity disorder and obsessive-compulsive disorder. Impaired synaptic neurotransmission has been implicated in its pathogenesis. Our aim was to investigate the association of 28 candidate genes, including genes related to synaptic neurotransmission and neurotrophic factors, with Tourette syndrome. We genotyped 506 polymorphisms in a discovery cohort from the United States composed of 112 families and 47 unrelated singletons with Tourette syndrome (201 cases and 253 controls). Genes containing significant polymorphisms were imputed to fine-map the signal(s) to potential causal variants. Allelic analyses in Tourette syndrome cases were performed to check the role in attention deficit hyperactivity disorder and obsessive-compulsive disorder comorbidities. Target polymorphisms were further studied in a replication cohort from southern Spain composed of 37 families and three unrelated singletons (44 cases and 73 controls). The polymorphism rs3096140 in glial cell line-derived neurotrophic factor gene (GDNF) was significant in the discovery cohort after correction (P = 1.5 × 10(-4) ). No linkage disequilibrium was found between rs3096140 and other functional variants in the gene. We selected rs3096140 as target polymorphism, and the association was confirmed in the replication cohort (P = 0.01). No association with any comorbidity was found. As a conclusion, a common genetic variant in GDNF is associated with Tourette syndrome. A defect in the production of GDNF could compromise the survival of parvalbumin interneurons, thus altering the excitatory/inhibitory balance in the corticostriatal circuitry. Validation of this variant in other family cohorts is necessary. © 2015 International Parkinson and Movement Disorder Society.

Genetic Polymorphisms of Cytochrome P4501A1 (CYP1A1) and Glutathione S-Transferase P1 (GSTP1) and Risk of Hepatocellular Carcinoma Among Chronic Hepatitis C Patients in Egypt.

PubMed

Abo-Hashem, Ekbal M; El-Emshaty, Wafaa M; Farag, Raghda El Sayed; Zakaria, Sahar; Abd El-Aziz, Mohammed; Ghonaim, Azza

2016-10-01

Cytochrome P450 1A1 (CYP1A1) and Glutathione S-transferase P1 (GSTP1) genes are involved in the metabolism of many carcinogens. Polymorphisms in these genes with altered enzyme activity have been reported. The present study evaluated the synergistic effect between CYP1A1 and GSTP1 gene polymorphisms and smoking on development of HCV-related liver disease and hepatocellular carcinoma (HCC). The patients group comprised 40 patients with HCC and 40 patients with liver cirrhosis. The control group comprised 40 healthy subjects having no history of malignancy. The genetic polymorphisms were studied using polymerase chain reaction restriction fragment length polymorphism (PCR RFLP) technique on blood samples. The number of current or former smoker among HCC and cirrhotic patients as well as the median Pack/year of cigarette smoked were significantly higher in HCC and liver cirrhotic patients than in control group. Subjects with CYP1A1 gene variants (m1 and m3) had no significant risk to develop cirrhosis or HCC compared to control group. Individuals carrying the Ile/Val genotype of GSTP1 had a significant increased risk of HCC (OR of 2.2, 95 % CI 1.143-4.261) and had larger tumor size. No significant risk was observed on combining both genes variants or on combining smoking with variants of both genes. In conclusion, the GSTP1 Ile/Val genotype and Val allele are associated with an increased risk of HCC. CYP1A1 and GSTP1 genes variants interaction did not increase the risk of HCC.

The Location of Peak Upper Trapezius Muscle Activity During Submaximal Contractions is not Associated With the Location of Myofascial Trigger Points: New Insights Revealed by High-density Surface EMG.

PubMed

Barbero, Marco; Falla, Deborah; Mafodda, Luca; Cescon, Corrado; Gatti, Roberto

2016-12-01

To apply topographical mapping of the electromyography (EMG) amplitude recorded from the upper trapezius muscle to evaluate the distribution of activity and the location of peak activity during a shoulder elevation task in participants with and without myofascial pain and myofascial trigger points (MTrP) and compare this location with the site of the MTrP. Thirteen participants with myofascial pain and MTrP in the upper trapezius muscle and 12 asymptomatic individuals participated. High-density surface EMG was recorded from the upper trapezius muscle using a matrix of 64 surface electrodes aligned with an anatomic landmark system (ALS). Each participant performed a shoulder elevation task consisting of a series of 30 s ramped contractions to 15% or 60% of their maximal voluntary contraction (MVC) force. Topographical maps of the EMG average rectified value were computed and the peak EMG amplitude during the ramped contractions was identified and its location determined with respect to the ALS. The location of the MTrP was also determined relative to the ALS and Spearman correlation coefficients were used to examine the relationship between MTrP and peak EMG amplitude location. The location of the peak EMG amplitude was significantly (P<0.05) different between groups (participants with pain/MTrP: -0.32±1.2 cm at 15% MVC and -0.35±0.9 cm at 60% MVC relative to the ALS; asymptomatic participants: 1.0±1.3 cm at 15% MVC and 1.3±1.1 cm relative to the ALS). However, no correlation was observed between the position of the MTrP and peak EMG amplitude during the ramped contractions at either force level (15%: rs=0.039, P=0.9; 60%: rs=-0.087, P=0.778). People with myofascial pain and MTrP displayed a caudal shift of the distribution of upper trapezius muscle activity compared with asymptomatic individuals during a submaximal shoulder elevation task. For the first time, we show that the location of peak muscle activity is not associated with the location of the MTrP.

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

PubMed

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

2011-01-01

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

Genetic variation in TNFα, PPARγ, and IRS-1 genes, and their association with breast-cancer survival in the HEAL cohort.

PubMed

Duggan, Catherine; Baumgartner, Richard N; Baumgartner, Kathy B; Bernstein, Leslie; George, Stephanie; Ballard, Rachel; Neuhouser, Marian L; McTiernan, Anne

2018-04-01

Tumor necrosis factor-α (TNF-α), peroxisome proliferator-activated receptor-γ (PPARγ), and insulin receptor substrate-1 (IRS-1) are associated with obesity, insulin resistance, and inflammation. Few data exist on associations between polymorphisms in these genes and mortality in breast cancer survivors. We investigated associations between TNF-α -308 G > A (rs1800629); PPARγ Pro 12 Ala (rs1801282); and IRS-1 Gly 972 Arg (rs1801278) polymorphisms and anthropometric variables, circulating levels of previously measured biomarkers, and tumor characteristics in 553 women enrolled in the Health, Eating, Activity, and Lifestyle Study, a multiethnic, prospective cohort study of women diagnosed with stage I-IIIA breast cancer between 1995 and 1999 (median follow-up 14.7 years).  Using Cox proportional hazards models adjusted for possible confounders, we evaluated associations between these polymorphisms and mortality. Carriers of the PPARγ variant allele had statistically significantly lower rates of type 2 diabetes (P = 0.04), lower BMI (P = 0.01), and HOMA scores [P = 0.004; non-Hispanic White (NHWs) only]; carriers of the TNF-α variant A allele had higher serum glucose (P = 0.004, NHW only); and the IRS-1 variant was associated with higher leptin levels (P = 0.003, Hispanics only). There were no associations between any of the polymorphisms and tumor characteristics. Among 141 deaths, 62 were due to breast cancer. Carriers of the TNF-α-variant A allele had a decreased risk of breast-cancer-specific mortality [hazard ratio (HR) 0.30; 95% confidence interval (CI) 0.10-0.83] and all-cause mortality (HR 0.51; 95% CI 0.28-0.91). Neither the PPARγ nor the IRS-1 polymorphism was associated with mortality outcome. The TNF-α -308 G > A polymorphism was associated with reduced breast-cancer-specific and all-cause mortality.

Genetic variants of dopamine D2 receptor impact heterodimerization with dopamine D1 receptor.

PubMed

Błasiak, Ewa; Łukasiewicz, Sylwia; Szafran-Pilch, Kinga; Dziedzicka-Wasylewska, Marta

2017-04-01

The human dopamine D2 receptor gene has three polymorphic variants that alter its amino acid sequence: alanine substitution by valine in position 96 (V96A), proline substitution by serine in position 310 (P310S) and serine substitution by cysteine in position 311 (S311C). Their functional role has never been the object of extensive studies, even though there is some evidence that their occurrence correlates with schizophrenia. The HEK293 cell line was transfected with dopamine D1 and D2 receptors (or genetic variants of the D2 receptor), coupled to fluorescent proteins which allowed us to measure the extent of dimerization of these receptors, using a highly advanced biophysical approach (FLIM-FRET). Additionally, Fluoro-4 AM was used to examine changes in the level of calcium release after ligand stimulation of cells expressing different combinations of dopamine receptors. Using FLIM-FRET experiments we have shown that in HEK 293 expressing dopamine receptors, polymorphic mutations in the D2 receptor play a role in dimmer formation with the dopamine D1 receptor. The association level of dopamine receptors is affected by ligand administration, with variable effects depending on polymorphic variant of the D2 dopamine receptor. We have found that the level of heteromer formation is reflected by calcium ion release after ligand stimulation and have observed variations of this effect dependent on the polymorphic variant and the ligand. The data presented in this paper support the hypothesis on the role of calcium signaling regulated by the D1-D2 heteromer which may be of relevance for schizophrenia etiology. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

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

DOE PAGES

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

2015-01-23

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

Methylenetetrahydrofolate reductase polymorphism C677T is a protective factor for pediatric acute lymphoblastic leukemia in the Chinese population: a meta-analysis.

PubMed

Wang, Haigang; Meng, Lujing; Zhao, Lixia; Wang, Jiali; Liu, Xinchun; Mi, Wenjie

2012-12-01

Two polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C, were hypothesized to decrease the risk of acute lymphoblastic leukemia (ALL). Studies examining the associations between these two polymorphisms and ALL susceptibility drew inconsistent results. To obtain a reliable conclusion in a Chinese population, we carried out a meta-analysis. In total, 11 studies on C677T polymorphism (1597 cases and 2295 controls) and 10 studies on A1298C polymorphism (1553 cases and 2224 controls) were included in the meta-analysis. We found a significant association between the 677T variant and reduced ALL risk in Chinese children (Dominant model: odds ratio [OR(FE)]=0.73, 95% confidence interval [CI]: 0.63-0.86, p<0.01). Heterogeneity between the studies in the children subgroup was weak and vanished after excluding one study deviating from HWE in the control group (p>0.1). In the adult subgroup, there was no significant association between the C677T variant and ALL risk (Dominant model: OR(RE)=0.88, 95% CI: 0.45-1.72, p=0.72). Significant heterogeneity was found in the adult subgroup in all the genetic model tests (p<0.1). The A1298C polymorphism had an effect on ALL risk neither in adults (Dominant model: OR(FE)=0.95, 95% CI: 0.71-1.27, p=0.72) nor in children (Dominant model: OR(FE)=1.02, 95% CI: 0.87-1.21, p=0.77). No significant heterogeneity between studies on A1298C polymorphism was found in the meta-analysis (p>0.1). The results showed that there was a protective effect of the MTHFR C677T variant on ALL risk in Chinese children.

[Association study between 834+7G/A and +1332C/T polymorphisms in the growth arrest specific 6 gene and risk of severe preeclampsia in Chinese population].

PubMed

Ye, Liyan; Guan, Linbo; Fan, Ping; Liu, Xinghui; Liu, Rui; Chen, Jinxin; Zhu, Yue; Wei, Xin; Liu, Yu; Bai, Huai

2017-02-10

To investigate the relationship between polymorphisms of the growth arrest specific 6 (GAS6) gene and severe preeclampsia in a South West Han Chinese population. Blood samples from 167 patients with severe preeclampsia and 312 normal pregnant women as controls from Han Chinese in Chengdu area were analyzed by polymerase chain reaction-restriction fragment length polymorphisms. C and T allele frequencies for +1332C/T site were 85.63% and 14.37% in the patient group, respectively, and 78.04% and 21.96% in control group, respectively. The TT genotype and variant T allelic frequencies of the +1332C/T polymorphism were significantly lower in patients with severe preeclampsia than in the control group (both P<0.05), and the odds ratio for the risk of severe preeclampsia was 0.602 (95%CI: 0.401-0.904) in carriers for the variant T allele (χ 2 =6.045, P=0.014). G and A allele frequencies for 834+7G/A site were 72.75% and 27.25% in case group, respectively, and 74.36% and 25.64% in control group, respectively. The genotype and allele frequencies of the 834+7G/A polymorphism in patients with severe preeclampsia and controls showed no significant differences (both P>0.05). In addition, there was no significant association between the polymorphisms and blood pressure levels in the patient or control groups. The variant GAS6+1332 T allele is associated with a decreased risk for severe preeclampsia in a South West Han Chinese population. On the other hand, the 834+7G/A polymorphism has no effect on the severe preeclampsia.

PNPLA3 I148M polymorphism and progressive liver disease

PubMed Central

Dongiovanni, Paola; Donati, Benedetta; Fares, Roberta; Lombardi, Rosa; Mancina, Rosellina Margherita; Romeo, Stefano; Valenti, Luca

2013-01-01

The 148 Isoleucine to Methionine protein variant (I148M) of patatin-like phospholipase domain-containing 3 (PNPLA3), a protein is expressed in the liver and is involved in lipid metabolism, has recently been identified as a major determinant of liver fat content. Several studies confirmed that the I148M variant predisposes towards the full spectrum of liver damage associated with fatty liver: from simple steatosis to steatohepatitis and progressive fibrosis. Furthermore, the I148M variant represents a major determinant of progression of alcohol related steatohepatitis to cirrhosis, and to influence fibrogenesis and related clinical outcomes in chronic hepatitis C virus hepatitis, and possibly chronic hepatitis B virus hepatitis, hereditary hemochromatosis and primary sclerosing cholangitis. All in all, studies suggest that the I148M polymorphism may represent a general modifier of fibrogenesis in liver diseases. Remarkably, the effect of the I148M variant on fibrosis was independent of that on hepatic steatosis and inflammation, suggesting that it may affect both the quantity and quality of hepatic lipids and the biology of non-parenchymal liver cells besides hepatocytes, directly promoting fibrogenesis. Therefore, PNPLA3 is a key player in liver disease progression. Assessment of the I148M polymorphism will possibly inform clinical practice in the future, whereas the determination of the effect of the 148M variant will reveal mechanisms involved in hepatic fibrogenesis. PMID:24222941

Further Evidence of the Association of the Diacylglycerol Kinase Kappa (DGKK) Gene With Hypospadias.

PubMed

Hozyasz, Kamil Konrad; Mostowska, Adrianna; Kowal, Andrzej; Mydlak, Dariusz; Tsibulski, Alexander; Jagodzinski, Pawel P

2018-02-18

Hypospadias is a common developmental anomaly of the male external genitalia. In previous studies conducted on West European, Californian, and Han Chinese populations the relationship between polymorphic variants of the diacylglycerol kinase kappa (DGKK) gene and hypospadias have been reported. The aim was to study the possible associations between polymorphic variants of the DGKK gene and hypospadias using an independent sample of the Polish population. Ten single nucleotide polymorphisms in DGKK, which were reported to have an impact on the risk of hypospadias in other populations, were genotyped using high-resolution melting curve analysis in a group of 166 boys with isolated anterior (66%) and middle (34%) forms of hypospadias and 285 properly matched controls without congenital anomalies. Two DGKK variants rs11091748 and rs12171755 were associated with increased risk of hypospadias in the Polish population. These results were statistically significant, even after applying the Bonferroni correction for multiple comparisons (P < .005). All the tested nucleotide variants were involved in haplotype combinations associated with hypospadias. The global p-values for haplotypes comprising of rs4143304-rs11091748, rs11091748-rs17328236, rs1934179-rs4554617, rs1934183-rs1934179-rs4554617 and rs12171755-rs1934183-rs1934179-rs4554617 were statistically significant, even after the permutation test correction. Our study provides strong evidence of an association between DGKK nucleotide variants, haplotypes and hypospadias susceptibility.

[Association between genetic polymorphisms of DNA repair genes XRCC1, XPD, XRCC3 and the capacity of DNA repair induce by benzene].

PubMed

Xu, Jianning; Yang, Min; Huang, Huilong; Wang, Quankai

2007-09-01

To explore the correlation between genetic polymorphisms of XRCC1, XPD, XRCC3 and DNA repair capacity induced by benzene. Eighty patients suffered from chronic benzene poisoning were investigated. PCR-RFLP was applied to detect the single nucleotide polymorphisms on C26304T, G27466A, G28152A, G36189A of XRCC1, C22541A, C23591T, A35931C of XPD, C18067T of XRCC3. Cytokinesis-block micronucleus (CBMN) and alkaline comet were applied to detect the DNA repair capacity. The DNA repair capacity of the subjects carrying XPD 35931C variant allele or carrying XRCC3 18067 C/T variant genotype were higher than those carrying corresponding mild genotype. There could be a correlation between polymorphisms of XRCC3 and DNA repair capacity of DNA damage induced by benzene.

Association of cytokine gene polymorphisms in CWP and its severity in Turkish coal workers

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

Ates, I.; Suzen, H.S.; Yucesoy, B.

2008-10-15

Cytokines appear to play a key role in some inflammatory reactions affecting the interactions among pro- and anti-inflammatory mechanisms that result in several diseases such as coal workers' pneumoconiosis (CWP). In this study, to determine the cytokine gene profiles of Turkish coal miners, we performed genotyping analysis to investigate the polymorphisms of CWP-related pro-inflammatory (TNFA, IL1A, IL1B, and IL6) and anti-inflammatory cytokines (IL-1RN and TGFB1). Genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. TNFA (-238) gene polymorphism principally affected CWP development and severity (OR=3.47: 95% CI, 1.12-10.77 and OR=4.30: 95% CI, 1.25-14.74, respectively) and alsomore » risk of CWP (OR=3.79: 95% CI, 1.37-10.46). The TNFA (-308) variant was associated with a risk for the CWP severity (OR = 2.84: 95% CI, 1.08-7.39). A protective effect of IL6 was found on the development (OR = 0.48: 95% CI, 0.21-0.93) and severity of CWP (OR = 0.37: 95% CI, 0.15-0.91). We suggest that TNFA (-238) variant may be a risk factor in both development and the severity, of CWP while TNFA (-308) variant seems to be important only in disease severity On the other hand, IL6 variant may have a protective effect on the development and disease severity.« less

Contribution of 20 single nucleotide polymorphisms of 13 genes to dyslipidemia associated with antiretroviral therapy.

PubMed

Arnedo, Mireia; Taffé, Patrick; Sahli, Roland; Furrer, Hansjakob; Hirschel, Bernard; Elzi, Luigia; Weber, Rainer; Vernazza, Pietro; Bernasconi, Enos; Darioli, Roger; Bergmann, Sven; Beckmann, Jacques S; Telenti, Amalio; Tarr, Philip E

2007-09-01

HIV-1 infected individuals have an increased cardiovascular risk which is partially mediated by dyslipidemia. Single nucleotide polymorphisms in multiple genes involved in lipid transport and metabolism are presumed to modulate the risk of dyslipidemia in response to antiretroviral therapy. The contribution to dyslipidemia of 20 selected single nucleotide polymorphisms of 13 genes reported in the literature to be associated with plasma lipid levels (ABCA1, ADRB2, APOA5, APOC3, APOE, CETP, LIPC, LIPG, LPL, MDR1, MTP, SCARB1, and TNF) was assessed by longitudinally modeling more than 4400 plasma lipid determinations in 438 antiretroviral therapy-treated participants during a median period of 4.8 years. An exploratory genetic score was tested that takes into account the cumulative contribution of multiple gene variants to plasma lipids. Variants of ABCA1, APOA5, APOC3, APOE, and CETP contributed to plasma triglyceride levels, particularly in the setting of ritonavir-containing antiretroviral therapy. Variants of APOA5 and CETP contributed to high-density lipoprotein-cholesterol levels. Variants of CETP and LIPG contributed to non-high-density lipoprotein-cholesterol levels, a finding not reported previously. Sustained hypertriglyceridemia and low high-density lipoprotein-cholesterol during the study period was significantly associated with the genetic score. Single nucleotide polymorphisms of ABCA1, APOA5, APOC3, APOE, and CETP contribute to plasma triglyceride and high-density lipoprotein-cholesterol levels during antiretroviral therapy exposure. Genetic profiling may contribute to the identification of patients at risk for antiretroviral therapy-related dyslipidemia.

Lessons from the canine Oxtr gene: populations, variants and functional aspects.

PubMed

Bence, M; Marx, P; Szantai, E; Kubinyi, E; Ronai, Z; Banlaki, Z

2017-04-01

Oxytocin receptor (OXTR) acts as a key behavioral modulator of the central nervous system, affecting social behavior, stress, affiliation and cognitive functions. Variants of the Oxtr gene are known to influence behavior both in animals and humans; however, canine Oxtr polymorphisms are less characterized in terms of possible relevance to function, selection criteria in breeding and domestication. In this report, we provide a detailed characterization of common variants of the canine Oxtr gene. In particular (1) novel polymorphisms were identified by direct sequencing of wolf and dog samples, (2) allelic distributions and pairwise linkage disequilibrium patterns of several canine populations were compared, (3) neighbor joining (NJ) tree based on common single nucleotide polymorphisms (SNPs) was constructed, (4) mRNA expression features were assessed, (5) a novel splice variant was detected and (6) in vitro functional assays were performed. Results indicate marked differences regarding Oxtr variations between purebred dogs of different breeds, free-ranging dog populations, wolf subspecies and golden jackals. This, together with existence of explicitly dog-specific alleles and data obtained from the NJ tree implies that Oxtr could indeed have been a target gene during domestication and selection for human preferred aspects of temperament and social behavior. This assumption is further supported by the present observations on gene expression patterns within the brain and luciferase reporter experiments, providing a molecular level link between certain canine Oxtr polymorphisms and differences in nervous system function and behavior. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Magnetization Transfer Ratio Relates to Cognitive Impairment in Normal Elderly

PubMed Central

Seiler, Stephan; Pirpamer, Lukas; Hofer, Edith; Duering, Marco; Jouvent, Eric; Fazekas, Franz; Mangin, Jean-Francois; Chabriat, Hugues; Dichgans, Martin; Ropele, Stefan; Schmidt, Reinhold

2014-01-01

Magnetization transfer imaging (MTI) can detect microstructural brain tissue changes and may be helpful in determining age-related cerebral damage. We investigated the association between the magnetization transfer ratio (MTR) in gray and white matter (WM) and cognitive functioning in 355 participants of the Austrian stroke prevention family study (ASPS-Fam) aged 38–86 years. MTR maps were generated for the neocortex, deep gray matter structures, WM hyperintensities, and normal appearing WM (NAWM). Adjusted mixed models determined whole brain and lobar cortical MTR to be directly and significantly related to performance on tests of memory, executive function, and motor skills. There existed an almost linear dose-effect relationship. MTR of deep gray matter structures and NAWM correlated to executive functioning. All associations were independent of demographics, vascular risk factors, focal brain lesions, and cortex volume. Further research is needed to understand the basis of this association at the tissue level, and to determine the role of MTR in predicting cognitive decline and dementia. PMID:25309438

Structure and function of Neisseria gonorrhoeae MtrF illuminates a class of antimetabolite efflux pumps

DOE PAGES

Su, Chih -Chia; Bolla, Jani  Reddy; Kumar, Nitin; ...

2015-04-01

Neisseria gonorrhoeae is an obligate human pathogen and the causative agent of the sexually transmitted disease gonorrhea. The control of this disease has been compromised by the increasing proportion of infections due to antibiotic-resistant strains, which are growing at an alarming rate. N. gonorrhoeae MtrF is an integral membrane protein that belongs to the AbgT family of transporters for which no structural information is available. Here, we describe the crystal structure of MtrF, revealing a dimeric molecule with architecture distinct from all other families of transporters. MtrF is a bowl-shaped dimer with a solvent-filled basin extending from the cytoplasm tomore » halfway across the membrane bilayer. Each subunit of the transporter contains nine transmembrane helices and two hairpins, posing a plausible pathway for substrate transport. A combination of the crystal structure and biochemical functional assays suggests that MtrF is an antibiotic efflux pump mediating bacterial resistance to sulfonamide antimetabolite drugs.« less

Structure and function of Neisseria gonorrhoeae MtrF illuminates a class of antimetabolite efflux pumps

PubMed Central

Su, Chih-Chia; Bolla, Jani Reddy; Kumar, Nitin; Radhakrishnan, Abhijith; Long, Feng; Delmar, Jared A.; Chou, Tsung-Han; Rajashankar, Kanagalaghatta R.; Shafer, William M.; Yu, Edward W.

2015-01-01

SUMMARY Neisseria gonorrhoeae is an obligate human pathogen and the causative agent of the sexually-transmitted disease gonorrhea. The control of this disease has been compromised by the increasing proportion of infections due to antibiotic-resistant strains, which are growing at an alarming rate. N. gonorrhoeae MtrF is an integral membrane protein, which belongs to the AbgT family of transporters for which no structural information is available. Here we describe the crystal structure of MtrF, revealing a dimeric molecule with architecture distinct from all other families of transporters. MtrF is a bowl-shaped dimer with a solvent-filled basin extending from the cytoplasm to halfway across the membrane bilayer. Each subunit of the transporter contains nine transmembrane helices and two hairpins, posing a plausible pathway for substrate transport. A combination of the crystal structure and biochemical functional assays suggests that MtrF is an antibiotic efflux pump, mediating bacterial resistance to sulfonamide antimetabolite drugs. PMID:25818299

Exosome cofactor hMTR4 competes with export adaptor ALYREF to ensure balanced nuclear RNA pools for degradation and export.

PubMed

Fan, Jing; Kuai, Bin; Wu, Guifen; Wu, Xudong; Chi, Binkai; Wang, Lantian; Wang, Ke; Shi, Zhubing; Zhang, Heng; Chen, She; He, Zhisong; Wang, Siyuan; Zhou, Zhaocai; Li, Guohui; Cheng, Hong

2017-10-02

The exosome is a key RNA machine that functions in the degradation of unwanted RNAs. Here, we found that significant fractions of precursors and mature forms of mRNAs and long noncoding RNAs are degraded by the nuclear exosome in normal human cells. Exosome-mediated degradation of these RNAs requires its cofactor hMTR4. Significantly, hMTR4 plays a key role in specifically recruiting the exosome to its targets. Furthermore, we provide several lines of evidence indicating that hMTR4 executes this role by directly competing with the mRNA export adaptor ALYREF for associating with ARS2, a component of the cap-binding complex (CBC), and this competition is critical for determining whether an RNA is degraded or exported to the cytoplasm. Together, our results indicate that the competition between hMTR4 and ALYREF determines exosome recruitment and functions in creating balanced nuclear RNA pools for degradation and export. © 2017 The Authors.

Impaired dacarbazine activation and 7-ethoxyresorufin deethylation in vitro by polymorphic variants of CYP1A1 and CYP1A2: implications for cancer therapy.

PubMed

Lewis, Benjamin C; Korprasertthaworn, Porntipa; Miners, John O

2016-10-01

To extend our understanding of how interindividual variability mediates the efficacy of cancer treatment. The kinetics of dacarbazine (DTIC) N-demethylation by the most frequent polymorphic variants of CYP1A1 (T461N, I462V) and CYP1A2 (F186L, D348N, I386F, R431W, R456H) were characterized, along with kinetic parameters for the O-deethylation of the prototypic CYP1A substrate 7-ethoxyresorufin, using recombinant protein expression and high-performance liquid chromatographic techniques. A reduction of ∼30% in the catalytic efficiencies (measured as in-vitro intrinsic clearance, CLint) was observed for DTIC N-demethylation by the two CYP1A1 variants relative to wild type. Although a modest increase in the CLint value for DTIC N-demethylation was observed for the CYP1A2 D348N variant relative to the wild type, the CLint for the F186L variant was reduced and the I386F, R431W, and R456H variants all showed loss of catalytic function. Comparison of the kinetic data for DTIC N-demethylation and 7-ethoxyresorufin O-deethylation indicated that alterations in the kinetic parameters (Km, Vmax, CLint) observed with each of the CYP1A1 and CYP1A2 polymorphic variants were substrate dependent. These data indicate that cancer patients treated with DTIC who possess any of the CYP1A1-T461N and I462V variants or the CYP1A2-F186L, D348N, I386F, R431W, and R456H variants are likely to have decreased prodrug activation, and hence may respond less favorably to DTIC treatment compared with individuals with wild-type CYP1A alleles.

Multi-trigger resist patterning with ASML NXE3300 EUV scanner

NASA Astrophysics Data System (ADS)

Vesters, Yannick; McClelland, Alexandra; De Simone, Danilo; Popescu, Carmen; Dawson, Guy; Roth, John; Theis, Wolfgang; Vandenberghe, Geert; Robinson, Alex P. G.

2018-03-01

Irresistible Materials (IM) is developing novel resist systems based on the multi-trigger concept, which incorporates a dose dependent quenching-like behaviour. The Multi Trigger Resist (MTR) is a negative tone crosslinking resist that does not need a post exposure bake (PEB), and during the past years, has been mainly tested using interference lithography at PSI. In this study, we present the results that have been obtained using MTR resists, performing EUV exposures on ASML NXE3300B EUV scanner at IMEC. We present the lithography performance of the MTR1 resist series in two formulations - a high-speed baseline, and a formulation designed to enhance the multi-trigger behaviour. Additionally, we present results for the MTR2 resist series, which has been designed for lower line edge roughness. The high-speed baseline resist (MTR1), showed 18 nm resolution at 20mJ/cm2. The MTR2 resist shows 16nm half pitch lines patterned with a dose of 38mJ/cm2, giving a LER of 3.7 nm. Performance across multiple process conditions are discussed. We performed etch rate measurement and the multi-trigger resist showed etch resistance equivalent or better than standard chemically amplified resist. This could compensate for the lower film thickness required to avoid pattern collapse at pitch 32nm.

Probable Mechanisms of Needling Therapies for Myofascial Pain Control

PubMed Central

Chou, Li-Wei; Kao, Mu-Jung; Lin, Jaung-Geng

2012-01-01

Myofascial pain syndrome (MPS) has been defined as a regional pain syndrome characterized by muscle pain caused by myofascial trigger points (MTrPs) clinically. MTrP is defined as the hyperirritable spot in a palpable taut band of skeletal muscle fibers. Appropriate treatment to MTrPs can effectively relieve the clinical pain of MPS. Needling therapies, such as MTrP injection, dry needling, or acupuncture (AcP) can effectively eliminate pain immediately. AcP is probably the first reported technique in treating MPS patients with dry needling based on the Traditional Chinese Medicine (TCM) theory. The possible mechanism of AcP analgesia were studied and published in recent decades. The analgesic effect of AcP is hypothesized to be related to immune, hormonal, and nervous systems. Compared to slow-acting hormonal system, nervous system acts in a faster manner. Given these complexities, AcP analgesia cannot be explained by any single mechanism. There are several principles for selection of acupoints based on the TCM principles: “Ah-Shi” point, proximal or remote acupoints on the meridian, and extra-meridian acupoints. Correlations between acupoints and MTrPs are discussed. Some clinical and animal studies of remote AcP for MTrPs and the possible mechanisms of remote effectiveness are reviewed and discussed. PMID:23346211

Myofascial Trigger Points Then and Now: A Historical and Scientific Perspective

PubMed Central

Shah, Jay P.; Thaker, Nikki; Heimur, Juliana; Aredo, Jacqueline V.; Sikdar, Siddhartha; Gerber, Lynn H.

2015-01-01

The intent of this paper is to discuss the evolving role of the myofascial trigger point (MTrP) in myofascial pain syndrome (MPS) from both a historical and scientific perspective. MTrPs are hard, discrete, palpable nodules in a taut band of skeletal muscle that may be spontaneously painful (i.e. active), or painful only on compression (i.e. latent). MPS is a term used to describe a pain condition which can be acute or, more commonly, chronic and involves the muscle and its surrounding connective tissue (e.g. fascia). According to Travell and Simons, MTrPs are central to the syndrome—but are they necessary? Although the clinical study of muscle pain and MTrPs has proliferated over the past two centuries, the scientific literature often seems disjointed and confusing. Unfortunately, much of the terminology, theories, concepts, and diagnostic criteria are inconsistent, incomplete, or controversial. In order to address these deficiencies, investigators have recently applied clinical, imaging (of skeletal muscle and brain), and biochemical analyses to systematically and objectively study the MTrP and its role in MPS. Data suggest that the soft tissue milieu around the MTrP, neurogenic inflammation, sensitization, and limbic system dysfunction may all play a role in the initiation, amplification, and perpetuation of MPS. The authors will chronicle the advances that have led to the current understanding of MTrP pathophysiology and its relationship to MPS, and review the contributions of clinicians and researchers who have influenced and expanded our contemporary level of clinical knowledge and practice. PMID:25724849

MTR and In-vivo 1H-MRS studies on mouse brain with parkinson's disease

NASA Astrophysics Data System (ADS)

Yoon, Moon-Hyun; Kim, Hyeon-Jin; Chung, Jin-Yeung; Doo, Ah-Reum; Park, Hi-Joon; Kim, Seung-Nam; Choe, Bo-Young

2012-12-01

The aim of this study was to investigate whether the changes in the magnetization transfer ratio (MTR) histogram are related to specific characteristics of Parkinson's disease (PD) and to investigate whether the MTR histogram parameters are associated with neurochemical dysfunction by performing in vivo proton magnetic resonance spectroscopy (1H-MRS). MTR and in vivo 1H-MRS studies were performed on control mice (n = 10) and 1-methyl-1,2,3,6-tetrahydropyridine intoxicated mice (n = 10). All the MTR and in vivo 1H-MRS experiments were performed on a 9.4 T MRI/MRS system (Bruker Biospin, Germany) using a standard head coil. The protondensity fast spin echo (FSE) images and the T2-weighted spin echo (SE) images were acquired with no gap. Outer volume suppression (OVS), combined with the ultra-short echo-time stimulated echo acquisition mode (STEAM), was used for the localized in-vivo 1H-MRS. The quantitative analysis of metabolites was performed from the 1H spectra obtained in vivo on the striatum (ST) by using jMRUI (Lyon, France). The peak height of the MTR histograms in the PD model group was significantly lower than that in the control group (p < 0.05). The midbrain MTR values for volume were lower in the PD group than the control group(p < 0.05). The complex peak (Glx: glutamine+glutamate+ GABA)/creatine (Cr) ratio of the right ST in the PD group was significantly increased as compared to that of the control group. The present study revealed that the peak height of the MTR histogram was significantly decreased in the ST and substantia nigra, and a significant increase in the Gl x /Cr ratio was found in the ST of the PD group, as compared with that of the control group. These findings could reflect the early phase of neuronal dysfunction of neurotransmitters.

Myofascial trigger points, pain, disability, and sleep quality in individuals with mechanical neck pain.

PubMed

Muñoz-Muñoz, Sonsoles; Muñoz-García, María T; Alburquerque-Sendín, Francisco; Arroyo-Morales, Manuel; Fernández-de-las-Peñas, César

2012-10-01

The purpose of this study was to investigate the presence of active myofascial trigger points (MTrPs) in a greater number of muscles than previous studies and the relation between the presence of MTrPs, the intensity of pain, disability, and sleep quality in mechanical neck pain. Fifteen patients with mechanical neck pain (80% women) and 12 comparable controls participated. Myofascial trigger points were bilaterally explored in the upper trapezius, splenius capitis, semispinalis capitis, sternocleidomastoid, levator scapulae, and scalene muscles in a blinded design. Myofascial trigger points were considered active if the subject recognized the elicited referred pain as a familiar symptom. Myofascial trigger points were considered latent if the elicited referred pain was not recognized as a symptom. Pain was collected with a numerical pain rate scale (0-10); disability was assessed with Neck Disability Index; and sleep quality, with the Pittsburgh Sleep Quality Index. Patients exhibited a greater disability and worse sleep quality than controls (P < .001). The Pittsburgh Sleep Quality Index score was associated with the worst intensity of pain (r = 0.589; P = .021) and disability (r = 0.552; P = .033). Patients showed a greater (P = .002) number of active MTrPs (mean, 2 ± 2) and similar number (P = .505) of latent MTrPs (1.6 ± 1.4) than controls (latent MTrPs, 1.3 ± 1.4). No significant association between the number of latent or active MTrPs and pain, disability, or sleep quality was found. The referred pain elicited by active MTrPs in the neck and shoulder muscles contributed to symptoms in mechanical neck pain. Patients exhibited higher disability and worse sleep quality than controls. Sleep quality was associated with pain intensity and disability. No association between active MTrPs and the intensity of pain, disability, or sleep quality was found. Copyright © 2012 National University of Health Sciences. Published by Mosby, Inc. All rights reserved.

Identification and functional characterization of three novel human melanocortin-4 receptor gene variants in an obese Chinese population.

PubMed

Rong, Rong; Tao, Ya-Xiong; Cheung, Bernard M Y; Xu, Aimin; Cheung, Grace C N; Lam, Karen S L

2006-08-01

Mutations in the melanocortin-4 receptor gene (MC4R) are the most common monogenic form of human obesity. However, the contribution of MC4R mutations to obesity in Chinese has not been investigated. We studied the frequency of MC4R mutations in an obese southern Chinese population and the functional consequences of the novel variants identified. We screened for MC4R mutations in 227 obese [body mass index (BMI) 35.29 +/- 5.75 kg/m2] and 100 lean (BMI 21.57 +/- 0.29 kg/m2) southern Chinese subjects using PCR-direct sequencing. In vitro functional studies, including cell surface expression, ligand binding, and cyclic adenosine monophosphate (cAMP) accumulation, were performed to examine the functional properties of three novel missense mutations. Apart from two previously reported polymorphisms, V103I and -176 A > C, three novel missense heterozygous variants (Y35C, C40R and M218T) were identified. The polymorphisms -176 A > C and Y35C were detected in both obese and normal subjects with similar frequency. C40R was identified only in an obese subject. Pedigree analysis revealed M218T carriers in both lean and obese subjects. The prevalence of V103I carriers in normal-weight controls was significantly higher than that in obese subjects (5.3%vs. 1.3%, P < 0.05). In vitro functional studies showed that all three novel missense variants have normal functions. Two known polymorphisms and three novel variants of the MC4R were identified. No overt functional defects were observed for the three novel MC4R variants, suggesting that they might not be the cause of obesity in variant carriers.

Association of donor and recipient SUMO4 rs237025 genetic variant with new-onset diabetes mellitus after liver transplantation in a Chinese population.

PubMed

Zhang, Tao; Liu, Yuan; Hu, Yibo; Zhang, Xiaoqing; Zhong, Lin; Fan, Junwei; Peng, Zhihai

2017-09-05

New-onset diabetes mellitus (NODM) is a common complication after liver transplantation (LT). The small ubiquitin-like modifier 4 (SUMO4) rs237025 polymorphism has been reported to be associated with type 2 diabetes mellitus (T2DM). In this study, we aimed to evaluate the association of donor and recipient SUMO4 rs237025 polymorphisms with NODM and the long-term consequences of NODM after LT. A total of 126 liver transplant patients were enrolled in the study. One single nucleotide polymorphism, SUMO4 rs237025, was genotyped in both donors and recipients. Both donor and recipient SUMO4 rs237025 polymorphisms were found to be significantly associated with NODM after LT. In multivariate analysis, recipient age>50 years, tacrolimus trough concentrations>10ng/mL at 1month after LT, donor and recipient rs237025 genetic variant, and the combined donor and recipient rs237025 genetic variant were independent predictive factors of NODM. Area under the receiver operating characteristic curve (AUROC) analysis indicated the higher predictive ability of the model containing combined donor and recipient rs237025 polymorphisms than the clinical model (p=0.046). Furthermore, Kaplan-Meier survival analysis demonstrated that NODM was related to significantly poorer patient survival in comparison with non-NODM patients (p=0.041). Both donor and recipient SUMO4 rs237025 polymorphisms contribute to the development of NODM after LT and NODM is a frequent complication that negatively affects patient survival. Copyright © 2017. Published by Elsevier B.V.

Thiopurine methyltransferase polymorphisms and mercaptopurine tolerance in Turkish children with acute lymphoblastic leukemia.

PubMed

Albayrak, Meryem; Konyssova, Uljan; Kaya, Zuhre; Gursel, Turkiz; Guntekin, Sezen; Percin, E Ferda; Kocak, Ulker

2011-11-01

Thiopurine methyltransferase (TPMT) enzyme is involved in the metabolism of 6-mercaptopurine (6-MP), a key component of acute lymphoblastic leukemia (ALL) treatment protocols in children. The aims of this study were to investigate the frequency of common genetic polymorphisms associated with low TPMT activity and correlations of polymorphic variants with 6-MP tolerance in a group of Turkish children with ALL. Genotyping for G238C, A719G, and G460A mutations were performed by using NanoChip Technology. Adverse reactions during the first 6 months of maintenance therapy with oral 6-MP and methotrexate were retrospectively analyzed from patient's files. Five (8.6%) of 58 children with ALL had a polymorphic TPMT allele: 4 (3.4%) were heterozygous for TPMT*3A (G460A and A719G), and one (0.9%) was heterozygous for TPMT*3C (A719G). No cases with TPMT*3B (G460A) or TPMT*2 (G238C) variants were identified. Children with TPMT*3A and *3C had significantly lower leukocyte and neutrophil counts and percentage of target 6-MP dosage, and longer periods with ≥grade 2 infections, ≥grade 2 liver toxicity, and chemotherapy interruptions than the children with wild-type TPMT during the first 24 weeks of maintenance therapy. The frequency and distribution of common TPMT polymorphisms in Turkish children with ALL is similar to other Caucasian populations. Polymorphic variants were associated with excessive 6-MP toxicity supporting the suggestion that TPMT genotyping should be performed before institution of 6-MP therapy.

The Role of PAI-1 4G/5G Promoter Polymorphism and Its Levels in the Development of Ischemic Stroke in Young Indian Population.

PubMed

Akhter, Mohammad Suhail; Biswas, Arijit; Abdullah, Saleh Mohammed; Behari, Madhuri; Saxena, Renu

2017-11-01

The plasminogen activator inhibitor-1 (PAI-1) gene has been found to be associated with the pathogenesis and progression of vascular diseases including stroke. A 4G/5G, PAI-1 gene polymorphism has been found to be associated with the plasma PAI-1 levels in different ethnic populations but results are still controversial. The aim of this study was to determine the potential association of 4G/5G polymorphism and plasma PAI-1 levels in the development of ischemic stroke (IS) in young Asian Indians. One hundred patients with IS and an equal number of age- and sex-matched controls were studied. The 4G/5G polymorphism was genotyped in the study population through allele-specific polymerase chain reaction. Plasma PAI-1 levels were evaluated using a commercial kit. The PAI-1 levels were significantly higher in patients when compared to the controls ( P = .03). The variant 4G allele for the PAI-I 4G/5G polymorphism showed both genotypic ( P = .0013, χ 2 = 10.303; odds ratio [OR] = 3.75) as well as allelic association ( P = .0004, χ 2 = 12.273; OR = 1.99) with IS. The homozygous variant 4G/4G also was found to be associated with the higher PAI-1 levels (0.005). The variant allele 4G of PAI-1 4G/5G polymorphism and higher plasma PAI-1 levels were found to be significantly associated with IS in young Asian Indians.

Breast and Prostate Cancer and Hormone-Related Gene Variant Study

Cancer.gov

The Breast and Prostate Cancer and Hormone-Related Gene Variant Study allows large-scale analyses of breast and prostate cancer risk in relation to genetic polymorphisms and gene-environment interactions that affect hormone metabolism.

Read count-based method for high-throughput allelic genotyping of transposable elements and structural variants.

PubMed

Kuhn, Alexandre; Ong, Yao Min; Quake, Stephen R; Burkholder, William F

2015-07-08

Like other structural variants, transposable element insertions can be highly polymorphic across individuals. Their functional impact, however, remains poorly understood. Current genome-wide approaches for genotyping insertion-site polymorphisms based on targeted or whole-genome sequencing remain very expensive and can lack accuracy, hence new large-scale genotyping methods are needed. We describe a high-throughput method for genotyping transposable element insertions and other types of structural variants that can be assayed by breakpoint PCR. The method relies on next-generation sequencing of multiplex, site-specific PCR amplification products and read count-based genotype calls. We show that this method is flexible, efficient (it does not require rounds of optimization), cost-effective and highly accurate. This method can benefit a wide range of applications from the routine genotyping of animal and plant populations to the functional study of structural variants in humans.

Genetic analysis of LRRK2 functional domains in Brazilian patients with Parkinson's disease.

PubMed

Abdalla-Carvalho, C B; Santos-Rebouças, C B; Guimarães, B C; Campos, M; Pereira, J S; de Rosso, A L Zuma; Nicaretta, D H; Marinho e Silva, M; dos Santos, Mendonça J; Pimentel, M M G

2010-12-01

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have been associated with Parkinson's disease (PD), and the majority of the pathogenic variants are located in the ROC and MAPKKK domains. Exons 29-31 and 38-44 (ROC and MAPKKK domains) were sequenced in 204 patients with PD, mostly Brazilian. We identified four polymorphisms, a novel silent variant p.R1398R and four substitutions: p.T1410M, p.G2019S, p.Y2189C and the novel variant p.C2139S. The most prevalent mutation was the p.G2019S (2.4%). We consider that the p.T1410M and the p.Y2189C variants are probably polymorphisms and that the p.C2139S mutation is potentially pathogenic. © 2010 The Author(s). European Journal of Neurology © 2010 EFNS.

MTR MAIN FLOOR. MEN DEMONSTRATE INSERTION OF DUMMY PLUG INTO ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

MTR MAIN FLOOR. MEN DEMONSTRATE INSERTION OF DUMMY PLUG INTO AN MTR BEAM HOLE. ONE MAN CHECKS RADIATION LEVEL AT THE END OF THE UNIVERSAL COFFIN, WHILE ANOTHER USES TOOL TO INSERT PLUG INTO HOLE THROUGH COFFIN. MEN WEAR "ANTI-C" (ANTI-CONTAMINATION) CLOTHING. INL NEGATIVE NO. 6198. R.G. Larsen, Photographer, 6/27/1952 - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

Genetic polymorphisms associated with heart failure: A literature review.

PubMed

Guo, Mengqi; Guo, Guanlun; Ji, Xiaoping

2016-02-01

To review possible associations reported between genetic variants and the risk, therapeutic response and prognosis of heart failure. Electronic databases (PubMed, Web of Science and CNKI) were systematically searched for relevant papers, published between January 1995 and February 2015. Eighty-two articles covering 29 genes and 39 polymorphisms were identified. Genetic association studies of heart failure have been highly controversial. There may be interaction or synergism of several genetic variants that together result in the ultimate pathological phenotype for heart failure. © The Author(s) 2016.

beta3-Adrenergic receptor Trp64Arg polymorphism and increased body mass index in sleep apnoea.

PubMed

Piérola, J; Barceló, A; de la Peña, M; Barbé, F; Soriano, J B; Sánchez Armengol, A; Martínez, C; Agustí, A

2007-10-01

Obesity is an important risk factor for obstructive sleep apnoea syndrome (OSAS), insulin resistance and cardiovascular disease. The substitution of tryptophan 64 with arginine (Trp64Arg) polymorphism (Arg variant) of the beta(3)-adrenergic receptor (ADRB3) has been associated with obesity. In this study, the prevalence of the Trp64Arg ADRB3 polymorphism in a large group of patients with OSAS and its association with body mass index (BMI), insulin resistance and hypertension were evaluated. ADRB3 genotype was determined in 387 patients with OSAS and 137 healthy subjects recruited from three Spanish tertiary hospitals. The distributions of the ADRB3 genotypes were similar in OSAS and controls, and, in a multivariate model, the risk of OSAS was not associated with the presence of the Arg variant of the ADRB3 gene. However, BMI was higher in those patients with OSAS who carried this genetic variant than in those with the Trp variant. Furthermore, a linear trend for higher BMI was found in those with the Arg variant (56, 75 and 100% for Trp/Trp, Trp/Arg and Arg/Arg, respectively). Insulin resistance, blood pressures and serum levels of lipids and glucose were not associated with the presence of the Arg variant of the ADRB3 gene. The presence of the arginine 64 allele of the beta(3)-adrenergic receptor gene does not increase the risk of obstructive sleep apnoea syndrome, but is associated with the development of obesity in those patients who suffer obstructive sleep apnoea syndrome.

Variant allele of CHEK2 is associated with a decreased risk of esophageal cancer lymph node metastasis in a Chinese population.

PubMed

Gu, Haiyong; Qiu, Wanshan; Wan, Ying; Ding, Guowen; Tang, Weifeng; Liu, Chao; Shi, Yijun; Chen, Yijang; Chen, Suocheng

2012-05-01

Growing evidence suggests that the checkpoint kinase 2 (CHEK2) signaling pathway occupies a central position in the signaling networks of DNA-damage signaling. Many functional and molecular epidemiological studies have evaluated the association between genetic variants of CHEK2 and various cancers. To evaluate the relationship between CHEK2 functional genetic variants and esophageal cancer risk and the risk of lymph node metastasis among a Chinese population. We genotyped CHEK2 rs738722, rs2236141 and rs2236142 single nucleotide polymorphisms (SNPs) using the matrix assisted laser desorption/ionization time-of-flight mass spectrometry assay in a case-controlled study, including 380 esophageal cancer cases and 380 healthy controls in a Chinese population. We found that none of the three polymorphisms achieved significant difference in their distributions between esophageal cancer cases and controls. Multiple logistic regression analyses revealed that esophageal cancer risk was not associated significantly with the variant genotypes of the three CHEK2 polymorphisms as compared with their wild-type genotypes. However, we found that functional variant rs738722 and rs2236142 in CHEK2 might contribute to susceptibility to lymph node metastasis. Our data did not support a significant association between CHEK2 SNPs and the risk of esophageal cancer. Functional variant CHEK2 rs738722 and rs2236142 might contribute to lymph node metastasis susceptibility. The CT allele of SNP rs738722 and the GC allele of SNP rs2236142 might be a protective factor of the risk for lymph node metastasis of esophageal cancer.

A survey of single nucleotide polymorphisms identified from whole-genome sequencing and their functional effect in the porcine genome

USDA-ARS?s Scientific Manuscript database

Genetic variants detected from sequence have been used to successfully identify causal variants and map complex traits in several organisms. High and moderate impact variants, those expected to alter or disrupt the protein coded by a gene and those that regulate protein production, likely have a mor...

VCFR: A package to manipulate and visualize variant call format data in R

USDA-ARS?s Scientific Manuscript database

Software to call single nucleotide polymorphisms or related genetic variants has converged on the variant call format (vcf) as their output format of choice. This has created a need for tools to work with vcf files. While an increasing number of software exists to read vcf data, many of them only ex...

The Arg72 variant of the p53 functional polymorphism (rs1042522) is associated with coronary artery disease in young South Africans of Indian ancestry.

PubMed

Khan, Sajidah; Phulukdaree, Alisa; Ramkaran, Prithiksha; Moodley, Devapregasan; Chuturgoon, Anil A

2016-11-30

Tumor protein p53 (p53), classically referred to as a tumor suppressor gene, is involved in cell cycle regulation and may be related to atherosclerosis by affecting smooth muscle cell proliferation, a feature of atherogenesis. A polymorphism at codon 72 (rs1042522) results in functional variability and hence plays a role in the pathophysiology of coronary artery disease (CAD). This polymorphism has been well established for its role in cancer and has only recently been investigated in CAD. Limited data is available on South Africans (SA) of Indian ancestry. We examined associations of this polymorphism and clinical markers in a cohort of young SA Indian CAD patients. A total of 284 subjects were recruited into this study which included 100 CAD patients (diagnosed on angiography, mean age 37.5, range 24-45years), 100 age- and sex-matched Indian controls and 84 age- and sex-matched Black controls. Polymorphic variants were assessed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Data for clinical markers were obtained from pathology reports. Genotype distribution differed significantly between CAD patients and Indian controls (Pro/Pro, Pro/Arg, Arg/Arg: 24%, 48%, 28% vs. 30%, 61%, 9% respectively, p=0.0025). There was a significant genotype distribution between Indian and Black controls (Pro/Pro, Pro/Arg, Arg/Arg: 30%, 61%, 9% vs. 45.2% 40.5%, 14.3% respectively, p=0.0212). A significantly higher frequency of the p53 Arg72 allele was found in CAD patients compared to controls (52% vs. 39.5% respectively, p=0.0159). The variant allele was slightly higher in Indian controls (39.5%) compared to Black controls (34.5%), but this did not reach statistical significance (p=0.3324). The levels of total cholesterol, LDL, HDL, triglycerides, fasting glucose, fasting insulin and %HbA1c were not significantly influenced by the p53 genotypic variants. Although the p53 codon 72 SNP is not associated with clinical markers of disease in CAD, the higher frequency of the variant allele in SA Indians may be a contributing factor for this population having an increased risk of developing premature CAD. Copyright © 2016. Published by Elsevier B.V.

New genetic variants associated with prostate cancer

Cancer.gov

Researchers have newly identified 23 common genetic variants -- one-letter changes in DNA known as single-nucleotide polymorphisms or SNPs -- that are associated with risk of prostate cancer. These results come from an analysis of more than 10 million SNP

Tumor necrosis factor-α -308 G/A and interleukin 10 -1082 A/G gene polymorphisms in patients with acne vulgaris.

PubMed

Al-Shobaili, Hani A; Salem, Tarek A; Alzolibani, Abdullateef A; Robaee, Ahmad Al; Settin, Ahmad A

2012-10-01

Cytokines play an important role in the pathogenesis of acne vulgaris together with other genetic and environmental factors. To check for the association of TNF-α and IL-10 gene polymorphisms with the susceptibility and severity of acne in Saudi patients. Study subjects included 166 Saudi patients (65 males, 101 females) with acne vulgaris. Their mean age±SD was 21.6±5.1 years. These cases were compared to 390 unrelated healthy controls (208 males, 182 females) with a mean age±SD of 20.1±3.3 years. Cases were sub-grouped on the basis of their severity of acne affection into mild, moderate and severe groups. For all participants, genotypic variants of the TNF-α -308 G/A and IL-10 -1082 A/G genes were determined using the real time PCR technique. Frequencies of genotypic variants of the TNF-α -308 polymorphism were significantly different in acne cases compared to controls. Further analysis showed that acne cases had significantly higher frequency of both the GG and AA homozygous forms than controls (73.8% vs. 63.6%, p=0.02, odds ratio=1.6). It was also interestingly noticed that the amount of GG homozygosity was notably higher among female cases than male ones (76.0% vs. 54.7%, p=0.006, odds ratio=2.6) whereas male cases had a higher frequency of AA and GA genotypes than female ones (9.4% and 35.9% vs. 4% and 20% respectively). Differences in the frequencies of IL-10 -1082 genotypic variants were statistically insignificant comparing cases to controls (p=0.3). On the other hand, comparing cases-subgroups in terms of the age of onset of the disease, consanguinity, family history, obesity and acne severity; no statistical significance was observed regarding frequencies of genotypic variants related to the both TNF-α -308 and IL-10 -1082 polymorphisms (>0.05). TNF-α -308 polymorphic variants might be a predisposing factor for acne susceptibility, with no apparent relation to its severity whereas IL-10 -1082 variants showed no association with both acne susceptibility and severity. Copyright © 2012 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Interferon Regulatory Factor 5 Gene Polymorphisms in Iranian Women with Unexplained Recurrent Pregnancy Loss.

PubMed

Amiri Jahromi, Rakhshan; Nasiri, Mahboobeh; Jahromi, Athar Rasekh

2017-01-01

This study aimed to examine the association of three functional IRF5 rs10954213, rs3757385, and rs41298401 polymorphisms with susceptibility to unexplained recurrent pregnancy loss (RPL) among Iranian women from south of Iran. 176 women with unexplained RPL and 173 healthy postmenopausal controls were enrolled in this case-control study. Genotyping of the polymorphisms rs10954213 and rs3757385 was carried out using touchdown tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS PCR), and polymorphism rs41298401 was typed using PCR-restriction fragment length polymorphism (PCR-RFLP). Genotype frequencies were significantly different between RPL cases and controls regarding AG heterozygote genotype of rs10954213, GT genotype of rs3757385, and GG genotype of rs41298401. In addition, allele variants (G for rs10954213, T for rs3757385, and G for rs41298401) showed protective role against RPL, while GG haplotype of two first variants was shown to be a susceptibility factor for the disease. These data provide the first evidence, to our knowledge, of the protective role of the studied IRF5 gene polymorphisms against unexplained RPL among Iranian women from south of Iran.

Genetic variants in 3′-UTRs of methylenetetrahydrofolate reductase (MTHFR) predict colorectal cancer susceptibility in Koreans

PubMed Central

Joo Jeon, Young; Woo Kim, Jong; Mi Park, Hye; Kim, Jung O; Geun Jang, Hyo; Oh, Jisu; Gyu Hwang, Seong; Won Kwon, Sung; Oh, Doyeun; Keun Kim, Nam

2015-01-01

Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) play important roles in tumor development, progression, and metastasis. Moreover, recent studies have reported that a number of 3′-UTR polymorphisms potentially bind to specific microRNAs in a variety of cancers. The aim of this study was to investigate the association of four MTHFR polymorphisms, 2572C>A [rs4846049], 4869C>G [rs1537514], 5488C>T [rs3737967], and 6685T>C [rs4846048] with colorectal cancer (CRC) in Koreans. A total of 850 participants (450 CRC patients and 400 controls) were enrolled in the study. The genotyping of MTHFR 3′-UTR polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism analysis or TaqMan allelic discrimination assay. We found that MTHFR 2572C>A, 4869C>G, and 5488C>T genotypes were substantially associated with CRC susceptibility. Of the potentially susceptible polymorphisms, MTHFR 2572C>A was associated with increased homocysteine and decreased folate levels in the plasma based on MTHFR 677CC. Our study provides the evidences for 3′-UTR variants in MTHFR gene as potential biomarkers for use in CRC prevention. PMID:26046315

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

PubMed

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

2012-04-01

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

Association between RTEL1, PHLDB1, and TREH Polymorphisms and Glioblastoma Risk: A Case-Control Study

PubMed Central

Yang, Bo; Heng, Liang; Du, Shuli; Yang, Hua; Jin, Tianbo; Lang, Hongjuan; Li, Shanqu

2015-01-01

Background Glioblastoma (GBM) is a highly invasive, aggressive, and incurable brain tumor. Genetic factors play important roles in GBM risk. The aim of this study was to elucidate the influence of gene polymorphism on GBM susceptibility. Material/Methods In this case-control study, we included 72 GBM patients and 320 healthy controls to analyze the association between 29 single-nucleotide polymorphisms and GBM cancer risk in the Chinese Han population. The single-nucleotide polymorphisms were determined by Sequenom MassARRAY RS1000 and statistical analysis was performed using SPSS software and SNPStats software. Results Using the χ2 test, we found that rs2297440 and rs6010620 in RTEL1 increased risk of GBM. In the recessive model, we also found that the genotypes “CC” of rs2297440 and “GG” of rs6010620 in RTEL1 significantly increased GBM risk. The variant TT genotype of TREH rs17748 and the variant TT genotype of PHLDB1 rs498872 decreased GBM risk in the recessive model. We also found that the TREH rs17748 variant C allele showed an increased risk in males in the dominant model. Conclusions Our results suggest a significant association between the RETL1, TREH, and PHLDB1 genes and GBM development in the Han Chinese population. PMID:26156397

Association between RTEL1, PHLDB1, and TREH Polymorphisms and Glioblastoma Risk: A Case-Control Study.

PubMed

Yang, Bo; Heng, Liang; Du, Shuli; Yang, Hua; Jin, Tianbo; Lang, Hongjun; Li, Shanqu

2015-07-09

Glioblastoma (GBM) is a highly invasive, aggressive, and incurable brain tumor. Genetic factors play important roles in GBM risk. The aim of this study was to elucidate the influence of gene polymorphism on GBM susceptibility. In this case-control study, we included 72 GBM patients and 320 healthy controls to analyze the association between 29 single-nucleotide polymorphisms and GBM cancer risk in the Chinese Han population. The single-nucleotide polymorphisms were determined by Sequenom MassARRAY RS1000 and statistical analysis was performed using SPSS software and SNPStats software. Using the χ(2) test, we found that rs2297440 and rs6010620 in RTEL1 increased risk of GBM. In the recessive model, we also found that the genotypes "CC" of rs2297440 and "GG" of rs6010620 in RTEL1 significantly increased GBM risk. The variant TT genotype of TREH rs17748 and the variant TT genotype of PHLDB1 rs498872 decreased GBM risk in the recessive model. We also found that the TREH rs17748 variant C allele showed an increased risk in males in the dominant model. Our results suggest a significant association between the RETL1, TREH, and PHLDB1 genes and GBM development in the Han Chinese population.

Effect of Treatment with Interferon Beta-1a on Changes in Voxel-Wise Magnetization Transfer Ratio in Normal Appearing Brain Tissue and Lesions of Patients with Relapsing–Remitting Multiple Sclerosis: A 24-Week, Controlled Pilot Study

PubMed Central

Zivadinov, Robert; Dwyer, Michael G.; Markovic-Plese, Silva; Kennedy, Cheryl; Bergsland, Niels; Ramasamy, Deepa P.; Durfee, Jacqueline; Hojnacki, David; Hayward, Brooke; Dangond, Fernando; Weinstock-Guttman, Bianca

2014-01-01

Background This pilot study investigated changes in remyelinating and demyelinating activity in normal appearing brain tissue (NABT) and lesions, by using voxel-wise magnetization transfer ratio (VW-MTR), in patients with relapsing–remitting multiple sclerosis (RRMS) receiving interferon beta-1a 44 mcg subcutaneously (IFN β-1a SC) three times weekly versus healthy controls (HCs) (NCT01085318). Methods Increasing (suggestive of remyelination) and decreasing (suggestive of demyelination) VW-MTR changes in NABT and in T2, T1 and gadolinium (Gd)-enhancing lesion volume were measured over 24 weeks in 23 patients treated with IFN β-1a SC and in 15 HCs (where applicable). VW-MTR changes were tested using the Wilcoxon signed–rank or Wilcoxon rank–sum test. Results A trend for greater volume of NABT with increasing VW-MTR at 24 weeks was observed for patients versus HCs (median [range] 1206 [0–15278]; 342 [0–951] mm3; p = 0.061). NABT volume with increasing VW-MTR at 12 weeks was significantly greater in patients than in HCs (852 [6–11577]; 360 [0–1755] mm3; p = 0.028). Similar findings were detected for lesion volumes. Two patients with notably high numbers of Gd-enhancing lesions at baseline had a markedly greater volume of tissue with increasing VW-MTR compared with other patients. Volume of NABT tissue with decreasing VW-MTR was significantly greater in patients versus HCs at 24 weeks (942 [0–6141]; 297 [0–852] mm3; p<0.001). Conclusions The significant change in NABT volume with increasing VW-MTR at 12 weeks suggests that active remyelination in patients with RRMS may occur during treatment with IFN β-1a SC. Findings from two patients with the highest number of Gd-enhancing lesions at baseline suggest that extensive remyelination in NABT may occur in patients with high disease activity. Tissue volume with decreasing VW-MTR was greater in patients than in HCs, despite treatment, validating the sensitivity of this technique for detecting MS disease activity. Trial Registration ClinicalTrials.gov NCT01085318. PMID:24625687

Role of Mex67-Mtr2 in the Nuclear Export of 40S Pre-Ribosomes

PubMed Central

Occhipinti, Laura; Kemmler, Stefan; Panse, Vikram G.

2012-01-01

Nuclear export of mRNAs and pre-ribosomal subunits (pre40S and pre60S) is fundamental to all eukaryotes. While genetic approaches in budding yeast have identified bona fide export factors for mRNAs and pre60S subunits, little is known regarding nuclear export of pre40S subunits. The yeast heterodimeric transport receptor Mex67-Mtr2 (TAP-p15 in humans) binds mRNAs and pre60S subunits in the nucleus and facilitates their passage through the nuclear pore complex (NPC) into the cytoplasm by interacting with Phe-Gly (FG)-rich nucleoporins that line its transport channel. By exploiting a combination of genetic, cell-biological, and biochemical approaches, we uncovered an unanticipated role of Mex67-Mtr2 in the nuclear export of 40S pre-ribosomes. We show that recruitment of Mex67-Mtr2 to pre40S subunits requires loops emanating from its NTF2-like domains and that the C-terminal FG-rich nucleoporin interacting UBA-like domain within Mex67 contributes to the transport of pre40S subunits to the cytoplasm. Remarkably, the same loops also recruit Mex67-Mtr2 to pre60S subunits and to the Nup84 complex, the respective interactions crucial for nuclear export of pre60S subunits and mRNAs. Thus Mex67-Mtr2 is a unique transport receptor that employs a common interaction surface to participate in the nuclear export of both pre-ribosomal subunits and mRNAs. Mex67-Mtr2 could engage a regulatory crosstalk among the three major export pathways for optimal cellular growth and proliferation. PMID:22956913

Role of the 2 adenine (g.11293_11294insAA) insertion polymorphism in the 3' untranslated region of the factor VII (FVII) gene: molecular characterization of a patient with severe FVII deficiency.

PubMed

Peyvandi, F; Garagiola, I; Palla, R; Marziliano, N; Mannucci, P M

2005-11-01

Polymorphic variants in the gene encoding factor VII (F7) affect the plasma levels of this coagulation protein and modify the clinical phenotype of FVII deficiency in some patients. In this study we report the in vitro functional analysis of a novel polymorphic variant located in the 3' untranslated region of F7: g.11293_11294insAA. To determine whether this variant regulates FVII expression, we initially compared an expression vector containing FVII cDNA with g.11293_11294insAA with the FVII wild-type (WT) construct. The kinetics of mRNA production showed that the insertion decreases the steady-state FVII mRNA levels. To assess whether the insertion influences the phenotype of FVII-deficient patients, we evaluated its effect on the expression of FVII in a patient with severe FVII deficiency (undetectable FVII activity and antigen) carrying two additional homozygous missense variations (p.Arg277Cys and p.Arg353Gln). The two substitutions alone reduced the expression of FVII activity and antigen in vitro, but with the insertion polymorphism in our expression vector the patient's phenotype of undetectable plasma FVII was recapitulated. The insertion polymorphism in the 3' untranslated region of F7 is another modifier of FVII expression that might explain the poor genotype-phenotype correlation in some FVII-deficient patients. Copyright 2005 Wiley-Liss, Inc.

Glutathione S-transferase gene polymorphisms in celiac disease and their correlation with genomic instability phenotype.

PubMed

Fundia, Ariela F; Weich, Natalia; Crivelli, Adriana; La Motta, Graciela; Larripa, Irene B; Slavutsky, Irma

2014-06-01

Genomic instability and reduced glutathione S-transferase (GST) activity have been identified as potential risk factors for malignant complications in celiac disease (CD). In this study, we assessed the possible influence of GST polymorphisms on genome instability phenotypes in a genetically characterised group of celiac patients from previous studies. The deletion polymorphisms in GSTM1 and GSTT1 genes and the single-nucleotide polymorphism GSTP1 c.313A>G were genotyped using PCR in a set of 20 untreated adult patients with a known genomic instability phenotype and 69 age- and sex-matched healthy individuals. The frequencies of variant genotypes in patients were GSTM1-null (30%), GSTT1-null (5%), GSTP1-AG (60%) and GSTP1-GG (15%), and they showed no differences from controls. No significant differences were found in the genotype distribution based on telomere length. Cases with GSTM1-null genotype (83%) and microsatellite stability were more frequent than those with genomic instability. Moreover, carriers of GSTP1-variant genotype (73%) and stable phenotype were significantly increased compared to unstable patients (27%) (P=0.031). No differences were found according to the clinical-pathological characteristics of celiac cases. No association between GST polymorphic variants and celiac-associated genomic instability was proven in our cohort. Future studies should explore the usefulness of other biomarkers to distinguish celiac patients who are susceptible to cancer development. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

No evidence for involvement of genetic variants in the X-linked neuroligin genes NLGN3 and NLGN4X in probands with autism spectrum disorder on high functioning level.

PubMed

Wermter, Anne-Kathrin; Kamp-Becker, Inge; Strauch, Konstantin; Schulte-Körne, Gerd; Remschmidt, Helmut

2008-06-05

Several lines of evidence indicate a role of mutations in the two X-linked genes neuroligin 3 (NLGN3) and neuroligin 4 (NLGN4X) in the etiology of autistic spectrum disorders. To analyze whether genetic variants in the NLGN3 and NLGN4X genes occurs in patients with autistic disorders on high functioning level, we performed a mutation screen of both genes using SSCP in 107 probands with Asperger syndrome, high-functioning autism and atypical autism. We identified four polymorphisms (rs2290488, rs7049300, rs3747333, rs3747334) and one novel synonymous variant (A558) in the NLGN4X. The polymorphisms rs7049300, rs3747333, and rs3747334 did not cause any amino acid substitutions in the total of the eight detected carriers. A family-based association study for rs2290488 in 101 trios did not reveal association of this polymorphism with autistic disorders on high functioning level. We conclude that there is no evidence for an involvement of NLGN3 and NLGN4X genetic variants with autism spectrum disorder on high functioning level in our study group. (c) 2008 Wiley-Liss, Inc.

Functional Interaction of the Ankylosing Spondylitis-associated Endoplasmic Reticulum Aminopeptidase 1 Polymorphism and HLA-B27 in Vivo*

PubMed Central

García-Medel, Noel; Sanz-Bravo, Alejandro; Van Nguyen, Dung; Galocha, Begoña; Gómez-Molina, Patricia; Martín-Esteban, Adrián; Alvarez-Navarro, Carlos; de Castro, José A. López

2012-01-01

The association of ERAP1 with ankylosing spondylitis (AS)1 among HLA-B27-positive individuals suggests that ERAP1 polymorphism may affect pathogenesis by altering peptide-dependent features of the HLA-B27 molecule. Comparisons of HLA-B*27:04-bound peptidomes from cells expressing different natural variants of ERAP1 revealed significant differences in the size, length, and amount of many ligands, as well as in HLA-B27 stability. Peptide analyses suggested that the mechanism of ERAP1/HLA-B27 interaction is a variant-dependent alteration in the balance between epitope generation and destruction determined by the susceptibility of N-terminal flanking and P1 residues to trimming. ERAP1 polymorphism associated with AS susceptibility ensured efficient peptide trimming and high HLA-B27 stability. Protective polymorphism resulted in diminished ERAP1 activity, less efficient trimming, suboptimal HLA-B27 peptidomes, and decreased molecular stability. This study demonstrates that natural ERAP1 polymorphism affects HLA-B27 antigen presentation and stability in vivo and proposes a mechanism for the interaction between these molecules in AS. PMID:22918227

Association of Leukotrichia in Vitiligo and Asp148Glu Polymorphism of Apurinic/Apyrimidinic Endonuclease 1.

PubMed

Aydin, A Fatih; Aydıngöz, İkbal Esen; Doğru-Abbasoğlu, Semra; Vural, Pervin; Uysal, Müjdat

2017-01-01

Oxidative stress and increased DNA damage have been implicated in the etiopathogenesis of vitiligo. Oxidative DNA damage is mainly repaired by the base excision repair (BER) pathway. We sought to determine whether polymorphisms in DNA repair genes may have a role in the pathogenesis of vitiligo. We conducted a study including 100 patients with vitiligo and age- and sex-matched 193 control subjects to examine the role of single-nucleotide polymorphisms of BER genes, human 8-oxoG DNA N-glycosylase 1 (codon 326), apurinic/apyrimidinic endonuclease 1 (APE1) (codon 148), and X-ray repair cross-complementing group 1 (codon 399) as risk factors for vitiligo. These polymorphisms were determined by quantitative real-time polymerase chain reaction and melting curve analysis. No significant association was observed between the variant alleles of studied genes and vitiligo. However, we showed that the presence of APE1 148Glu variant allele is associated with leukotrichia. This preliminary study suggests that APE1 (codon 148) polymorphism may play a role in vitiligo pathogenesis.

Decreased Spontaneous Electrical Activity and Acetylcholine at Myofascial Trigger Spots after Dry Needling Treatment: A Pilot Study.

PubMed

Liu, Qing-Guang; Liu, Lin; Huang, Qiang-Min; Nguyen, Thi-Tham; Ma, Yan-Tao; Zhao, Jia-Min

2017-01-01

The aims of this study are to investigate the changes in spontaneous electrical activities (SEAs) and in acetylcholine (ACh), acetylcholine receptor (AChR), and acetylcholine esterase (AChE) levels after dry needling at myofascial trigger spots in model rats. Forty-eight male Sprague-Dawley rats were divided into four groups. Thirty-six rats were assigned to three model groups, which underwent MTrSs modeling intervention. Twelve rats were assigned to the blank control (BC) group. After model construction, the 36 model rats were randomly subdivided into three groups according to treatment: MTrSs model control (MC) and two dry needling groups. One dry needling group received puncturing at MTrSs (DN-M), whereas the other underwent puncturing at non-MTrSs (DN-nM). Dry needling treatment will last for two weeks, once a week. SEAs and ACh, AChR, and AChE levels were measured after one-week rest of dry needling treatment. The amplitudes and frequencies of endplate noise (EPN) and endplate spike (EPS) significantly decreased after dry needling treatment in the DN-M group. Moreover, ACh and AChR levels significantly decreased, whereas AChE significantly increased after dry needling treatment in the DN-M group. Dry needling at the exact MTrSs is more effective than dry needling at non-MTrSs.

Decreased Spontaneous Electrical Activity and Acetylcholine at Myofascial Trigger Spots after Dry Needling Treatment: A Pilot Study

PubMed Central

2017-01-01

Objective The aims of this study are to investigate the changes in spontaneous electrical activities (SEAs) and in acetylcholine (ACh), acetylcholine receptor (AChR), and acetylcholine esterase (AChE) levels after dry needling at myofascial trigger spots in model rats. Materials and Methods Forty-eight male Sprague-Dawley rats were divided into four groups. Thirty-six rats were assigned to three model groups, which underwent MTrSs modeling intervention. Twelve rats were assigned to the blank control (BC) group. After model construction, the 36 model rats were randomly subdivided into three groups according to treatment: MTrSs model control (MC) and two dry needling groups. One dry needling group received puncturing at MTrSs (DN-M), whereas the other underwent puncturing at non-MTrSs (DN-nM). Dry needling treatment will last for two weeks, once a week. SEAs and ACh, AChR, and AChE levels were measured after one-week rest of dry needling treatment. Results The amplitudes and frequencies of endplate noise (EPN) and endplate spike (EPS) significantly decreased after dry needling treatment in the DN-M group. Moreover, ACh and AChR levels significantly decreased, whereas AChE significantly increased after dry needling treatment in the DN-M group. Conclusion Dry needling at the exact MTrSs is more effective than dry needling at non-MTrSs. PMID:28592980

Evaluation of ATG5 polymorphisms in Italian patients with systemic lupus erythematosus: contribution to disease susceptibility and clinical phenotypes.

PubMed

Ciccacci, C; Perricone, C; Alessandri, C; Latini, A; Politi, C; Delunardo, F; Pierdominici, M; Conti, F; Novelli, G; Ortona, E; Borgiani, P

2018-01-01

Systemic lupus erythematosus (SLE) is a common heterogeneous autoimmune disease that is caused by the involvement both of genetic and environmental factors. There is evidence that autophagy is involved in several aspects of SLE pathogenesis. In particular, polymorphisms in the ATG5 gene have been observed to be associated with disease susceptibility. Our aim was to verify if ATG5 polymorphisms are involved in the susceptibility to disease and its clinical phenotypes in an Italian cohort of SLE patients. This study involved 315 SLE patients and 265 healthy controls. Three polymorphisms in the ATG5 gene (rs573775, rs6568431 and rs2245214) were investigated by allelic discrimination assay. A case-control association study, a genotype/phenotype correlation analysis and a haplotype study were performed. Moreover, an expression study was conducted in peripheral blood mononuclear cells from 15 SLE patients to verify a possible effect of the three SNPs on the expression of ATG5. Among the three investigated SNPs, only the rs573775 SNP was significantly associated with disease susceptibility with the variant allele conferring a higher risk of developing SLE (OR = 1.50, p = 0.018 and OR = 1.48, p = 0.007 at the genotypic and allelic level, respectively). The variant allele of rs6568431 SNP was more present in patients with anemia (OR = 1.86, p = 0.009) and renal involvement (OR = 1.63, p = 0.06), while the variant allele of rs2245214 SNP was significantly associated with a higher risk of producing anti-DNA autoantibodies (OR = 1.66, p = 0.04). Carriers of the rs6568431 variant allele showed higher messenger RNA levels compared to the carriers of the wild-type allele, suggesting also a potential variant allele dose-dependent effect on gene expression. In conclusion, our study confirms a role for ATG5 polymorphisms both in disease susceptibility and in the modulation of clinical phenotypes in an Italian SLE cohort. These results further suggest that genetic variations in autophagy genes could play a role in autoimmune diseases susceptibility and are worth further investigation.

Characterization of hMTr1, a Human Cap1 2′-O-Ribose Methyltransferase*

PubMed Central

Bélanger, François; Stepinski, Janusz; Darzynkiewicz, Edward; Pelletier, Jerry

2010-01-01

Cellular eukaryotic mRNAs are capped at their 5′ ends with a 7-methylguanosine nucleotide, a structural feature that has been shown to be important for conferring mRNA stability, stimulating mRNA biogenesis (splicing, poly(A) addition, nucleocytoplasmic transport), and increasing translational efficiency. Whereas yeast mRNAs have no additional modifications to the cap, called cap0, higher eukaryotes are methylated at the 2′-O-ribose of the first or the first and second transcribed nucleotides, called cap1 and cap2, respectively. In the present study, we identify the methyltransferase responsible for cap1 formation in human cells, which we call hMTr1 (also known as FTSJD2 and ISG95). We show in vitro that hMTr1 catalyzes specific methylation of the 2′-O-ribose of the first nucleotide of a capped RNA transcript. Using siRNA-mediated knockdown of hMTr1 in HeLa cells, we demonstrate that hMTr1 is responsible for cap1 formation in vivo. PMID:20713356

RAAS polymorphisms alter the acute blood pressure response to aerobic exercise among men with hypertension.

PubMed

Blanchard, Bruce E; Tsongalis, Gregory J; Guidry, Margaux A; LaBelle, Lisa A; Poulin, Michelle; Taylor, Amy L; Maresh, Carl M; Devaney, Joseph; Thompson, Paul D; Pescatello, Linda S

2006-05-01

Limited evidence suggests renin-angiotensin-aldosterone system (RAAS) polymorphisms alter the blood pressure (BP) response to aerobic exercise training. We examined if RAAS polymorphisms influenced postexercise hypotension in men with high normal to Stage 1 hypertension. Forty-seven men (44.2+/-1.4 years, 145.1+/-1.6/85.5+/-1.1 mmHg) randomly completed three experiments: seated rest (control) and two cycle exercise bouts at 40% (LITE) and 60% (MOD) of maximal oxygen consumption. Ambulating BP was measured for 14 h after each experiment. RAAS polymorphisms associated with hypertension (i.e. angiotensin converting I enzyme, ACE I/D; angiotensin II type 1 receptor, AT1R A/C; and intron 2 of aldosterone synthase, Int2 W/C) were analyzed using polymerase chain reaction and restriction enzyme digestion. Repeated measure ANOVA tested if BP differed between experimental conditions by RAAS genotypes. Compared to men with 0-2 variant alleles, men with > or =3 combined RAAS variant alleles had lower average systolic BP (SBP) (P=0.030) and lower average diastolic BP (DBP) (P=0.009) for 14 h only after LITE. In contrast, average BP was not different for MOD and control between RAAS variant allele groups over this time period (P> or =0.05). LITE reduced BP in men with > or =3 variant RAAS alleles for 14 h, whereas MOD had no influence on BP in these men. In order to optimally prescribe exercise for its BP lowering benefits in those with hypertension, additional knowledge of how genetic variation affects the BP response to exercise is needed.

Identification of novel potential genetic predictors of urothelial bladder carcinoma susceptibility in Pakistani population.

PubMed

Ali, Syeda Hafiza Benish; Bangash, Kashif Sardar; Rauf, Abdur; Younis, Muhammad; Anwar, Khursheed; Khurram, Raja; Khawaja, Muhammad Athar; Azam, Maleeha; Qureshi, Abid Ali; Akhter, Saeed; Kiemeney, Lambertus A; Qamar, Raheel

2017-10-01

Urothelial bladder carcinoma (UBC) is the most common among urinary bladder neoplasms. We carried out a preliminary study to determine the genetic etiology of UBC in Pakistani population, for this 25 sequence variants from 17 candidate genes were studied in 400 individuals by using polymerase chain reaction-based techniques. Multivariate logistic regression analysis was performed for association analysis of the overall data as well as the data stratified by smoking status, tumor grade and tumor stage. Variants of GSTM1, IGFBP3, LEPR and ACE were found to be associated with altered UBC risk in the overall comparison. CYP1B1 and CDKN1A variants displayed a risk modulation among smokers; IGFBP3 and LEPR variants among non-smokers while GSTM1 polymorphism exhibited association with both. GSTM1 and LEPR variants conferred an altered susceptibility to low grade UBC; GSTT1, IGFBP3 and PPARG variants to high grade UBC while ACE polymorphism to both grades. GSTM1 and LEPR variants exhibited risk modulation for non-muscle-invasive bladder cancer (NMIBC); GSTT1 and PPARG variants for muscle-invasive bladder cancer (MIBC), and ACE variant for NMIBC as well as MIBC. In general, the susceptibility markers were common for low grade and NMIBC; and distinct from those for high grade and MIBC indicating the distinct pathologies of both groups. In brief, our results conform to reports of previously associated variants in addition to identifying novel potential genetic predictors of UBC susceptibility.

Further mapping of 10q26 supports strong association of HTRA1 polymorphisms with age-related macular degeneration.

PubMed

Gibbs, Daniel; Yang, Zhenglin; Constantine, Ryan; Ma, Xiang; Camp, Nicola J; Yang, Xian; Chen, Hayou; Jorgenson, Adam; Hau, Vincent; Dewan, Andrew; Zeng, Jiexi; Harmon, Jennifer; Buehler, Jeanette; Brand, John M; Hoh, Josephine; Cameron, D Joshua; Dixit, Manjusha; Tong, Zongzhong; Zhang, Kang

2008-02-01

Age-related macular degeneration (AMD) is a complex disorder with genetic and environmental influences. The genetic influences affecting AMD are not well understood and few genes have been consistently implicated and replicated for this disease. A polymorphism (rs11200638) in a transcription factor binding site of the HTRA1 gene has been described, in previous reports, as being most significantly associated with AMD. In this paper, we investigate haplotype association and individual polymorphic association by genotyping additional variants in the AMD risk-associated region of chromosome 10q26. We demonstrate that rs11200638 in the promoter region and rs2293870 in exon 1 of HTRA1, are among the most significantly associated variants for advanced forms of AMD.

Asymptomatic Dengue Infection in a Cuban Population Confirms the Protective Role of the RR Variant of the FcγRIIa Polymorphism

PubMed Central

García, Gissel; Sierra, Beatriz; Pérez, Ana B.; Aguirre, Eglys; Rosado, Ileana; Gonzalez, Narjara; Izquierdo, Alienys; Pupo, Maritza; Danay Díaz, Didye Ruiz; Sánchez, Lizet; Marcheco, Beatriz; Hirayama, Kenji; Guzmán, María G.

2010-01-01

The role of human Fcγ receptors (FcγR) has been recognized considerably over the last years. These receptors vary in their affinity for IgG subclasses and the intracellular signals elicited by them. Allelic variants of FcγR genes may influence the biological phagocyte activity, accounting for an inherited pre-disposition to disease. The specific FcγRIIa (CD32) contains a polymorphic variant (H/R131) that has been associated to a reduced risk for developing dengue hemorrhagic fever (DHF). Here, we investigated the role of this polymorphism in a very well-characterized group of Cuban individuals with antecedents of DHF, dengue fever (DF), or subclinical dengue infection. The HH131 genotype was significantly associated with dengue disease, either DF (*P = 0.016; odds ratio = 4.425; 95% confidence interval = 1.10–20.52) or DHF (P = 0.00018; odds ratio = 10.56; 95% confidence interval = 2.33–54.64) with respect to the subclinical infection. PMID:20519616

Three major glucose-6-phosphate dehydrogenase-deficient polymorphic variants identified in Mazandaran state of Iran.

PubMed

Mesbah-Namin, Seyed A; Sanati, Mohammad H; Mowjoodi, Alireza; Mason, Philip J; Vulliamy, Tom J; Noori-Daloii, Mohammad R

2002-06-01

We report the first investigation of glucose- 6-phosphate dehydrogenase (G6PD) deficiency among the Mazandaranians in the north of Iran. We analysed the G6PD gene in 74 unrelated G6PD-deficient men with a history of favism. Molecular analysis revealed three major different polymorphic variants: G6PD Mediterranean 66.2% (49 out of 74), G6PD Chatham 27% (20 out of 74), G6PD Cosenza 6.75% (5 out of 74). These findings indicated a higher prevalence of G6PD Chatham in this Iranian population than anywhere else in the world. In addition, the distribution of these G6PD variants is more similar to that found in an Italian population than in other Middle Eastern countries.

Folate and One-Carbon Metabolism Gene Polymorphisms and Their Associations With Oral Facial Clefts

PubMed Central

Boyles, Abee L.; Wilcox, Allen J.; Taylor, Jack A.; Meyer, Klaus; Fredriksen, Åse; Ueland, Per Magne; Drevon, Christian A.; Vollset, Stein Emil; Lie, Rolv Terje

2008-01-01

Folate metabolism plays a critical role in embryonic development. Prenatal folate supplementation reduces the risk of neural tube defects and probably oral facial clefts. Previous studies of related metabolic genes have associated polymorphisms in cystathionine-beta-synthase (CBS) and 5,10-methylenetetrahydrofolate reductase (MTHFR) with cleft risk. We explored associations between genes related to one-carbon metabolism and clefts in a Norwegian population-based study that included 362 families with cleft lip with or without cleft palate (CL/P) and 191 families with cleft palate only (CPO). We previously showed a 39% reduction in risk of CL/P with folic acid supplementation in this population. In the present study we genotyped 12 polymorphisms in nine genes related to one-carbon metabolism and looked for associations of clefting risk with fetal polymorphisms, maternal polymorphisms, as well as parent-of-origin effects, using combined likelihood-ratio tests (LRT). We also stratified by maternal periconceptional intake of folic acid (>400 μg) to explore gene-exposure interactions. We found a reduced risk of CL/P with mothers who carried the CBS C699T variant (rs234706); relative risk was 0.94 with one copy of the T allele (95% CI 0.63-1.4) and 0.50 (95% CI 0.26-0.96) with two copies (P = 0.008). We found no evidence of interaction of this variant with folate status. We saw no evidence of risk from the MTHFR C677T variant (rs1801133) either overall or after stratifying by maternal folate intake. No associations were found between any of the polymorphisms and CPO. Genetic variations in the nine metabolic genes examined here do not confer a substantial degree of risk for clefts. Published 2008 Wiley-Liss, Inc.† PMID:18203168

TGF{beta}1 polymorphisms and late clinical radiosensitivity in patients treated for gynecologic tumors

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

Ruyck, Kim de; Van Eijkeren, Marc; Claes, Kathleen

2006-07-15

Purpose: To investigate the association between six transforming growth factor {beta}1 gene (TGF{beta}1) polymorphisms (-1.552delAGG, -800G>A, -509C>T, Leu10Pro, Arg25Pro, Thr263Ile) and the occurrence of late normal tissue reactions after gynecologic radiotherapy (RT). Methods and Materials: Seventy-eight women with cervical or endometrial cancer and 140 control individuals were included in the study. According to the Common Terminology Criteria for Adverse Events version 3.0 (CTCAEv3.0) scale, 25 patients showed late adverse RT reactions (CTC2+), of whom 11 had severe complications (CTC3+). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), single base extension and genotyping assays were performed to examine the polymorphic sites inmore » TGF{beta}1. Results: Homozygous variant -1.552delAGG, -509TT, and 10Pro genotypes were associated with the risk of developing late severe RT reactions. Triple (variant) homozygous patients had a 3.6 times increased risk to develop severe RT reactions (p = 0.26). Neither the -800A allele, nor the 25Pro allele or the 263Ile allele were associated with clinical radiosensitivity. There was perfect linkage disequilibrium (LD) between the -1.552delAGG and the -509C>T polymorphisms, and tight LD between the -1.552/-509 and the Leu10Pro polymorphisms. Haplotype analysis revealed two major haplotypes but could not distinguish radiosensitive from nonradiosensitive patients. Conclusions: The present study shows that homozygous variant TGF{beta}1 -1.552delAGG, -509TT, and 10Pro genotypes may be associated with severe clinical radiosensitivity after gynecologic RT.« less

Polymorphisms in adenosine receptor genes are associated with infarct size in patients with ischemic cardiomyopathy.

PubMed

Tang, Z; Diamond, M A; Chen, J-M; Holly, T A; Bonow, R O; Dasgupta, A; Hyslop, T; Purzycki, A; Wagner, J; McNamara, D M; Kukulski, T; Wos, S; Velazquez, E J; Ardlie, K; Feldman, A M

2007-10-01

The goal of this experiment was to identify the presence of genetic variants in the adenosine receptor genes and assess their relationship to infarct size in a population of patients with ischemic cardiomyopathy. Adenosine receptors play an important role in protecting the heart during ischemia and in mediating the effects of ischemic preconditioning. We sequenced DNA samples from 273 individuals with ischemic cardiomyopathy and from 203 normal controls to identify the presence of genetic variants in the adenosine receptor genes. Subsequently, we analyzed the relationship between the identified genetic variants and infarct size, left ventricular size, and left ventricular function. Three variants in the 3'-untranslated region of the A(1)-adenosine gene (nt 1689 C/A, nt 2206 Tdel, nt 2683del36) and an informative polymorphism in the coding region of the A3-adenosine gene (nt 1509 A/C I248L) were associated with changes in infarct size. These results suggest that genetic variants in the adenosine receptor genes may predict the heart's response to ischemia or injury and might also influence an individual's response to adenosine therapy.

Genetic variations in NADPH-CYP450 oxidoreductase in a Czech Slavic cohort

PubMed Central

Tomková, Mária; Panda, Satya Prakash; Šeda, Ondřej; Baxová, Alice; Hůlková, Martina; Masters, Bettie Sue Siler; Martásek, Pavel

2015-01-01

Background Gene polymorphisms encoding the enzyme NADPH–cytochrome P450 oxidoreductase (POR) contribute to inter-individual differences in drug response. Aim To estimate polymorphic allele frequencies of the POR gene in a Czech Slavic population. Materials & Methods The gene POR was analyzed in 322 Czech Slavic individuals from a control cohort by sequencing and HRM analysis. Results Twenty-five SNP genetic variations were identified. Of these variants, 7 were new, unreported SNPs, including two SNPs in the 5´flanking region (g.4965 C>T and g.4994 G>T), one intronic variant (c.1899 −20C>T), one synonymous SNP (p.20Ala=) and three nonsynonymous SNPs (p.Thr29Ser, p.Pro384Leu and p.Thr529Met). The p.Pro384Leu variant exhibited reduced enzymatic activities compared to wild type. Conclusion New POR variant identification indicates that the number of uncommon variants might be specific for each subpopulation being investigated, particularly germane to the singular role that POR plays in providing reducing equivalents to all CYPs in the endoplasmic reticulum. PMID:25712184

CDK5RAP2 gene and tau pathophysiology in late-onset sporadic Alzheimer's disease.

PubMed

Miron, Justin; Picard, Cynthia; Nilsson, Nathalie; Frappier, Josée; Dea, Doris; Théroux, Louise; Poirier, Judes

2018-06-01

Because currently known Alzheimer's disease (AD) single-nucleotide polymorphisms only account for a small fraction of the genetic variance in this disease, there is a need to identify new variants associated with AD. Our team performed a genome-wide association study in the Quebec Founder Population isolate to identify novel protective or risk genetic factors for late-onset sporadic AD and examined the impact of these variants on gene expression and AD pathology. The rs10984186 variant is associated with an increased risk of developing AD and with a higher CDK5RAP2 mRNA prevalence in the hippocampus. On the other hand, the rs4837766 variant, which is among the best cis-expression quantitative trait loci in the CDK5RAP2 gene, is associated with lower mild cognitive impairment/AD risk and conversion rate. The rs10984186 risk and rs4837766 protective polymorphic variants of the CDK5RAP2 gene might act as potent genetic modifiers for AD risk and/or conversion by modulating the expression of this gene. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

PUMP HOUSE FOR MTR WELL NO. 1, TRA601. FLOOR PLAN, ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

PUMP HOUSE FOR MTR WELL NO. 1, TRA-601. FLOOR PLAN, ELEVATIONS, SECTION SHOWING WELL CASING, ROOF FRAMING PLAN. AS BUILT. WELL HOUSE FOR WELL NO. 2, TRA-602, WAS IDENTICAL IN ALL PARTICULARS EXCEPT FLOOR DIMENSIONS AND ARRANGEMENT OF PUMP AND ELECTRICAL EQUIPMENT INSIDE. IDAHO OPERATIONS OFFICE MTR-601-IDO-1, 12/1954. INL INDEX NO. 531-0601-00-396-110463, REV. 2. - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

Charge carrier transport in polycrystalline organic thin film based field effect transistors

NASA Astrophysics Data System (ADS)

Rani, Varsha; Sharma, Akanksha; Ghosh, Subhasis

2016-05-01

The charge carrier transport mechanism in polycrystalline thin film based organic field effect transistors (OFETs) has been explained using two competing models, multiple trapping and releases (MTR) model and percolation model. It has been shown that MTR model is most suitable for explaining charge carrier transport in grainy polycrystalline organic thin films. The energetic distribution of traps determined independently using Mayer-Neldel rule (MNR) is in excellent agreement with the values obtained by MTR model for copper phthalocyanine and pentacene based OFETs.

Possible Dynamically Gated Conductance along Heme Wires in Bacterial Multiheme Cytochromes

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

Smith, Dayle MA; Rosso, Kevin M.

2014-07-24

The staggered cross decaheme configuration of electron transfer co-factors in the outer-membrane cytochrome MtrF may serve as a prototype for conformationally-gated multi-heme electron transport. Derived from the bacterium Shewanella oneidensis, the staggered cross configuration reveals intersecting c-type octaheme and tetraheme “wires” containing thermodynamic “hills” and “valleys”, suggesting that the protein structure may include a dynamical mechanism for conductance and pathway switching depending on enzymatic functional need. Recent molecular simulations have established the pair-wise electronic couplings, redox potentials, and reorganization energies to predict the maximum conductance along the various heme wire pathways by sequential hopping of a single electron (PNAS (2014)more » 11,611-616). Here, we expand this information with classical molecular and statistical mechanics calculations of large-amplitude protein dynamics in MtrF, to address its potential to modulate pathway conductance, including assessment of the effect of the total charge state. Explicit solvent molecular dynamics simulations of fully oxidized and fully reduced MtrF employing ten independent 50-ns simulations at 300 K and 1 atm showed that reduced MtrF is more expanded and explores more conformational space than oxidized MtrF, and that heme reduction leads to increased heme solvent exposure. The slowest mode of collective decaheme motion is 90% similar between the oxidized and reduced states, and consists primarily of inter-heme separation with minor rotational contributions. The frequency of this motion is 1.7×107 s 1 for fully-oxidized and fully-reduced MtrF, respectively, slower than the downhill electron transfer rates between stacked heme pairs at the octaheme termini and faster than the electron transfer rates between parallel hemes in the tetraheme chain. This implies that MtrF uses slow conformational fluctuations to modulate electron flow along the octaheme pathway, apparently for the purpose of increasing the residence time of electrons on lowest potential hemes 4 and 9. This apparent gating mechanism should increase the success rate of electron transfer from MtrF to low potential environmental acceptors via these two solvent-exposed hemes.« less

Multivariate combination of magnetization transfer, T2* and B0 orientation to study the myelo-architecture of the in vivo human cortex

PubMed Central

Mangeat, G.; Govindarajan, S. T.; Mainero, C.; Cohen-Adad, J.

2015-01-01

Recently, T2* imaging at 7 tesla (T) MRI was shown to reveal microstructural features of the cortical myeloarchitecture thanks to an increase in contrast-to-noise ratio. However, several confounds hamper the specificity of T2* measures (iron content, blood vessels, tissues orientation). Another metric, magnetization transfer ratio (MTR), is known to also be sensitive to myelin content and thus would be an excellent complementary measure because its underlying contrast mechanisms are different than that from T2*. The goal of this study was thus to combine MTR and T2* using multivariate statistics in order to gain insights into cortical myelin content. Seven healthy subjects were scanned at 7T and 3T to obtain T2* and MTR data, respectively. A multivariate myelin estimation model (MMEM) was developed, and consists in (i) normalizing T2* and MTR values and (ii) extracting their shared information using independent component analysis (ICA). B0 orientation dependence and cortical thickness were also computed and included in the model. Results showed high correlation between MTR and T2* in the whole cortex (r=0.76, p<10−16), suggesting that both metrics are partly driven by a common source of contrast, here assumed to be the myelin. Average MTR and T2* were respectively 31.0 +/− 0.3% and 32.1 +/− 1.4 ms. Results of the MMEM spatial distribution showed similar trends to that from histological work stained for myelin (r=0.77, p<0.01). Significant right-left differences were detected in the primary motor cortex (p<0.05), the posterior cingulate cortex (p<0.05) and the visual cortex (p<0.05). This study demonstrates that MTR and T2* are highly correlated in the cortex. The combination of MTR, T2*, CT and B0 orientation may be a useful means to study cortical myeloarchitecture with more specificity than using any of the individual methods. The MMEM framework is extendable to other contrasts such as T1 and diffusion MRI. PMID:26095090

SCN1A, ABCC2 and UGT2B7 gene polymorphisms in association with individualized oxcarbazepine therapy.

PubMed

Ma, Chun-Lai; Wu, Xun-Yi; Jiao, Zheng; Hong, Zhen; Wu, Zhi-Yuan; Zhong, Ming-Kang

2015-01-01

Associations between the effects of SCN1A, SCN2A, ABCC2 and UGT2B7 genetic polymorphisms and oxcarbazepine (OXC) maintenance doses in Han Chinese epileptic patients were investigated. Genetic polymorphisms were detected in 184 epileptic patients receiving OXC monotherapy by high-resolution melting curve and TaqMan method. Carriers of the SCN1A IVS5-91G>A, UGT2B7 c.802T>C and ABCC2 c.1249G>A variant alleles required significantly higher OXC maintenance doses than noncarriers (p < 0.05). Corresponding relative ln (concentration-dose ratios) values for SCN1A IVS5-91 variants differed by the genotypic order GG > GA > AA. SCN1A, UGT2B7 and ABCC2 genetic polymorphisms are associated with OXC maintenance doses and may be useful for the personalization of OXC therapy in epileptic patients. Further studies are needed. Original submitted 6 June 2014; Revision submitted 5 September 2014.

Maltreatment, MAOA, and delinquency: sex differences in gene-environment interaction in a large population-based cohort of adolescents.

PubMed

Aslund, C; Nordquist, N; Comasco, E; Leppert, J; Oreland, L; Nilsson, K W

2011-03-01

The present study investigated a possible interaction between a functional polymorphism in the MAOA gene promoter (MAOA-VNTR) and childhood maltreatment in the prediction of adolescent male and female delinquency. A cohort of 1,825 high school students, 17-18 years old, completed an anonymous questionnaire during class hours which included questions on childhood maltreatment, sexual abuse, and delinquency. Saliva samples were collected for DNA isolation, and analyzed for the MAOA-VNTR polymorphism. Self-reported maltreatment was a strong risk factor for adolescent delinquent behavior. The MAOA genotype also showed a significant main effect when controlled for maltreatment. Boys with a short variant and girls with one or two long variants of the polymorphism showed a higher risk for delinquency when exposed to maltreatment. Our results confirm previous findings of an interaction between the MAOA-VNTR polymorphism and self-reported maltreatment. Results for boys and girls differ according to MAOA-VNTR genotype and direction of phenotypic expression.

Abdominal fat interacts with PNPLA3 I148M, but not with the APOC3 variant in the pathogenesis of liver steatosis in chronic hepatitis C.

PubMed

Zampino, R; Coppola, N; Cirillo, G; Boemio, A; Pisaturo, M; Marrone, A; Macera, M; Sagnelli, E; Perrone, L; Adinolfi, L E; Miraglia del Giudice, E

2013-08-01

The patatin-like phospholipase domain-containing 3 gene (PNPLA3) and the apolipoprotein C3 gene (APOC3) have been studied in relation to liver steatosis and liver disease outcome. The aim of this study was to evaluate the influence of PNPLA3 p.I148M and APOC3 rs2854116 and rs2854117 polymorphisms on the clinical and histological presentation of chronic hepatitis C in an Italian population and their relationship with viral and anthropometric parameters. Patients with hepatitis C (n = 166) entered the study receiving a clinical, histological, virological and biochemical evaluation. APOC3 (rs2854116 and rs2854117) and PNPLA3 (p.I148M) variants were genotyped. PNPLA3 polymorphisms were associated with liver steatosis, which was significantly higher in patients with p.148I/M (P = 0.034) and p.148M/M (P = 0.004) variants than those homozygous for the PNPLA3 wild type. Excluding patients with HCV genotype 3, the association with liver steatosis and PNPLA3 variants was more marked (p.148I/I genotype vs p.148I/M, P = 0.02, and vs p.148M/M, P = 0.005). The APOC3 polymorphism was not associated with any of the evaluated parameters. Among the interacting factors, BMI and waist circumference correlated with liver steatosis (P = 0.008 and 0.004, respectively). Relationship between waist circumference and liver steatosis was analysed for the different PNPLA3 genotypes. Homozygous 148M patients showed a stronger correlation between waist circumference and steatosis than those carrying the other genotypes (P = 0.0047). In our hepatitis C-infected population, the PNPLA3 polymorphism influenced the development of liver steatosis, but not fibrosis progression. APOC3 polymorphisms had no effect on the development of steatosis and no influence on the PNPLA3 polymorphism. The amount of abdominal fat can increase the association of PNPLA3 p.I148M with liver steatosis. © 2013 John Wiley & Sons Ltd.

TM6SF2 Glu167Lys polymorphism is associated with low levels of LDL-cholesterol and increased liver injury in obese children.

PubMed

Grandone, A; Cozzolino, D; Marzuillo, P; Cirillo, G; Di Sessa, A; Ruggiero, L; Di Palma, M R; Perrone, L; Miraglia Del Giudice, E

2016-04-01

The Glu167Lys (E167K) transmembrane 6 superfamily member 2 (TM6SF2) variant has been associated with liver steatosis, high alanine transaminase (ALT) levels and reduced plasma levels of liver-derived triglyceride-rich lipoproteins. The objectives of this study were to investigate in a group of obese children the association among the 167K allele of TM6SF2 gene and ALT, cholesterol and triglycerides levels, and hepatic steatosis, and to evaluate the potential interaction between this variant and the I148M patatin like phospholipase 3 gene (PNPLA3) polymorphism on liver enzymes. We genotyped 1010 obese children for TM6SF2 E167K and PNPLA3 I148M polymorphisms. Anthropometrical and biochemical data were collected. Ultrasound imaging of the liver was performed. The 167K allele showed an association with steatosis (P < 0.0001), higher ALT levels (P < 0.001) and lower total cholesterol (P < 0.00001), low-density lipoprotein cholesterol (P < 0.0001), triglycerides (P = 0.02) and non-high-density lipoprotein cholesterol levels (P < 0.000001). The subjects homozygous for the PNPLA3 148M allele carrying the rare variant of TM6SF2 showed an odds ratio of 12.2 (confidence interval 3.8-39.6, P = 0.000001) to present hypertransaminasaemia compared with the remaining patients. Although the TMS6SF2 E167K variant predisposes the obese children to non-alcoholic fatty liver disease, there is an association between this variant and lower levels of cardiovascular risk factors. Overall, the data suggest differential effects of TMS6SF2 E167K variant on liver and heart health. © 2015 World Obesity.

The genetic validation of heterogeneity in schizophrenia.

PubMed

Tsutsumi, Atsushi; Glatt, Stephen J; Kanazawa, Tetsufumi; Kawashige, Seiya; Uenishi, Hiroyuki; Hokyo, Akira; Kaneko, Takao; Moritani, Makiko; Kikuyama, Hiroki; Koh, Jun; Matsumura, Hitoshi; Yoneda, Hiroshi

2011-10-07

Schizophrenia is a heritable disorder, however clear genetic architecture has not been detected. To overcome this state of uncertainty, the SZGene database has been established by including all published case-control genetic association studies appearing in peer-reviewed journals. In the current study, we aimed to determine if genetic variants strongly suggested by SZGene are associated with risk of schizophrenia in our case-control samples of Japanese ancestry. In addition, by employing the additive model for aggregating the effect of seven variants, we aimed to verify the genetic heterogeneity of schizophrenia diagnosed by an operative diagnostic manual, the DSM-IV. Each positively suggested genetic polymorphism was ranked according to its p-value, then the seven top-ranked variants (p < 0.0005) were selected from DRD2, DRD4, GRIN2B, TPH1, MTHFR, and DTNBP1 (February, 2007). 407 Schizophrenia cases and 384 controls participated in this study. To aggregate the vulnerability of the disorder based on the participants' genetic information, we calculated the "risk-index" by adding the number of genetic risk factors. No statistically significant deviation between cases and controls was observed in the genetic risk-index derived from all seven variants on the top-ranked polymorphisms. In fact, the average risk-index score in the schizophrenia group (6.5+/-1.57) was slightly lower than among controls (6.6+/-1.39). The current work illustrates the difficulty in identifying universal and definitive risk-conferring polymorphisms for schizophrenia. Our employed number of samples was small, so we can not preclude the possibility that some or all of these variants are minor risk factors for schizophrenia in the Japanese population. It is also important to aggregate the updated positive variants in the SZGene database when the replication work is conducted.

Different non-synonymous polymorphisms modulate the interaction of the WRN protein to its protein partners and its enzymatic activities

PubMed Central

Gagné, Jean-Philippe; Lachapelle, Sophie; Garand, Chantal; Tsofack, Serges P.; Coulombe, Yan; Caron, Marie-Christine; Poirier, Guy G.; Masson, Jean-Yves; Lebel, Michel

2016-01-01

Werner syndrome (WS) is characterized by the premature onset of several age-associated pathologies including cancer. The protein defective in WS patients (WRN) is a helicase/exonuclease involved in DNA replication and repair. Here, we present the results of a large-scale proteome analysis that has been undertaken to determine protein partners of different polymorphic WRN proteins found with relatively high prevalence in the human population. We expressed different fluorescently tagged-WRN (eYFP-WRN) variants in human 293 embryonic kidney cells (HEK293) and used a combination of affinity-purification and mass spectrometry to identify different compositions of WRN-associated protein complexes. We found that a WRN variant containing a phenylalanine residue at position 1074 and an arginine at position 1367 (eYFP-WRN(F-R)) possesses more affinity for DNA-PKc, KU86, KU70, and PARP1 than a variant containing a leucine at position 1074 and a cysteine at position 1367 (eYFP-WRN(L-C)). Such results were confirmed in a WRN-deficient background using WS fibroblasts. Interestingly, the exonuclase activity of WRN recovered from immunoprecipitated eYFP-WRN(L-C) variant was lower than the eYFP-WRN(F-R) in WS cells. Finally, HEK293 cells and WS fibroblasts overexpressing the eYFP-WRN(F-R) variant were more resistant to the benzene metabolite hydroquinone than cells expressing the eYFP-WRN(L-C) variant. These results indicate that the protein-protein interaction landscape of WRN is subject to modulation by polymorphic amino acids, a characteristic associated with distinctive cell survival outcome. PMID:27863399

Fc gamma receptor IIIb polymorphism and systemic lupus erythematosus: association with disease susceptibility and identification of a novel FCGR3B*01 variant.

PubMed

Santos, V C; Grecco, M; Pereira, K M C; Terzian, C C N; Andrade, L E C; Silva, N P

2016-10-01

The objective of this study was to evaluate the association between Fc gamma receptor IIIb polymorphism and susceptibility to systemic lupus erythematosus and clinical traits of the disease. Genomic DNA was obtained from 303 consecutive systemic lupus erythematosus patients and 300 healthy blood donors from the southeastern region of Brazil. The polymorphic region of the FCGR3B gene was sequenced and the alleles FCGR3B*01, FCGR3B*02 and FCGR3B*03 were analyzed. The FCGR3B*01 allele was more frequent in systemic lupus erythematosus patients (43.1%) while the FCGR3B*02 allele prevailed among controls (63.7%) (P = 0.001). The FCGR3B*03 allele was found equally in both groups. The FCGR3B*01/*01 (20.7%) and FCGR3B*01/*02 (41.1%) genotypes were more frequent among systemic lupus erythematosus patients (P = 0.028 and P = 0.012, respectively) while the FCGR3B*02/*02 genotype was more frequent in controls (45.5%) (P < 0.001). One variant of the FCGR3B*01 allele previously described in Germany was found in only one control. A new variant of the FCGR3B*01 allele with two substitutions (A227G/G277A) was found in one control. Three variants of the FCGR3B*02 allele previously described in African-Americans, Brazilians, Chinese and Japanese were found in ten 10 patients and two controls. In addition, several single nucleotide polymorphisms at non-polymorphic positions were identified in both patients and controls. Susceptibility to systemic lupus erythematosus was associated with the FCGR3B*01 allele, as well as with the FCGR3B*01/*01 and FCGR3B*01/*02 genotypes. No association was found between FCGR3B genotypes and clinical manifestations, disease severity or the presence of autoantibodies. © The Author(s) 2016.

E2F transcription factor 2 variants as predictive biomarkers for recurrence risk in patients with squamous cell carcinoma of the oropharynx.

PubMed

Li, Yuncheng; Sturgis, Erich M; Zhu, Lijun; Cao, Xiaoli; Wei, Qingyi; Zhang, Hua; Li, Guojun

2017-04-01

Because E2F transcription factor 2 (E2F2) promoter polymorphisms have been implicated in carcinogenesis and prognosis, we investigated associations between genetic variants in five E2F2 promoter polymorphisms and recurrence risk of squamous cell carcinoma of the oropharynx (SCCOP) in 1 008 patients. A log-rank test and multivariable Cox models were used to assess the associations. Compared with patients with variant genotypes of E2F2-rs2742976 and E2F2-rs3218123, patients with common homozygous genotypes had better disease-free survival (both log-rank, P < 0.001) and lower SCCOP recurrence risk (HR, 0.4, 95% CI, 0.3-0.6 and HR, 0.3, 95% CI, 0.2-0.5, respectively) after multivariable adjustment. Furthermore, among patients with HPV16-positive tumors, those with common homozygous genotypes of E2F2-rs2742976 and E2F2-rs3218123 had better disease-free survival rates (both log-rank, P < 0.001) and lower recurrence risk (HR, 0.1, 95% CI, 0.1-0.4 and HR, 0.1, 95% CI, 0.0-0.2, respectively) than patients with variant genotypes. However, no significant differences were found for the other three polymorphisms. After combining the risk genotypes of the five polymorphisms and using the high-risk group (2-5 risk genotypes) as the reference group, we found that the low-risk groups (0 or 1 risk genotype) had significantly lower recurrence risk among all patients (HR, 0.4, 95% CI, 0.3-0.6) and among HPV16-positive patients (HR, 0.2, 95% CI, 0.1-0.5). Our findings suggest that E2F2 polymorphisms may individually or jointly modify SCCOP recurrence risk, particularly for SCCOP patients with HPV16-positive tumors. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Polymorphisms of the thiopurine S-methyltransferase gene among the Libyan population

PubMed Central

Zeglam, Hamza Ben; Benhamer, Abdrazak; Aboud, Adel; Rtemi, Haitem; Mattardi, Meftah; Saleh, Saleh Suleiman; Bashein, Abdullah; Enattah, Nabil

2015-01-01

Background Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme that catalyses the S-methylation of 6-mercaptopurine and azathioprine. Low activity phenotypes are correlated with polymorphism in the TPMT gene. Patients with low or undetectable TMPT activity could develop severe myelosuppression when they are treated with standard doses of thiopurine drugs. Since ethnic differences in the TPMT gene polymorphism have been demonstrated worldwide, assessing it in the Libyan population is worthwhile. Methods We investigated TPMT gene polymorphism in a total of 246 Libyan healthy adult blood donors from three different Libyan regions (Tripoli, Yefren, and Tawargha) and 50 children with acute lymphoblastic leukaemia (ALL). We used polymerase chain reaction restriction length polymorphism (PCR-RFLP) and allele-specific PCR-based assays to analyse the TPMT gene for the variants *2 c.238 G>C, *3A (c.460 G>A and c.719 A>G), *3B (c.460 G>A), and *3C (c.719 A>G). Results Our results show that the TPMT variants associated with low enzymatic activity were detected in 3.25% (8 in 246) of adult Libyan individuals and the frequency of total mutant alleles was 1.63%. Heterozygous genotypes were TPMT*3A in three subjects (0.61%) and TPMT*3C in five subjects (1.02%). No TPMT*2 and TPMT*3B allelic variants and no homozygous or compound heterozygous mutant alleles were detected. The normal allele (wild-type) was found in 98.4% of the adult individuals studied. No mutant alleles were detected among the 50 children who had ALL. Conclusions We report on the presence of the TPMT*3C and *3A mutant alleles in the Libyan population. Therefore, monitoring the patients to be treated with doses of thiopurine drugs for TPMT variants is worthwhile to avoid the development of severe myelosuppression. PMID:25819542

Associations between period 3 gene polymorphisms and sleep- /chronotype-related variables in patients with late-life insomnia.

PubMed

Mansour, Hader A; Wood, Joel; Chowdari, Kodavali V; Tumuluru, Divya; Bamne, Mikhil; Monk, Timothy H; Hall, Martica H; Buysse, Daniel J; Nimgaonkar, Vishwajit L

2017-01-01

A variable number tandem repeat polymorphism (VNTR) in the period 3 (PER3) gene has been associated with heritable sleep and circadian variables, including self-rated chronotypes, polysomnographic (PSG) variables, insomnia and circadian sleep-wake disorders. This report describes novel molecular and clinical analyses of PER3 VNTR polymorphisms to better define their functional consequences. As the PER3 VNTR is located in the exonic (protein coding) region of PER3, we initially investigated whether both alleles (variants) are transcribed into messenger RNA in human fibroblasts. The VNTR showed bi-allelic gene expression. We next investigated genetic associations in relation to clinical variables in 274 older adult Caucasian individuals. Independent variables included genotypes for the PER3 VNTR as well as a representative set of single nucleotide polymorphisms (SNPs) that tag common variants at the PER3 locus (linkage disequilibrium (LD) between genetic variants < 0.5). In order to comprehensively evaluate variables analyzed individually in prior analyses, dependent measures included PSG total sleep time and sleep latency, self-rated chronotype, estimated with the Composite Scale (CS), and lifestyle regularity, estimated using the social rhythm metric (SRM). Initially, genetic polymorphisms were individually analyzed in relation to each outcome variable using analysis of variance (ANOVA). Nominally significant associations were further tested using regression analyses that incorporated individual ANOVA-associated DNA variants as potential predictors and each of the selected sleep/circadian variables as outcomes. The covariates included age, gender, body mass index and an index of medical co-morbidity. Significant genetic associations with the VNTR were not detected with the sleep or circadian variables. Nominally significant associations were detected between SNP rs1012477 and CS scores (p = 0.003) and between rs10462021 and SRM (p = 0.047); rs11579477 and average delta power (p = 0.043) (analyses uncorrected for multiple comparisons). In conclusion, alleles of the VNTR are expressed at the transcript level and may have a functional effect in cells expressing the PER3 gene. PER3 polymorphisms had a modest impact on selected sleep/circadian variables in our sample, suggesting that PER3 is associated with sleep and circadian function beyond VNTR polymorphisms. Further replicate analyses in larger, independent samples are recommended.

Interethnic diversity of the CD209 (rs4804803) gene promoter polymorphism in African but not American sickle cell disease.

PubMed

Noble, Jenelle A; Duru, Kimberley C; Guindo, Aldiouma; Yi, Li; Imumorin, Ikhide G; Diallo, Dapa A; Thomas, Bolaji N

2015-01-01

Elucidating the genomic diversity of CD209 gene promoter polymorphism could assist in clarifying disease pathophysiology as well as contribution to co-morbidities. CD209 gene promoter polymorphism has been shown to be associated with susceptibility to infection. We hypothesize that CD209 mutant variants occur at a higher frequency among Africans and in sickle cell disease. We analyzed the frequency of the CD209 gene (rs4804803) in healthy control and sickle cell disease (SCD) populations and determined association with disease. Genomic DNA was extracted from blood samples collected from 145 SCD and 231 control Africans (from Mali), 331 SCD and 379 control African Americans and 159 Caucasians. Comparative analysis among and between groups was carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Per ethnic diversification, we found significant disparity in genotypic (23.4% versus 16.9% versus 3.2%) and allelic frequencies (48.7% versus 42.1% versus 19.8%) of the homozygote mutant variant of the CD209 (snp 309A/G) gene promoter between Africans, African Americans and Caucasians respectively. Comparative evaluation between disease and control groups reveal a significant difference in genotypic (10.4% versus 23.4%; p = 0.002) and allelic frequencies (39.7% versus 48.7%; p = 0.02) of the homozygote mutant variant in African SCD and healthy controls respectively, an observation that is completely absent among Americans. Comparing disease groups, we found no difference in the genotypic (p = 0.19) or allelic (p = 0.72) frequencies of CD209 homozygote mutant variant between Africans and Americans with sickle cell disease. The higher frequency of CD209 homozygote mutant variants in the African control group reveals a potential impairment of the capacity to mount an immune response to infectious diseases, and possibly delineate susceptibility to or severity of infectious co-morbidities within and between groups.

Interethnic diversity of the CD209 (rs4804803) gene promoter polymorphism in African but not American sickle cell disease

PubMed Central

Noble, Jenelle A.; Duru, Kimberley C.; Guindo, Aldiouma; Yi, Li; Imumorin, Ikhide G.; Diallo, Dapa A.

2015-01-01

Elucidating the genomic diversity of CD209 gene promoter polymorphism could assist in clarifying disease pathophysiology as well as contribution to co-morbidities. CD209 gene promoter polymorphism has been shown to be associated with susceptibility to infection. We hypothesize that CD209 mutant variants occur at a higher frequency among Africans and in sickle cell disease. We analyzed the frequency of the CD209 gene (rs4804803) in healthy control and sickle cell disease (SCD) populations and determined association with disease. Genomic DNA was extracted from blood samples collected from 145 SCD and 231 control Africans (from Mali), 331 SCD and 379 control African Americans and 159 Caucasians. Comparative analysis among and between groups was carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Per ethnic diversification, we found significant disparity in genotypic (23.4% versus 16.9% versus 3.2%) and allelic frequencies (48.7% versus 42.1% versus 19.8%) of the homozygote mutant variant of the CD209 (snp 309A/G) gene promoter between Africans, African Americans and Caucasians respectively. Comparative evaluation between disease and control groups reveal a significant difference in genotypic (10.4% versus 23.4%; p = 0.002) and allelic frequencies (39.7% versus 48.7%; p = 0.02) of the homozygote mutant variant in African SCD and healthy controls respectively, an observation that is completely absent among Americans. Comparing disease groups, we found no difference in the genotypic (p = 0.19) or allelic (p = 0.72) frequencies of CD209 homozygote mutant variant between Africans and Americans with sickle cell disease. The higher frequency of CD209 homozygote mutant variants in the African control group reveals a potential impairment of the capacity to mount an immune response to infectious diseases, and possibly delineate susceptibility to or severity of infectious co-morbidities within and between groups. PMID:25755928

Gene Polymorphisms in the CCL5/CCR5 Pathway as a Genetic Biomarker for Outcome and Hand-Foot Skin Reaction in Metastatic Colorectal Cancer Patients Treated With Regorafenib.

PubMed

Suenaga, Mitsukuni; Schirripa, Marta; Cao, Shu; Zhang, Wu; Yang, Dongyun; Ning, Yan; Cremolini, Chiara; Antoniotti, Carlotta; Borelli, Beatrice; Mashima, Tetsuo; Okazaki, Satoshi; Berger, Martin D; Miyamoto, Yuji; Gopez, Roel; Barzi, Afsaneh; Lonardi, Sara; Yamaguchi, Toshiharu; Falcone, Alfredo; Loupakis, Fotios; Lenz, Heinz-Josef

2018-06-01

The C-C motif chemokine ligand 5/C-C motif chemokine receptor 5 (CCL5/CCR5) pathway has been shown to induce endothelial progenitor cell migration, resulting in increased vascular endothelial growth factor A expression. We hypothesized that genetic polymorphisms in the CCL5/CCR5 pathway predict efficacy and toxicity in patients with metastatic colorectal cancer (mCRC) treated with regorafenib. We analyzed genomic DNA extracted from 229 tumor samples from 2 different cohorts of patients who received regorafenib: an evaluation cohort of 79 Japanese patients and a validation cohort of 150 Italian patients. Single nucleotide polymorphisms of CCL5/CCR5 pathway-related genes were analyzed by PCR-based direct sequencing. CCL4 rs1634517 and CCL3 rs1130371 were associated with progression-free survival in the evaluation cohort (hazard ratio [HR] 1.54, P = .043; HR 1.48, P = .064), and progression-free survival (HR 1.74, P < .001; HR 1.66, P = .002) and overall survival (HR 1.65, P = .004; HR 1.65, P = .004) in the validation cohort. The allelic frequencies of CCL5 single nucleotide polymorphisms varied between the evaluation and validation cohorts (G/G variant in rs2280789, 21.5% vs. 1.3%, P < .001; T/T variant in rs3817655, 22.8% vs. 2.7%, P < .001). In the evaluation cohort, patients with the G/G variant in rs2280789 had a higher incidence of grade 3+ hand-foot skin reaction compared to any A allele (53% vs. 27%, P = .078), and similarly to the T/T variant in rs3817655 compared to any A allele (56% vs. 26%, P = .026). Genetic variants in the CCL5/CCR5 pathway may serve as prognostic markers and may predict severe hand-foot skin reaction in mCRC patients receiving regorafenib therapy. Copyright © 2018 Elsevier Inc. All rights reserved.

A polymorphism at the 3'-UTR region of the aromatase gene defines a subgroup of postmenopausal breast cancer patients with poor response to neoadjuvant letrozole

PubMed Central

2010-01-01

Background Aromatase (CYP19A1) regulates estrogen biosynthesis. Polymorphisms in CYP19A1 have been related to the pathogenesis of breast cancer (BC). Inhibition of aromatase with letrozole constitutes the best option for treating estrogen-dependent BC in postmenopausal women. We evaluate a series of polymorphisms of CYP19A1 and their effect on response to neoadjuvant letrozole in early BC. Methods We analyzed 95 consecutive postmenopausal women with stage II-III ER/PgR [+] BC treated with neoadjuvant letrozole. Response to treatment was measured by radiology at 4th month by World Health Organization (WHO) criteria. Three polymorphisms of CYP19A1, one in exon 7 (rs700519) and two in the 3'-UTR region (rs10046 and rs4646) were evaluated on DNA obtained from peripheral blood. Results Thirty-five women (36.8%) achieved a radiological response to letrozole. The histopathological and immunohistochemical parameters, including hormonal receptor status, were not associated with the response to letrozole. Only the genetic variants (AC/AA) of the rs4646 polymorphism were associated with poor response to letrozole (p = 0.03). Eighteen patients (18.9%) reported a progression of the disease. Those patients carrying the genetic variants (AC/AA) of rs4646 presented a lower progression-free survival than the patients homozygous for the reference variant (p = 0.0686). This effect was especially significant in the group of elderly patients not operated after letrozole induction (p = 0.009). Conclusions Our study reveals that the rs4646 polymorphism identifies a subgroup of stage II-III ER/PgR [+] BC patients with poor response to neoadjuvant letrozole and poor prognosis. Testing for the rs4646 polymorphism could be a useful tool in order to orientate the treatment in elderly BC patients. PMID:20144226

Functional polymorphisms in UDP-glucuronosyltransferases and recurrence in tamoxifen-treated breast cancer survivors

PubMed Central

Ahern, Thomas P.; Christensen, Mariann; Cronin-Fenton, Deirdre P.; Lunetta, Kathryn L.; Søiland, Håvard; Gjerde, Jennifer; Garne, Jens Peter; Rosenberg, Carol L.; Silliman, Rebecca A.; Sørensen, Henrik Toft; Lash, Timothy L.; Hamilton-Dutoit, Stephen

2011-01-01

Background Tamoxifen is oxidized by cytochrome-P450 enzymes (e.g., CYP2D6) to two active metabolites, which are eliminated via glucuronidation by UDP-glucuronosyltransferases (UGTs). We measured the association between functional polymorphisms in key UGTs (UGT2B15*2, UGT2B7*2, and UGT1A8*3) and the recurrence rate among breast cancer survivors. Methods We used the Danish Breast Cancer Cooperative Group registry to identify 541 cases of recurrent breast cancer among women with estrogen receptor-positive tumors treated with tamoxifen for at least one year (ER+/TAM+), and 300 cases of recurrent breast cancer among women with estrogen receptor-negative tumors who were not treated with tamoxifen (ER−/TAM−). We matched 1 control to each case on ER status, menopausal status, stage, calendar period, and county. UGT polymorphisms were genotyped from archived primary tumors. We estimated the recurrence odds ratio for the UGT polymorphisms using logistic regression models, with and without stratification on CYP2D6*4 genotype. Results No UGT polymorphism was associated with breast cancer recurrence in either the ER+/TAM+ or ER-/TAM- groups [in the ER+TAM+ group, compared with two normal alleles: adjusted OR for two UGT2B15*2 variant alleles = 1.0 (95% CI: 0.70, 1.5); adjusted OR for two for UGT2B7*2 variant alleles = 0.91 (95% CI: 0.65, 1.3); adjusted OR for 1 or 2 UGT1A8*3 variant alleles = 0.75 (0.41, 1.4)]. Associations were similar within strata of CYP2D6*4 genotype. Conclusions Functional polymorphisms in key tamoxifen-metabolizing enzymes were not associated with breast cancer recurrence risk. Impact Our results do not support the genotyping of key metabolic enzyme polymorphisms to predict response to tamoxifen therapy. PMID:21750172

Mobile Interspersed Repeats Are Major Structural Variants in the Human Genome

PubMed Central

Huang, Cheng Ran Lisa; Schneider, Anna M.; Lu, Yunqi; Niranjan, Tejasvi; Shen, Peilin; Robinson, Matoya A.; Steranka, Jared P.; Valle, David; Civin, Curt I.; Wang, Tao; Wheelan, Sarah J.; Ji, Hongkai; Boeke, Jef D.; Burns, Kathleen H.

2010-01-01

Summary Characterizing structural variants in the human genome is of great importance, but a genome wide analysis to detect interspersed repeats has not been done. Thus, the degree to which mobile DNAs contribute to genetic diversity, heritable disease, and oncogenesis remains speculative. We perform transposon insertion profiling by microarray (TIP-chip) to map human L1(Ta) retrotransposons (LINE-1 s) genome-wide. This identified numerous novel human L1(Ta) insertional polymorphisms with highly variant allelic frequencies. We also explored TIP-chip's usefulness to identify candidate alleles associated with different phenotypes in clinical cohorts. Our data suggest that the occurrence of new insertions is twice as high as previously estimated, and that these repeats are under-recognized as sources of human genomic and phenotypic diversity. We have just begun to probe the universe of human L1(Ta) polymorphisms, and as TIP-chip is applied to other insertions such as Alu SINEs, it will expand the catalog of genomic variants even further. PMID:20602999

The relationship of PON1 QR 192 and LM 55 polymorphisms with serum paraoxonase activities of Turkish diabetic patients.

PubMed

Altuner, Durdu; Ates, Ilker; Suzen, Sinan H; Koc, Gonul Varan; Aral, Yalcin; Karakaya, Asuman

2011-11-01

Paraoxonase (PON1) is a serum esterase responsible for the protection against xenobiotics toxicity such as paraoxon. Alterations in PON1 concentrations have been reported in a variety of diseases including diabetes mellitus (DM). It has been shown that the serum PON1 concentration and activity are decreased in patients with both type 1 and type 2 DM. This study aimed to investigate the lipid profiles and the relationship between PON1 activity and PON1, QR192 and LM55 polymorphisms in Turkish type 2 diabetic patients and non-diabetic control subjects. According to our results, RR variant had significantly higher PON activity than QQ and QR variants (p < 0.01) and LL variant had significantly higher PON activity than MM variant in both control and patient groups (p < 0.05). In conclusion, we found that PON1 192RR and 55LL genotypes are associated with higher PON activity than QQ and MM genotypes. This may be more protective to lipid peroxidation.

Polymorphism analysis of prion protein gene in 11 Pakistani goat breeds

PubMed Central

Hassan, Mohammad Farooque; Khan, Sher Hayat; Babar, Masroor Ellahi; Yang, Lifeng; Ali, Tariq; Khan, Jamal Muhammad; Shah, Syed Zahid Ali; Zhou, Xiangmei; Hussain, Tanveer; Zhu, Ting; Hussain, Tariq; Zhao, Deming

2016-01-01

ABSTRACT The association between caprine PrP gene polymorphisms and its susceptibility to scrapie has been investigated in current years. As the ORF of the PrP gene is extremely erratic in different breeds of goats, we studied the PrP gene polymorphisms in 80 goats which belong to 11 Pakistani indigenous goat breeds from all provinces of Pakistan. A total of 6 distinct polymorphic sites (one novel) with amino acid substitutions were identified in the PrP gene which includes 126 (A -> G), 304 (G -> T), 379 (A -> G), 414 (C -> T), 428 (A -> G) and 718 (C -> T). The locus c.428 was found highly polymorphic in all breeds as compare to other loci. On the basis of these PrP variants NJ phylogenetic tree was constructed through MEGA6.1 which showed that all goat breeds along with domestic sheep and Mauflon sheep appeared as in one clade and sharing its most recent common ancestors (MRCA) with deer species while Protein analysis has shown that these polymorphisms can lead to varied primary, secondary and tertiary structure of protein. Based on these polymorphic variants, genetic distance, multidimensional scaling plot and principal component analyses revealed the clear picture regarding greater number of substitutions in cattle PrP regions as compared to the small ruminant species. In particular these findings may pinpoint the fundamental control over the scrapie in Capra hircus on genetic basis. PMID:27388702

Genetic polymorphisms of Interleukin-18 are not associated with allograft function in kidney transplant recipients.

PubMed

do Nascimento, Wenna Gleyce Araújo; Cilião, Daiani Alves; Genre, Julieta; Gondim, Dikson Dibe; Alves, Renata Gomes; Hassan, Neife Deghaide; Lima, Francisco Pignataro; Pereira, Maurício Galvão; Donadi, Eduardo Antônio; de Oliveira Crispim, Janaina Cristiana

2014-06-01

Interleukin 18 (IL-18) is a proinflammatory cytokine that plays a role in host defense by upregulating both innate and acquired immune responses. Analysis of IL18 polymorphisms may be clinically important since their roles have been recognized in a variety of inflammatory and autoimmune disorders. However, the role of this cytokine polymorphisms in kidney transplant still remains unclear. In this study, we evaluated the associations between IL18 polymorphisms and graft function assessed by creatinine clearance in kidney transplant recipients. A total of 82 kidney transplant recipients and 183 healthy controls were enrolled, and frequencies of alleles, genotypes and haplotypes for IL18 polymorphisms were determined and compared with creatinine clearance. The -607C/A (rs1946518) and -137C/G (rs187238) variant alleles in the IL18 gene were determined by polymerase chain reaction. In our study, no significant association was found between the IL18 variants and creatinine clearance (p > 0.05). Nonetheless, polymorphism analysis revealed an increase in the frequency of the IL18 major haplotype -607C/-137G in kidney transplant patients (odds ratio 2.57, 95% confidence interval 1.45-4.55, p = 0.0014). Finally, we found that IL18 polymorphisms did not influence the renal function and that IL18 haplotype -607C/-137G seems to be associated with kidney transplant recipients.

Genetic polymorphisms of Interleukin-18 are not associated with allograft function in kidney transplant recipients

PubMed Central

do Nascimento, Wenna Gleyce Araújo; Cilião, Daiani Alves; Genre, Julieta; Gondim, Dikson Dibe; Alves, Renata Gomes; Hassan, Neife Deghaide; Lima, Francisco Pignataro; Pereira, Maurício Galvão; Donadi, Eduardo Antônio; de Oliveira Crispim, Janaina Cristiana

2014-01-01

Interleukin 18 (IL-18) is a proinflammatory cytokine that plays a role in host defense by upregulating both innate and acquired immune responses. Analysis of IL18 polymorphisms may be clinically important since their roles have been recognized in a variety of inflammatory and autoimmune disorders. However, the role of this cytokine polymorphisms in kidney transplant still remains unclear. In this study, we evaluated the associations between IL18 polymorphisms and graft function assessed by creatinine clearance in kidney transplant recipients. A total of 82 kidney transplant recipients and 183 healthy controls were enrolled, and frequencies of alleles, genotypes and haplotypes for IL18 polymorphisms were determined and compared with creatinine clearance. The -607C/A (rs1946518) and -137C/G (rs187238) variant alleles in the IL18 gene were determined by polymerase chain reaction. In our study, no significant association was found between the IL18 variants and creatinine clearance (p > 0.05). Nonetheless, polymorphism analysis revealed an increase in the frequency of the IL18 major haplotype -607C/-137G in kidney transplant patients (odds ratio 2.57, 95% confidence interval 1.45–4.55, p = 0.0014). Finally, we found that IL18 polymorphisms did not influence the renal function and that IL18 haplotype -607C/-137G seems to be associated with kidney transplant recipients. PMID:25071398

[Association between polymorphisms of XPD gene and susceptibility to chronic benzene poisoning].

PubMed

Huang, Hui-long; Xu, Jian-ning; Wang, Quan-kai; Wang, Ya-wen; Yang, Min; Chen, Yan; Li, Gui-lan

2006-07-01

To explore the relationship between genetic polymorphisms of XPD gene and susceptibility to chronic benzene poisoning. A case control study was conducted. Eighty patients diagnosed with chronic benzene poisoning and 62 workers occupationally exposed to benzene who were engaged in the same working time and job title as patients were investigated. PCR-RFLP was used for detecting the single nucleotide polymorphisms (SNPs) on codon156, codon312 and codon751 of XPD gene. There was a 2.903 times (95% CI: 1.054 - 7.959, P = 0.039 2) increased risk of chronic benzene poisoning in the subjects carrying XPD 751Gln variant allele compared with those carrying XPD 751Lys/Lys genotype, after adjusted for sex, length of service, smoking and drinking status. The subjects with XPD 751Gln variant allele are more susceptive to benzene.

The Role of the Asn40Asp Polymorphism of the Mu Opioid Receptor Gene (OPRM1) on Alcoholism Etiology and Treatment: A Critical Review

PubMed Central

Ray, Lara A.; Barr, Christina S.; Blendy, Julie A.; Oslin, David; Goldman, David; Anton, Raymond F.

2011-01-01

The endogenous opioid system has been implicated in the pathophysiology of alcoholism as it modulates the neurobehavioral effects of alcohol. A variant in the mu opioid receptor gene (OPRM1), the Asn40Asp polymorphism, has received attention as a functional variant that may influence a host of behavioral phenotypes for alcoholism as well as clinical response to opioid antagonists. This paper will review converging lines of evidence on the effect of the Asn40Asp SNP on alcoholism phenotypes, including: (i) genetic association studies; (ii) behavioral studies of alcoholism; (iii) neuroimaging studies; (iv) pharmacogenetic studies and clinical trials; and (v) preclinical animal studies. Together, these lines of research seek to elucidate the effects of this functional polymorphism on alcoholism etiology and treatment response. PMID:21895723

A Distinct and Parallel Pathway for the Nuclear Import of an mRNA-binding Protein

PubMed Central

Pemberton, Lucy F.; Rosenblum, Jonathan S.; Blobel, Günter

1997-01-01

Three independent pathways of nuclear import have so far been identified in yeast, each mediated by cognate nuclear transport factors, or karyopherins. Here we have characterized a new pathway to the nucleus, mediated by Mtr10p, a protein first identified in a screen for strains defective in polyadenylated RNA export. Mtr10p is shown to be responsible for the nuclear import of the shuttling mRNA-binding protein Npl3p. A complex of Mtr10p and Npl3p was detected in cytosol, and deletion of Mtr10p was shown to lead to the mislocalization of nuclear Npl3p to the cytoplasm, correlating with a block in import. Mtr10p bound peptide repeat-containing nucleoporins and Ran, suggesting that this import pathway involves a docking step at the nuclear pore complex and is Ran dependent. This pathway of Npl3p import is distinct and does not appear to overlap with another known import pathway for an mRNA-binding protein. Thus, at least two parallel pathways function in the import of mRNA-binding proteins, suggesting the need for the coordination of these pathways. PMID:9412460

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

Sarta, Jose A.; Castiblanco, Luis A

With cooperation of the International Atomic Energy Agency (IAEA) and the Department of Energy (DOE) of the United States, several calculations and tasks related to the waste disposal of spent MTR fuel enriched nominally to 93% were carried out for the conversion of the IAN-R1 Research Reactor from MTR-HEU fuel to TRIGA-LEU fuel. In order to remove the spent MTR-HEU fuel of the core and store it safely a program was established at the Instituto de Ciencias Nucleares y Energias Alternativas (INEA). This program included training, acquisition of hardware and software, design and construction of a decay pool, transfer ofmore » the spent HEU fuel elements into the decay pool and his final transport to Savannah River in United States. In this paper are presented data of activities calculated for each relevant radionuclide present in spent MTR-HEU fuel elements of the IAN-R1 Research Reactor and the total activity. The total activity calculated takes in consideration contributions of fission, activation and actinides products. The data obtained were the base for shielding calculations for the decay pool concerning the storage of spent MTR-HEU fuel elements and the respective dosimetric evaluations in the transferring operations of fuel elements into the decay pool.« less

Kinetic Monte Carlo Simulations and Molecular Conductance Measurements of the Bacterial Decaheme Cytochrome MtrF

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

Byun, H. S.; Pirbadian, S.; Nakano, Aiichiro

2014-09-05

Microorganisms overcome the considerable hurdle of respiring extracellular solid substrates by deploying large multiheme cytochrome complexes that form 20 nanometer conduits to traffic electrons through the periplasm and across the cellular outer membrane. Here we report the first kinetic Monte Carlo simulations and single-molecule scanning tunneling microscopy (STM) measurements of the Shewanella oneidensis MR-1 outer membrane decaheme cytochrome MtrF, which can perform the final electron transfer step from cells to minerals and microbial fuel cell anodes. We find that the calculated electron transport rate through MtrF is consistent with previously reported in vitro measurements of the Shewanella Mtr complex, asmore » well as in vivo respiration rates on electrode surfaces assuming a reasonable (experimentally verified) coverage of cytochromes on the cell surface. The simulations also reveal a rich phase diagram in the overall electron occupation density of the hemes as a function of electron injection and ejection rates. Single molecule tunneling spectroscopy confirms MtrF's ability to mediate electron transport between an STM tip and an underlying Au(111) surface, but at rates higher than expected from previously calculated heme-heme electron transfer rates for solvated molecules.« less

Performance of the MTR core with MOX fuel using the MCNP4C2 code.

PubMed

Shaaban, Ismail; Albarhoum, Mohamad

2016-08-01

The MCNP4C2 code was used to simulate the MTR-22 MW research reactor and perform the neutronic analysis for a new fuel namely: a MOX (U3O8&PuO2) fuel dispersed in an Al matrix for One Neutronic Trap (ONT) and Three Neutronic Traps (TNTs) in its core. Its new characteristics were compared to its original characteristics based on the U3O8-Al fuel. Experimental data for the neutronic parameters including criticality relative to the MTR-22 MW reactor for the original U3O8-Al fuel at nominal power were used to validate the calculated values and were found acceptable. The achieved results seem to confirm that the use of MOX fuel in the MTR-22 MW will not degrade the safe operational conditions of the reactor. In addition, the use of MOX fuel in the MTR-22 MW core leads to reduce the uranium fuel enrichment with (235)U and the amount of loaded (235)U in the core by about 34.84% and 15.21% for the ONT and TNTs cases, respectively. Copyright © 2016 Elsevier Ltd. All rights reserved.

Complementary Effects of Genetic Variations in LEPR on Body Composition and Soluble Leptin Receptor Concentration after 3-Month Lifestyle Intervention in Prepubertal Obese Children

PubMed Central

Gajewska, Joanna; Kuryłowicz, Alina; Mierzejewska, Ewa; Ambroszkiewicz, Jadwiga; Chełchowska, Magdalena; Weker, Halina; Puzianowska-Kuźnicka, Monika

2016-01-01

In obese individuals, weight loss might be affected by variants of the adipokine-encoding genes. We verified whether selected functional single nucleotide polymorphisms in LEP, LEPR and ADIPOQ are associated with changes in serum levels of the respective adipokines and weight loss in 100 prepubertal obese (SDS-BMI > 2) Caucasian children undergoing lifestyle intervention. Frequencies of the -2548G > A LEP, Q223R LEPR, K656N LEPR, -11377C > G and -11426A > G ADIPOQ polymorphisms were analyzed by restriction fragment length polymorphism. Serum adipokine and soluble leptin receptor (sOB-R) concentrations were measured using the ELISA method. Among the analyzed polymorphisms, only LEPR polymorphisms were associated with changes of SDS-BMI or sOB-R concentrations in children after therapy. Carriers of the wild-type K665N and at least one minor Q223R allele had the greatest likelihood of losing weight (OR = 5.09, p = 0.006), an increase in sOB-R (ptrend = 0.022) and decrease in SDS-BMI correlated with the decrease of fat mass (p < 0.001). In contrast, carrying of the wild-type Q223R and at least one minor K665N allele were associated with a decrease in sOB-R concentrations and a decrease in SDS-BMI correlated with a decrease in fat-free mass (p = 0.002). We suggest that the combination of different LEPR variants, not a single variant, might determine predisposition to weight loss in the prepubertal period. PMID:27240401

Endothelial nitric oxide synthase polymorphism and prognosis in systolic heart failure patients.

PubMed

Azzam, Naiel; Zafrir, Barak; Fares, Fuad; Smith, Yoav; Salman, Nabeeh; Nevzorov, Roman; Amir, Offer

2015-05-01

The endothelial nitric oxide synthase (eNOS) gene single nucleotide polymorphism G894T is associated with thrombotic vascular diseases. However, its functional significance is controversial and data are scarce concerning its influence in heart failure (HF). We studied 215 patients with chronic systolic HF. DNA was analyzed for eNOS gene G894T polymorphism using PCR and DNA sequencing. Evaluation of clinical characteristics and analysis of factors associated with 2-year mortality were performed for the homozygous G-allele G894T variant (GG), relative to the TT and GT variants. The genotype distributions of eNOS G894T alleles were: GG 135 patients (63%) and TT/GT 80 (37%). Two-year mortality was significantly higher in the GG variant (48%) than the combined TT/GT group (32%). The usage of nitrates was associated with increased 2-year mortality (HR 2.0, 95% CI 1.28-3.17; p = 0.003), which was most significant in the GG group treated with nitrates (73.5%) in comparison to the TT/GT group not treated with nitrates (34%); HR 2.75, 95% CI 1.57-4.79, P < 0.001. Homozygosity for the G allele of the eNOS G894T polymorphism was associated with worse survival in systolic HF patients, especially in those treated with nitrates. ENOS polymorphism may result in different mechanistic interactions in HF than in thrombotic vascular diseases, suggesting that overexpression of NO may be associated with deleterious effects in systolic HF. Copyright © 2015 Elsevier Inc. All rights reserved.

Frequencies of the Arg16Gly, Gln27Glu and Thr164Ile Adrenoceptor β2 Polymorphisms among Omanis

PubMed Central

Al-Balushi, Khalid; Zadjali, Fahad; Al-Sinani, Sawsan; Al-Zadjali, Al-Muatasim; Bayoumi, Riad

2015-01-01

Objectives: This study aimed to assess the distribution of missense mutations in the adrenoceptor β2 (ADRB2) gene in an Omani cohort. Methods: This study was carried out between May 2014 and March 2015 at the Sultan Qaboos University, Muscat, Oman. Blood samples were taken from 316 unrelated Omani subjects. Genotyping for rs1042713 (c.46A>G, p.Arg16Gly), rs1042714 (c.79C>G, p.Gln27Glu) and rs1800888 (c.491C>T, p.Thr164Ile) polymorphisms was performed by real-time polymerase chain reaction using single nucleotide polymorphism (SNP) genotyping assays. The allelic frequencies of these polymorphisms were estimated on the basis of the observed numbers of specific alleles from the genotype data for male and female subjects. The genotype frequencies for each polymorphism were tested for deviation from the Hardy-Weinberg equilibrium. Results: Gly16 and Glu27 were the most frequent variants found among the cohort (63% and 75%, respectively). The Ile164 variant was not detected in the study population. There was a significant linkage disequilibrium between the rs1042713 and rs1042714 SNPs (r2 = 0.209; P ≤0.001). The most observed haplotypes were Gly16-Gln27 and Arg16-Gln27 (0.37 and 0.38, respectively). The frequency of Gly16-Glu27 was 0.25, comprising all Glu27 carriers. Conclusion: The allelic distribution of variants in this Omani cohort was similar to distributions reported among Caucasian populations. PMID:26629374

eNOS gene Glu298Asp and 4b/a polymorphisms are associated with renal function parameters in Mexican patients with Fabry disease.

PubMed

Marin-Medina, A; Brambila-Tapia, A J L; Picos-Cárdenas, V J; Gallegos-Arreola, M P; Figuera, L E

2016-10-24

Fabry disease (FD) is an inherited X-linked lysosomal disease that causes renal failure in a high percentage of affected individuals. The eNOS gene encodes for endothelial nitric oxide synthase, which plays an important role in glomerular hemodynamics. This gene has two main polymorphisms (Glu298Asp and 4b/a) that have been studied in the context of many different diseases, including those involving cardiovascular and renal alterations. Considering the lack of information regarding eNOS variants and FD, we investigated whether there were associations between eNOS genetic variants and renal function parameters in Mexican patients with FD and renal impairment. In total, 15 FD patients with renal alterations were included in the present study, and associations between eNOS polymorphisms and renal function parameters (urea, creatinine, and GFR) were evaluated. The Asp298 and 4a alleles of the eNOS gene were found to be significantly associated with increased levels of urea and creatinine, and a decreased glomerular filtration rate in FD patients, and this association behaved in a co-dominant fashion. Our results coincide with previous reports showing an association between these polymorphisms and kidney disease, and along with other studies regarding their role in the nitric oxide pathway, suggest that these variants affect the severity of nephropathy in patients with FD.

Leptin promoter variant G2548A is associated with serum leptin and HDL-C levels in a case control observational study in association with obesity in a Pakistani cohort.

PubMed

Shabana, -; Hasnain, Shahida

2016-06-01

Leptin is a protein hormone synthesized by adipocytes and is involved in the regulation of food intake and energy expenditure. We hypothesized that any change in the promoter sequence can affect the expression of the gene and hence leptin protein levels in the serum. The aim of the current study was to investigate the relationship of such a promoter variant of the leptin gene, G-2548A polymorphism, with obesity and its effect on various anthropometric and metabolic parameters in a Pakistani cohort consisting of 250 obese and 225 non-obese control subjects. Body weight, height, waist circumference (WC), hip circumference (HC) and blood pressure (BP) were measured by standard methods and levels of fasting blood glucose (FBG), total cholesterol, triglycerides, HDLC, LDLC, and leptin were determined. Genotyping was done by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The results showed that the LEP G-2548A polymorphism showed significant association with obesity in Pakistan. In addition, the polymorphism showed association with weight, height, BMI, WC, HDLC and serum leptin levels. The findings suggest that the leptin promoter G-2548A variant may play its part in the progression to obesity by not only affecting the body's fat distribution but also by changing the serum leptin and HDLC levels.

Genetic variants in IL-6/JAK/STAT3 pathway and the risk of CRC.

PubMed

Wang, Shuwei; Zhang, Weidong

2016-05-01

Interleukin (IL)-6 and the downstream Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway have previously been reported to be important in the development of colorectal cancer (CRC), and several studies have shown the relationship between the polymorphisms of related genes in this pathway with the risk of CRC. However, the findings of these related studies are inconsistent. Moreover, there has no systematic review and meta-analysis to evaluate the relationship between genetic variants in IL-6/JAK/STAT3 pathway and CRC susceptibility. Hence, we conducted a meta-analysis to explore the relationship between polymorphisms in IL-6/JAK/STAT3 pathway genes and CRC risk. Eighteen eligible studies with a total of 13,795 CRC cases and 18,043 controls were identified by searching PubMed, Web of Science, Embase, and the Cochrane Library databases for the period up to September 15, 2015. Odds ratios (ORs) and their 95 % confidence intervals (CIs) were used to calculate the strength of the association. Our results indicated that IL-6 genetic variants in allele additive model (OR = 1.05, 95 % CI = 1.00, 1.09) and JAK2 genetic variants (OR = 1.40, 95 % CI = 1.15, 1.65) in genotype recessive model were significantly associated with CRC risk. Moreover, the pooled data revealed that IL-6 rs1800795 polymorphism significantly increased the risk of CRC in allele additive model in Europe (OR = 1.07, 95 % CI = 1.01, 1.14). In conclusion, the present findings indicate that IL-6 and JAK2 genetic variants are associated with the increased risk of CRC while STAT3 genetic variants not. We need more well-designed clinical studies covering more countries and population to definitively establish the association between genetic variants in IL-6/JAK/STAT3 pathway and CRC susceptibility.

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

PubMed

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

2015-11-01

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

Pre-B-cell colony-enhancing factor gene polymorphisms and risk of acute respiratory distress syndrome.

PubMed

Bajwa, Ednan K; Yu, Chu-Ling; Gong, Michelle N; Thompson, B Taylor; Christiani, David C

2007-05-01

Pre-B-cell colony-enhancing factor (PBEF) levels are elevated in bronchoalveolar lavage fluid and serum of patients with acute lung injury. There are several suspected functional polymorphisms of the corresponding PBEF gene. We hypothesized that variations in PBEF gene polymorphisms alter the risk of developing acute respiratory distress syndrome (ARDS). Nested case-control study. Tertiary academic medical center. We studied 375 patients with ARDS and 787 at-risk controls genotyped for the PBEF T-1001G and C-1543T polymorphisms. None. Patients with the -1001G (variant) allele had significantly greater odds of developing ARDS than wild-type homozygotes (odds ratio, 1.35; 95% confidence interval, 1.02-1.78). Patients with the -1543T (variant) allele did not have significantly different odds of developing ARDS than wild-type homozygotes (odds ratio, 0.86; 95% confidence interval, 0.65-1.13). When analysis was stratified by ARDS risk factor, -1543T was associated with decreased odds of developing ARDS in septic shock patients (odds ratio, 0.66; 95% confidence interval, 0.45-0.97). Also, -1001G was associated with increased hazard of intensive care unit mortality, whereas -1543T was associated with decreased hazard of 28-day and 60-day ARDS mortality, as well as shorter duration of mechanical ventilation. Similar results were found in analyses of the related GC (-1001G:-1543C) and TT (-1001T:-1543T) haplotypes. The PBEFT-1001G variant allele and related haplotype are associated with increased odds of developing ARDS and increased hazard of intensive care unit mortality among at-risk patients, whereas the C-1543T variant allele and related haplotype are associated with decreased odds of ARDS among patients with septic shock and better outcomes among patients with ARDS.

Common α2A and α2C adrenergic receptor polymorphisms do not affect plasma membrane trafficking.

PubMed

Hurt, Carl M; Sorensen, Matt W; Angelotti, Timothy

2014-06-01

Various naturally occurring polymorphic forms of human G protein-coupled receptors (GPCRs) have been identified and linked to diverse pathological diseases, including receptors for vasopressin type 2 (nephrogenic diabetes insipidus) and gonadotropin releasing hormone (hypogonadotropic hypogonadism). In most cases, polymorphic amino acid mutations disrupt protein folding, altering receptor function as well as plasma membrane expression. Other pathological GPCR variants have been found that do not alter receptor function, but instead affect only plasma membrane trafficking (e.g., delta opiate and histamine type 1 receptors). Thus, altered membrane trafficking with retained receptor function may be another mechanism causing polymorphic GPCR dysfunction. Two common human α2A and α2C adrenergic receptor (AR) variants have been identified (α2A N251K and α2C Δ322-325 ARs), but pharmacological analysis of ligand binding and second messenger signaling has not consistently demonstrated altered receptor function. However, possible alterations in plasma membrane trafficking have not been investigated. We utilized a systematic approach previously developed for the study of GPCR trafficking motifs and accessory proteins to assess whether these α2 AR variants affected intracellular trafficking or plasma membrane expression. By combining immunofluorescent microscopy, glycosidic processing analysis, and quantitative fluorescent-activated cell sorting (FACS), we demonstrate that neither variant receptor had altered intracellular localization, glycosylation, nor plasma membrane expression compared to wild-type α2 ARs. Therefore, pathopharmacological properties of α2A N251K and α2C Δ322-325 ARs do not appear to be due to altered receptor pharmacology or plasma membrane trafficking, but may involve interactions with other intracellular signaling cascades or proteins.

Association studies on ghrelin and ghrelin receptor gene polymorphisms with obesity.

PubMed

Gueorguiev, Maria; Lecoeur, Cécile; Meyre, David; Benzinou, Michael; Mein, Charles A; Hinney, Anke; Vatin, Vincent; Weill, Jacques; Heude, Barbara; Hebebrand, Johannes; Grossman, Ashley B; Korbonits, Márta; Froguel, Philippe

2009-04-01

Ghrelin exerts a stimulatory effect on appetite and regulates energy homeostasis. Ghrelin gene variants have been shown to be associated with metabolic traits, although there is evidence suggesting linkage and association with obesity and the ghrelin receptor (GHSR). We hypothesized that these genes are good candidates for susceptibility to obesity. Direct sequencing identified 12 ghrelin single-nucleotide polymorphisms (SNPs) and 8 GHSR SNPs. The 10 common SNPs were genotyped in 1,275 obese subjects and in 1,059 subjects from a general population cohort of European origin. In the obesity case-control study, the GHSR SNP rs572169 was found to be associated with obesity (P = 0.007 in additive model, P = 0.001 in dominant model, odds ratio (OR) 1.73, 95% confidence interval (1.23-2.44)). The ghrelin variant, g.A265T (rs4684677), showed an association with obesity (P = 0.009, BMI adjusted for age and sex) in obese families. The ghrelin variant, g.A-604G (rs27647), showed an association with insulin levels at 2-h post-oral glucose tolerance test (OGTT) (P = 0.009) in obese families. We found an association between the eating behavior "overeating" and the GHSR SNP rs2232169 (P = 0.02) in obese subjects. However, none of these associations remained significant when corrected for multiple comparisons. Replication of the nominal associations with obesity could not be confirmed in a German genome-wide association (GWA) study for rs4684677 and rs572169 polymorphisms. Our data suggest that common polymorphisms in ghrelin and its receptor genes are not major contributors to the development of polygenic obesity, although common variants may alter body weight and eating behavior and contribute to insulin resistance, in particular in the context of early-onset obesity.

Screening of SHOX gene sequence variants in Saudi Arabian children with idiopathic short stature.

PubMed

Alharthi, Abdulla A; El-Hallous, Ehab I; Talaat, Iman M; Alghamdi, Hamed A; Almalki, Matar I; Gaber, Ahmed

2017-10-01

Short stature affects approximately 2%-3% of children, representing one of the most frequent disorders for which clinical attention is sought during childhood. Despite assumed genetic heterogeneity, mutations or deletions in the short stature homeobox-containing gene ( SHOX ) are frequently detected in subjects with short stature. Idiopathic short stature (ISS) refers to patients with short stature for various unknown reasons. The goal of this study was to screen all the exons of SHOX to identify related mutations. We screened all the exons of SHOX for mutations analysis in 105 ISS children patients (57 girls and 48 boys) living in Taif governorate, KSA using a direct DNA sequencing method. Height, arm span, and sitting height were recorded, and subischial leg length was calculated. A total of 30 of 105 ISS patients (28%) contained six polymorphic variants in exons 1, 2, 4, and 6. One mutation was found in the DNA domain binding region of exon 4. Three of these polymorphic variants were novel, while the others were reported previously. There were no significant differences in anthropometric measures in ISS patients with and without identifiable polymorphic variants in SHOX . In Saudi Arabia ISS patients, rather than SHOX , it is possible that new genes are involved in longitudinal growth. Additional molecular analysis is required to diagnose and understand the etiology of this disease.

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

PubMed Central

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

2013-01-01

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

Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1.

PubMed

Cheng, Timothy H T; Thompson, Deborah; Painter, Jodie; O'Mara, Tracy; Gorman, Maggie; Martin, Lynn; Palles, Claire; Jones, Angela; Buchanan, Daniel D; Win, Aung Ko; Hopper, John; Jenkins, Mark; Lindor, Noralane M; Newcomb, Polly A; Gallinger, Steve; Conti, David; Schumacher, Fred; Casey, Graham; Giles, Graham G; Pharoah, Paul; Peto, Julian; Cox, Angela; Swerdlow, Anthony; Couch, Fergus; Cunningham, Julie M; Goode, Ellen L; Winham, Stacey J; Lambrechts, Diether; Fasching, Peter; Burwinkel, Barbara; Brenner, Hermann; Brauch, Hiltrud; Chang-Claude, Jenny; Salvesen, Helga B; Kristensen, Vessela; Darabi, Hatef; Li, Jingmei; Liu, Tao; Lindblom, Annika; Hall, Per; de Polanco, Magdalena Echeverry; Sans, Monica; Carracedo, Angel; Castellvi-Bel, Sergi; Rojas-Martinez, Augusto; Aguiar Jnr, Samuel; Teixeira, Manuel R; Dunning, Alison M; Dennis, Joe; Otton, Geoffrey; Proietto, Tony; Holliday, Elizabeth; Attia, John; Ashton, Katie; Scott, Rodney J; McEvoy, Mark; Dowdy, Sean C; Fridley, Brooke L; Werner, Henrica M J; Trovik, Jone; Njolstad, Tormund S; Tham, Emma; Mints, Miriam; Runnebaum, Ingo; Hillemanns, Peter; Dörk, Thilo; Amant, Frederic; Schrauwen, Stefanie; Hein, Alexander; Beckmann, Matthias W; Ekici, Arif; Czene, Kamila; Meindl, Alfons; Bolla, Manjeet K; Michailidou, Kyriaki; Tyrer, Jonathan P; Wang, Qin; Ahmed, Shahana; Healey, Catherine S; Shah, Mitul; Annibali, Daniela; Depreeuw, Jeroen; Al-Tassan, Nada A; Harris, Rebecca; Meyer, Brian F; Whiffin, Nicola; Hosking, Fay J; Kinnersley, Ben; Farrington, Susan M; Timofeeva, Maria; Tenesa, Albert; Campbell, Harry; Haile, Robert W; Hodgson, Shirley; Carvajal-Carmona, Luis; Cheadle, Jeremy P; Easton, Douglas; Dunlop, Malcolm; Houlston, Richard; Spurdle, Amanda; Tomlinson, Ian

2015-12-01

High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10(-9)) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10(-8)), with the alleles showing opposite effects on the risks of the two cancers.

Serotonin transporter promoter polymorphism and monoamine oxidase type A VNTR allelic variants together influence alcohol binge drinking risk in young women.

PubMed

Herman, Aryeh I; Kaiss, Kristi M; Ma, Rui; Philbeck, John W; Hasan, Asfar; Dasti, Humza; DePetrillo, Paolo B

2005-02-05

The short allelic variant of the serotonin transporter protein promoter polymorphism (5HTTLPR) appears to influence binge drinking in college students. Both monoamine oxidase type A (MAOA) and the serotonin transporter protein are involved in the processing of serotonin, and allelic variants are both associated with differences in the efficiency of expression. We hypothesized that a significant gene x gene interaction would further stratify the risk of binge drinking in this population. Participants were college students (n = 412) who completed the College Alcohol Study, used to measure binge drinking behaviors. Genomic DNA was extracted from saliva for PCR based genotyping. The risk function for binge drinking was modeled using logistic regression, with final model fit P < 0.0005. This model was valid only for Caucasian females (n = 223), but the power to detect sex and ethnic effects was small. Young Caucasian women carrying higher expression MAOA VNTR alleles homozygous for the short allelic variant of the 5HTTLPR demonstrated the highest rate of binge drinking by self-report, odds ratio (genotype odds: population odds) and 95% confidence intervals, 3.11 (1.14-18.10). Individuals carrying higher expression MAOA VNTR alleles carrying at least one long 5HTTLPR allelic variant had the lowest risk of binge drinking 0.46 (0.28-0.71). These results support the hypothesis that binge drinking behavior in young adulthood may be influenced by neurobiological differences in serotonergic function conferred by functional polymorphisms in genes involved in serotonin processing. (c) 2004 Wiley-Liss, Inc.

Genomic Prediction for Quantitative Traits Is Improved by Mapping Variants to Gene Ontology Categories in Drosophila melanogaster

PubMed Central

Edwards, Stefan M.; Sørensen, Izel F.; Sarup, Pernille; Mackay, Trudy F. C.; Sørensen, Peter

2016-01-01

Predicting individual quantitative trait phenotypes from high-resolution genomic polymorphism data is important for personalized medicine in humans, plant and animal breeding, and adaptive evolution. However, this is difficult for populations of unrelated individuals when the number of causal variants is low relative to the total number of polymorphisms and causal variants individually have small effects on the traits. We hypothesized that mapping molecular polymorphisms to genomic features such as genes and their gene ontology categories could increase the accuracy of genomic prediction models. We developed a genomic feature best linear unbiased prediction (GFBLUP) model that implements this strategy and applied it to three quantitative traits (startle response, starvation resistance, and chill coma recovery) in the unrelated, sequenced inbred lines of the Drosophila melanogaster Genetic Reference Panel. Our results indicate that subsetting markers based on genomic features increases the predictive ability relative to the standard genomic best linear unbiased prediction (GBLUP) model. Both models use all markers, but GFBLUP allows differential weighting of the individual genetic marker relationships, whereas GBLUP weighs the genetic marker relationships equally. Simulation studies show that it is possible to further increase the accuracy of genomic prediction for complex traits using this model, provided the genomic features are enriched for causal variants. Our GFBLUP model using prior information on genomic features enriched for causal variants can increase the accuracy of genomic predictions in populations of unrelated individuals and provides a formal statistical framework for leveraging and evaluating information across multiple experimental studies to provide novel insights into the genetic architecture of complex traits. PMID:27235308

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

PubMed

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

2018-06-04

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

The influence of PRNP polymorphisms on human prion disease susceptibility: an update.

PubMed

Kobayashi, Atsushi; Teruya, Kenta; Matsuura, Yuichi; Shirai, Tsuyoshi; Nakamura, Yoshikazu; Yamada, Masahito; Mizusawa, Hidehiro; Mohri, Shirou; Kitamoto, Tetsuyuki

2015-08-01

Two normally occurring polymorphisms of the human PRNP gene, methionine (M)/valine (V) at codon 129 and glutamic acid (E)/lysine (K) at codon 219, can affect the susceptibility to prion diseases. It has long been recognized that 129M/M homozygotes are overrepresented in sporadic Creutzfeldt-Jakob disease (CJD) patients and variant CJD patients, whereas 219E/K heterozygotes are absent in sporadic CJD patients. In addition to these pioneering findings, recent progress in experimental transmission studies and worldwide surveillance of prion diseases have identified novel relationships between the PRNP polymorphisms and the prion disease susceptibility. For example, although 219E/K heterozygosity confers resistance against the development of sporadic CJD, this genotype is not entirely protective against acquired forms (iatrogenic CJD and variant CJD) or genetic forms (genetic CJD and Gerstmann-Sträussler-Scheinker syndrome) of prion diseases. In addition, 129M/V heterozygotes predispose to genetic CJD caused by a pathogenic PRNP mutation at codon 180. These findings show that the effects of the PRNP polymorphisms may be more complicated than previously thought. This review aims to summarize recent advances in our knowledge about the influence of the PRNP polymorphisms on the prion disease susceptibility.

Alcohol and aggressive behavior in men--moderating effects of oxytocin receptor gene (OXTR) polymorphisms.

PubMed

Johansson, A; Bergman, H; Corander, J; Waldman, I D; Karrani, N; Salo, B; Jern, P; Algars, M; Sandnabba, K; Santtila, P; Westberg, L

2012-03-01

We explored if the disposition to react with aggression while alcohol intoxicated was moderated by polymorphic variants of the oxytocin receptor gene (OXTR). Twelve OXTR polymorphisms were genotyped in 116 Finnish men [aged 18-30, M = 22.7, standard deviation (SD) = 2.4] who were randomly assigned to an alcohol condition in which they received an alcohol dose of 0.7 g pure ethanol/kg body weight or a placebo condition. Aggressive behavior was measured using a laboratory paradigm in which it was operationalized as the level of aversive noise administered to a fictive opponent. No main effects of the polymorphisms on aggressive behavior were found after controlling for multiple testing. The interactive effects between alcohol and two of the OXTR polymorphisms (rs4564970 and rs1488467) on aggressive behavior were nominally significant and remained significant for the rs4564970 when controlled for multiple tests. To the best of our knowledge, this is the first experimental study suggesting interactive effects of specific genetic variants and alcohol on aggressive behavior in humans. © 2011 The Authors. Genes, Brain and Behavior © 2011 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

L-Area STS MTR/NRU/NRX Grapple Assembly Closure Mechanics Review

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

Huizenga, D. J.

2016-06-08

A review of the closure mechanics associated with the Shielded Transfer System (STS) MTR/NRU/NRX grapple assembly utilized at the Savannah River Site (SRS) was performed. This review was prompted by an operational event which occurred at the Canadian Nuclear Laboratories (CNL) utilizing a DTS-XL grapple assembly which is essentially identical to the STS MTR/NRU/NRX grapple assembly used at the SRS. The CNL operational event occurred when a NRU/NRX fuel basket containing spent nuclear fuel assemblies was inadvertently released by the DTS-XL grapple assembly during a transfer. The SM review of the STS MTR/NRU/NRX grapple assembly will examine the operational aspectsmore » of the STS and the engineered features of the STS which prevent such an event at the SRS. The design requirements for the STS NRU/NRX modifications and the overall layout of the STS are provided in other documents.« less

Changes in blood flow and cellular metabolism at a myofascial trigger point with trigger point release (ischemic compression): a proof-of-principle pilot study

PubMed Central

Moraska, Albert F.; Hickner, Robert C.; Kohrt, Wendy M.; Brewer, Alan

2012-01-01

Objective To demonstrate proof-of-principle measurement for physiological change within an active myofascial trigger point (MTrP) undergoing trigger point release (ischemic compression). Design Interstitial fluid was sampled continuously at a trigger point before and after intervention. Setting A biomedical research clinic at a university hospital. Participants Two subjects from a pain clinic presenting with chronic headache pain. Interventions A single microdialysis catheter was inserted into an active MTrP of the upper trapezius to allow for continuous sampling of interstitial fluid before and after application of trigger point therapy by a massage therapist. Main Outcome Measures Procedural success, pain tolerance, feasibility of intervention during sample collection, determination of physiologically relevant values for local blood flow, as well as glucose and lactate concentrations. Results Both patients tolerated the microdialysis probe insertion into the MTrP and treatment intervention without complication. Glucose and lactate concentrations were measured in the physiological range. Following intervention, a sustained increase in lactate was noted for both subjects. Conclusions Identifying physiological constituents of MTrP’s following intervention is an important step toward understanding pathophysiology and resolution of myofascial pain. The present study forwards that aim by showing proof-of-concept for collection of interstitial fluid from an MTrP before and after intervention can be accomplished using microdialysis, thus providing methodological insight toward treatment mechanism and pain resolution. Of the biomarkers measured in this study, lactate may be the most relevant for detection and treatment of abnormalities in the MTrP. PMID:22975226

Migraineurs without aura show microstructural abnormalities in the cerebellum and frontal lobe.

PubMed

Granziera, C; Romascano, D; Daducci, A; Roche, A; Vincent, M; Krueger, G; Hadjikhani, N

2013-12-01

The involvement of the cerebellum in migraine pathophysiology is not well understood. We used a biparametric approach at high-field MRI (3 T) to assess the structural integrity of the cerebellum in 15 migraineurs with aura (MWA), 23 migraineurs without aura (MWoA), and 20 healthy controls (HC). High-resolution T1 relaxation maps were acquired together with magnetization transfer images in order to probe microstructural and myelin integrity. Clusterwise analysis was performed on T1 and magnetization transfer ratio (MTR) maps of the cerebellum of MWA, MWoA, and HC using an ANOVA and a non-parametric clusterwise permutation F test, with age and gender as covariates and correction for familywise error rate. In addition, mean MTR and T1 in frontal regions known to be highly connected to the cerebellum were computed. Clusterwise comparison among groups showed a cluster of lower MTR in the right Crus I of MWoA patients vs. HC and MWA subjects (p = 0.04). Univariate and bivariate analysis on T1 and MTR contrasts showed that MWoA patients had longer T1 and lower MTR in the right and left pars orbitalis compared to MWA (p < 0.01 and 0.05, respectively), but no differences were found with HC. Lower MTR and longer T1 point at a loss of macromolecules and/or micro-edema in Crus I and pars orbitalis in MWoA patients vs. HC and vs. MWA. The pathophysiological implications of these findings are discussed in light of recent literature.

Characteristics of lesional and extra-lesional cortical grey matter in relapsing-remitting and secondary progressive multiple sclerosis: A magnetisation transfer and diffusion tensor imaging study.

PubMed

Yaldizli, Özgür; Pardini, Matteo; Sethi, Varun; Muhlert, Nils; Liu, Zheng; Tozer, Daniel J; Samson, Rebecca S; Wheeler-Kingshott, Claudia Am; Yousry, Tarek A; Miller, David H; Chard, Declan T

2016-02-01

In multiple sclerosis (MS), diffusion tensor and magnetisation transfer imaging are both abnormal in lesional and extra-lesional cortical grey matter, but differences between clinical subtypes and associations with clinical outcomes have only been partly assessed. To compare mean diffusivity, fractional anisotropy and magnetisation transfer ratio (MTR) in cortical grey matter lesions (detected using phase-sensitive inversion recovery (PSIR) imaging) and extra-lesional cortical grey matter, and assess associations with disability in relapse-onset MS. Seventy-two people with MS (46 relapsing-remitting (RR), 26 secondary progressive (SP)) and 36 healthy controls were included in this study. MTR, mean diffusivity and fractional anisotropy were measured in lesional and extra-lesional cortical grey matter. Mean fractional anisotropy was higher and MTR lower in lesional compared with extra-lesional cortical grey matter. In extra-lesional cortical grey matter mean fractional anisotropy and MTR were lower, and mean diffusivity was higher in the MS group compared with controls. Mean MTR was lower and mean diffusivity was higher in lesional and extra-lesional cortical grey matter in SPMS when compared with RRMS. These differences were independent of disease duration. In multivariate analyses, MTR in extra-lesional more so than lesional cortical grey matter was associated with disability. Magnetic resonance abnormalities in lesional and extra-lesional cortical grey matter are greater in SPMS than RRMS. Changes in extra-lesional compared with lesional cortical grey matter are more consistently associated with disability. © The Author(s), 2015.

White and gray matter damage in primary progressive MS

PubMed Central

Chard, Declan; Altmann, Daniel R.; Tozer, Daniel; Miller, David H.; Thompson, Alan J.; Wheeler-Kingshott, Claudia; Ciccarelli, Olga

2016-01-01

Objective: The temporal relationship between white matter (WM) and gray matter (GM) damage in vivo in early primary progressive multiple sclerosis (PPMS) was investigated testing 2 hypotheses: (1) WM tract abnormalities predict subsequent changes in the connected cortex (“primary WM damage model”); and (2) cortical abnormalities predict later changes in connected WM tracts (“primary GM damage model”). Methods: Forty-seven patients with early PPMS and 18 healthy controls had conventional and magnetization transfer imaging at baseline; a subgroup of 35 patients repeated the protocol after 2 years. Masks of the corticospinal tracts, genu of the corpus callosum and optic radiations, and of connected cortical regions, were used for extracting the mean magnetization transfer ratio (MTR). Multiple regressions within each of 5 tract-cortex pairs were performed, adjusting for the dependent variable's baseline MTR; tract lesion load and MTR, spinal cord area, age, and sex were examined for potential confounding. Results: The baseline MTR of most regions was lower in patients than in healthy controls. The tract-cortex pair relationships in the primary WM damage model were significant for the bilateral motor pair and right visual pair, while those in the primary GM damage model were only significant for the right motor pair. Lower lesion MTR at baseline was associated with lower MTR in the same tract normal-appearing WM at 2 years in 3 tracts. Conclusion: These results are consistent with the hypothesis that in early PPMS, cortical damage is for the most part a sequela of normal-appearing WM pathology, which, in turn, is predicted by abnormalities within WM lesions. PMID:26674332

White and gray matter damage in primary progressive MS: The chicken or the egg?

PubMed

Bodini, Benedetta; Chard, Declan; Altmann, Daniel R; Tozer, Daniel; Miller, David H; Thompson, Alan J; Wheeler-Kingshott, Claudia; Ciccarelli, Olga

2016-01-12

The temporal relationship between white matter (WM) and gray matter (GM) damage in vivo in early primary progressive multiple sclerosis (PPMS) was investigated testing 2 hypotheses: (1) WM tract abnormalities predict subsequent changes in the connected cortex ("primary WM damage model"); and (2) cortical abnormalities predict later changes in connected WM tracts ("primary GM damage model"). Forty-seven patients with early PPMS and 18 healthy controls had conventional and magnetization transfer imaging at baseline; a subgroup of 35 patients repeated the protocol after 2 years. Masks of the corticospinal tracts, genu of the corpus callosum and optic radiations, and of connected cortical regions, were used for extracting the mean magnetization transfer ratio (MTR). Multiple regressions within each of 5 tract-cortex pairs were performed, adjusting for the dependent variable's baseline MTR; tract lesion load and MTR, spinal cord area, age, and sex were examined for potential confounding. The baseline MTR of most regions was lower in patients than in healthy controls. The tract-cortex pair relationships in the primary WM damage model were significant for the bilateral motor pair and right visual pair, while those in the primary GM damage model were only significant for the right motor pair. Lower lesion MTR at baseline was associated with lower MTR in the same tract normal-appearing WM at 2 years in 3 tracts. These results are consistent with the hypothesis that in early PPMS, cortical damage is for the most part a sequela of normal-appearing WM pathology, which, in turn, is predicted by abnormalities within WM lesions. © 2015 American Academy of Neurology.

TNFA gene variants related to the inflammatory status and its association with cellular aging: From the CORDIOPREV study

USDA-ARS?s Scientific Manuscript database

Background: Several single nucleotide polymorphisms have been proposed as potential predictors of the development of age-related diseases. Objective: To explore whether Tumor Necrosis Factor Alpha (TNFA) gene variants were associated with inflammatory status, thus facilitating the rate of telomere s...

The folate hydrolase 1561 C>T polymorphism is associated with depressive symptoms in Puerto Rican adults

USDA-ARS?s Scientific Manuscript database

Low plasma folate has been associated with depression. Variants of genes involved in the uptake, retention and metabolism of folate have been linked with plasma folate and homocysteine concentrations. It remains unclear whether such variants are also associated with depressive symptoms, directly or ...

Common variants of the EPDR1 gene and the risk of Dupuytren’s disease.

PubMed

Dębniak, T; Żyluk, A; Puchalski, P; Serrano-Fernandez, P

2013-10-01

The object of this study was the investigation of 3 common variants of single nucleotide polymorphisms of the ependymin-related gene 1 and its association with the occurrence of Dupuytren's disease. DNA samples were obtained from the peripheral blood of 508 consecutive patients. The control group comprised 515 healthy adults who were age-matched with the Dupuytren's patients. 3 common variants were analysed using TaqMan® genotyping assays and sequencing. The differences in the frequencies of variants of single nucleotide polymorphisms in patients and the control group were statistically tested. Additionally, haplotype frequency and linkage disequilibrium were analysed for these variants. A statistically significant association was noted between rs16879765_CT, rs16879765_TT and rs13240429_AA variants and Dupuytren's disease. 2 haplotypes: rs2722280_C+rs13240429_A+rs16879765_C and rs2722280_C+rs13240429_G+rs16879765_T were found to be statistically significantly associated with Dupuytren's disease. Moreover, we found that rs13240429 and rs16879765 variants were in strong linkage disequilibrium, while rs2722280 was only in moderate linkage disequilibrium. No significant differences were found in the frequencies of the variants of the gene between the groups with a positive and negative familial history of Dupuytren's disease. In conclusion, results of this study suggest that EPDR1 gene can be added to a growing list of genes associated with Dupuytren's disease development. © Georg Thieme Verlag KG Stuttgart · New York.

In vitro digestion of purified β-casein variants A(1), A(2), B, and I: effects on antioxidant and angiotensin-converting enzyme inhibitory capacity.

PubMed

Petrat-Melin, B; Andersen, P; Rasmussen, J T; Poulsen, N A; Larsen, L B; Young, J F

2015-01-01

Genetic polymorphisms of bovine milk proteins affect the protein profile of the milk and, hence, certain technological properties, such as casein (CN) number and cheese yield. However, reports show that such polymorphisms may also affect the health-related properties of milk. Therefore, to gain insight into their digestion pattern and bioactive potential, β-CN was purified from bovine milk originating from cows homozygous for the variants A(1), A(2), B, and I by a combination of cold storage, ultracentrifugation, and acid precipitation. The purity of the isolated β-CN was determined by HPLC, variants were verified by mass spectrometry, and molar extinction coefficients at λ=280nm were determined. β-Casein from each of the variants was subjected to in vitro digestion using pepsin and pancreatic enzymes. Antioxidant and angiotensin-converting enzyme (ACE) inhibitory capacities of the hydrolysates were assessed at 3 stages of digestion and related to that of the undigested samples. Neither molar extinction coefficients nor overall digestibility varied significantly between these 4 variants; however, clear differences in digestion pattern were indicated by gel electrophoresis. In particular, after 60min of pepsin followed by 5min of pancreatic enzyme digestion, one ≈4kDa peptide with the N-terminal sequence (106)H-K-E-M-P-F-P-K- was absent from β-CN variant B. This is likely a result of the (122)Ser to (122)Arg substitution in variant B introducing a novel trypsin cleavage site, leading to the changed digestion pattern. All investigated β-CN variants exhibited a significant increase in antioxidant capacity upon digestion, as measured by the Trolox-equivalent antioxidant capacity assay. After 60min of pepsin + 120min of pancreatic enzyme digestion, the accumulated increase in antioxidant capacity was ≈1.7-fold for the 4 β-CN variants. The ACE inhibitory capacity was also significantly increased by digestion, with the B variant reaching the highest inhibitory capacity at the end of digestion (60min of pepsin + 120min of pancreatic enzymes), possibly because of the observed alternative digestion pattern. These results demonstrate that genetic polymorphisms affect the digestion pattern and bioactivity of milk proteins. Moreover, their capacity for radical scavenging and ACE inhibition is affected by digestion. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

MTR BASEMENT. GENERAL ELECTRIC CONTROL CONSOLE FOR AIRCRAFT NUCLEAR PROPULSION ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

MTR BASEMENT. GENERAL ELECTRIC CONTROL CONSOLE FOR AIRCRAFT NUCLEAR PROPULSION EXPERIMENT NO. 1. INL NEGATIVE NO. 6510. Unknown Photographer, 9/29/1959 - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

PRECAST CONCRETE WALL PANELS ARE LIFTED INTO PLACE ON MTR ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

PRECAST CONCRETE WALL PANELS ARE LIFTED INTO PLACE ON MTR STEEL FRAME STRUCTURE. INL NEGATIVE NO. 1330. Unknown Photographer, 1/1951 - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

Treatment of myofascial trigger points in patients with chronic shoulder pain: a randomized, controlled trial

PubMed Central

2011-01-01

Background Shoulder pain is a common musculoskeletal problem that is often chronic or recurrent. Myofascial trigger points (MTrPs) cause shoulder pain and are prevalent in patients with shoulder pain. However, few studies have focused on MTrP therapy. The aim of this study was to assess the effectiveness of multimodal treatment of MTrPs in patients with chronic shoulder pain. Methods A single-assessor, blinded, randomized, controlled trial was conducted. The intervention group received comprehensive treatment once weekly consisting of manual compression of the MTrPs, manual stretching of the muscles and intermittent cold application with stretching. Patients were instructed to perform muscle-stretching and relaxation exercises at home and received ergonomic recommendations and advice to assume and maintain good posture. The control group remained on the waiting list for 3 months. The Disabilities of Arm, Shoulder and Hand (DASH) questionnaire score (primary outcome), Visual Analogue Scale for Pain (VAS-P), Global Perceived Effect (GPE) scale and the number of muscles with MTrPs were assessed at 6 and 12 weeks in the intervention group and compared with those of a control group. Results Compared with the control group, the intervention group showed significant improvement (P < 0.05) on the DASH after 12 weeks (mean difference, 7.7; 95% confidence interval (95% CI), 1.2 to 14.2), on the VAS-P1 for current pain (mean difference, 13.8; 95% CI, 2.6 to 25.0), on the VAS-P2 for pain in the past 7 days (mean difference, 10.2; 95% CI, 0.7 to 19.7) and VAS-P3 most severe pain in the past 7 days (mean difference, 13.8; 95% CI, 0.8 to 28.4). After 12 weeks, 55% of the patients in the intervention group reported improvement (from slightly improved to completely recovered) versus 14% in the control group. The mean number of muscles with active MTrPs decreased in the intervention group compared with the control group (mean difference, 2.7; 95% CI, 1.2 to 4.2). Conclusions The results of this study show that 12-week comprehensive treatment of MTrPs in shoulder muscles reduces the number of muscles with active MTrPs and is effective in reducing symptoms and improving shoulder function in patients with chronic shoulder pain. Trial registration number ISRCTN: ISRCTN75722066 PMID:21261971

Serum protein polymorphisms in a Liberian population.

PubMed

Willcox, M; Beckman, G; Beckman, L

1986-01-01

Serum protein variations were studied in a Liberian population living in Buchanan town. Of the alpha 1-antitrypsin genes only M1 and M3 were polymorphic. The frequencies of the haptoglobin and Gc genes were in accordance with earlier known estimates in African populations. There was, however, a relatively low frequency of Hp 0 which may be related to the low malarial parasite prevalence in this group. The transferrin C2 gene was found in a significantly lower frequency among Liberians compared to European and Asiatic populations. A new transferrin variant was observed by isoelectric focusing. This variant could not be identified with conventional starch or polyacrylamide electrophoresis.

Review and meta-analysis of genetic polymorphisms associated with exceptional human longevity.

PubMed

Revelas, Mary; Thalamuthu, Anbupalam; Oldmeadow, Christopher; Evans, Tiffany-Jane; Armstrong, Nicola J; Kwok, John B; Brodaty, Henry; Schofield, Peter R; Scott, Rodney J; Sachdev, Perminder S; Attia, John R; Mather, Karen A

2018-06-08

Many factors contribute to exceptional longevity, with genetics playing a significant role. However, to date, genetic studies examining exceptional longevity have been inconclusive. This comprehensive review seeks to determine the genetic variants associated with exceptional longevity by undertaking meta-analyses. Meta-analyses of genetic polymorphisms previously associated with exceptional longevity (85+) were undertaken. For each variant, meta-analyses were performed if there were data from at least three independent studies available, including two unpublished additional cohorts. Five polymorphisms, ACE rs4340, APOE ε2/3/4, FOXO3A rs2802292, KLOTHO KL-VS and IL6 rs1800795 were significantly associated with exceptional longevity, with the pooled effect sizes (odds ratios) ranging from 0.42 (APOE ε4) to 1.45 (FOXO3A males). In general, the observed modest effect sizes of the significant variants suggest many genes of small influence play a role in exceptional longevity, which is consistent with results for other polygenic traits. Our results also suggest that genes related to cardiovascular health may be implicated in exceptional longevity. Future studies should examine the roles of gender and ethnicity and carefully consider study design, including the selection of appropriate controls. Copyright © 2018. Published by Elsevier B.V.

Isolation of a complementary DNA clone for the human complement protein C2 and its use in the identification of a restriction fragment length polymorphism.

PubMed Central

Woods, D E; Edge, M D; Colten, H R

1984-01-01

Complementary DNA (cDNA) clones corresponding to the major histocompatibility (MHC) class III antigen, complement protein C2, have been isolated from human liver cDNA libraries with the use of a complex mixture of synthetic oligonucleotides (17 mer) that contains 576 different oligonucleotide sequences. The C2 cDNA were used to identify a DNA restriction enzyme fragment length polymorphism that provides a genetic marker within the MHC that was not detectable at the protein level. An extensive search for genomic polymorphisms using a cDNA clone for another MHC class III gene, factor B, failed to reveal any DNA variants. The genomic variants detected with the C2 cDNA probe provide an additional genetic marker for analysis of MHC-linked diseases. Images PMID:6086718

Androgen Receptor Gene Polymorphisms and Alterations in Prostate Cancer: Of Humanized Mice and Men

PubMed Central

Robins, Diane M.

2011-01-01

Germline polymorphisms and somatic mutations of the androgen receptor (AR) have been intensely investigated in prostate cancer but even with genomic approaches their impact remains controversial. To assess the functional significance of AR genetic variation, we converted the mouse gene to the human sequence by germline recombination and engineered alleles to query the role of a polymorphic glutamine (Q) tract implicated in cancer risk. In a prostate cancer model, AR Q tract length influences progression and castration response. Mutation profiling in mice provides direct evidence that somatic AR variants are selected by therapy, a finding validated in human metastases from distinct treatment groups. Mutant ARs exploit multiple mechanisms to resist hormone ablation, including alterations in ligand specificity, target gene selectivity, chaperone interaction and nuclear localization. Regardless of their frequency, these variants permute normal function to reveal novel means to target wild type AR and its key interacting partners. PMID:21689727

No Association between Oxytocin Receptor (OXTR) Gene Polymorphisms and Experimentally Elicited Social Preferences

PubMed Central

Apicella, Coren L.; Cesarini, David; Johannesson, Magnus; Dawes, Christopher T.; Lichtenstein, Paul; Wallace, Björn; Beauchamp, Jonathan; Westberg, Lars

2010-01-01

Background Oxytocin (OXT) has been implicated in a suite of complex social behaviors including observed choices in economic laboratory experiments. However, actual studies of associations between oxytocin receptor (OXTR) gene variants and experimentally elicited social preferences are rare. Methodology/Principal Findings We test hypotheses of associations between social preferences, as measured by behavior in two economic games, and 9 single nucleotide polymorphisms (SNPs) of the OXTR gene in a sample of Swedish twins (n = 684). Two standard economic games, the dictator game and the trust game, both involving real monetary consequences, were used to elicit such preferences. After correction for multiple hypothesis testing, we found no significant associations between any of the 9 single nucleotide polymorphisms (SNPs) and behavior in either of the games. Conclusion We were unable to replicate the most significant association reported in previous research between the amount donated in a dictator game and an OXTR genetic variant. PMID:20585395

DNA variants in DHFR gene and response to treatment in children with childhood B ALL: revisited in AIEOP-BFM protocol.

PubMed

Ceppi, Francesco; Gagné, Vincent; Douyon, Laurance; Quintin, Camille J; Colombini, Antonella; Parasole, Rosanna; Buldini, Barbara; Basso, Giuseppe; Conter, Valentino; Cazzaniga, Giovanni; Krajinovic, Maja

2018-01-01

We have previously reported an association of dihydrofolate reductase promoter polymorphisms with reduced event-free survival in childhood acute lymphoblastic leukemia (ALL) patients treated with Dana Farber Cancer Institute protocol. Here, we assessed whether these associations are applicable to other protocol, based on different methotrexate doses. Genotypes for six tag polymorphisms and resulting haplotypes were analyzed for an association with ALL outcome. The association was found with the polymorphisms A-680C, A-317G and C-35T in high-risk group patients. Carriers of haplotype *1 had a remarkably higher risk of events compared with noncarriers and a lower probability of event-free survival (21.4 vs 81.3%). The role of DHFR variants in predicting the outcome of childhood ALL extends beyond single-treatment protocol and can be useful biomarker in personalizing treatment.

No association between oxytocin receptor (OXTR) gene polymorphisms and experimentally elicited social preferences.

PubMed

Apicella, Coren L; Cesarini, David; Johannesson, Magnus; Dawes, Christopher T; Lichtenstein, Paul; Wallace, Björn; Beauchamp, Jonathan; Westberg, Lars

2010-06-16

Oxytocin (OXT) has been implicated in a suite of complex social behaviors including observed choices in economic laboratory experiments. However, actual studies of associations between oxytocin receptor (OXTR) gene variants and experimentally elicited social preferences are rare. We test hypotheses of associations between social preferences, as measured by behavior in two economic games, and 9 single nucleotide polymorphisms (SNPs) of the OXTR gene in a sample of Swedish twins (n = 684). Two standard economic games, the dictator game and the trust game, both involving real monetary consequences, were used to elicit such preferences. After correction for multiple hypothesis testing, we found no significant associations between any of the 9 single nucleotide polymorphisms (SNPs) and behavior in either of the games. We were unable to replicate the most significant association reported in previous research between the amount donated in a dictator game and an OXTR genetic variant.

Polymorphic human somatostatin gene is located on chromosome 3.

PubMed Central

Naylor, S L; Sakaguchi, A Y; Shen, L P; Bell, G I; Rutter, W J; Shows, T B

1983-01-01

Somatostatin is a 14-amino-acid neuropeptide and hormone that inhibits the secretion of several peptide hormones. The human gene for somatostatin SST has been cloned, and the sequence has been determined. This clone was used as a probe in chromosome mapping studies to detect the human somatostatin sequence in human-rodent hybrids. Southern blot analysis of 41 hybrids, including some containing translocations of human chromosomes, placed SST in the q21 leads to qter region of chromosome 3. Human DNAs from unrelated individuals were screened for restriction fragment polymorphisms detectable by the somatostatin gene probe. Two polymorphisms were found: (i) an EcoRI variant located at the 3' end of the gene, found in Caucasian, U.S. Black, and Asian populations with a frequency of approximately 0.10 and (ii) a BamHI variant in the intron, which occurs in Caucasians at a frequency of 0.13. Images PMID:6133281

MTR FAST NEUTRON FLUX MEASUREMENTS FOR CYCLE 146

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

Weber, L D; Hogg, C H

1962-03-20

The fast neutron fluxes in selected positions of the MTR were measured for Cycle 146. The measurements were made at the beginning, throughout, and at the end of the cycle (564 Mwd). Vertical traverses for each position monitors are shown. (auth)

MTR,TRA603. EXPERIMENTERS' SPACE ALLOCATIONS IN BASEMENT AS OF 1963. SHIELDED ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

MTR,TRA-603. EXPERIMENTERS' SPACE ALLOCATIONS IN BASEMENT AS OF 1963. SHIELDED CUBICLES WERE IDENTIFIED BY SPONSORING LABORATORY AND ITS TEST HOLE NUMBER IN THE REACTOR, IE, "KAPL HB-1" SIGNIFIED KNOLLS ATOMIC POWER LABORATORY, HORIZONTAL BEAM NO. 1. "WAPD" WAS WESTINGHOUSE ATOMIC POWER DIVISION. CATCH TANKS AND SAMPLE STATIONS FOR TEST LOOPS WERE ASSOCIATED WITH THESE CUBICLES. NOTE DESKS, STORAGE CABINETS, SWITCH GEAR, INSTRUMENT PANELS. PHILLIPS PETROLEUM COMPANY MTR-E-5205, 4/1963. INL INDEX NO. 531-0603-00-706-009757, REV. 5. - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

Mutation of a Rice Gene Encoding a Phenylalanine Biosynthetic Enzyme Results in Accumulation of Phenylalanine and Tryptophan[W

PubMed Central

Yamada, Tetsuya; Matsuda, Fumio; Kasai, Koji; Fukuoka, Shuichi; Kitamura, Keisuke; Tozawa, Yuzuru; Miyagawa, Hisashi; Wakasa, Kyo

2008-01-01

Two distinct biosynthetic pathways for Phe in plants have been proposed: conversion of prephenate to Phe via phenylpyruvate or arogenate. The reactions catalyzed by prephenate dehydratase (PDT) and arogenate dehydratase (ADT) contribute to these respective pathways. The Mtr1 mutant of rice (Oryza sativa) manifests accumulation of Phe, Trp, and several phenylpropanoids, suggesting a link between the synthesis of Phe and Trp. Here, we show that the Mtr1 mutant gene (mtr1-D) encodes a form of rice PDT with a point mutation in the putative allosteric regulatory region of the protein. Transformed callus lines expressing mtr1-D exhibited all the characteristics of Mtr1 callus tissue. Biochemical analysis revealed that rice PDT possesses both PDT and ADT activities, with a preference for arogenate as substrate, suggesting that it functions primarily as an ADT. The wild-type enzyme is feedback regulated by Phe, whereas the mutant enzyme showed a reduced feedback sensitivity, resulting in Phe accumulation. In addition, these observations indicate that rice PDT is critical for regulating the size of the Phe pool in plant cells. Feeding external Phe to wild-type callus tissue and seedlings resulted in Trp accumulation, demonstrating a connection between Phe accumulation and Trp pool size. PMID:18487352

Distribution of the most common polymorphisms in TYMS gene in Slavic population of central Europe.

PubMed

Pastorakova, A; Chandogova, D; Chandoga, J; Luha, J; Bohmer, D; Malova, J; Braxatorisova, T; Juhosova, M; Reznakova, S; Petrovic, R

2017-01-01

Thymidylate synthetase (TS) plays a critical role in the de novo synthesis of dTMP inside the cell. Therefore, TS is a suitable target for cytotoxic drugs such as fluoropyrimidines. Drug efficacy and toxicity depend on the intracellular level of TS, which is significantly influenced by the polymorphisms in the 5'UTR (TSER - rs45445694, TSER*3G>C - rs2853542) and 3'UTR (1494del TTAAAG - rs151264360) of TYMS gene. Polymorphic variants of TYMS gene affect TS activity via gene expression and transcript stability. Patients who undergo fluoropyrimidine therapy may benefit from genetic testing prior to the administration of chemotherapy. At the 5' terminus of TYMS, there is a polymorphic region represented by a variable number of 28bp long tandem repeats (2-9 tandems) with the G or C nucleotide variant (SNP G>C). The 3'end of TYMS gene may decrease the stability of mRNA in the case of 6 base deletion (1494del6, D). In our study, we have focused on testing of TYMS gene polymorphisms, determination of TYMS variant frequencies in Western Slavic population and comparison of Slovak population with other populations.We performed identification of 5'UTR (rs45445694 - TSER*2 or TSER*3; rs2853542 - TSER*3G>C; TSER*3+ins6) and 3'UTR (rs151264360/1494del6/D) polymorphic regions of TYMS gene among 96 volunteers by PCR-RFLP and fragment analysis. Slovak frequencies of selected polymorphisms were established as follows: the frequency of TSER*2, TSER*3, TSER*3G>C, 1494del6/D and I to be 41%, 59%, 34%, 37.5% and 62.5% respectively. The high resolution of the capillary electrophoresis technique allowed among TSER*3 group identification of a subgroup of four individuals with rare 6bp insertion in 3R allele, id est 2.1% TSER*3+ins6 allele frequency. In our study, we have revealed individuals with rare G>C substitution in the first 28bp tandem repeat of TSER*2 promoter enhancer region (rs183205964) as well, the overall frequency of this polymorphic allele in Slovak population was 2.1%. Our results proved that Slovak population is in Hardy-Weinberg equilibrium and proportion of TYMS polymorphisms is in accordance with other published data.

A resource of single-nucleotide polymorphisms for rainbow trout generated by restriction-site associated DNA sequencing of doubled haploids

USDA-ARS?s Scientific Manuscript database

Salmonid genomes are considered to be in a pseudo-tetraploid state as a result of an evolutionarily recent genome duplication event. This situation complicates single nucleotide polymorphism (SNP) discovery in rainbow trout as many putative SNPs are actually paralogous sequence variants (PSVs) and ...

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

PubMed

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

2017-09-01

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

Polymorphisms of Mannose-binding Lectin and Toll-like Receptors 2, 3, 4, 7 and 8 and the Risk of Respiratory Infections and Acute Otitis Media in Children.

PubMed

Toivonen, Laura; Vuononvirta, Juho; Mertsola, Jussi; Waris, Matti; He, Qiushui; Peltola, Ville

2017-05-01

Mannose-binding lectin (MBL) and toll-like receptors (TLRs) are important components of the innate immune system. We assessed the susceptibility of children with genetic variants in these factors to respiratory infections, rhinovirus infections and acute otitis media. In a prospective cohort study, blood samples from 381 Finnish children were analyzed for polymorphisms in MBL2 at codons 52, 54 and 57, TLR2 Arg753Gln, TLR3 Leu412Phe, TLR4 Asp299Gly, TLR7 Gln11Leu and TLR8 Leu651Leu. Children were followed up for respiratory infections until 24 months of age with daily diaries. Polymerase chain reaction and antigen tests were used for detection of respiratory viruses from nasal swabs. Children with MBL variant genotype had a mean of 59 days with symptoms of respiratory infection per year, compared with 49 days in those with wild-type (P = 0.01). TLR8 polymorphisms were associated with an increased risk and TLR7 polymorphisms with a decreased risk of recurrent rhinovirus infections (P = 0.02 for both). TLR2 polymorphisms were associated with recurrent acute otitis media (P = 0.02). MBL polymorphisms were associated with an increased and TLR7 polymorphisms with a decreased risk of rhinovirus-associated acute otitis media (P = 0.03 and P = 0.006, respectively). Genetic polymorphisms in MBL and TLRs promote susceptibility to or protection against respiratory infections. In addition to environmental factors, genetic variations may explain why some children are more prone to respiratory infections.

Association of catalase gene polymorphisms with catalase activity and susceptibility to systemic lupus erythematosus in the Suez Canal area, Egypt.

PubMed

Ghaly, M S; Ghattas, M H; Labib, S M

2012-10-01

The present study evaluated the relationship of genetic variants in both promoter (-262 C/T) and in exonic (389 C/T) regions of the catalase (CAT) gene to CAT activity and risk of systemic lupus erythematosus (SLE) in Suez Canal-area patients. CAT gene polymorphisms were assessed by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). CAT activity was measured by using a spectrophotometer. We compared the frequencies of CAT 389 C/T and -262 C/T polymorphic variants between SLE patients (n = 103) and healthy controls (n = 103). CAT 389 C/T is associated with SLE susceptibility, with the T allele being significantly more frequent among SLE patients than healthy controls. There was no association, however, between CAT activity and genotypes of 389 C/T. We did not observe significant differences in the prevalence of CAT -262 C/T polymorphic variants in SLE patients and controls, however, we found that patients with the CAT -262 CT and TT genotypes had low CAT activity, and these genotypes showed a significant association with thrombocytopaenia, leukopaenia and the presence of anti-snRNP in SLE patients. In conclusion, the present study supports the notion of in vivo oxidative stress in SLE as indicated by the decrease in CAT activity. The allelic variations in the CAT gene -262 are more likely to affect the expression or the function of the enzyme. Since CAT may be pathogenetically linked to SLE, and owing to its free-radical origin, it appears reasonable to target lipid peroxidation by dietary and/or pharmacological antioxidants.

Polymorphisms of iodothyronine deiodinases (DIO1, DIO3) genes are not associated with recurrent depressive disorder.

PubMed

Gałecka, Elżbieta; Talarowska, Monika; Maes, Michael; Su, Kuan-Pin; Górski, Paweł; Szemraj, Janusz

2016-10-01

Depressive disorder is characterized by disturbances in the hypothalamic-pituitary-thyroid (HPT) axis and in the metabolism of thyroid hormones (TH). The evidence for changes in TH levels is observed in human sera and cerebrospinal fluid as well as in animal model studies. Iodothyronine deiodinases (DIOs) type 1, 2 and 3 (DIO1, DIO2, DIO3) are important enzymes for the synthesis and determination of TH concentration. This study aims to examine the link between recurrent depressive disorders (rDD) and two functionally known polymorphisms DIO1a-C/T (rs11206244) and DIO1b-A/G (rs12095080) within the DIO1 gene encoding DIO1 and two polymorphisms DIO3-C/T (rs17716499), DIO3-A/C (rs7150269) within the DIO3 gene encoding DIO3. Both variants were genotyped in 254 rDD patients and 197 healthy subjects using polymerase chain reaction. Basic methods and statistical analyses were used to estimate genetic variants in the risk of the disease. No significant associations were found between the polymorphisms examined here and rDD. There were no significant associations between genotypes distribution and demographic/medical variables. Odds ratios (ORdis) and corresponding 95% confidence interval (95% CI) were calculated, for example: for CC genotype of DIO1a C/T (ORdis=0.86, 95% CI: 0.59, 1.25). Functional variants within the DIO1 gene, which affect TH levels and polymorphisms in DIO3, are not confirmed to be associated with rDD. Nevertheless, considering previous data which indicate that the DIO1 gene is related to the depression, further studies on a larger sample size are recommended. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Methylenetetrahydrofolate reductase polymorphisms and therapy response in pediatric acute lymphoblastic leukemia.

PubMed

Aplenc, Richard; Thompson, Jennifer; Han, Peggy; La, Mei; Zhao, Huaqing; Lange, Beverly; Rebbeck, Timothy

2005-03-15

A significant portion of patients treated for pediatric acute lymphoblastic leukemia (ALL) relapse. We hypothesized that common polymorphisms with moderate effect sizes and large attributive risks could explain an important fraction of ALL relapses. Methylenetetrahydrofolate reductase (MTHFR) is central to folate metabolism and has two common functional polymorphisms (C677T and A1298G). Methotrexate (MTX), which interrupts folate metabolism, is a mainstay of pediatric ALL therapy. MTX inhibits the synthesis of dTMP needed for DNA replication by blocking the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate by MTHFR. We hypothesized that a deactivating MTHFR allele would increase ALL relapse risk by potentially increasing 5,10-methylenetetrahydrofolate and dTMP, enhancing DNA synthesis and thus opposing MTX. To test this hypothesis, we genotyped 520 patients on the Children's Cancer Study Group ALL study, CCG-1891. The MTHFR C677T variant allele was statistically significantly associated with relapse (chi2 = 4.38, P = 0.036). This association remained significant (hazard ratio = 1.82, P = 0.008), controlling for important covariates, and was more predictive of relapse than other predictors, including day 7 bone marrow response. The MTHFR C677T variant allele was not associated with an increased risk of toxicity or infection. The MTHFR A1298G polymorphism was not associated with altered risks of relapse, toxicity, or infection. Haplotype analysis showed six common haplotypes that did not provide additional information predictive for relapse. These data provide evidence that the MTHFR C677T polymorphism is a common genetic variant conferring a moderate relative risk and a high attributable risk for relapse in pediatric ALL patients.

Association of SLC11A1 with tuberculosis interactions with NOS2A and TLR2 in African-Americans and Caucasians

PubMed Central

Velez, D.R.; Hulme, W.F.; Myers, J.L.; Stryjewski, M.E.; Abbate, E.; Estevan, R.; Patillo, S.G.; Gilbert, J.R.; Hamilton, C.D.; Scott, W.K.

2010-01-01

SETTING Host defense factors may influence the development of active tuberculosis (TB). OBJECTIVE To test variants in solute carrier family 11A, member 1 (SLC11A1), for an association with TB. METHODS A mixed case-control study of TB cases, relatives or close contact controls, consisting of 474 African-Americans (243 families) and 381 Caucasians (192 families), examined 13 SLC11A1 polymorphisms for association with pulmonary TB using generalized estimating equations adjusting for age and gender. RESULTS Two associations were observed in Caucasians (rs3731863, P = 0.03, and rs17221959, P = 0.04) and one in African-Americans (rs3731865, P = 0.05). Multilocus analyses between polymorphisms in SLC11A1 and 11 TB candidate genes detected interactions between SLC11A1 and inducible nitric oxide synthase (NOS2A) in Caucasians (rs3731863 [SLC11A1] × rs8073782 [NOS2A], P = 0.009; rs3731863 [SLC11A1] × rs17722851 [NOS2A], P = 0.007) and toll-like receptor 2 (TLR2) in African-Americans (rs3731865 [SLC11A1] x rs1816702, P = 0.005). CONCLUSIONS No association was detected with 5′(GT)n promoter polymorphism previously associated with lower SLC11A1 expression, rs17235409 (D543N), or rs17235416 (3′ TGTG insertion/deletion polymorphism). SLC11A1 polymorphism rs3731865 was associated with TB in African-Americans, consistent with previous findings in West Africans. These results suggest that variants in SLC11A1 increase susceptibility to pulmonary TB and interact with other variants that differ by race. PMID:19723394

Triosephosphate isomerase gene promoter variation: -5G/A and -8G/A polymorphisms in clinical malaria groups in two African populations.

PubMed

Guerra, Mónica; Machado, Patrícia; Manco, Licínio; Fernandes, Natércia; Miranda, Juliana; Arez, Ana Paula

2015-06-01

TPI1 promoter polymorphisms occur in high prevalence in individuals from African origin. Malaria-patients from Angola and Mozambique were screened for the TPI1 gene promoter variants rs1800200A>G, (-5G>A), rs1800201G>A, (-8G>A), rs1800202T>G, (-24T>G), and for the intron 5 polymorphism rs2071069G>A, (2262G>A). -5G>A and -8G>A variants occur in 47% and 53% in Angola and Mozambique, respectively while -24T>G was monomorphic for the wild-type T allele. Six haplotypes were identified and -8A occurred in 45% of the individuals, especially associated with the GAG haplotype and more frequent in non-severe malaria groups, although not significantly. The arising and dispersion of -5G>A and -8G>A polymorphisms is controversial. Their age was estimated by analyses of two microsatellite loci, CD4 and ATN1, adjacent to TPI1 gene. The -5G>A is older than -8G>A, with an average estimate of approximately 35,000 years. The -8A variant arose in two different backgrounds, suggesting independent mutational events. The first, on the -5G background, may have occurred in East Africa around 20,800 years ago; the second, on the -5A background, may have occurred in West Africa some 7500 years ago. These estimates are within the period of spread of agriculture and the malaria mosquito vector in Africa, which could has been a possible reason for the selection of -8A polymorphism in malaria endemic countries. Copyright © 2015 Elsevier B.V. All rights reserved.

FLT-1 gene polymorphisms and protein expression profile in rheumatoid arthritis

PubMed Central

Paradowska-Gorycka, Agnieszka; Sowinska, Anna; Pawlik, Andrzej; Malinowski, Damian; Stypinska, Barbara; Haladyj, Ewa; Romanowska-Prochnicka, Katarzyna; Olesinska, Marzena

2017-01-01

Objectives Inflammation and angiogenesis are a significant element of pathogenesis in rheumatoid arthritis (RA). The FLT-1- triggering factor for production of proinflammatory cytokines-might contributes to inflammation in patients with RA. Association of the FLT-1 polymorphisms with different “angiogenic diseases” suggests that it may be a novel genetic risk factor also for RA. The aim of the study was to identify FLT-1 genetic variants and their possible association with sFLT-1 levels, susceptibility to and severity of RA. Methods The FLT-1 gene polymorphisms were genotyped for 471 RA patients and 684 healthy individuals. Correlation analysis was performed with clinical parameters, cardiovascular disease (CVD) and anti-citrullinated peptide/protein antibody (ACPA) presence. The sFLT-1 serum levels were evaluated. Results The FLT-1 gene polymorphisms showed no significant differences in the proportion of cases and controls. Furthermore, the FLT-1 rs2296188 T/C polymorphism was associated with ACPA-positive RA. Overall, rs9943922 T/C and rs2296283 G/A are in almost completed linkage disequilibrium (LD) with D’ = 0.97 and r2 = 0.83. The FLT-1 rs7324510 A allele has shown association with VAS score (p = 0.035), DAS-28 score (p = 0.013) and ExRA presence (p = 0.027). Moreover, other clinical parameters were also higher in RA patients with this allele. In addition, FLT-1 genetic variants conferred higher sFLT-1 levels in RA patients compared to controls. Conclusion FLT-1 rs7324510 C/A variant may be a new genetic risk factor for severity of RA. Examined factor highly predispose to more severe disease activity as well as higher sFLT-1 levels in RA. PMID:28323906

Temporal Genetic Dynamics of an Experimental, Biparental Field Population of Phytophthora capsici

PubMed Central

Carlson, Maryn O.; Gazave, Elodie; Gore, Michael A.; Smart, Christine D.

2017-01-01

Defining the contributions of dispersal, reproductive mode, and mating system to the population structure of a pathogenic organism is essential to estimating its evolutionary potential. After introduction of the devastating plant pathogen, Phytophthora capsici, into a grower’s field, a lack of aerial spore dispersal restricts migration. Once established, coexistence of both mating types results in formation of overwintering recombinant oospores, engendering persistent pathogen populations. To mimic these conditions, in 2008, we inoculated a field with two P. capsici isolates of opposite mating type. We analyzed pathogenic isolates collected in 2009–2013 from this experimental population, using genome-wide single-nucleotide polymorphism markers. By tracking heterozygosity across years, we show that the population underwent a generational shift; transitioning from exclusively F1 in 2009–2010, to multi-generational in 2011, and ultimately all inbred in 2012–2013. Survival of F1 oospores, characterized by heterozygosity excess, coupled with a low rate of selfing, delayed declines in heterozygosity due to inbreeding and attainment of equilibrium genotypic frequencies. Large allele and haplotype frequency changes in specific genomic regions accompanied the generational shift, representing putative signatures of selection. Finally, we identified an approximately 1.6 Mb region associated with mating type determination, constituting the first detailed genomic analysis of a mating type region (MTR) in Phytophthora. Segregation patterns in the MTR exhibited tropes of sex-linkage, where maintenance of allele frequency differences between isolates of opposite mating type was associated with elevated heterozygosity despite inbreeding. Characterizing the trajectory of this experimental system provides key insights into the processes driving persistent, sexual pathogen populations. PMID:28348576

Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1

PubMed Central

Cheng, Timothy HT; Thompson, Deborah; Painter, Jodie; O’Mara, Tracy; Gorman, Maggie; Martin, Lynn; Palles, Claire; Jones, Angela; Buchanan, Daniel D.; Ko Win, Aung; Hopper, John; Jenkins, Mark; Lindor, Noralane M.; Newcomb, Polly A.; Gallinger, Steve; Conti, David; Schumacher, Fred; Casey, Graham; Giles, Graham G; Pharoah, Paul; Peto, Julian; Cox, Angela; Swerdlow, Anthony; Couch, Fergus; Cunningham, Julie M; Goode, Ellen L; Winham, Stacey J; Lambrechts, Diether; Fasching, Peter; Burwinkel, Barbara; Brenner, Hermann; Brauch, Hiltrud; Chang-Claude, Jenny; Salvesen, Helga B.; Kristensen, Vessela; Darabi, Hatef; Li, Jingmei; Liu, Tao; Lindblom, Annika; Hall, Per; de Polanco, Magdalena Echeverry; Sans, Monica; Carracedo, Angel; Castellvi-Bel, Sergi; Rojas-Martinez, Augusto; Aguiar Jnr, Samuel; Teixeira, Manuel R.; Dunning, Alison M; Dennis, Joe; Otton, Geoffrey; Proietto, Tony; Holliday, Elizabeth; Attia, John; Ashton, Katie; Scott, Rodney J; McEvoy, Mark; Dowdy, Sean C; Fridley, Brooke L; Werner, Henrica MJ; Trovik, Jone; Njolstad, Tormund S; Tham, Emma; Mints, Miriam; Runnebaum, Ingo; Hillemanns, Peter; Dörk, Thilo; Amant, Frederic; Schrauwen, Stefanie; Hein, Alexander; Beckmann, Matthias W; Ekici, Arif; Czene, Kamila; Meindl, Alfons; Bolla, Manjeet K; Michailidou, Kyriaki; Tyrer, Jonathan P; Wang, Qin; Ahmed, Shahana; Healey, Catherine S; Shah, Mitul; Annibali, Daniela; Depreeuw, Jeroen; Al-Tassan, Nada A.; Harris, Rebecca; Meyer, Brian F.; Whiffin, Nicola; Hosking, Fay J; Kinnersley, Ben; Farrington, Susan M.; Timofeeva, Maria; Tenesa, Albert; Campbell, Harry; Haile, Robert W.; Hodgson, Shirley; Carvajal-Carmona, Luis; Cheadle, Jeremy P.; Easton, Douglas; Dunlop, Malcolm; Houlston, Richard; Spurdle, Amanda; Tomlinson, Ian

2015-01-01

High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10−9) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10−8), with the alleles showing opposite effects on the risks of the two cancers. PMID:26621817

Impact of Genetic Polymorphisms on the Smoking-related Risk of Periodontal Disease: the Population-based Study SHIP

PubMed Central

Meisel, P; Heins, G; Carlsson, LE; Giebel, J; John, U; Schwahn, C; Kocher, T

2003-01-01

Periodontitis is a bacterial inflammatory disease leading to attachment loss with the consequence of tooth loss. There exists a multifactorial risk pattern including bacterial challenge, smoking, age, sex, diabetes, socio-economic and genetic factors. Smoking has the highest impact on the course of the disease modulated by all the other factors. Here, we report the relationship between smoking and the polymorphisms of genetic polymorphisms inflicted in the pathogenesis. In a randomly selected population-based study, 1083 subjects were typed for the polymorphisms of the IL-1 genotype, Fcγ RIIIb receptor gene, myeloperoxidase and N-acetyltransferase (NAT2) and related to their periodontal state. Smoking behavior was assessed including present and past quality and quantity of smoking. There is a significant dose-effect relationship between the exposure to tobacco smoke and the extent of periodontal disease assessed as attachment loss and tooth loss. Moreover, there are gene-environmental interactions as subjects bearing variant genotypes show an enhanced smoking-associated risk of the disease modulated by these genotypes. In non-smokers, the impact of these genetic polymorphisms is mostly negligible. This study provides support for the hypothesis that subjects bearing genetic variants of polymorphically expressed phenotypes are at an increased risk of periodontitis when smoking. Mostly, this may be accomplished via the influence of smoking-related impairment on defense mechanisms rather than on the pathogenic pathways. PMID:19570260

Impact of Genetic Polymorphisms on the Smoking-related Risk of Periodontal Disease: the Population-based Study SHIP

PubMed Central

Meisel, P; Heins, G; Carlsson, LE; Giebel, J; John, U; Schwahn, C; Kocher, T

2003-01-01

Periodontitis is a bacterial inflammatory disease leading to attachment loss with the consequence of tooth loss. There exists a multifactorial risk pattern including bacterial challenge, smoking, age, sex, diabetes, socio-economic and genetic factors. Smoking has the highest impact on the course of the disease modulated by all the other factors. Here, we report the relationship between smoking and the polymorphisms of genetic polymorphisms inflicted in the pathogenesis. In a randomly selected population-based study, 1083 subjects were typed for the polymorphisms of the IL-1 genotype, Fcγ RIIIb receptor gene, myeloperoxidase and N-acetyltransferase (NAT2) and related to their periodontal state. Smoking behavior was assessed including present and past quality and quantity of smoking. There is a significant dose-effect relationship between the exposure to tobacco smoke and the extent of periodontal disease assessed as attachment loss and tooth loss. Moreover, there are gene-environmental interactions as subjects bearing variant genotypes show an enhanced smoking-associated risk of the disease modulated by these genotypes. In non-smokers, the impact of these genetic polymorphisms is mostly negligible. This study provides support for the hypothesis that subjects bearing genetic variants of polymorphically expressed phenotypes are at an increased risk of periodontitis when smoking. Mostly, this may be accomplished via the influence of smoking-related impairment on defense mechanisms rather than on the pathogenic pathways.

Meta-analyses of four polymorphisms of lipoprotein lipase associated with the risk of Alzheimer's disease.

PubMed

Ren, Liang; Ren, Xingxing

2016-04-21

We evaluated the contributions of four polymorphisms of the lipoprotein lipase (LPL) gene to the risk of Alzheimer's disease (AD). Through a comprehensive literature search for genetic variants of LPL involved in AD association studies, we found four polymorphisms for the current meta-analyses. These polymorphisms were Asn291Ser(rs268), PvuII(rs285), HindIII(rs320) and Ser447Ter(rs328). In total, eight studies with 5064 cases and 5016 controls were retrieved for the meta-analyses of the four genetic variants. The analyses showed that Asn291Ser(rs268) (OR=2.34, 95% CI=1.05-5.25, P=0.04), HindIII(rs320) (OR=1.44, 95% CI=1.17-1.78, P=0.0006), and Ser447Ter(rs328) (OR=0.80, 95% CI=0.66-0.98, P=0.03) were significantly associated with a risk of AD. No association was found between the PvuII(rs285) polymorphism and the risk of AD. Our results showed that Asn291Ser(rs268), HindIII(rs320) and Ser447Ter(rs328) polymorphisms of LPL were associated with a risk of AD. Asn291Ser(rs268) and HindIII(rs320) were predisposing factors of AD, whereas Ser447Ter(rs328) showed a protective effect for AD. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

MTR CONTROL ROOM WITH CONTROL CONSOLE AND STATUS READOUTS ALONG ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

MTR CONTROL ROOM WITH CONTROL CONSOLE AND STATUS READOUTS ALONG WALL. WORKERS MAKE ELECTRICAL AND OTHER CONNECTIONS. INL NEGATIVE NO. 4289. Unknown Photographer, 2/26/1952 - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

SOUTH WING, TRA661. SOUTH SIDE. CAMERA FACING NORTH. MTR HIGH ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

SOUTH WING, TRA-661. SOUTH SIDE. CAMERA FACING NORTH. MTR HIGH BAY BEYOND. INL NEGATIVE NO. HD46-45-3. Mike Crane, Photographer, 4/2005 - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

Polymorphic Variants 279R and 668Q Augment Activity of Matrix Metalloproteinase-9 in Breath Condensates of Children with Asthma.

PubMed

Grzela, Katarzyna; Zagórska, Wioletta; Krejner, Alicja; Litwiniuk, Malgorzata; Zawadzka-Krajewska, Anna; Kulus, Marek; Grzela, Tomasz

2017-04-01

Matrix metalloproteinase (MMP)-9 is involved in pathophysiology of asthma, mainly asthma-associated airway remodeling. Exhaled breath condensates (EBC) of asthmatics contain increased amounts of MMP-9 with activity higher, than in healthy controls. The increased activity of MMP-9 may originate from its excessive production and activation, but may also result from variations in MMP-9 structure, which are determined by single nucleotide polymorphisms (SNPs). In this pilot study we aimed to assess the possible influence of two functional MMP-9 polymorphisms, Q279R and R668Q, on enzymatic activity of MMP-9, measured in EBC of asthmatic children. The concentration and activity of MMP-9 were analyzed in EBC of 20 children with allergic asthma using specific standard ELISA and novel immunoenzymatic activity assay. The SNPs of MMP-9 were assessed using real-time PCR-based genotyping test. We have found that MMP-9 concentration in breath condensates of children with stable asthma was slightly higher in ELISA, than in the activity assay. Moreover, these results and activity-to-amount ratio have revealed some relationship with a presence of specific 279R and/or 668Q MMP-9 gene variants. Our observation suggests that at least in some patients MMP-9 hyperactivity may result from genetic predisposition, determined by polymorphic variants of MMP-9 gene. Moreover, it supports previous reports postulating significance of MMP-9 in pathogenesis of asthma. However, this issue still requires further studies.

ADRB2 and LEPR gene polymorphisms: synergistic effects on the risk of obesity in Japanese.

PubMed

Pereira, Tiago V; Mingroni-Netto, Regina C; Yamada, Yoshiji

2011-07-01

The objective of the present study was to validate a recently reported synergistic effect between variants located in the leptin receptor (LEPR) gene and in the β-2 adrenergic receptor (ADRB2) gene on the risk of overweight/obesity. We studied a middle-aged/elderly sample of 4,193 nondiabetic Japanese subjects stratified according gender (1,911 women and 2,282 men). The LEPR Gln223Arg (rs1137101) variant as well as both ADRB2 Arg16Gly (rs1042713) and Gln27Glu (rs1042714) polymorphisms were analyzed. The primary outcome was the risk of overweight/obesity defined as BMI ≥25 kg/m(2), whereas secondary outcomes included the risk of a BMI ≥27 kg/m(2) and BMI as a continuous variable. None of the studied polymorphisms showed statistically significant individual effects, regardless of the group or phenotype studied. Haplotype analysis also did not disclose any associations of ADRB2 polymorphisms with BMI. However, dimensionality reduction-based models confirmed significant interactions among the investigated variants for BMI as a continuous variable as well as for the risk of obesity defined as BMI ≥27 kg/m(2). All disclosed interactions were found in men only. Our results provide external validation for a male specific ADRB2-LEPR interaction effect on the risk of overweight/obesity, but indicate that effect sizes associated with these interactions may be smaller in the population studied.

Interleukin 1β (+3954, -511 and -31) polymorphism in chronic periodontitis patients from North India.

PubMed

Amirisetty, Ramesh; Patel, Ritu Prabha; Das, Satrupa; Saraf, Jitendra; Jyothy, Akka; Munshi, Anjana

2015-07-01

Several studies have implicated the role of interleukin-1 in various chronic diseases including periodontitis. The present study was carried out with an aim to evaluate the role of interleukin 1β polymorphisms, namely +3954C/T, -511C/T and -31T/C, in the development of chronic periodontitis. Twenty-nine chronic periodontitis patients and 31 healthy controls of North Indian origin from Chhattisgarh were recruited for the study. The genotypes for the three variants were determined using the PCR-RFLP technique and the strength of association between genotypes and periodontitis was determined by odds ratio with 95% confidence interval (CI) and chi-square analysis. Analysis for the +3954 allelic and genotypic frequencies of the polymorphism revealed a significant difference in the CT genotype between periodontitits patients and controls (p = 0.03). A significant difference was also observed in the allelic frequencies between the two groups (p = 0.02). For the -511 site, TT genotype revealed a significant association with the disease (p = 0.01). A significant association was also found following the co-dominant model (p = 0.007). However, the -31 polymorphism revealed no significant difference between patients and controls. In conclusion, the present study suggests a strong association of the TT genotype of -511 and CT genotype of +3954 variant of interleukin 1β with chronic periodontitis. However, the -31 variant did not show a significant association with the disease.

Analysis of PTPN22, ZFAT and MYO9B polymorphisms in Turner Syndrome and risk of autoimmune disease.

PubMed

Villanueva-Ortega, E; Ahedo, B; Fonseca-Sánchez, M A; Pérez-Durán, J; Garibay-Nieto, N; Macías-Galavíz, M T; Trujillo-Cabrera, Y; García-Latorre, E; Queipo, G

2017-08-01

Turner syndrome (TS) is one of the most common sexual chromosome abnormalities and is clearly associated with an increased risk of autoimmune diseases, particularly thyroid disease and coeliac disease (CD). Single-nucleotide polymorphism analyses have been shown to provide correlative evidence that specific genes are associated with autoimmune disease. Our aim was to study the functional polymorphic variants of PTPN22 and ZFAT in relation to thyroid disease and those of MYO9B in relation to CD. A cross-sectional comparative analysis was performed on Mexican mestizo patients with TS and age-matched healthy females. Our data showed that PTPN22 C1858T (considered a risk variant) is not associated with TS (X 2  = 3.50, p = .61, and OR = 0.33 [95% CI = 0.10-1.10]). Also, ZFAT was not associated with TS (X 2  = 1.2, p = .28, and OR = 1.22 [95% CI = 0.84-1.79]). However, for the first time, rs2305767 MYO9B was revealed to have a strong association with TS (X 2  = 58.6, p = .0001, and OR = 10.44 [95% C = 5.51-19.80]), supporting a high level of predisposition to CD among TS patients. This report addresses additional data regarding the polymorphic variants associated with autoimmune disease, one of the most common complications in TS. © 2017 John Wiley & Sons Ltd.

Genetic Variation in Iron Metabolism Is Associated with Neuropathic Pain and Pain Severity in HIV-Infected Patients on Antiretroviral Therapy

PubMed Central

Kallianpur, Asha R.; Jia, Peilin; Ellis, Ronald J.; Zhao, Zhongming; Bloss, Cinnamon; Wen, Wanqing; Marra, Christina M.; Hulgan, Todd; Simpson, David M.; Morgello, Susan; McArthur, Justin C.; Clifford, David B.; Collier, Ann C.; Gelman, Benjamin B.; McCutchan, J. Allen; Franklin, Donald; Samuels, David C.; Rosario, Debralee; Holzinger, Emily; Murdock, Deborah G.; Letendre, Scott; Grant, Igor

2014-01-01

HIV sensory neuropathy and distal neuropathic pain (DNP) are common, disabling complications associated with combination antiretroviral therapy (cART). We previously associated iron-regulatory genetic polymorphisms with a reduced risk of HIV sensory neuropathy during more neurotoxic types of cART. We here evaluated the impact of polymorphisms in 19 iron-regulatory genes on DNP in 560 HIV-infected subjects from a prospective, observational study, who underwent neurological examinations to ascertain peripheral neuropathy and structured interviews to ascertain DNP. Genotype-DNP associations were explored by logistic regression and permutation-based analytical methods. Among 559 evaluable subjects, 331 (59%) developed HIV-SN, and 168 (30%) reported DNP. Fifteen polymorphisms in 8 genes (p<0.05) and 5 variants in 4 genes (p<0.01) were nominally associated with DNP: polymorphisms in TF, TFRC, BMP6, ACO1, SLC11A2, and FXN conferred reduced risk (adjusted odds ratios [ORs] ranging from 0.2 to 0.7, all p<0.05); other variants in TF, CP, ACO1, BMP6, and B2M conferred increased risk (ORs ranging from 1.3 to 3.1, all p<0.05). Risks associated with some variants were statistically significant either in black or white subgroups but were consistent in direction. ACO1 rs2026739 remained significantly associated with DNP in whites (permutation p<0.0001) after correction for multiple tests. Several of the same iron-regulatory-gene polymorphisms, including ACO1 rs2026739, were also associated with severity of DNP (all p<0.05). Common polymorphisms in iron-management genes are associated with DNP and with DNP severity in HIV-infected persons receiving cART. Consistent risk estimates across population subgroups and persistence of the ACO1 rs2026739 association after adjustment for multiple testing suggest that genetic variation in iron-regulation and transport modulates susceptibility to DNP. PMID:25144566

Colour Polymorphism Protects Prey Individuals and Populations Against Predation.

PubMed

Karpestam, Einat; Merilaita, Sami; Forsman, Anders

2016-02-23

Colour pattern polymorphism in animals can influence and be influenced by interactions between predators and prey. However, few studies have examined whether polymorphism is adaptive, and there is no evidence that the co-occurrence of two or more natural prey colour variants can increase survival of populations. Here we show that visual predators that exploit polymorphic prey suffer from reduced performance, and further provide rare evidence in support of the hypothesis that prey colour polymorphism may afford protection against predators for both individuals and populations. This protective effect provides a probable explanation for the longstanding, evolutionary puzzle of the existence of colour polymorphisms. We also propose that this protective effect can provide an adaptive explanation for search image formation in predators rather than search image formation explaining polymorphism.

Colour Polymorphism Protects Prey Individuals and Populations Against Predation

PubMed Central

Karpestam, Einat; Merilaita, Sami; Forsman, Anders

2016-01-01

Colour pattern polymorphism in animals can influence and be influenced by interactions between predators and prey. However, few studies have examined whether polymorphism is adaptive, and there is no evidence that the co-occurrence of two or more natural prey colour variants can increase survival of populations. Here we show that visual predators that exploit polymorphic prey suffer from reduced performance, and further provide rare evidence in support of the hypothesis that prey colour polymorphism may afford protection against predators for both individuals and populations. This protective effect provides a probable explanation for the longstanding, evolutionary puzzle of the existence of colour polymorphisms. We also propose that this protective effect can provide an adaptive explanation for search image formation in predators rather than search image formation explaining polymorphism. PMID:26902799

Genome-wide copy number variant analysis reveals variants associated with 10 diverse production traits in Holstein cattle

USDA-ARS?s Scientific Manuscript database

Copy number variation (CNV) is an important type of genetic variation contributing to phenotypic differences among mammals and may serve as an alternative molecular marker to single nucleotide polymorphism (SNP) for genome-wide association study (GWAS). Recently, GWAS analysis using CNV has been app...

Duplication polymorphisms in exon 4 of κ-casein gene in yak breeds/populations.

PubMed

Pingcuo, S; Gao, J; Jiang, Z R; Jin, S Y; Fu, C Y; Liu, X; Huang, L; Zheng, Y C

2015-08-28

The objective of this study was to compare 12 bp-duplication polymorphisms in exon 4 of the κ-casein gene among 3 breeds/populations of yak (Bos grunniens). Genomic DNA was extracted from yak blood or muscle samples (N = 211) and a partial sequence of exon 4 of κ-casein gene was amplified by polymerase chain reaction. A polyacrylamide gel electrophoresis assay of the products (169 bp) revealed 2 variants. These variants differed in a 12-bp duplication of the nucleotide sequence corresponding to amino acids 147-150 (Glu-Ala-Ser-Pro) or 148-151 (Ala-Ser-Pro-Glu). The genotype frequency and gene frequency of the 2 κ-casein variants differed among the 3 yak breeds/populations. The long form of the κ-casein gene was the predominant allele, and the Jiulong yak showed the highest frequency of the short form variant of the κ-casein gene. In addition, 2 nucleotide differences resulting in amino acid substitutions were also identified in yaks. These results are significant for designing a breeding strategy to improve the genetic makeup of yak herds.

Association of the VDAC3 gene polymorphism with sperm count in Han-Chinese population with idiopathic male infertility.

PubMed

Pan, Lianjun; Liu, Qingzhen; Li, Jingyun; Wu, Wei; Wang, Xinru; Zhao, Dan; Ma, Jiehua

2017-07-11

Voltage-dependent anion channel (VDAC) is a multifunctional channel protein across the outer mitochondrial membrane of somatic cells and participates in many physiological and pathophysiological processes. Up to now, only a few studies, including our previous studies, showed that VDAC exists in mammalian spermatozoa and is involved in spermatogenesis and sperm functions. There is no report about VDAC genetic variants in germinal tissues or cells. To investigate the possible association between VDAC genetic variants and human sperm quality, we performed semen analysis and variant Genotyping of VDAC3 subtype (rs7004637, rs16891278 and rs6773) of 523 Han-Chinese males with idiopathic infertility respectively by computer assisted semen analysis (CASA) and single nucleotide polymorphism (SNP) Genotyping assay. No significant association was found between rs7004637 and rs6773 genotypes and semen quality. However, the AG genotype of rs16891278 showed a significantly lower sperm concentration compared with the AA genotype (P = 0.044). Our findings suggest that VDAC3 genetic variants may be associated with human sperm count.

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

PubMed

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

2004-01-01

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

Impact of inflammation, gene variants, and cigarette smoking on coronary artery disease risk.

PubMed

Merhi, Mahmoud; Demirdjian, Sally; Hariri, Essa; Sabbah, Nada; Youhanna, Sonia; Ghassibe-Sabbagh, Michella; Naoum, Joseph; Haber, Marc; Othman, Raed; Kibbani, Samer; Chammas, Elie; Kanbar, Roy; Bayeh, Hamid El; Chami, Youssef; Abchee, Antoine; Platt, Daniel E; Zalloua, Pierre; Khazen, Georges

2015-06-01

The role of inflammation in coronary artery disease (CAD) pathogenesis is well recognized. Moreover, smoking inhalation increases the activity of inflammatory mediators through an increase in leukotriene synthesis essential in atherosclerosis pathogenesis. The aim of this study is to investigate the effect of "selected" genetic variants within the leukotriene (LT) pathway and other variants on the development of CAD. CAD was detected by cardiac catheterization. Logistic regression was performed to investigate the association of smoking and selected susceptibility variants in the LT pathway including ALOX5AP, LTA4H, LTC4S, PON1, and LTA as well as CYP1A1 on CAD risk while controlling for age, gender, BMI, family history, diabetes, hyperlipidemia, and hypertension. rs4769874 (ALOX5AP), rs854560 (PON1), and rs4646903 (CYP1A1 MspI polymorphism) are significantly associated with an increased risk of CAD with respective odds ratios of 1.53703, 1.67710, and 1.35520; the genetic variant rs9579646 (ALOX5AP) is significantly associated with a decreased risk of CAD (OR 0.76163). Moreover, a significant smoking-gene interaction is determined with CYP1A1 MspI polymorphism rs4646903 and is associated with a decreased risk of CAD in current smokers (OR 0.52137). This study provides further evidence that genetic variation of the LT pathway, PON1, and CYP1A1 can modulate the atherogenic processes and eventually increase the risk of CAD in our study population. Moreover, it also shows the effect of smoking-gene interaction on CAD risk, where the CYP1A1 MspI polymorphism revealed a decreased risk in current smokers.

A note on the use of the generalized odds ratio in meta-analysis of association studies involving bi- and tri-allelic polymorphisms.

PubMed

Pereira, Tiago V; Mingroni-Netto, Regina C

2011-06-06

The generalized odds ratio (GOR) was recently suggested as a genetic model-free measure for association studies. However, its properties were not extensively investigated. We used Monte Carlo simulations to investigate type-I error rates, power and bias in both effect size and between-study variance estimates of meta-analyses using the GOR as a summary effect, and compared these results to those obtained by usual approaches of model specification. We further applied the GOR in a real meta-analysis of three genome-wide association studies in Alzheimer's disease. For bi-allelic polymorphisms, the GOR performs virtually identical to a standard multiplicative model of analysis (e.g. per-allele odds ratio) for variants acting multiplicatively, but augments slightly the power to detect variants with a dominant mode of action, while reducing the probability to detect recessive variants. Although there were differences among the GOR and usual approaches in terms of bias and type-I error rates, both simulation- and real data-based results provided little indication that these differences will be substantial in practice for meta-analyses involving bi-allelic polymorphisms. However, the use of the GOR may be slightly more powerful for the synthesis of data from tri-allelic variants, particularly when susceptibility alleles are less common in the populations (≤10%). This gain in power may depend on knowledge of the direction of the effects. For the synthesis of data from bi-allelic variants, the GOR may be regarded as a multiplicative-like model of analysis. The use of the GOR may be slightly more powerful in the tri-allelic case, particularly when susceptibility alleles are less common in the populations.

CRAWview: for viewing splicing variation, gene families, and polymorphism in clusters of ESTs and full-length sequences.

PubMed

Chou, A; Burke, J

1999-05-01

DNA sequence clustering has become a valuable method in support of gene discovery and gene expression analysis. Our interest lies in leveraging the sequence diversity within clusters of expressed sequence tags (ESTs) to model gene structure for the study of gene variants that arise from, among other things, alternative mRNA splicing, polymorphism, and divergence after gene duplication, fusion, and translocation events. In previous work, CRAW was developed to discover gene variants from assembled clusters of ESTs. Most importantly, novel gene features (the differing units between gene variants, for example alternative exons, polymorphisms, transposable elements, etc.) that are specialized to tissue, disease, population, or developmental states can be identified when these tools collate DNA source information with gene variant discrimination. While the goal is complete automation of novel feature and gene variant detection, current methods are far from perfect and hence the development of effective tools for visualization and exploratory data analysis are of paramount importance in the process of sifting through candidate genes and validating targets. We present CRAWview, a Java based visualization extension to CRAW. Features that vary between gene forms are displayed using an automatically generated color coded index. The reporting format of CRAWview gives a brief, high level summary report to display overlap and divergence within clusters of sequences as well as the ability to 'drill down' and see detailed information concerning regions of interest. Additionally, the alignment viewing and editing capabilities of CRAWview make it possible to interactively correct frame-shifts and otherwise edit cluster assemblies. We have implemented CRAWview as a Java application across windows NT/95 and UNIX platforms. A beta version of CRAWview will be freely available to academic users from Pangea Systems (http://www.pangeasystems.com). Contact :

Flavin binding to the deca-heme cytochrome MtrC: Insights from computational molecular simulation

DOE PAGES

Breuer, Marian; Rosso, Kevin  M.; Blumberger, Jochen

2015-12-15

Here, certain dissimilatory bacteria have the remarkable ability to use extracellular metal oxide minerals instead of oxygen as terminal electron sinks, using a process known as “extracellular respiration”. Specialized multiheme cytochromes located on the outer membrane of the microbe were shown to be crucial for electron transfer from the cell surface to the mineral. This process is facilitated by soluble, biogenic flavins secreted by the organism for the purpose of acting as an electron shuttle. However, their interactions with the outer-membrane cytochromes are not established on a molecular scale. Here, we study the interaction between the outer-membrane deca-heme cytochrome MtrCmore » from Shewanella oneidensis and flavin mononucleotide (FMN in fully oxidized quinone form) using computational docking. We find that interaction of FMN with MtrC is significantly weaker than with known FMN-binding proteins, but identify a mildly preferred interaction site close to heme 2 with a dissociation constant (K d) = 490 μM, in good agreement with recent experimental estimates, K d = 255 μM. The weak interaction with MtrC can be qualitatively explained by the smaller number of hydrogen bonds that the planar headgroup of FMN can form with this protein compared to FMN-binding proteins. Molecular dynamics simulation gives indications for a possible conformational switch upon cleavage of the disulphide bond of MtrC, but without concomitant increase in binding affinities according to this docking study. Overall, our results suggest that binding of FMN to MtrC is reversible and not highly specific, which may be consistent with a role as redox shuttle that facilitates extracellular respiration.« less

Predictors of upper trapezius pain with myofascial trigger points in food service workers: The STROBE study.

PubMed

Hwang, Ui-Jae; Kwon, Oh-Yun; Yi, Chung-Hwi; Jeon, Hye-Seon; Weon, Jong-Hyuck; Ha, Sung-Min

2017-06-01

Shoulder pain occurs commonly in food service workers (FSWs) who repetitively perform motions of the upper limbs. Myofascial trigger points (MTrPs) on the upper trapezius (UT) are among the most common musculoskeletal shoulder pain syndromes. This study determined the psychological, posture, mobility, and strength factors associated with pain severity in FSWs with UT pain due to MTrPs.In this cross-sectional study, we measured 17 variables in 163 FSWs with UT pain due to MTrPs: a visual analog scale (VAS) pain score, age, sex, Borg rating of perceived exertion (BRPE) scale, beck depression inventory, forward head posture angle, rounded shoulder angle (RSA), shoulder slope angle, scapular downward rotation ratio, cervical lateral-bending side difference angle, cervical rotation side difference angle, glenohumeral internal rotation angle, shoulder horizontal adduction angle, serratus anterior (SA) strength, lower trapezius (LT) strength, bicep strength, and glenohumeral external rotator strength, in 163 FSWs with UT pain due to MTrPs.The model for factors influencing UT pain with MTrPs included SA strength, age, BRPE, LT strength, and RSA as predictor variables that accounted for 68.7% of the variance in VAS (P < .001) in multiple regression models with a stepwise selection procedure. The following were independent variables influencing the VAS in the order of standardized coefficients: SA strength (β = -0.380), age (β = 0.287), BRPE (β = 0.239), LT strength (β = -0.195), and RSA (β = 0.125).SA strength, age, BRPE, LT strength, and RSA variables should be considered when evaluating and intervening in UT pain with MTrPs in FSWs.

Predictors of upper trapezius pain with myofascial trigger points in food service workers

PubMed Central

Hwang, Ui-Jae; Kwon, Oh-Yun; Yi, Chung-Hwi; Jeon, Hye-Seon; Weon, Jong-Hyuck; Ha, Sung-Min

2017-01-01

Abstract Shoulder pain occurs commonly in food service workers (FSWs) who repetitively perform motions of the upper limbs. Myofascial trigger points (MTrPs) on the upper trapezius (UT) are among the most common musculoskeletal shoulder pain syndromes. This study determined the psychological, posture, mobility, and strength factors associated with pain severity in FSWs with UT pain due to MTrPs. In this cross-sectional study, we measured 17 variables in 163 FSWs with UT pain due to MTrPs: a visual analog scale (VAS) pain score, age, sex, Borg rating of perceived exertion (BRPE) scale, beck depression inventory, forward head posture angle, rounded shoulder angle (RSA), shoulder slope angle, scapular downward rotation ratio, cervical lateral-bending side difference angle, cervical rotation side difference angle, glenohumeral internal rotation angle, shoulder horizontal adduction angle, serratus anterior (SA) strength, lower trapezius (LT) strength, bicep strength, and glenohumeral external rotator strength, in 163 FSWs with UT pain due to MTrPs. The model for factors influencing UT pain with MTrPs included SA strength, age, BRPE, LT strength, and RSA as predictor variables that accounted for 68.7% of the variance in VAS (P < .001) in multiple regression models with a stepwise selection procedure. The following were independent variables influencing the VAS in the order of standardized coefficients: SA strength (β = −0.380), age (β = 0.287), BRPE (β = 0.239), LT strength (β = −0.195), and RSA (β = 0.125). SA strength, age, BRPE, LT strength, and RSA variables should be considered when evaluating and intervening in UT pain with MTrPs in FSWs. PMID:28658117

Therapeutic effects of dry needling in patients with upper trapezius myofascial trigger points

PubMed Central

Abbaszadeh-Amirdehi, Maryam; Ansari, Noureddin Nakhostin; Naghdi, Soofia; Olyaei, Gholamreza; Nourbakhsh, Mohammad Reza

2017-01-01

Background Active myofascial trigger points (MTrPs) are major pain generators in myofascial pain syndrome. Dry needling (DN) is an effective method for the treatment of MTrPs. Objective To assess the immediate neurophysiological and clinical effects of DN in patients with upper trapezius MTrPs. Methods This was a prospective, clinical trial study of 20 patients with upper trapezius MTrPs and 20 healthy volunteers (matched for height, weight, body mass index and age), all of whom received one session of DN. Primary outcome measures were neuromuscular junction response (NMJR) and sympathetic skin response (SSR). Secondary outcomes were pain intensity (PI) and pressure pain threshold (PPT). Data were collected at baseline and immediately post-intervention. Results At baseline, SSR amplitude was higher in patients versus healthy volunteers (p<0.003). With respect to NMJR, a clinically abnormal increment and normal reduction was observed in patients and healthy volunteers, respectively. Moreover, PPT of patients was less than healthy volunteers (p<0.0001). After DN, SSR amplitude decreased significantly in patients (p<0.01), but did not change in healthy volunteers. A clinically important reduction in the NMJR of patients and increment in healthy volunteers was demonstrated after DN. PPT increased after DN in patients, but decreased in healthy volunteers (p<0.0001). PI improved after DN in patients (p<0.001). Conclusions The results of this study showed that one session of DN targeting active MTrPs appears to reduce hyperactivity of the sympathetic nervous system and irritability of the motor endplate. DN seems effective at improving symptoms and deactivating active MTrPs, although further research is needed. Trial registration number IRCT20130316128. PMID:27697768

Effectiveness of dry needling on the lower trapezius in patients with mechanical neck pain: a randomized controlled trial.

PubMed

Pecos-Martín, Daniel; Montañez-Aguilera, F Javier; Gallego-Izquierdo, Tomás; Urraca-Gesto, Alicia; Gómez-Conesa, Antonia; Romero-Franco, Natalia; Plaza-Manzano, Gustavo

2015-05-01

To evaluate the effect of dry needling into a myofascial trigger point (MTrP) in the lower trapezius muscle of patients with mechanical idiopathic neck pain. A single-center, randomized, double-blinded controlled study. Patients were recruited from the student population of a local hospital by advertisement in the university clinic from January 2010 to December 2011. Patients (N=72) with unilateral neck pain, neck pain for ≥3 months, and active trigger points in the lower trapezius muscle were randomly assigned to 1 of 2 treatment groups. All the patients completed the study. Dry needling in an MTrP in the lower trapezius muscle, or dry needling in the lower trapezius muscle but not at an MTrP. The visual analog scale (VAS), Neck Pain Questionnaire (NPQ), and pressure-pain threshold (PPT) were assessed before the intervention and 1 week and 1 month postintervention. Treatment with dry needling of the lower trapezius muscle close to the MTrP showed decreases in pain and PPT as well as an improvement in the degree of disability (P<.001) compared with the baseline and control group measurements (P<.001). The dry-needling technique performed in the MTrP showed more significant therapeutic effects (P<.001). The application of dry needling into an active MTrP of the lower trapezius muscle induces significant changes in the VAS, NPQ, and PPT levels compared with the application of dry needling in other locations of the same muscle in patients with mechanical neck pain. Copyright © 2015 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Therapeutic effects of dry needling in patients with upper trapezius myofascial trigger points.

PubMed

Abbaszadeh-Amirdehi, Maryam; Ansari, Noureddin Nakhostin; Naghdi, Soofia; Olyaei, Gholamreza; Nourbakhsh, Mohammad Reza

2017-04-01

Active myofascial trigger points (MTrPs) are major pain generators in myofascial pain syndrome. Dry needling (DN) is an effective method for the treatment of MTrPs. To assess the immediate neurophysiological and clinical effects of DN in patients with upper trapezius MTrPs. This was a prospective, clinical trial study of 20 patients with upper trapezius MTrPs and 20 healthy volunteers (matched for height, weight, body mass index and age), all of whom received one session of DN. Primary outcome measures were neuromuscular junction response (NMJR) and sympathetic skin response (SSR). Secondary outcomes were pain intensity (PI) and pressure pain threshold (PPT). Data were collected at baseline and immediately post-intervention. At baseline, SSR amplitude was higher in patients versus healthy volunteers (p<0.003). With respect to NMJR, a clinically abnormal increment and normal reduction was observed in patients and healthy volunteers, respectively. Moreover, PPT of patients was less than healthy volunteers (p<0.0001). After DN, SSR amplitude decreased significantly in patients (p<0.01), but did not change in healthy volunteers. A clinically important reduction in the NMJR of patients and increment in healthy volunteers was demonstrated after DN. PPT increased after DN in patients, but decreased in healthy volunteers (p<0.0001). PI improved after DN in patients (p<0.001). The results of this study showed that one session of DN targeting active MTrPs appears to reduce hyperactivity of the sympathetic nervous system and irritability of the motor endplate. DN seems effective at improving symptoms and deactivating active MTrPs, although further research is needed. IRCT20130316128. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

A myofascial component of pain in knee osteoarthritis.

PubMed

Dor, Adi; Kalichman, Leonid

2017-07-01

Osteoarthritis (OA) is the most common cause of musculoskeletal pain and disability. The knee is the most common site of OA. Numerous studies have shown an inconsistency between patients' reports of pain and their radiographic findings. This inconsistency may be partially explained by the fact that a portion of the pain originates from the myofascial trigger points (MTrPs) located in the surrounding muscles. To assess the role of myofascial pain in OA patients. Critical review. PubMed, Google Scholar, Scopus, and PEDro databases were searched from inception until December 2016 for the following keywords: "myofascial pain", "osteoarthritis", "trigger points", "knee" or any combination of these words. The reference lists of all articles retrieved were searched as well. The current review included two observational studies evaluating the prevalence of MTrPs in OA patients and six interventional studies describing the treatment of myofascial pain in OA patients. Data from two of the interventional studies also included an observational section. The reviewed observational studies offered initial evidence as to the assumption that myofascial pain and the presence of MTrPs may play a role in pain and disability of knee OA. Because of the cross-sectional design of these studies, the causal relationships could not be established. Additional studies are needed to confirm this assumption as well as to clarify if MTrPs are a portion of OA etiology or that OA is the basis for MTrPs formation. Each interventional study elaborated on various myofascial treatment techniques. However, treatment focusing on MTrPs seems to be effective in reducing pain and improving function in OA patients. Due to the heterogeneity in treatment methods and outcome measures, it is difficult to attain a definite conclusion and therefore, additional high-quality randomized controlled trials are warranted. Copyright © 2017 Elsevier Ltd. All rights reserved.

The neurophysiological effects of dry needling in patients with upper trapezius myofascial trigger points: study protocol of a controlled clinical trial

PubMed Central

Abbaszadeh-Amirdehi, Maryam; Ansari, Noureddin Nakhostin; Naghdi, Soofia; Olyaei, Gholamreza; Nourbakhsh, Mohammad Reza

2013-01-01

Introduction Dry needling (DN) is an effective method for the treatment of myofascial trigger points (MTrPs). There is no report on the neurophysiological effects of DN in patients with MTrPs. The aim of the present study will be to assess the immediate neurophysiological efficacy of deep DN in patients with upper trapezius MTrPs. Methods and analysis A prospective, controlled clinical trial was designed to include patients with upper trapezius MTrPs and volunteered healthy participants to receive one session of DN. The primary outcome measures are neuromuscular junction response and sympathetic skin response. The secondary outcomes are pain intensity and pressure pain threshold. Data will be collected at baseline and immediately after intervention. Ethics and dissemination This study protocol has been approved by the Research Council, School of Rehabilitation and the Ethics Committee of Tehran University of Medical Sciences. The results of the study will be disseminated in a peer-reviewed journal and presented at international congresses. PMID:23793673

High Performance Reduction of H2O2 with an Electron Transport Decaheme Cytochrome on a Porous ITO Electrode

PubMed Central

2017-01-01

The decaheme cytochrome MtrC from Shewanella oneidensis MR-1 immobilized on an ITO electrode displays unprecedented H2O2 reduction activity. Although MtrC showed lower peroxidase activity in solution compared to horseradish peroxidase, the ten heme cofactors enable excellent electronic communication and a superior activity on the electrode surface. A hierarchical ITO electrode enabled optimal immobilization of MtrC and a high current density of 1 mA cm–2 at 0.4 V vs SHE could be obtained at pH 6.5 (Eonset = 0.72 V). UV–visible and Resonance Raman spectroelectrochemical studies suggest the formation of a high valent iron-oxo species as the catalytic intermediate. Our findings demonstrate the potential of multiheme cytochromes to catalyze technologically relevant reactions and establish MtrC as a new benchmark in biotechnological H2O2 reduction with scope for applications in fuel cells and biosensors. PMID:28221032

Neurophysiological and clinical effects of dry needling in patients with upper trapezius myofascial trigger points.

PubMed

Abbaszadeh-Amirdehi, Maryam; Ansari, Noureddin Nakhostin; Naghdi, Soofia; Olyaei, Gholamreza; Nourbakhsh, Mohammad Reza

2017-01-01

Dry needling (DN) is a widely used in treatment of myofascial trigger points (MTrPs). The purpose of this pretest-posttest clinical trial was to investigate the neurophysiological and clinical effects of DN in patients with MTrPs. A sample of 20 patients (3 man, 17 women; mean age 31.7 ± 10.8) with upper trapezius MTrPs received one session of deep DN. The outcomes of neuromuscular junction response (NMJR), sympathetic skin response (SSR), pain intensity (PI) and pressure pain threshold (PPT) were measured at baseline and immediately after DN. There were significant improvements in SSR latency and amplitude, pain, and PPT after DN. The NMJR decreased and returned to normal after DN. A single session of DN to the active upper trapezius MTrP was effective in improving pain, PPT, NMJR, and SSR in patients with myofascial trigger points. Further studies are needed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Association of Interleukin-2-330T/G and Interleukin-10-1082A/G Genetic Polymorphisms with B-Cell Non-Hodgkin Lymphoma in a Cohort of Egyptians.

PubMed

Abdel Rahman, Hala Aly; Khorshied, Mervat Mamdooh; Reda Khorshid, Ola Mohamed; Mourad, Heba Mahmoud

2018-05-25

Polymorphisms in the interleukin (IL)-2 and IL-10 genes are known to be associated with susceptibility to different immune-dysregulated disorders and cancers such as non-Hodgkin lymphoma (NHL). To explore the possible association between IL-2-330T/G and IL-10-1082A/G single-nucleotide polymorphisms and the susceptibility to B-cell NHL (B-NHL) in Egyptians, we conducted a case-control study. Genotyping of the studied genetic variations was done for 100 B-NHL patients as well as 100 age- and sex-matched healthy controls. The IL-2 variant allele occurred at a significantly higher rate in patients than controls and was associated with susceptibility to B-NHL [odds ratio (OR): 1.91, 95% confidence interval (CI): 1.28-2.85]. It was also associated with advanced performance status score. IL-2 polymorphism conferred an almost threefold increased risk of diffuse large B-cell lymphoma (OR: 2.64, 95% CI: 1.35-5.15) and a fourfold increased risk of indolent subtypes (OR: 4.34, 95% CI: 1.20-15.7). The distribution of IL-10-1082A/G genotypes in our patients was close to that of the controls. Co-inheritance of the variant genotypes of IL-2 and the common genotype of IL-10 conferred an almost sixfold increased risk (OR: 5.75, 95% CI: 1.39-23.72), while co-inheritance of the variant genotypes of IL-2 and IL-10 conferred fivefold increased risk of B-NHL (OR: 5.43, 95% CI: 1.44-20.45). The variant genotypes of IL-2-330T/G and IL-10-1082A/G had no effect on the disease-free survival of B-NHL patients. The present study highlights the possible involvement of the IL-2-330T/G genetic polymorphism in the susceptibility to B-NHL in Egypt, especially indolent subtypes. Moreover, IL-10-1082A/G is not a molecular susceptibility marker for B-NHL in Egyptians.

4G/5G Plasminogen Activator Inhibitor-1 Polymorphisms and Haplotypes Are Associated with Pneumonia

PubMed Central

Yende, Sachin; Angus, Derek C.; Ding, Jingzhong; Newman, Anne B.; Kellum, John A.; Li, Rongling; Ferrell, Robert E.; Zmuda, Joseph; Kritchevsky, Stephen B.; Harris, Tamara B.; Garcia, Melissa; Yaffe, Kristine; Wunderink, Richard G.

2007-01-01

Rationale: Plasminogen activator inhibitor (PAI)-1 inhibits urokinase and tissue plasminogen activator, required for host response to infection. Whether variation within the PAI-1 gene is associated with increased susceptibility to infection is unknown. Objectives: To ascertain the role of the 4G/5G polymorphism and other genetic variants within the PAI-1 gene. We hypothesized that variants associated with increased PAI-1 expression would be associated with an increased occurrence of community-acquired pneumonia (CAP). Methods: Longitudinal analysis (>12 yr) of the Health, Aging, and Body Composition cohort, aged 65–74 years at start of analysis. Measurements and Main Results: We genotyped the 4G/5G PAI-1 polymorphism and six additional single nucleotide polymorphisms. Of the 3,075 subjects, 272 (8.8%) had at least one hospitalization for CAP. Among whites, variants at the PAI4G,5G, PAI2846, and PAI7343 sites had higher risk of CAP (P = 0.018, 0.021, and 0.021, respectively). At these sites, variants associated with higher PAI-1 expression were associated with increased CAP susceptibility. Compared with the 5G/5G genotypes at PAI4G,5G site, the 4G/4G and 4G/5G genotypes were associated with a 1.98-fold increased risk of CAP (95% confidence interval, 1.2–3.2; P = 0.006). In whole blood stimulation assay, subjects with a 4G allele had 3.3- and 1.9-fold increased PAI-1 expression (P = 0.043 and 0.034, respectively). In haplotype analysis, the 4G/G/C/A haplotype at the PAI4G,5G, PAI2846, PAI4588, and PAI7343 single nucleotide polymorphisms was associated with higher CAP susceptibility, whereas the 5G/G/C/A haplotype was associated with lower CAP susceptibility. No associations were seen among blacks. Conclusions: Genotypes associated with increased expression of PAI-1 were associated with increased susceptibility to CAP in elderly whites. PMID:17761618

Genetic polymorphism in Leishmania infantum isolates from human and animals determined by nagt PCR-RFLP.

PubMed

El Hamouchi, Adil; El Kacem, Sofia; Ejghal, Rajaa; Lemrani, Meryem

2018-06-14

Leishmania infantum is the causative agent of human visceral leishmaniasis (VL) and sporadic human cutaneous leishmaniasis (CL) in the Mediterranean region. The genetic variation of the Leishmania parasites may result in different phenotypes that can be associated with the geographical distribution and diversity of the clinical manifestations. The main objective of this study was to explore the genetic polymorphism in L. infantum isolates from human and animal hosts in different regions of Morocco. The intraspecific genetic variability of 40 Moroccan L. infantum MON-1 strains isolated from patients with VL (n = 31) and CL (n = 2) and from dogs (n = 7) was evaluated by PCR-RFLP of nagt, a single-copy gene encoding N-acetylglucosamine-1-phosphate transferase. For a more complete analysis of L. infantum polymorphism, we included the restriction patterns of nagt from 17 strains available in the literature and patterns determined by in-silico digestion of three sequences from the GenBank database. Moroccan L. infantum strains presented a certain level of genetic diversity and six distinct nagt-RFLP genotypes were identified. Three of the six genotypes were exclusively identified in the Moroccan population of L. infantum: variant M1 (15%), variant M2 (7.5%), and variant M3 (2.5%). The most common genotype (65%), variant 2 (2.5%), and variant 4 (7.5%), were previously described in several countries with endemic leishmaniasis. Phylogenetic analysis segregated our L. infantum population into two distinct clusters, whereas variant M2 was clearly distinguished from both cluster I and cluster II. This distribution highlights the degree of genetic variability among the Moroccan L. infantum population. The nagt PCR-RFLP method presented here showed an important genetic heterogeneity among Moroccan L. infantum strains isolated from human and canine reservoirs with 6 genotypes identified. Three of the six Moroccan nagt genotypes, have not been previously described and support the particular genetic diversity of the Moroccan L. infantum population reported in other studies.

Systematic meta-analyses and field synopsis of genetic association studies in colorectal adenomas

PubMed Central

Montazeri, Zahra; Theodoratou, Evropi; Nyiraneza, Christine; Timofeeva, Maria; Chen, Wanjing; Svinti, Victoria; Sivakumaran, Shanya; Gresham, Gillian; Cubitt, Laura; Carvajal-Carmona, Luis; Bertagnolli, Monica M; Zauber, Ann G; Tomlinson, Ian; Farrington, Susan M; Dunlop, Malcolm G; Campbell, Harry; Little, Julian

2018-01-01

Background Low penetrance genetic variants, primarily single nucleotide polymorphisms, have substantial influence on colorectal cancer (CRC) susceptibility. Most CRCs develop from colorectal adenomas (CRA). Here, we report the first comprehensive field synopsis that catalogues all genetic association studies on CRA, with a parallel online database (http://www.chs.med.ed.ac.uk/CRAgene/). Methods We performed a systematic review, reviewing 9750 titles and then extracted data from 130 publications reporting on 181 polymorphisms in 74 genes. We conducted meta-analyses to derive summary effect estimates for 37 polymorphisms in 26 genes. We applied the Venice criteria and Bayesian False Discovery Probability (BFDP) to assess the levels of the credibility of associations. Results We considered the association with the rs6983267 variant at 8q24 as “highly credible”, reaching genome wide statistical significance in at least one meta-analysis model. We identified “less credible” associations (higher heterogeneity, lower statistical power, BFDP>0.02) with a further four variants of four independent genes: MTHFR c.677C>T p.A222V (rs1801133), TP53 c.215C>G p.R72P (rs1042522), NQO1 c.559C>T p.P187S (rs1800566), and NAT1 alleles imputed as fast acetylator genotypes. For the remaining 32 variants of 22 genes for which positive associations with CRA risk have been previously reported, the meta-analyses revealed no credible evidence to support these as true associations. Conclusions The limited number of credible associations between low penetrance genetic variants and CRA reflects the lower volume of evidence and associated lack of statistical power to detect associations of the magnitude typically observed for genetic variants and chronic diseases. The CRAgene database provides context for CRA genetic association data and will help inform future research directions. PMID:26451011

Complement factor H gene (CFH) polymorphisms C-257T, G257A and haplotypes are associated with protection against severe dengue phenotype, possible related with high CFH expression

PubMed Central

Pastor, André F.; Moura, Laís Rodrigues; Neto, José W.D.; Nascimento, Eduardo J.M.; Calzavara-Silva, Carlos E.; Gomes, Ana Lisa V.; da Silva, Ana Maria; Cordeiro, Marli T.; Braga-Neto, Ulisses; Crovella, Sergio; Gil, Laura H.V.G.; Marques, Ernesto T.A.; Acioli-Santos, Bartolomeu

2013-01-01

Four genetic polymorphisms located at the promoter (C-257T) and coding regions of CFH gene (exon 2 G257A, exon 14 A2089G and exon 19 G2881T) were investigated in 121 dengue patients (DENV-3) in order to assess the relationship between allele/haplotypes variants and clinical outcomes. A statistical value was found between the CFH-257T allele (TT/TC genotypes) and reduced susceptibility to severe dengue (SD). Statistical associations indicate that individuals bearing a T allele presented significantly higher protein levels in plasma. The –257T variant is located within a NF-κB binding site, suggesting that this variant might have effect on the ability of the CFH gene to respond to signals via the NF-κB pathway. The G257A allelic variant showed significant protection against severe dengue. When CFH haplotypes effect was considered, the ancestral CG/CG promoter-exon 2 SNP genotype showed significant risk to SD either in a general comparison (ancestral × all variant genotypes), as well as in individual genotypes comparison (ancestral × each variant genotype), where the most prevalent effect was observed in the CG/CG × CA/TG comparison. These findings support the involvement of –257T, 257A allele variants and haplotypes on severe dengue phenotype protection, related with high basal CFH expression. PMID:23747994

Lack of association between thrombophilic gene variants and recurrent pregnancy loss.

PubMed

Dutra, Caroline Gross; Fraga, Lucas Rosa; Nácul, Andréa Prestes; Passos, Eduardo Pandolfi; Gonçalves, Rozana Oliveira; Nunes, Olívia Lucia; De Godoy, Bibiane Armiliato; Leistner-Segal, Sandra; Vianna, Fernanda Sales Luiz; Schüler-Faccini, Lavínia; Sanseverino, Maria Teresa Vieira

2014-06-01

Recurrent pregnancy loss (RPL) is defined as the occurrence of two or more consecutive pregnancy losses. It is an important reproductive condition with a complex etiology. In approximately 50% of RPL cases an explanation for the cause is not found and they are therefore classified as idiopathic RPL. One of the causes implicated in RPL is thrombophilia, which consists of hemostatic disorders that lead to an increase in thromboembolic processes. The aim of this study was to evaluate polymorphic variants in genes related to thrombophilia as a risk factor in women with RPL. We investigated 145 women with at least two consecutive pregnancy losses and 135 women with at least two children and no history of pregnancy loss. Genotypes for the polymorphisms MTHFR C677T, FVL, FII (prothrombin), eNOS T-786C, and eNOS Glu298Asp were determined using a real-time PCR. Information about the exposure to environmental risk factors was also collected. There was no significant association between the environmental risk factors assessed and the polymorphisms studied. We did not find statistically significant differences in genotypic or allelic frequencies for the polymorphisms studied, in either the women with RPL or in the control group. Such polymorphisms should therefore not be considered as risk factors for this condition in this population.

CHRNA7 Polymorphisms and Response to Cholinesterase Inhibitors in Alzheimer's Disease

PubMed Central

Weng, Pei-Hsuan; Chen, Jen-Hau; Chen, Ta-Fu; Sun, Yu; Wen, Li-Li; Yip, Ping-Keung; Chu, Yi-Min; Chen, Yen-Ching

2013-01-01

Background CHRNA7 encodes the α7 nicotinic acetylcholine receptor subunit, which is important to Alzheimer's disease (AD) pathogenesis and cholinergic neurotransmission. Previously, CHRNA7 polymorphisms have not been related to cholinesterase inhibitors (ChEI) response. Methods Mild to moderate AD patients received ChEIs were recruited from the neurology clinics of three teaching hospitals from 2007 to 2010 (n = 204). Nine haplotype-tagging single nucleotide polymorphisms of CHRNA7 were genotyped. Cognitive responders were those showing improvement in the Mini-Mental State Examination score ≧2 between baseline and 6 months after ChEI treatment. Results AD women carrying rs8024987 variants [GG+GC vs. CC: adjusted odds ratio (AOR) = 3.62, 95% confidence interval (CI) = 1.47–8.89] and GG haplotype in block1 (AOR = 3.34, 95% CI = 1.38–8.06) had significantly better response to ChEIs (false discovery rate <0.05). These variant carriers using galantamine were 11 times more likely to be responders than female non-carriers using donepezil or rivastigmine. Conclusion For the first time, this study found a significant association between CHRNA7 polymorphisms and better ChEI response. If confirmed by further studies, CHRNA7 polymorphisms may aid in predicting ChEI response and refining treatment choice. PMID:24391883

In silico dissection of miRNA targetome polymorphisms and their role in regulating miRNA-mediated gene expression in esophageal cancer.

PubMed

Nariman-Saleh-Fam, Ziba; Bastami, Milad; Somi, Mohammad Hossein; Samadi, Naser; Abbaszadegan, Mohammad Reza; Behjati, Farkhondeh; Ghaedi, Hamid; Tavakkoly-Bazzaz, Javad; Masotti, Andrea

2016-12-01

Esophageal cancer is the eighth most common cancer worldwide. Also middle-aged obese adults with higher body mass index during childhood have a greater risk to develop esophageal cancer. The contribution of microRNAs to esophageal cancer has been extensively studied and it became clear that these noncoding RNAs may play crucial roles in pathogenesis, diagnosis and prognosis of the disease. Increasing evidences have suggested that polymorphisms perturbing microRNA targetome (i.e., the compendium of all microRNA target sites) are associated with cancers including esophageal cancer. However, the extent to which such variants contribute to esophageal cancer is still unclear. In this study, we applied an in silico approach to systematically identify polymorphisms perturbing microRNA targetome in esophageal cancer and performed various analyses to predict the functional consequences of the occurrence of these variants. The computational results were integrated to provide a prioritized list of the most potentially disrupting esophageal cancer-implicated microRNA targetome polymorphisms along with the in silico insight into the mechanisms with which such variations may modulate microRNA-mediated regulation. The results of this study will be valuable for future functional experiments aimed at dissecting the roles of microRNA targetome polymorphisms in the onset and progression of esophageal cancer.

Role of 2 common variants of 5HT2A gene in medication overuse headache.

PubMed

Terrazzino, Salvatore; Sances, Grazia; Balsamo, Francesca; Viana, Michele; Monaco, Francesco; Bellomo, Giorgio; Martignoni, Emilia; Tassorelli, Cristina; Nappi, Giuseppe; Canonico, Pier Luigi; Genazzani, Armando A

2010-11-01

The aim of the present study was to evaluate a possible involvement of 2 polymorphisms of the serotonin 5HT2A receptor gene (A-1438G and C516T) as risk factors for medication overuse headache (MOH) and whether the presence of these polymorphic variants might determine differences within MOH patients in monthly drug consumption. Despite a growing scientific interest in the mechanisms underlying the pathophysiology of MOH, few studies have focused on the role of genetics in the development of the disease, as well as on the genetic determinants of the inter-individual variability in the number of drug doses taken per month. Our study was performed by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism on genomic DNA extracted from peripheral blood of 227 MOH patients and 312 control subjects. Genotype-specific risks were estimated as odds ratios with associated 95% confidence intervals by unconditional logistic regression and adjusted for age and gender. A stepwise multiple linear regression analysis was employed to identify significant predictors of the number of drug doses taken per month. No significant association was found between 5HT2A A and 1438G and C516T gene polymorphisms and MOH risk. In contrast, a higher consumption of monthly drug doses was observed among 516T 5HT2A carriers (median 50, range 13-120) compared to 516CC patients (median 30, range 12-128) (Mann-Whitney U-test, P = .018). In the stepwise multiple regression analysis, C516T 5HT2A polymorphism (P = .018) and class of overused drug (P = .047) emerged as significant, independent predictors of the monthly drug consumption in MOH patients. Although our results do not support a major role of the A-1438G and C516T polymorphic variants of the 5HT2A gene in the susceptibility of MOH, our findings support an influence of the C516T polymorphism on the number of symptomatic drug doses taken and, possibly, on the drug-seeking behavior in these patients. © 2010 American Headache Society.

Inflammatory Gene Polymorphisms in Lung Cancer Susceptibility.

PubMed

Eaton, Keith D; Romine, Perrin E; Goodman, Gary E; Thornquist, Mark D; Barnett, Matt J; Petersdorf, Effie W

2018-05-01

Chronic inflammation has been implicated in carcinogenesis, with increasing evidence of its role in lung cancer. We aimed to evaluate the role of genetic polymorphisms in inflammation-related genes in the risk for development of lung cancer. A nested case-control study design was used, and 625 cases and 625 well-matched controls were selected from participants in the β-Carotene and Retinol Efficacy Trial, which is a large, prospective lung cancer chemoprevention trial. The association between lung cancer incidence and survival and 23 polymorphisms descriptive of 11 inflammation-related genes (interferon gamma gene [IFNG], interleukin 10 gene [IL10], interleukin 1 alpha gene [IL1A], interleukin 1 beta gene [IL1B], interleukin 2 gene [IL2], interleukin 4 receptor gene [IL4R], interleukin 4 gene [IL4], interleukin 6 gene [IL6], prostaglandin-endoperoxide synthase 2 gene [PTGS2] (also known as COX2), transforming growth factor beta 1 gene [TGFB1], and tumor necrosis factor alpha gene [TNFA]) was evaluated. Of the 23 polymorphisms, two were associated with risk for lung cancer. Compared with individuals with the wild-type (CC) variant, individuals carrying the minor allele variants of the IL-1β-511C>T promoter polymorphism (rs16944) (CT and TT) had decreased odds of lung cancer (OR = 0.74, [95% confidence interval (CI): 0.58-0.94] and OR = 0.71 [95% CI: 0.50-1.01], respectively, p = 0.03). Similar results were observed for the IL-1β-1464 C>G promoter polymorphism (rs1143623), with presence of the minor variants CG and CC having decreased odds of lung cancer (OR = 0.75 [95% CI: 0.59-0.95] and OR = 0.69 [95% CI: 0.46-1.03], respectively, p = 0.03). Survival was not influenced by genotype. This study provides further evidence that IL1B promoter polymorphisms may modulate the risk for development of lung cancer. Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

CD44 Gene Polymorphisms in Breast Cancer Risk and Prognosis: A Study in North Indian Population

PubMed Central

Tulsyan, Sonam; Agarwal, Gaurav; Lal, Punita; Agrawal, Sushma; Mittal, Rama Devi; Mittal, Balraj

2013-01-01

Background Cell surface biomarker CD44 plays an important role in breast cancer cell growth, differentiation, invasion, angiogenesis and tumour metastasis. Therefore, we aimed to investigate the role of CD44 gene polymorphisms in breast cancer risk and prognosis in North Indian population. Materials & Methods A total of 258 breast cancer patients and 241 healthy controls were included in the case-control study for risk prediction. According to RECIST, 114 patients who received neo-adjuvant chemotherapy were recruited for the evaluation of breast cancer prognosis. We examined the association of tagging SNP (rs353639) of Hapmap Gujrati Indians in Houston (GIH population) in CD44 gene along with a significant reported SNP (rs13347) in Chinese population by genotyping using Taqman allelic discrimination assays. Statistical analysis was done using SPSS software, version 17. In-silico analysis for prediction of functional effects was done using F-SNP and FAST-SNP. Results No significant association of both the genetic variants of the CD44 gene polymorphisms was found with breast cancer risk. On performing univariate analysis with clinicopathological characteristics and treatment response, we found significant association of genotype (CT+TT) of rs13347 polymorphism with earlier age of onset (P = 0.029, OR = 0.037). However, significance was lost in multivariate analysis. For rs353639 polymorphism, significant association was seen with clinical tumour size, both at the genotypic (AC+CC) (P = 0.039, OR = 3.02) as well as the allelic (C) (P = 0.042, OR = 2.87) levels. On performing multivariate analysis, increased significance of variant genotype (P = 0.017, OR = 4.29) and allele (P = 0.025, OR = 3.34) of rs353639 was found with clinical tumour size. In-silico analysis using F-SNP, showed altered transcriptional regulation for rs353639 polymorphism. Conclusions These findings suggest that CD44 rs353639 genetic variants may have significant effect in breast cancer prognosis. However, both the polymorphisms- rs13347 and rs353639 had no effect on breast cancer susceptibility. PMID:23940692

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

Mangoni, Monica; Bisanzi, Simonetta; Carozzi, Francesca

Purpose: Clinical radiosensitivity varies considerably among patients, and radiation-induced side effects developing in normal tissue can be therapy limiting. Some single nucleotide polymorphisms (SNPs) have been shown to correlate with hypersensitivity to radiotherapy. We conducted a prospective study of 87 female patients with breast cancer who received radiotherapy after breast surgery. We evaluated the association between acute skin reaction following radiotherapy and 11 genetic polymorphisms in DNA repair genes: XRCC1 (Arg399Gln and Arg194Trp), XRCC3 (Thr241Met), XPD (Asp312Asn and Lys751Gln), MSH2 (gIVS12-6T>C), MLH1 (Ile219Val), MSH3 (Ala1045Thr), MGMT (Leu84Phe), and in damage-detoxification GSTM1 and GSTT1 genes (allele deletion). Methods and Materials: Individualmore » genetic polymorphisms were determined by polymerase chain reaction and single nucleotide primer extension for single nucleotide polymorphisms or by a multiplex polymerase chain reaction assay for deletion polymorphisms. The development of severe acute skin reaction (moist desquamation or interruption of radiotherapy due to toxicity) associated with genetic polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose. Results: Radiosensitivity developed in eight patients and was increased in carriers of variants XRCC3-241Met allele (hazard ratio [HR] unquantifiably high), MSH2 gIVS12-6nt-C allele (HR = 53.36; 95% confidence intervals [95% CI], 3.56-798.98), and MSH3-1045Ala allele (HR unquantifiably high). Carriers of XRCC1-Arg194Trp variant allele in combination with XRCC1-Arg399Gln wild-type allele had a significant risk of radiosensitivity (HR = 38.26; 95% CI, 1.19-1232.52). Conclusions: To our knowledge, this is the first report to find an association between MSH2 and MSH3 genetic variants and the development of radiosensitivity in breast cancer patients. Our findings suggest the hypothesis that mismatch repair mechanisms may be involved in cellular response to radiotherapy. Genetic polymorphisms may be promising candidates for predicting acute radiosensitivity, but further studies are necessary to confirm our findings.« less

Implication of common and disease specific variants in CLU, CR1, and PICALM.

PubMed

Ferrari, Raffaele; Moreno, Jorge H; Minhajuddin, Abu T; O'Bryant, Sid E; Reisch, Joan S; Barber, Robert C; Momeni, Parastoo

2012-08-01

Two recent genome-wide association studies (GWAS) for late onset Alzheimer's disease (LOAD) revealed 3 new genes: clusterin (CLU), phosphatidylinositol binding clathrin assembly protein (PICALM), and complement receptor 1 (CR1). In order to evaluate association with these genome-wide association study-identified genes and to isolate the variants contributing to the pathogenesis of LOAD, we genotyped the top single nucleotide polymorphisms (SNPs), rs11136000 (CLU), rs3818361 (CR1), and rs3851179 (PICALM), and sequenced the entire coding regions of these genes in our cohort of 342 LOAD patients and 277 control subjects. We confirmed the association of rs3851179 (PICALM) (p = 7.4 × 10(-3)) with the disease status. Through sequencing we identified 18 variants in CLU, 3 of which were found exclusively in patients; 8 variants (out of 65) in CR1 gene were only found in patients and the 16 variants identified in PICALM gene were present in both patients and controls. In silico analysis of the variants in PICALM did not predict any damaging effect on the protein. The haplotype analysis of the variants in each gene predicted a common haplotype when the 3 single nucleotide polymorphisms rs11136000 (CLU), rs3818361 (CR1), and rs3851179 (PICALM), respectively, were included. For each gene the haplotype structure and size differed between patients and controls. In conclusion, we confirmed association of CLU, CR1, and PICALM genes with the disease status in our cohort through identification of a number of disease-specific variants among patients through the sequencing of the coding region of these genes. Published by Elsevier Inc.

Characterization of the c.(-203)A>G variant in the glucocerebrosidase gene and its association with phenotype in Gaucher disease.

PubMed

Alfonso, Pilar; Pampín, Sandra; García-Rodríguez, Beatriz; Tejedor, Teresa; Domínguez, Carmen; Rodríguez-Rey, Jose C; Giraldo, Pilar; Pocoví, Miguel

2011-01-30

Gaucher disease (GD) is a rare autosomal recessive disorder caused mainly by mutations in the glucocerebrosidase (GBA) gene. Great phenotypic variability has been observed among patients with the same genotype, suggesting other factors, such as polymorphic variants, might influence GD phenotypes. We previously reported the c.(-203)A>G (g.1256A>G) variant in exon 1 of the GBA gene in Spanish GD patients. We analyzed the frequency and transcriptional activity of the promoter carrying the G-allele using restriction isotyping, electrophoretic mobility shift assay, cell culture, transfection, and luciferase assays. We found the variant is present at a similar frequency to the control group. In our patients, the G-allele was always found in combination with another mutation in the same allele, and patients carrying the c.(-203)A>G variant showed a more severe GD phenotype. The promoter containing the G-allele showed a 35% reduction in promoter activity when transfected into HepG2 cells. The c.(-203)A>G variant seems to be a polymorphism resulting in a decrease in activity of the GBA promoter. The change, per se, is not enough to elicit a GD phenotype, but it may produce a more severe phenotype in GD patients when combined with an already defective GBA protein. Copyright © 2010 Elsevier B.V. All rights reserved.

Association analysis of calpain 10 gene variants/haplotypes with gestational diabetes mellitus among Mexican women.

PubMed

Castro-Martínez, Anna Gabriela; Sánchez-Corona, José; Vázquez-Vargas, Adriana Patricia; García-Zapién, Alejandra Guadalupe; López-Quintero, Andres; Villalpando-Velazco, Héctor Javier; Flores-Martínez, Silvia Esperanza

2018-02-28

Gestational diabetes mellitus (GDM) is a metabolically complex disease with major genetic determinants. GDM has been associated with insulin resistance and dysfunction of pancreatic beta cells, so the GDM candidate genes are those that encode proteins modulating the function and secretion of insulin, such as that for calpain 10 (CAPN10). This study aimed to assess whether single nucleotide polymorphism (SNP)-43, SNP-44, SNP-63, and the indel-19 variant, and specific haplotypes of the CAPN10 gene were associated with gestational diabetes mellitus. We studied 116 patients with gestational diabetes mellitus and 83 women with normal glucose tolerance. Measurements of anthropometric and biochemical parameters were performed. SNP-43, SNP-44, and SNP-63 were identified by polymerase chain reaction (PCR)-restriction fragment length polymorphisms, while the indel-19 variant was detected by TaqMan qPCR assays.  The allele, genotype, and haplotype frequencies of the four variants did not differ significantly between women with gestational diabetes mellitus and controls. However, in women with gestational diabetes mellitus, glucose levels were significantly higher bearing the 3R/3R genotype than in carriers of the 3R/2R genotype of the indel-19 variant (p = 0.006). In conclusion, the 3R/3R genotype of the indel-19 variant of the CAPN-10 gene influenced increased glucose levels in these Mexican women with gestational diabetes mellitus.

MTR WING, TRA604, INTERIOR. BASEMENT. INTERIOR VIEW FROM SAME LOCATION ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

MTR WING, TRA-604, INTERIOR. BASEMENT. INTERIOR VIEW FROM SAME LOCATION IN WEST CORRIDOR AS PHOTO ID-33-G-42 BUT CAMERA FACES SOUTH. SIGN ON DOOR FOR "PIPE TUNNEL" WARNS OF RADIOLOGICAL AND ASBESTOS HAZARDS. DOOR HAS METAL HASPS. SIGN ON OVERHEAD WASTE HEAT RECOVERY PIPES SAYS THEY CONTAIN "ASBESTOS FREE INSULATION." FIRE DOOR AT LEFT LEADS TO STAIRWAY TO FIRST FLOOR. DOOR AT RIGHT LEADS TO ROOM WHICH ONCE CONTAINED MTR LIBRARY. INL NEGATIVE NO. HD46-13-4. Mike Crane, Photographer, 2/2005 - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

Inheritance of allozyme variants in bishop pine (Pinus muricata D.Don)

Treesearch

Constance I. Millar

1985-01-01

Isozyme phenotypes are described for 45 structural loci and I modifier locus in bishop pine (Pinus muricata D. Don,) and segregation data are presented for a subset of 31 polymorphic loci from 19 enzyme systems. All polymorphic loci had alleles that segregated within single-focus Mendelian expectations, although one pair of alleles at each of three...

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

PubMed

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

2007-04-01

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

Screening for rare variants in the PNPLA3 gene in obese liver biopsy patients.

PubMed

Zegers, Doreen; Verrijken, An; Francque, Sven; de Freitas, Fenna; Beckers, Sigri; Aerts, Evi; Ruppert, Martin; Hubens, Guy; Michielsen, Peter; Van Hul, Wim; Van Gaal, Luc F

2016-12-01

Previous research has clearly implicated the PNPLA3 gene in the etiology of nonalcoholic fatty liver disease as a polymorphism in the gene was found to be robustly associated to the disease. However, data on the involvement of rare PNPLA3 variants in the development of nonalcoholic fatty liver disease (NAFLD) is currently limited. Therefore, we performed an extensive mutation analysis study on a cohort of obese liver biopsy patients to determine PNPLA3 variation and its correlation with fatty liver disease. We screened the entire coding region of the PNPLA3 gene in DNA samples of 393 obese liver biopsy patients with varying degrees of fatty liver disease. Mutation analysis was performed by high-resolution melting curve analysis in combination with direct sequencing. We identified several common polymorphisms as well as one rare synonymous variant (c.867G>A rs139896256), one rare intronic variant (c.979+13C>T) and 3 nonsynonymous coding variants (p.A76T, p.A104V and p.T200M) in the PNPLA3 gene. In silico analysis indicated that the p.A104V variant will probably have no functional effect, whereas for the p.A76T and p.T200M variant a possible pathogenic effect is suggested. Overall, we showed that novel variants in PNPLA3 are very rare in our liver biopsy cohort, thereby indicating that their impact on the etiology of NAFLD is probably limited. Nevertheless, for the three rare coding variants that were identified in patients with advanced liver disease, further functional characterization will be essential to verify their potential disease causality. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Whole-genome sequencing and genetic variant analysis of a Quarter Horse mare.

PubMed

Doan, Ryan; Cohen, Noah D; Sawyer, Jason; Ghaffari, Noushin; Johnson, Charlie D; Dindot, Scott V

2012-02-17

The catalog of genetic variants in the horse genome originates from a few select animals, the majority originating from the Thoroughbred mare used for the equine genome sequencing project. The purpose of this study was to identify genetic variants, including single nucleotide polymorphisms (SNPs), insertion/deletion polymorphisms (INDELs), and copy number variants (CNVs) in the genome of an individual Quarter Horse mare sequenced by next-generation sequencing. Using massively parallel paired-end sequencing, we generated 59.6 Gb of DNA sequence from a Quarter Horse mare resulting in an average of 24.7X sequence coverage. Reads were mapped to approximately 97% of the reference Thoroughbred genome. Unmapped reads were de novo assembled resulting in 19.1 Mb of new genomic sequence in the horse. Using a stringent filtering method, we identified 3.1 million SNPs, 193 thousand INDELs, and 282 CNVs. Genetic variants were annotated to determine their impact on gene structure and function. Additionally, we genotyped this Quarter Horse for mutations of known diseases and for variants associated with particular traits. Functional clustering analysis of genetic variants revealed that most of the genetic variation in the horse's genome was enriched in sensory perception, signal transduction, and immunity and defense pathways. This is the first sequencing of a horse genome by next-generation sequencing and the first genomic sequence of an individual Quarter Horse mare. We have increased the catalog of genetic variants for use in equine genomics by the addition of novel SNPs, INDELs, and CNVs. The genetic variants described here will be a useful resource for future studies of genetic variation regulating performance traits and diseases in equids.

Single nucleotide polymorphisms associated with nonsyndromic cryptorchidism in Mexican patients.

PubMed

Chávez-Saldaña, M; Vigueras-Villaseñor, R M; Yokoyama-Rebollar, E; Landero-Huerta, D A; Rojas-Castañeda, J C; Taja-Chayeb, L; Cuevas-Alpuche, J O; Zambrano, E

2018-02-01

Cryptorchidism is a frequent genitourinary malformation considered as an important risk factor for infertility and testicular malignancy. The aetiology of cryptorchidism is multifactorial in which certain SNPs, capable of inhibiting the development of the gubernaculum, are implicated. We analysed 16 SNPs by allelic discrimination and automated sequencing in 85 patients and 99 healthy people, with the objective to identify the association between these variants and isolated cryptorchidism. In two different patients with unilateral cryptorchidism, we found the variants rs121912556 and p.R105R of INSL3 gene in a heterozygous form associated with cryptorchidism, so we could considered them as risk factors for cryptorchidism. On the other hand, SNPs rs10421916 of INSL3 gene, as well as the variants rs1555633 and rs7325513 in the RXFP2 gene, and rs3779456 variant of the HOXA10 gene were statistically significant, when the patients and controls were compared and could be considered as protective factors since are predominantly present in controls. The genotype-phenotype correlation did not show statistical significance. With these results, we could conclude that these polymorphisms can be considered as important variants in our population and would contribute in the future knowledge of the aetiology and physiopathology of cryptorchidism. © 2017 Blackwell Verlag GmbH.

Rapid and cost-effective method for the detection of the c.533G>A mutation in the HEXA gene.

PubMed

Ribeiro, Diogo; Duarte, Ana Joana; Amaral, Olga

2011-03-01

Tay-Sachs disease is a rare autosomal recessive neurodegenerative disorder that results from mutations in the HEXA gene, leading to β-hexosaminidase A (HexA) α subunit deficiency. An unusual variant of Tay-Sachs disease is known as the B1 variant. Previous studies indicated that, in northern Portugal, this is not only the most common variant but also one of the most prevalent lysosomal storage diseases. Additionally, this variant might also show a higher prevalence in populations of Portuguese and Spanish ancestry. A single mutation is invariably present in at least one of the alleles of B1 variant patients, HEXA mutation c.533G >A. To implement a method for c.533G >A testing in individuals and populations, we have optimized two distinct mutation analysis techniques, one based on restriction fragment length polymorphism analysis and the other based on allelic discrimination. We present the comparison of both methods and their advantages. Mutation screening by allelic discrimination proved to be particularly useful for the studying of large samples of individuals. It is time saving and highly reproducible, and under the conditions used, its cost is lower than the cost of polymerase chain reaction-based restriction fragment length polymorphism analysis.

Identification of a novel valosin-containing protein polymorphism in late-onset Alzheimer's disease.

PubMed

Kaleem, M; Zhao, A; Hamshere, M; Myers, A J

2007-01-01

Recently, mutations in the valosin-containing protein gene (VCP) were found to be causative for a rare form of dementia [Watts GDJ, et al.: Nat Genet 2004;36:377-381]. This gene lies within a region on the genome that has been linked to late onset Alzheimer's disease (LOAD) [Myers A, et al.: Am J Med Genet 2002;114:233-242]. In this study, we investigated whether variation within VCP could account for the LOAD linkage peak on chromosome 9. We sequenced 188 individuals from the set of sibling pairs we had used to obtain the linkage results for chromosome 9 to look for novel polymorphisms that could explain the linkage signal. Any variant that was found was then typed in 2 additional sets of neuropathologically confirmed samples to look for associations with Alzheimer's disease. We found 2 variants when we sequenced VCP. One was a novel rare variant (R92H) and the other is already reported within the publicly available databases (rs10972300). Neither explained the chromosome 9 linkage signal for LOAD. We have found a novel rare variant within the VCP gene, but we did not find a variant that could explain the linkage signal for LOAD on chromosome 9. Copyright (c) 2007 S. Karger AG, Basel.

Exploring the feasibility of using copy number variants as genetic markers through large-scale whole genome sequencing experiments

USDA-ARS?s Scientific Manuscript database

Copy number variants (CNV) are large scale duplications or deletions of genomic sequence that are caused by a diverse set of molecular phenomena that are distinct from single nucleotide polymorphism (SNP) formation. Due to their different mechanisms of formation, CNVs are often difficult to track us...

Regionally clustered ABCC8 polymorphisms in a prospective cohort predict cerebral oedema and outcome in severe traumatic brain injury.

PubMed

Jha, Ruchira Menka; Koleck, Theresa A; Puccio, Ava M; Okonkwo, David O; Park, Seo-Young; Zusman, Benjamin E; Clark, Robert S B; Shutter, Lori A; Wallisch, Jessica S; Empey, Philip E; Kochanek, Patrick M; Conley, Yvette P

2018-04-19

ABCC8 encodes sulfonylurea receptor 1, a key regulatory protein of cerebral oedema in many neurological disorders including traumatic brain injury (TBI). Sulfonylurea-receptor-1 inhibition has been promising in ameliorating cerebral oedema in clinical trials. We evaluated whether ABCC8 tag single-nucleotide polymorphisms predicted oedema and outcome in TBI. DNA was extracted from 485 prospectively enrolled patients with severe TBI. 410 were analysed after quality control. ABCC8 tag single-nucleotide polymorphisms (SNPs) were identified (Hapmap, r 2 >0.8, minor-allele frequency >0.20) and sequenced (iPlex-Gold, MassArray). Outcomes included radiographic oedema, intracranial pressure (ICP) and 3-month Glasgow Outcome Scale (GOS) score. Proxy SNPs, spatial modelling, amino acid topology and functional predictions were determined using established software programs. Wild-type rs7105832 and rs2237982 alleles and genotypes were associated with lower average ICP (β=-2.91, p=0.001; β=-2.28, p=0.003) and decreased radiographic oedema (OR 0.42, p=0.012; OR 0.52, p=0.017). Wild-type rs2237982 also increased favourable 3-month GOS (OR 2.45, p=0.006); this was partially mediated by oedema (p=0.03). Different polymorphisms predicted 3-month outcome: variant rs11024286 increased (OR 1.84, p=0.006) and wild-type rs4148622 decreased (OR 0.40, p=0.01) the odds of favourable outcome. Significant tag and concordant proxy SNPs regionally span introns/exons 2-15 of the 39-exon gene. This study identifies four ABCC8 tag SNPs associated with cerebral oedema and/or outcome in TBI, tagging a region including 33 polymorphisms. In polymorphisms predictive of oedema, variant alleles/genotypes confer increased risk. Different variant polymorphisms were associated with favourable outcome, potentially suggesting distinct mechanisms. Significant polymorphisms spatially clustered flanking exons encoding the sulfonylurea receptor site and transmembrane domain 0/loop 0 (juxtaposing the channel pore/binding site). This, if validated, may help build a foundation for developing future strategies that may guide individualised care, treatment response, prognosis and patient selection for clinical trials. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Association between genetic polymorphisms in the XRCC1, XRCC3, XPD, GSTM1, GSTT1, MSH2, MLH1, MSH3, and MGMT genes and radiosensitivity in breast cancer patients.

PubMed

Mangoni, Monica; Bisanzi, Simonetta; Carozzi, Francesca; Sani, Cristina; Biti, Giampaolo; Livi, Lorenzo; Barletta, Emanuela; Costantini, Adele Seniori; Gorini, Giuseppe

2011-09-01

Clinical radiosensitivity varies considerably among patients, and radiation-induced side effects developing in normal tissue can be therapy limiting. Some single nucleotide polymorphisms (SNPs) have been shown to correlate with hypersensitivity to radiotherapy. We conducted a prospective study of 87 female patients with breast cancer who received radiotherapy after breast surgery. We evaluated the association between acute skin reaction following radiotherapy and 11 genetic polymorphisms in DNA repair genes: XRCC1 (Arg399Gln and Arg194Trp), XRCC3 (Thr241Met), XPD (Asp312Asn and Lys751Gln), MSH2 (gIVS12-6T>C), MLH1 (Ile219Val), MSH3 (Ala1045Thr), MGMT (Leu84Phe), and in damage-detoxification GSTM1 and GSTT1 genes (allele deletion). Individual genetic polymorphisms were determined by polymerase chain reaction and single nucleotide primer extension for single nucleotide polymorphisms or by a multiplex polymerase chain reaction assay for deletion polymorphisms. The development of severe acute skin reaction (moist desquamation or interruption of radiotherapy due to toxicity) associated with genetic polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose. Radiosensitivity developed in eight patients and was increased in carriers of variants XRCC3-241Met allele (hazard ratio [HR] unquantifiably high), MSH2 gIVS12-6nt-C allele (HR=53.36; 95% confidence intervals [95% CI], 3.56-798.98), and MSH3-1045Ala allele (HR unquantifiably high). Carriers of XRCC1-Arg194Trp variant allele in combination with XRCC1-Arg399Gln wild-type allele had a significant risk of radiosensitivity (HR=38.26; 95% CI, 1.19-1232.52). To our knowledge, this is the first report to find an association between MSH2 and MSH3 genetic variants and the development of radiosensitivity in breast cancer patients. Our findings suggest the hypothesis that mismatch repair mechanisms may be involved in cellular response to radiotherapy. Genetic polymorphisms may be promising candidates for predicting acute radiosensitivity, but further studies are necessary to confirm our findings. Copyright © 2011 Elsevier Inc. All rights reserved.

Regulatory role of Cdx-2 and Taq I polymorphism of vitamin D receptor gene on chemokine expression in pulmonary tuberculosis.

PubMed

Harishankar, M; Selvaraj, P

2016-06-01

Vitamin D receptor (VDR) gene variants have been shown to be regulating the immune response in tuberculosis. We studied the regulatory role of VDR promoter Cdx-2 and 3'UTR TaqI gene variants on chemokine levels from culture filtrate antigen (CFA) stimulated with or without 1,25(OH)2D3 treated peripheral blood mononuclear cells of 50 pulmonary tuberculosis patients (PTB) and 51 normal healthy controls (HCs). In CFA with 1,25(OH)2D3 treated cultures, the MIP-1α, MIP-1β, RANTES levels were significantly decreased in Cdx-2 AA genotype compared to GG genotype, while a significantly increased MIG level was observed in Cdx-2 AA genotype (p<0.05). In TaqI polymorphism, tt genotype significantly decreased MIP-1β and RANTES levels compared to TT genotype. Moreover, a significantly increased level of IP-10 and MIG was observed in TaqI tt genotype compared with TT genotype (p<0.05). The results suggests that the 1,25(OH)2D3 may alter the chemokine response through the VDR polymorphic variants during infection. Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Pharmacogenetics of drug-metabolizing enzymes in US Hispanics

PubMed Central

Duconge, Jorge; Cadilla, Carmen L.; Ruaño, Gualberto

2015-01-01

Although the Hispanic population is continuously growing in the United States, they are underrepresented in pharmacogenetic studies. This review addresses the need for compiling available pharmacogenetic data in US Hispanics, discussing the prevalence of clinically relevant polymorphisms in pharmacogenes encoding for drug-metabolizing enzymes. CYP3A5*3 (0.245–0.867) showed the largest frequency in a US Hispanic population. A higher prevalence of CYP2C9*3, CYP2C19*4, and UGT2B7 IVS1+985 A>Gwas observed in US Hispanic vs. non-Hispanic populations. We found interethnic and intraethnic variability in frequencies of genetic polymorphisms for metabolizing enzymes, which highlights the need to define the ancestries of participants in pharmacogenetic studies. New approaches should be integrated in experimental designs to gain knowledge about the clinical relevance of the unique combination of genetic variants occurring in this admixed population. Ethnic subgroups in the US Hispanic population may harbor variants that might be part of multiple causative loci or in linkage-disequilibrium with functional variants. Pharmacogenetic studies in Hispanics should not be limited to ascertain commonly studied polymorphisms that were originally identified in their parental populations. The success of the Personalized Medicine paradigm will depend on recognizing genetic diversity between and within US Hispanics and the uniqueness of their genetic backgrounds. PMID:25431893

Evaluation of the association between the TAS1R2 and TAS1R3 variants and food intake and nutritional status in children.

PubMed

Melo, Silvia V; Agnes, Grasiela; Vitolo, Márcia R; Mattevi, Vanessa S; Campagnolo, Paula D B; Almeida, Silvana

2017-01-01

Taste perception plays a key role in determining individual food preferences and dietary habits and may influence nutritional status. This study aimed to investigate the association of TAS1R2 (Ile191Val - rs35874116) and TAS1R3 (-1266 C/T - rs35744813) variants with food intake and nutritional status in children followed from birth until 7.7 years old. The nutritional status and food intake data of 312 children were collected at three developmental stages (1, 3.9 and 7.7 years old). DNA was extracted from blood samples and the polymorphisms were analyzed by real-time polymerase chain reactions (qPCR) using hydrolysis probes as the detection method. Food intake and nutritional status were compared among individuals with different single nucleotide polymorphism (SNP) genotypes. At 3.9 years old, children homozygous (Val/Val) for the TAS1R2 Ile191Val polymorphism ingested less sugar and sugar-dense foods than children who were *Ile carriers. This finding demonstrated that a genetic variant of the T1R2 taste receptor is associated with the intake of different amounts of high sugar-content foods in childhood. This association may provide new perspectives for studying dietary patterns and nutritional status in childhood.

Molecular characterization of allelic variants of (GATA)n microsatellite loci in parthenogenetic lizards Darevskia unisexualis (Lacertidae).

PubMed

Korchagin, V I; Badaeva, T N; Tokarskaya, O N; Martirosyan, I A; Darevsky, I S; Ryskov, A P

2007-05-01

Populations of parthenogenetic lizards of the genus Darevskia consist of genetically identical animals, and represent a unique model for studying the molecular mechanisms underlying the variability and evolution of hypervariable DNA repeats. As unisexual lineages, parthenogenetic lizards are characterized by some level of genetic diversity at microsatellite loci. We cloned and sequenced a number of (GATA)n microsatellite loci of Darevskia unisexualis. PCR products from these loci were also sequenced and the degree of intraspecific polymorphism was assessed. Among the five (GATA)n loci analysed, two (Du215 and Du281) were polymorphic. Cross-species analysis of Du215 and Du281 indicate that the priming sites at the D. unisexualis loci are conserved in the bisexual parental species, D. raddei and D. valentini. Sequencing the PCR products amplified from Du215 and Du281 and from monomorphic Du323 showed that allelic differences at the polymorphic loci are caused by microsatellite mutations and by point mutations in the flanking regions. The haplotypes identified among the allelic variants of Du281 and among its orthologues in the parental species provide new evidence of the cross-species origin of D. unisexualis. To our knowledge, these data are the first to characterize the nucleotide sequences of allelic variants at microsatellite loci within parthenogenetic vertebrate animals.

MTR WING, TRA604, INTERIOR. BASEMENT. WEST CORRIDOR. CAMERA FACES NORTH. ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

MTR WING, TRA-604, INTERIOR. BASEMENT. WEST CORRIDOR. CAMERA FACES NORTH. HVAC AREA IS AT RIGHT OF CORRIDOR. INL NEGATIVE NO. HD46-13-3. Mike Crane, Photographer, 2/2005 - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

MTR STACK, TRA710, CONTEXTUAL VIEW, CAMERA FACING SOUTH. PERIMETER SECURITY ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

MTR STACK, TRA-710, CONTEXTUAL VIEW, CAMERA FACING SOUTH. PERIMETER SECURITY FENCE AND SECURITY LIGHTING IN VIEW AT LEFT. INL NEGATIVE NO. HD52-1-1. Mike Crane, Photographer, 5/2005 - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

MTR WING, TRA604. PRECAST CONCRETE PANELS AND DIMENSIONS FOR PANELS ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

MTR WING, TRA-604. PRECAST CONCRETE PANELS AND DIMENSIONS FOR PANELS K THROUGH Q. BLAW-KNOX 3150-804-21, SHEET #2, 11/1950. INL INDEX NO. 531-0604-62-098-100645, REV. 2. - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

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

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

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

1996-06-01

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

ESR1 and ESR2 polymorphisms in the BIG 1-98 trial comparing adjuvant letrozole versus tamoxifen or their sequence for early breast cancer.

PubMed

Leyland-Jones, Brian; Gray, Kathryn P; Abramovitz, Mark; Bouzyk, Mark; Young, Brandon; Long, Bradley; Kammler, Roswitha; Dell'Orto, Patrizia; Biasi, Maria Olivia; Thürlimann, Beat; Harvey, Vernon; Neven, Patrick; Arnould, Laurent; Maibach, Rudolf; Price, Karen N; Coates, Alan S; Goldhirsch, Aron; Gelber, Richard D; Pagani, Olivia; Viale, Giuseppe; Rae, James M; Regan, Meredith M

2015-12-01

Estrogen receptor 1 (ESR1) and ESR2 gene polymorphisms have been associated with endocrine-mediated physiological mechanisms, and inconsistently with breast cancer risk and outcomes, bone mineral density changes, and hot flushes/night sweats. DNA was isolated and genotyped for six ESR1 and two ESR2 single-nucleotide polymorphisms (SNPs) from tumor specimens from 3691 postmenopausal women with hormone receptor-positive breast cancer enrolled in the BIG 1-98 trial to receive tamoxifen and/or letrozole for 5 years. Associations with recurrence and adverse events (AEs) were assessed using Cox proportional hazards models. 3401 samples were successfully genotyped for five SNPs. ESR1 rs9340799(XbaI) (T>C) variants CC or TC were associated with reduced breast cancer risk (HR = 0.82,95% CI = 0.67-1.0), and ESR1 rs2077647 (T>C) variants CC or TC was associated with reduced distant recurrence risk (HR = 0.69, 95% CI = 0.53-0.90), both regardless of the treatments. No differential treatment effects (letrozole vs. tamoxifen) were observed for the association of outcome with any of the SNPs. Letrozole-treated patients with rs2077647 (T>C) variants CC and TC had a reduced risk of bone AE (HR = 0.75, 95% CI = 0.58-0.98, P interaction = 0.08), whereas patients with rs4986938 (G>A) genotype variants AA and AG had an increased risk of bone AE (HR = 1.37, 95% CI = 1.01-1.84, P interaction = 0.07). We observed that (1) rare ESR1 homozygous polymorphisms were associated with lower recurrence, and (2) ESR1 and ESR2 SNPs were associated with bone AEs in letrozole-treated patients. Genes that are involved in estrogen signaling and synthesis have the potential to affect both breast cancer recurrence and side effects, suggesting that individual treatment strategies can incorporate not only oncogenic drivers but also SNPs related to estrogen activity.

Common non-synonymous polymorphisms in the BRCA1 Associated RING Domain (BARD1) gene are associated with breast cancer susceptibility: a case-control analysis.

PubMed

Huo, Xiang; Hu, Zhibin; Zhai, Xiangjun; Wang, Yan; Wang, Shui; Wang, Xuechen; Qin, Jianwei; Chen, Wenseng; Jin, Guangfu; Liu, Jiyong; Gao, Jun; Wei, Qingyi; Wang, Xinru; Shen, Hongbing

2007-05-01

The BRCA1 Associated RING Domain (BARD1) gene has been identified as a high penetrance gene for breast cancer, whose germline and somatic mutations were reported in both non-BRCA1/2 hereditary site-specific and sporadic breast cancer cases. BARD1 plays a crucial role in tumor repression, along with its heterodimeric partner BRCA1. In the current study, we tested the hypothesis that common non-synonymous polymorphisms in BARD1 are associated with breast cancer susceptibility in a case-control study of 507 patients with incident breast cancer and 539 frequency-matched cancer-free controls in Chinese women. We genotyped all three common (minor allele frequency (MAF)>0.10) non-synonymous polymorphisms (Pro24Ser, Arg378Ser, and Val507Met) in BARD1. We found that the BARD1 Pro24Ser variant genotypes (24Pro/Ser and 24Ser/Ser) and Arg378Ser variant homozygote 378Ser/Ser were associated with a significantly decreased breast cancer risk, compared with their wild-type homozygotes, respectively. Furthermore, a significant locus-locus interaction was evident between Pro24Ser and Arg378Ser (P(int )= 0.032). Among the 378Ser variant allele carriers, the 24Pro/Pro wild-type homozygote was associated with a significantly increased breast cancer risk (adjusted OR=1.81, 95% CI=1.11-2.95), but the subjects having 24Pro/Ser or Ser/Ser variant genotypes had a significantly decreased risk (adjusted OR=0.74, 95% CI=0.56-0.99). In stratified analysis, this locus-locus interaction was more evident among subjects without family cancer history, those with positive estrogen receptor (ER) and individuals with negative progesterone receptor (PR). These findings indicate that the potentially functional polymorphisms Pro24Ser and Arg378Ser in BARD1 may jointly contribute to the susceptibility of breast cancer.

Identification of Genetic Polymorphisms of CYP2W1 in the Three Main Chinese Ethnicities: Han, Tibetan, and Uighur.

PubMed

Li, Yanwei; Kang, Xing; Yang, Ge; Dai, Penggao; Chen, Chao; Wang, Huijuan

2016-09-01

CYP2W1 is an orphan member of the cytochrome P450 superfamily. Recently, CYP2W1 has gained great research interest because of its unknown enzymatic function and tumor-specific expression property. This study aims to investigate the genetic polymorphisms of the CYP2W1 gene in Chinese populations and explore the functions of the detected variants. All of the nine exons and exon-intron junction regions of the CYP2W1 gene were sequenced in 150 Chinese subjects, including 50 Han Chinese, 50 Tibetans, and 50 Uighurs. A total of 26 genetic variants were identified in this study, and 19 polymorphisms were detected in each population. Frequency comparison between populations showed that nine variants exhibited significantly different allelic distributions. A total of 12 different haplotypes were inferred from 150 samples by using the genotype data of nine exonic variants found in this study. CYP2W1*1A, *1B, *2, *4, and *6 were detected as the main alleles/haplotypes. Moreover, one, three, and two ethnically specific haplotypes were observed in the Han, Tibetan, and Uighur samples, respectively. Then, the effects of four detected missense mutations (Ala181Thr, Gly376Ser, Val432Ile, and Pro488Leu) on the CYP2W1 protein function were predicted using three in silico tools: Polymorphism Phenotyping v2, Sorts Intolerant from Tolerant, and MutationTaster. The results showed that Gly376Ser and Pro488Leu may have deleterious effects. In summary, this study showed that the genetic pattern of CYP2W1 is interethnically different among the three Chinese populations, and this finding can extend our understanding of population genetics of CYP2W1 in the Chinese population. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Genetic variants in NTCP exon gene are associated with HBV infection status in a Chinese Han population.

PubMed

Wu, Wennan; Zeng, Yongbin; Lin, Jinpiao; Wu, Yingying; Chen, Tianbin; Xun, Zhen; Ou, Qishui

2018-04-01

Sodium taurocholate co-transporting polypeptide (NTCP) plays an important role in the enterohepatic circulation of bile acids. Recently, NTCP was identified as a hepatitis B virus (HBV) receptor. The aim of this study is to investigate the association of NTCP polymorphisms with HBV clinical outcomes and investigate the relationship between NTCP polymorphisms and the serum bile acid level in a Chinese Han population. The single nucleotide polymorphisms rs2296651 and rs4646285 were genotyped in 1619 Chinese Han individuals. Improved multiple ligase detection reaction was utilized to genotype. The level of bile acids was measured by the enzymatic cycling method. Quantitative polymerase chain reaction analysis was carried out to analyze the potential function. In logistic regression analysis, the frequency of rs2296651 (S267F) CT genotype was higher in HBV immune recovery and healthy control groups than in the chronic HBV infection group (P = 0.001 and P < 0.001, respectively). Patients who carried allele T showed a higher bile acid level than patients who did not carry allele T (P = 0.009). The rs4646285 AA genotype was more common in the immune recovery group than in the chronic HBV infection group (P = 0.011). No difference in serum bile acid was detected between the rs4646285 wild-type patients and mutant-type patients. Quantitative reverse transcription-polymerase chain reaction showed the NTCP mRNA levels were lower in rs4646285 variants than wild types. NTCP gene polymorphisms may be associated with the natural course of HBV infection in a Chinese Han population. The S267F variant may be a protective factor to resist chronic hepatitis B progression which showed a higher bile acid level in Chinese Han chronic HBV infection patients. The rs4646285 variants could influence the expression of NTCP at the level of transcription, and ultimately may be associated with HBV infection immune recovery. © 2017 The Japan Society of Hepatology.

Combined effects of ankylosing spondylitis-associated ERAP1 polymorphisms outside the catalytic and peptide-binding sites on the processing of natural HLA-B27 ligands.

PubMed

Martín-Esteban, Adrian; Gómez-Molina, Patricia; Sanz-Bravo, Alejandro; López de Castro, José A

2014-02-14

ERAP1 polymorphism involving residues 528 and 575/725 is associated with ankylosing spondylitis among HLA-B27-positive individuals. We used four recombinant variants to address the combined effects of the K528R and D575N polymorphism on the processing of HLA-B27 ligands. The hydrolysis of a fluorogenic substrate, Arg-528/Asp-575 < Lys-528/Asp-575 < Arg-528/Asn-575 < Lys-528/Asn-575, indicated that the relative activity of variants carrying Arg-528 or Lys-528 depends on residue 575. Asp-575 conferred lower activity than Asn-575, but the difference depended on residue 528. The same hierarchy was observed with synthetic precursors of HLA-B27 ligands, but the effects were peptide-dependent. Sometimes the epitope yields were variant-specific at all times. For other peptides, concomitant generation and destruction led to similar epitope amounts with all the variants at long, but not at short, digestion times. The generation/destruction balance of two related HLA-B27 ligands was analyzed in vitro and in live cells. Their relative yields at long digestion times were comparable with those from HLA-B27-positive cells, suggesting that ERAP1 was a major determinant of the abundance of these peptides in vivo. The hydrolysis of fluorogenic and peptide substrates by an HLA-B27 ligand or a shorter peptide, respectively, was increasingly inhibited as a function of ERAP1 activity, indicating that residues 528 and 575 affect substrate inhibition of ERAP1 trimming. The significant and complex effects of co-occurring ERAP1 polymorphisms on multiple HLA-B27 ligands, and their potential to alter the immunological and pathogenetic features of HLA-B27 as a function of the ERAP1 context, explain the epistatic association of both molecules in ankylosing spondylitis.

Combined Effects of Ankylosing Spondylitis-associated ERAP1 Polymorphisms Outside the Catalytic and Peptide-binding Sites on the Processing of Natural HLA-B27 Ligands*

PubMed Central

Martín-Esteban, Adrian; Gómez-Molina, Patricia; Sanz-Bravo, Alejandro; López de Castro, José A.

2014-01-01

ERAP1 polymorphism involving residues 528 and 575/725 is associated with ankylosing spondylitis among HLA-B27-positive individuals. We used four recombinant variants to address the combined effects of the K528R and D575N polymorphism on the processing of HLA-B27 ligands. The hydrolysis of a fluorogenic substrate, Arg-528/Asp-575 < Lys-528/Asp-575 < Arg-528/Asn-575 < Lys-528/Asn-575, indicated that the relative activity of variants carrying Arg-528 or Lys-528 depends on residue 575. Asp-575 conferred lower activity than Asn-575, but the difference depended on residue 528. The same hierarchy was observed with synthetic precursors of HLA-B27 ligands, but the effects were peptide-dependent. Sometimes the epitope yields were variant-specific at all times. For other peptides, concomitant generation and destruction led to similar epitope amounts with all the variants at long, but not at short, digestion times. The generation/destruction balance of two related HLA-B27 ligands was analyzed in vitro and in live cells. Their relative yields at long digestion times were comparable with those from HLA-B27-positive cells, suggesting that ERAP1 was a major determinant of the abundance of these peptides in vivo. The hydrolysis of fluorogenic and peptide substrates by an HLA-B27 ligand or a shorter peptide, respectively, was increasingly inhibited as a function of ERAP1 activity, indicating that residues 528 and 575 affect substrate inhibition of ERAP1 trimming. The significant and complex effects of co-occurring ERAP1 polymorphisms on multiple HLA-B27 ligands, and their potential to alter the immunological and pathogenetic features of HLA-B27 as a function of the ERAP1 context, explain the epistatic association of both molecules in ankylosing spondylitis. PMID:24352655

Polymorphisms in genes of interleukin 12 and its receptors and their association with protection against severe malarial anaemia in children in western Kenya.

PubMed

Zhang, Lyna; Prather, Donald; Vanden Eng, Jodi; Crawford, Sara; Kariuki, Simon; ter Kuile, Feiko; Terlouw, Dianne; Nahlen, Bernard; Lal, Altaf A; Slutsker, Laurence; Udhayakumar, Venkatachalam; Shi, Ya Ping

2010-03-29

Malarial anaemia is characterized by destruction of malaria infected red blood cells and suppression of erythropoiesis. Interleukin 12 (IL12) significantly boosts erythropoietic responses in murine models of malarial anaemia and decreased IL12 levels are associated with severe malarial anaemia (SMA) in children. Based on the biological relevance of IL12 in malaria anaemia, the relationship between genetic polymorphisms of IL12 and its receptors and SMA was examined. Fifty-five tagging single nucleotide polymorphisms covering genes encoding two IL12 subunits, IL12A and IL12B, and its receptors, IL12RB1 and IL12RB2, were examined in a cohort of 913 children residing in Asembo Bay region of western Kenya. An increasing copy number of minor variant (C) in IL12A (rs2243140) was significantly associated with a decreased risk of SMA (P = 0.006; risk ratio, 0.52 for carrying one copy of allele C and 0.28 for two copies). Individuals possessing two copies of a rare variant (C) in IL12RB1 (rs429774) also appeared to be strongly protective against SMA (P = 0.00005; risk ratio, 0.18). In addition, children homozygous for another rare allele (T) in IL12A (rs22431348) were associated with reduced risk of severe anaemia (SA) (P = 0.004; risk ratio, 0.69) and of severe anaemia with any parasitaemia (SAP) (P = 0.004; risk ratio, 0.66). In contrast, AG genotype for another variant in IL12RB1 (rs383483) was associated with susceptibility to high-density parasitaemia (HDP) (P = 0.003; risk ratio, 1.21). This study has shown strong associations between polymorphisms in the genes of IL12A and IL12RB1 and protection from SMA in Kenyan children, suggesting that human genetic variants of IL12 related genes may significantly contribute to the development of anaemia in malaria patients.

Genetic variants in the cell cycle control pathways contribute to early onset colorectal cancer in Lynch syndrome.

PubMed

Chen, Jinyun; Etzel, Carol J; Amos, Christopher I; Zhang, Qing; Viscofsky, Nancy; Lindor, Noralane M; Lynch, Patrick M; Frazier, Marsha L

2009-11-01

Lynch syndrome is an autosomal dominant syndrome of familial malignancies resulting from germ line mutations in DNA mismatch repair (MMR) genes. Our goal was to take a pathway-based approach to investigate the influence of polymorphisms in cell cycle-related genes on age of onset for Lynch syndrome using a tree model. We evaluated polymorphisms in a panel of cell cycle-related genes (AURKA, CDKN2A, TP53, E2F2, CCND1, TP73, MDM2, IGF1, and CDKN2B) in 220 MMR gene mutation carriers from 129 families. We applied a novel statistical approach, tree modeling (Classification and Regression Tree), to the analysis of data on patients with Lynch syndrome to identify individuals with a higher probability of developing colorectal cancer at an early age and explore the gene-gene interactions between polymorphisms in cell cycle genes. We found that the subgroup with CDKN2A C580T wild-type genotype, IGF1 CA-repeats >or=19, E2F2 variant genotype, AURKA wild-type genotype, and CCND1 variant genotype had the youngest age of onset, with a 45-year median onset age, while the subgroup with CDKN2A C580T wild-type genotype, IGF1 CA-repeats >or=19, E2F2 wild-type genotype, and AURKA variant genotype had the latest median age of onset, which was 70 years. Furthermore, we found evidence of a possible gene-gene interaction between E2F2 and AURKA genes related to CRC age of onset. Polymorphisms in these cell cycle-related genes work together to modify the age at the onset of CRC in patients with Lynch syndrome. These studies provide an important part of the foundation for development of a model for stratifying age of onset risk among those with Lynch syndrome.

Importance of 5α-reductase gene polymorphisms on circulating and intraprostatic androgens in prostate cancer.

PubMed

Lévesque, Éric; Laverdière, Isabelle; Lacombe, Louis; Caron, Patrick; Rouleau, Mélanie; Turcotte, Véronique; Têtu, Bernard; Fradet, Yves; Guillemette, Chantal

2014-02-01

Polymorphisms in the genes SRD5A1 and SRD5A2 encoding androgen biosynthetic 5α-reductase enzymes have been associated with an altered risk of biochemical recurrence after radical prostatectomy in localized prostate cancer. To gain potential insights into SRD5A biologic effects, we examined the relationship between SRD5A prognostic markers and endogenous sex-steroid levels measured by mass spectrometry in plasma samples and corresponding prostatic tissues of patients with prostate cancer. We report that five of the seven SRD5A markers differentially affect sex-steroid profiles of dihydrotestosterone and its metabolites in both the circulation and prostatic tissues of patients with prostate cancer. Remarkably, a 32% increase in intraprostatic testosterone levels was observed in the presence of the high-risk SRD5A rs2208532 polymorphism. Moreover, SRD5A2 markers were associated predominantly with circulating levels of inactive glucuronides. Indeed, the rs12470143 SRD5A2 protective allele was associated with high circulating androstane-3α, 17β-diol-17-glucuronide (3α-diol-17G) levels as opposed to lower levels of both 3α-diol-17G and androsterone-glucuronide observed with the rs2208532 SRD5A2 risk allele. Moreover, SRD5A2 rs676033 and rs523349 (V89L) risk variants, in strong linkage disequilibrium, were associated with higher circulating levels of 3α-diol-3G. The SRD5A2 rs676033 variant further correlated with enhanced intraprostatic exposure to 5α-reduced steroids (dihydrotestosterone and its metabolite 3β-diol). Similarly, the SRD5A1 rs166050C risk variant was associated with greater prostatic exposure to androsterone, whereas no association was noted with circulating steroids. Our data support the association of 5α-reductase germline polymorphisms with the hormonal milieu in patients with prostate cancer. Further studies are needed to evaluate if these variants influence 5α-reductase inhibitor efficacy. ©2013 AACR.

WDR36 and P53 Gene Variants and Susceptibility to Primary Open-Angle Glaucoma: Analysis of Gene-Gene Interactions

PubMed Central

Blanco-Marchite, Cristina; Sánchez-Sánchez, Francisco; López-Garrido, María-Pilar; Iñigez-de-Onzoño, Mercedes; López-Martínez, Francisco; López-Sánchez, Enrique; Alvarez, Lydia; Rodríguez-Calvo, Pedro-Pablo; Méndez-Hernández, Carmen; Fernández-Vega, Luis; García-Sánchez, Julián; Coca-Prados, Miguel; García-Feijoo, Julián

2011-01-01

Purpose. To investigate the role of WDR36 and P53 sequence variations in POAG susceptibility. Methods. The authors performed a case-control genetic association study in 268 unrelated Spanish patients (POAG1) and 380 control subjects matched for sex, age, and ethnicity. WDR36 sequence variations were screened by either direct DNA sequencing or denaturing high-performance liquid chromatography. P53 polymorphisms p.R72P and c.97–147ins16bp were analyzed by single-nucleotide polymorphism (SNP) genotyping and PCR, respectively. Positive SNP and haplotype associations were reanalyzed in a second sample of 211 patients and in combined cases (n = 479). Results. The authors identified almost 50 WDR36 sequence variations, of which approximately two-thirds were rare and one-third were polymorphisms. Approximately half the variants were novel. Eight patients (2.9%) carried rare mutations that were not identified in the control group (P = 0.001). Six Tag SNPs were expected to be structured in three common haplotypes. Haplotype H2 was consistently associated with the disease (P = 0.0024 in combined cases). According to a dominant model, genotypes containing allele P of the P53 p.R72P SNP slightly increased glaucoma risk. Glaucoma susceptibility associated with different WDR36 genotypes also increased significantly in combination with the P53 RP risk genotype, indicating the existence of a genetic interaction. For instance, the OR of the H2 diplotype estimated for POAG1 and combined cases rose approximately 1.6 times in the two-locus genotype H2/RP. Conclusions. Rare WDR36 variants and the P53 p.R72P polymorphism behaved as moderate glaucoma risk factors in Spanish patients. The authors provide evidence for a genetic interaction between WDR36 and P53 variants in POAG susceptibility, although this finding must be confirmed in other populations. PMID:21931130

SLC39A2 and FSIP1 polymorphisms as potential modifiers of arsenic-related bladder cancer

PubMed Central

Andrew, Angeline S.; Nelson, Heather H.; Li, Zhongze; Punshon, Tracy; Schned, Alan; Marsit, Carmen J.; Morris, J. Steven; Moore, Jason H.; Tyler, Anna L.; Gilbert-Diamond, Diane; Guerinot, Mary-Lou; Kelsey, Karl T.

2012-01-01

Arsenic is a carcinogen that contaminates drinking water worldwide. Accumulating evidence suggests that both exposure and genetic factors may influence susceptibility to arsenic-induced malignancies. We sought to identify novel susceptibility loci for arsenic-related bladder cancer in a US population with low to moderate drinking water levels of arsenic. We first screened a subset of bladder cancer cases using a panel of approximately 10,000 non-synonymous single nucleotide polymorphisms (SNPs). Top ranking hits on the SNP array then were considered for further analysis in our population-based case–control study (n = 832 cases and 1,191 controls). SNPs in the fibrous sheath interacting protein 1 (FSIP1) gene (rs10152640) and the solute carrier family 39, member 2 (SLC39A2) in the ZIP gene family of metal transporters (rs2234636) were detected as potential hits in the initial scan and validated in the full case–control study. The adjusted odds ratio (OR) for the FSIP1 polymorphism was 2.57 [95% confidence interval (CI) 1.13, 5.85] for heterozygote variants (AG) and 12.20 (95% CI 2.51, 59.30) for homozygote variants (GG) compared to homozygote wild types (AA) in the high arsenic group (greater than the 90th percentile), and unrelated in the low arsenic group (equal to or below the 90th percentile) (P for interaction = 0.002). For the SLC39A2 polymorphism, the adjusted ORs were 2.96 (95% CI 1.23, 7.15) and 2.91 (95% CI 1.00, 8.52) for heterozygote (TC) and homozygote (CC) variants compared to homozygote wild types (TT), respectively, and close to one in the low arsenic group (P for interaction = 0.03). Our findings suggest novel variants that may influence risk of arsenic-associated bladder cancer and those who may be at greatest risk from this widespread exposure. PMID:21947419

SLC39A2 and FSIP1 polymorphisms as potential modifiers of arsenic-related bladder cancer.

PubMed

Karagas, Margaret R; Andrew, Angeline S; Nelson, Heather H; Li, Zhongze; Punshon, Tracy; Schned, Alan; Marsit, Carmen J; Morris, J Steven; Moore, Jason H; Tyler, Anna L; Gilbert-Diamond, Diane; Guerinot, Mary-Lou; Kelsey, Karl T

2012-03-01

Arsenic is a carcinogen that contaminates drinking water worldwide. Accumulating evidence suggests that both exposure and genetic factors may influence susceptibility to arsenic-induced malignancies. We sought to identify novel susceptibility loci for arsenic-related bladder cancer in a US population with low to moderate drinking water levels of arsenic. We first screened a subset of bladder cancer cases using a panel of approximately 10,000 non-synonymous single nucleotide polymorphisms (SNPs). Top ranking hits on the SNP array then were considered for further analysis in our population-based case-control study (n = 832 cases and 1,191 controls). SNPs in the fibrous sheath interacting protein 1 (FSIP1) gene (rs10152640) and the solute carrier family 39, member 2 (SLC39A2) in the ZIP gene family of metal transporters (rs2234636) were detected as potential hits in the initial scan and validated in the full case-control study. The adjusted odds ratio (OR) for the FSIP1 polymorphism was 2.57 [95% confidence interval (CI) 1.13, 5.85] for heterozygote variants (AG) and 12.20 (95% CI 2.51, 59.30) for homozygote variants (GG) compared to homozygote wild types (AA) in the high arsenic group (greater than the 90th percentile), and unrelated in the low arsenic group (equal to or below the 90th percentile) (P for interaction = 0.002). For the SLC39A2 polymorphism, the adjusted ORs were 2.96 (95% CI 1.23, 7.15) and 2.91 (95% CI 1.00, 8.52) for heterozygote (TC) and homozygote (CC) variants compared to homozygote wild types (TT), respectively, and close to one in the low arsenic group (P for interaction = 0.03). Our findings suggest novel variants that may influence risk of arsenic-associated bladder cancer and those who may be at greatest risk from this widespread exposure.

Polymorphisms of pesticide-metabolizing genes in children living in intensive farming communities.

PubMed

Gómez-Martín, Antonio; Hernández, Antonio F; Martínez-González, Luis Javier; González-Alzaga, Beatriz; Rodríguez-Barranco, Miguel; López-Flores, Inmaculada; Aguilar-Garduno, Clemente; Lacasana, Marina

2015-11-01

Polymorphisms in genes encoding xenobiotic-metabolizing enzymes (XME) are important parameters accounting for the wide inter-individual variability to environmental exposures. Paraoxonase-1 (PON1), butyrylcholinesterase (BChE) and Cytochrome-P450 constitute major classes of XME involved in the detoxification of pesticide chemicals, in particular organophosphates. This study explored the allelic frequency, linkage disequilibrium and haplotype analysis of ten common polymorphic variants of seven key genes involved in organophosphate metabolism (BCHE-K, BCHE-A, PON1 Q192R, PON1 L55M, PON1 -108C/T, CYP2C19 G681A, CYP2D6 G1846A, CYP3AP1 -44G/A, GSTM1∗0 and GSTT1∗0) in a children population living near an intensive agriculture area in Spain. It was hypothesized that individuals with unfavorable combinations of gene variants will be more susceptible to adverse effects from organophosphate exposure. Genomic DNA from 496 healthy children was isolated and amplified by PCR. Hydrolysis probes were used for the detection of eight specific SNPs and two copy number variants (CNVs) by using TaqMan® Assay-based real-time PCR. Frequencies of SNPs and CNVs in the target genes were in Hardy-Weinberg equilibrium and broadly consistent with European populations. Linkage disequilibrium was found between the three PON1 genetic polymorphisms studied and between BCHE-K and BCHE-A. The adverse genotype combination (unusual BCHE variants, PON1 55MM/-108TT and null genotype for both GSTM1 and GSTT1) potentially conferring a greater genetic risk from exposure to organophosphates was observed in 0.2% of our study population. This information allows broadening our knowledge about differential susceptibility toward environmental toxicants and may be helpful for further research to understand the inter-individual toxicokinetic variability in response to organophosphate pesticides exposure. Copyright © 2015 Elsevier Ltd. All rights reserved.

Association of single nucleotide polymorphisms in WNT genes with the risk of nonsyndromic cleft lip with or without cleft palate.

PubMed

Rafighdoost, Houshang; Hashemi, Mohammad; Asadi, Hossein; Bahari, Gholamreza

2018-01-22

Nonsyndromic cleft lip with or without cleft palate is a common congenital deformity worldwide with multifaceted etiology. Interaction of genes and environmental factors has been indicated to be related with susceptibility to nonsyndromic cleft lip with or without cleft palate. Some WNT genes which are involved in craniofacial embryogenesis may play a key role in the pathogenesis of nonsyndromic cleft lip with or without cleft palate. In the present study, we aimed to inspect the relationship between WNT3 (rs3809857 and rs9890413), WNT3A (rs752107 and rs3121310), and WNT10a rs201002930 (c.392 C>T) polymorphisms and nonsyndromic cleft lip with or without cleft palate in an Iranian population. The present case-control study was carried out on 120 unrelated nonsyndromic cleft lip with or without cleft palate patients and 112 healthy subjects. The variants were genotyped by polymerase chain reaction-restriction fragment length polymorphism method. The findings suggest that the rs3809857 polymorphism significantly decreased the risk of nonsyndromic cleft lip with or without cleft palate in codominant (odds ratio = 0.16, 95% confidence interval = 0.03-0.75, P = 0.020, TT vs GG), recessive (odds ratio = 0.16, 95% confidence interval = 0.03-0.72, P = 0.009, TT vs GG + GT) inheritance models. The rs9890413 variant marginally decreased the risk of nonsyndromic cleft lip with or without cleft palate in codominant (odds ratio = 0.41, 95% confidence interval = 0.17-0.99, P = 0.047, AG vs AA) model. Regarding C392T variant, the findings revealed that this variant significantly decreased the risk of nonsyndromic cleft lip with or without cleft palate in codominant (odds ratio = 0.24, 95% confidence interval = 0.10-0.58, P = 0.002, CT vs CC) and allele (odds ratio = 0.26, 95% confidence interval = 0.11-0.62, P = 0.002, T vs C) models. No significant association was observed between the rs752107 and rs3121310 variants and risk/protection of nonsyndromic cleft lip with or without cleft palate. Stratified analysis showed that WNT10a rs201002930 (c.392 C>T) significantly decreased the risk of cleft lip with cleft palate and cleft palate only. In summary, the results suggest an association between WNT genes polymorphisms and the risk nonsyndromic cleft lip with or without cleft palate in a sample of the southeast Iranian population. © 2018 Japanese Teratology Society.

Genetic Variants in SDC3 Gene are Significantly Associated with Growth Traits in Two Chinese Beef Cattle Breeds.

PubMed

Huang, Yong-Zhen; Wang, Qin; Zhang, Chun-Lei; Fang, Xing-Tang; Song, En-Liang; Chen, Hong

2016-01-01

Identification of the genes and polymorphisms underlying quantitative traits, and understanding these genes and polymorphisms affect economic growth traits, are important for successful marker-assisted selection and more efficient management strategies in commercial cattle (Bos taurus) population. Syndecan-3 (SDC3), a member of the syndecan family of type I transmembrane heparan sulfate proteoglycans is a novel regulator of feeding behavior and body weight. The aim of this study is to examine the association of the SDC3 polymorphism with growth traits in Chinese Jiaxian and Qinchuan cattle breeds (). Four single nucleotide polymorphisms (SNPs: 1-4) were detected in 555 cows from three Chinese native cattle breeds by means of sequencing pooled DNA samples and polymerase chain reaction-single stranded conformational polymorphism (PCR-SSCP) methods. We found one SNP (g.28362A > G) in intron and three SNPs (g.30742T > G, g.30821C > T and 33418 A > G) in exons. The statistical analyses indicated that these SNPs of SDC3 gene were associated with bovine body height, body length, chest circumference, and circumference of cannon bone (P < 0.05). The mutant-type variant was superior for growth traits; the heterozygote was associated with higher growth traits compared to wild-type homozygote. Our result confirms the polymorphisms in the SDC3 gene are associated with growth traits that may be used for marker-assisted selection in beef cattle breeding programs.

Association of TERT Polymorphisms with Clinical Outcome of Non-Small Cell Lung Cancer Patients.

PubMed

Zhao, Xueying; Wang, Shiming; Wu, Junjie; Li, Xiaoying; Wang, Xun; Gao, Zhiqiang; Wu, Wenting; Wang, Haijian; Wang, Jiucun; Qian, Ji; Ma, Ke; Li, Hui; Han, Baohui; Bai, Chunxue; Li, Qiang; Liu, Wenbin; Lu, Daru

2015-01-01

TERT is of great importance in cancer initiation and progression. Many studies have demonstrated the TERT polymorphisms as risk factors for many cancer types, including lung cancer. However, the impacts of TERT variants on cancer progression and treatment efficacy have remained controversial. This study aimed to investigate the association of TERT polymorphisms with clinical outcome of advanced non-small cell lung cancer (NSCLC) patients receiving first-line platinum-based chemotherapy, including response rate, clinical benefit, progression-free survival (PFS), overall survival (OS), and grade 3 or 4 toxicity. Seven polymorphisms of TERT were assessed, and a total of 1004 inoperable advanced NSCLC patients treated with platinum-based chemotherapy were enrolled. It is exhibited that the variant heterozygote of rs4975605 showed significant association with a low rate of clinical benefit, and displayed a much stronger effect in never-smoking female subset, leading to the clinical benefit rate decreased from 82.9% (C/C genotype) to 56.4% (C/A genotype; adjusted OR, 3.58; P=1.40×10(-4)). It is also observed that the polymorphism rs2736109 showed significant correlation with PFS (log-rank P=0.023). In age > 58 subgroup, patients carrying the heterozygous genotype had a longer median PFS than those carrying the wild-type genotypes (P=0.002). The results from the current study, for the first time to our knowledge, provide suggestive evidence of an effect of TERT polymorphisms on disease progression variability among Chinese patients with platinum-treated advanced NSCLC.

Relationship between ABCB1 gene polymorphisms and severe neutropenia in patients with breast cancer treated with doxorubicin/cyclophosphamide chemotherapy.

PubMed

Ikeda, Midori; Tsuji, Daiki; Yamamoto, Keisuke; Kim, Yong-Il; Daimon, Takashi; Iwabe, Yutaro; Hatori, Masahiro; Makuta, Ryo; Hayashi, Hideki; Inoue, Kazuyuki; Nakamichi, Hidenori; Shiokawa, Mitsuru; Itoh, Kunihiko

2015-04-01

Chemotherapy-induced neutropenia is one of the major adverse events which results in the reduction of chemotherapy. Doxorubicin is a substrate of the adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) transporter; reportedly, ABCB1 polymorphisms influence doxorubicin pharmacokinetics. We evaluated the association between chemotherapy-induced neutropenia and ABCB1 polymorphisms in patients with breast cancer. We investigated 141 patients with breast cancer treated with doxorubicin and cyclophosphamide (AC) chemotherapy. Peripheral blood samples obtained from patients were genotyped for the ABCB1 2677G>T/A and 3435C>T polymorphisms. The genotypes were then investigated for their association with grade 3 or greater neutropenia, and further their risk factors were examined using a multivariate logistic regression. The proportion of patients with grade 3 or greater neutropenia was 85.7% in the homozygous variant group, and 80% and 58.6% in the heterozygous variant and GG genotype groups, respectively (p = 0.021). The multivariate logistic regression analysis revealed that the ABCB1 2677G>T/A polymorphism was a strong predictor of grade 3 or greater neutropenia (odds ratio: 3.76; 95% confidence interval: 1.44-9.81; p = 0.007). ABCB1 polymorphisms may influence the extent of chemotherapy-induced neutropenia in AC combination-treated patients with breast cancer. Copyright © 2014 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Fine Mapping of a Clubroot Resistance Gene in Chinese Cabbage Using SNP Markers Identified from Bulked Segregant RNA Sequencing

PubMed Central

Huang, Zhen; Peng, Gary; Liu, Xunjia; Deora, Abhinandan; Falk, Kevin C.; Gossen, Bruce D.; McDonald, Mary R.; Yu, Fengqun

2017-01-01

Clubroot, caused by Plasmodiophora brassicae, is an important disease of canola (Brassica napus) in western Canada and worldwide. In this study, a clubroot resistance gene (Rcr2) was identified and fine mapped in Chinese cabbage cv. “Jazz” using single-nucleotide polymorphisms (SNP) markers identified from bulked segregant RNA sequencing (BSR-Seq) and molecular markers were developed for use in marker assisted selection. In total, 203.9 million raw reads were generated from one pooled resistant (R) and one pooled susceptible (S) sample, and >173,000 polymorphic SNP sites were identified between the R and S samples. One significant peak was observed between 22 and 26 Mb of chromosome A03, which had been predicted by BSR-Seq to contain the causal gene Rcr2. There were 490 polymorphic SNP sites identified in the region. A segregating population consisting of 675 plants was analyzed with 15 SNP sites in the region using the Kompetitive Allele Specific PCR method, and Rcr2 was fine mapped between two SNP markers, SNP_A03_32 and SNP_A03_67 with 0.1 and 0.3 cM from Rcr2, respectively. Five SNP markers co-segregated with Rcr2 in this region. Variants were identified in 14 of 36 genes annotated in the Rcr2 target region. The numbers of poly variants differed among the genes. Four genes encode TIR-NBS-LRR proteins and two of them Bra019410 and Bra019413, had high numbers of polymorphic variants and so are the most likely candidates of Rcr2. PMID:28894454

A functionally significant SNP in TP53 and breast cancer risk in African-American women.

PubMed

Murphy, Maureen E; Liu, Song; Yao, Song; Huo, Dezheng; Liu, Qin; Dolfi, Sonia C; Hirshfield, Kim M; Hong, Chi-Chen; Hu, Qiang; Olshan, Andrew F; Ogundiran, Temidayo O; Adebamowo, Clement; Domchek, Susan M; Nathanson, Katherine L; Nemesure, Barbara; Ambs, Stefan; Blot, William J; Feng, Ye; John, Esther M; Bernstein, Leslie; Zheng, Wei; Hu, Jennifer J; Ziegler, Regina G; Nyante, Sarah; Ingles, Sue A; Press, Michael F; Deming, Sandra L; Rodriguez-Gil, Jorge L; Haiman, Christopher A; Olopade, Olufunmilayo I; Lunetta, Kathryn L; Palmer, Julie R; Ambrosone, Christine B

2017-01-01

A coding region polymorphism exists in the TP53 gene (Pro47Ser; rs1800371) in individuals of African descent, which reduces p53 tumor suppressor function in a mouse model. It has been unclear whether this functionally significant polymorphism alters cancer risk in humans. This analysis included 6907 women with breast cancer and 7644 controls from the AMBER, ROOT, and AABC consortia. We used multivariable logistic regression to estimate associations between the TP53 Pro47Ser allele and overall breast cancer risk. Because polymorphisms in TP53 tend to be associated with cancer risk in pre-menopausal women, we also limited our analyses to this population in the AMBER and ROOT consortia, where menopausal status was known, and conducted a fixed effects meta-analysis. In an analysis of all women in the AMBER, ROOT, and AABC consortia, we found no evidence for association of the Pro47Ser variant with breast cancer risk. However, when we restricted our analysis to only pre-menopausal women from the AMBER and ROOT consortia, there was a per allele odds ratio of 1.72 (95% confidence interval 1.08-2.76; p -value = 0.023). Although the Pro47Ser variant was not associated with overall breast cancer risk, it may increase risk among pre-menopausal women of African ancestry. Following up on more studies in human populations may better elucidate the role of this variant in breast cancer etiology. However, because of the low frequency of the polymorphism in women of African ancestry, its impact at a population level may be minimal.

Genetic variants in oxytocin receptor gene (OXTR) and childhood physical abuse collaborate to modify the risk of aggression in chinese adolescents.

PubMed

Zhang, Yanmei; Wu, Chunxia; Chang, Hongjuan; Yan, Qiuge; Wu, Linguo; Yuan, Shanshan; Xiang, Jingjing; Hao, Wen; Yu, Yizhen

2018-03-15

Accumulating evidence suggests that genetic and environmental factors may influence aggression susceptibility. However, the etiology of aggressive behavior remains unknown. Compared to some extensively studied candidate genes of aggression, very little is known about the OXTR gene. The objective of this study was to determine whether OXTR genetic variants were associated with aggression risk and whether these polymorphisms showed interactive effects with childhood maltreatment on aggression in Chinese adolescents. A total of 996 participants including 488 cases and 488 controls were selected in our study. Aggression, childhood maltreatment were measured by self-reported questionnaire. Buccal cells were collected. Genotyping was performed using SNPscan. Logistic regressions were used to estimate both main effects of OXTR polymorphisms and the interactive effects with childhood maltreatment on aggressive behavior. Participants who carried the rs237885 TT genotypes in OXTR had a higher risk of aggression compared to those who carried GG or GT genotypes under the recessive model (OR=1.40, 95% CI, 1.04-1.89) after controlling for potential confounders. In addition, we also found that the polymorphism had a synergic additive interaction with childhood physical abuse on the aggression risk. The subjects in the present study were only males, thus our findings and conclusions could not be generalized to females. The present study provides evidence that OXTR genetic variants may contribute to aggression susceptibility. Moreover, this is the first study reporting significant interactive effects of OXTR polymorphism and childhood physical abuse on aggressive behavior in Chinese adolescents. Copyright © 2018 Elsevier B.V. All rights reserved.

Genetic Diversity of the Q Fever Agent, Coxiella burnetii, Assessed by Microarray-Based Whole-Genome Comparisons†

PubMed Central

Beare, Paul A.; Samuel, James E.; Howe, Dale; Virtaneva, Kimmo; Porcella, Stephen F.; Heinzen, Robert A.

2006-01-01

Coxiella burnetii, a gram-negative obligate intracellular bacterium, causes human Q fever and is considered a potential agent of bioterrorism. Distinct genomic groups of C. burnetii are revealed by restriction fragment-length polymorphisms (RFLP). Here we comprehensively define the genetic diversity of C. burnetii by hybridizing the genomes of 20 RFLP-grouped and four ungrouped isolates from disparate sources to a high-density custom Affymetrix GeneChip containing all open reading frames (ORFs) of the Nine Mile phase I (NMI) reference isolate. We confirmed the relatedness of RFLP-grouped isolates and showed that two ungrouped isolates represent distinct genomic groups. Isolates contained up to 20 genomic polymorphisms consisting of 1 to 18 ORFs each. These were mostly complete ORF deletions, although partial deletions, point mutations, and insertions were also identified. A total of 139 chromosomal and plasmid ORFs were polymorphic among all C. burnetii isolates, representing ca. 7% of the NMI coding capacity. Approximately 67% of all deleted ORFs were hypothetical, while 9% were annotated in NMI as nonfunctional (e.g., frameshifted). The remaining deleted ORFs were associated with diverse cellular functions. The only deletions associated with isogenic NMI variants of attenuated virulence were previously described large deletions containing genes involved in lipopolysaccharide (LPS) biosynthesis, suggesting that these polymorphisms alone are responsible for the lower virulence of these variants. Interestingly, a variant of the Australia QD isolate producing truncated LPS had no detectable deletions, indicating LPS truncation can occur via small genetic changes. Our results provide new insight into the genetic diversity and virulence potential of Coxiella species. PMID:16547017

Analysis of single nucleotide polymorphisms in case-control studies.

PubMed

Li, Yonghong; Shiffman, Dov; Oberbauer, Rainer

2011-01-01

Single nucleotide polymorphisms (SNPs) are the most common type of genetic variants in the human genome. SNPs are known to modify susceptibility to complex diseases. We describe and discuss methods used to identify SNPs associated with disease in case-control studies. An outline on study population selection, sample collection and genotyping platforms is presented, complemented by SNP selection, data preprocessing and analysis.

Pathologic and biochemical characterization of PrPSc from elk with PRNP polymorphisms at codon 132 after experimental infection with the chronic wasting disease agent

USDA-ARS?s Scientific Manuscript database

The Rocky Mountain elk (Cervus elaphus nelsoni) prion protein gene (PRNP) is polymorphic at codon 132, with leucine (L132) and methionine (M132) allelic variants present in the population. In elk experimentally inoculated with the chronic wasting disease (CWD) agent, different incubation periods are...

IFNL4 and IFNL3 Associated Polymorphisms Strongly Influence the Spontaneous IFN-Alpha Receptor-1 Expression in HCV-Infected Patients

PubMed Central

Bordi, Licia; Caglioti, Claudia; Garbuglia, Anna Rosa; Lapa, Daniele; Castilletti, Concetta; Taibi, Chiara; Capobianchi, Maria Rosaria; Lalle, Eleonora

2015-01-01

Single-nucleotide polymorphism in IFNL3 gene (rs12979860) predicts spontaneous and therapy-induced HCV clearance. In a previous study from our group PBMC from patients with favourable rs12979860 genotype showed higher levels of IFNAR-1 mRNA. Recently, a dinucleotide polymorphism, ss469415590 (TT or ΔG), has been discovered in the region upstream IFNL3 gene, which is in high linkage disequilibrium with rs12979860. ss469415590[ΔG] is a frameshift variant that creates a novel gene, designed IFNL4, encoding the interferon-lambda 4 protein (IFNL4). The aim of the present study was to extend the analysis of IFNAR-1 mRNA levels to the ss469415590 variants. Our results highlight that the difference of IFNAR-1 mRNA levels between favourable and unfavourable genotype combinations, at both rs12979860 and ss469415590 loci, is stronger than that observed for single polymorphisms at each locus. These findings suggest may represent the biological basis for the observed association between IFNL3 CC and IFNL4 TT/TT genotypes and favourable outcome of either natural HCV infection (clearance vs chronic evolution) or IFN-based therapy. PMID:25675103

Arsenic exposure assists ccm3 genetic polymorphism in elevating blood pressure

PubMed Central

Liu, Xinxia; Xing, Xiumei; Zhang, Huimin; Yun, Jianpei; Ou, Xiaoyan; Su, Xiaolin; Lu, Yao; Sun, Yi; Yang, Yarui; Jiang, Jun; Cui, Dong; Zhuang, Zhixiong; He, Yun

2018-01-01

Epidemiologic study has suggested that arsenic exposure is positively related to increased blood pressure. However, the underlying mechanism concerning interaction between genetic polymorphisms and arsenic exposure remains unclear. In present study, within 395 Chinese, the effects of interaction between arsenic exposure and CCM3 gene polymorphisms on elevation of blood pressure were probed by multiple Logistic regression models after adjusting for confounding factors. Firstly, we found that serum arsenic was positively associated with blood pressure, cholesterol, glucose and C-reactive protein. Then, adjusted for confounding factors of age, gender, smoking, alcohol consumption, BMI and degree of education, arsenic exposure incurred the hazard of increased systolic pressure and diastolic pressure, with odds ratios (ORs) being 1.725 and 1.425, respectively. Distinctly, we found that interactions between rs3804610* rs9818496, rs6784267*rs9818496, and rs3804610* rs6784267 variant genotype can increase significantly risks of SBP. Additionally, interactions between rs9818496, rs3804610 and rs6784267 genotypic variantions and arsenic exposure boosted the hazard of increased systolic pressure, with ORs being 1.496, 1.496 and 1.312. In conclusion, our fingdings suggest that As exposure of population can assist CCM3 polymorphism in elevating SBP. PMID:29435151

Hybridization capture reveals evolution and conservation across the entire Koala retrovirus genome.

PubMed

Tsangaras, Kyriakos; Siracusa, Matthew C; Nikolaidis, Nikolas; Ishida, Yasuko; Cui, Pin; Vielgrader, Hanna; Helgen, Kristofer M; Roca, Alfred L; Greenwood, Alex D

2014-01-01

The koala retrovirus (KoRV) is the only retrovirus known to be in the midst of invading the germ line of its host species. Hybridization capture and next generation sequencing were used on modern and museum DNA samples of koala (Phascolarctos cinereus) to examine ca. 130 years of evolution across the full KoRV genome. Overall, the entire proviral genome appeared to be conserved across time in sequence, protein structure and transcriptional binding sites. A total of 138 polymorphisms were detected, of which 72 were found in more than one individual. At every polymorphic site in the museum koalas, one of the character states matched that of modern KoRV. Among non-synonymous polymorphisms, radical substitutions involving large physiochemical differences between amino acids were elevated in env, potentially reflecting anti-viral immune pressure or avoidance of receptor interference. Polymorphisms were not detected within two functional regions believed to affect infectivity. Host sequences flanking proviral integration sites were also captured; with few proviral loci shared among koalas. Recently described variants of KoRV, designated KoRV-B and KoRV-J, were not detected in museum samples, suggesting that these variants may be of recent origin.

Hybridization Capture Reveals Evolution and Conservation across the Entire Koala Retrovirus Genome

PubMed Central

Ishida, Yasuko; Cui, Pin; Vielgrader, Hanna; Helgen, Kristofer M.; Roca, Alfred L.; Greenwood, Alex D.

2014-01-01

The koala retrovirus (KoRV) is the only retrovirus known to be in the midst of invading the germ line of its host species. Hybridization capture and next generation sequencing were used on modern and museum DNA samples of koala (Phascolarctos cinereus) to examine ca. 130 years of evolution across the full KoRV genome. Overall, the entire proviral genome appeared to be conserved across time in sequence, protein structure and transcriptional binding sites. A total of 138 polymorphisms were detected, of which 72 were found in more than one individual. At every polymorphic site in the museum koalas, one of the character states matched that of modern KoRV. Among non-synonymous polymorphisms, radical substitutions involving large physiochemical differences between amino acids were elevated in env, potentially reflecting anti-viral immune pressure or avoidance of receptor interference. Polymorphisms were not detected within two functional regions believed to affect infectivity. Host sequences flanking proviral integration sites were also captured; with few proviral loci shared among koalas. Recently described variants of KoRV, designated KoRV-B and KoRV-J, were not detected in museum samples, suggesting that these variants may be of recent origin. PMID:24752422

MTR MAIN FLOOR. NEUTRON TUNNEL (SPANNED BY STILELIKE STEPS) PROJECTS ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

MTR MAIN FLOOR. NEUTRON TUNNEL (SPANNED BY STILE-LIKE STEPS) PROJECTS FROM THE SOUTHEAST CORNER OF THE MTR TOWARD SOUTHEAST CORNER OF BUILDING, WHERE SHIELDING BLOCKS BEGIN TO SURROUND THE TUNNEL AS IT NEARS DETECTING INSTRUMENTS NEAR THE BUILDING WALL. GEAR RELATED TO CRYSTAL NEUTRON SPECTROMETER IS IN FOREGROUND SURROUNDED BY SHIELDING. DATA CONSOLES ARE AT MID-LEVEL OF EAST FACE. OTHER WORK PROCEEDS ON TOP OF AND ELSEWHERE AROUND REACTOR. NOTE TOOLS HANGING AGAINST SOUTHEAST CORNER, USED TO CHANGE FUEL ELEMENTS AND OTHER REACTOR ITEMS DURING REFUELING CYCLES. INL NEGATIVE NO. 10439. Unknown Photographer, 4/20/1954 - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

Associations between serotonin-related gene polymorphisms and panic disorder.

PubMed

Maron, Eduard; Lang, Aavo; Tasa, Gunnar; Liivlaid, Liivi; Tõru, Innar; Must, Anne; Vasar, Veiko; Shlik, Jakov

2005-06-01

Studies suggest that vulnerability to panic attacks and panic disorder (PD) may be related to a deficient serotonin (5-HT) neurotransmission. In the present case-control study we investigated possible associations between PD phenotype and five candidate polymorphisms including 5-HT transporter (5-HTTLPR and VNTR), monoamine oxidase A (MAOA promoter region), tryptophan hydroxylase 1 (TPH1 218A/C) and 5-HT1B receptor (5-HT1BR 861G/C) genes. The study sample consisted of 158 patients with PD and 215 healthy control subjects. The analysis showed higher frequencies of LL genotype (p = 0.016) and L allele variant (p = 0.007) of 5-HTTLPR in the patients. No significant associations were observed between PD and other candidate gene polymorphisms. However, a higher frequency of longer allele genotypes of the MAOA promoter region was observed in female PD patients with agoraphobia than in female controls (p = 0.016). These findings indicate that genetic variants conceivably related to lower 5-HT neurotransmission may be involved in the development of PD.

Failure of replicating the association between hippocampal volume and 3 single-nucleotide polymorphisms identified from the European genome-wide association study in Asian populations.

PubMed

Li, Ming; Ohi, Kazutaka; Chen, Chunhui; He, Qinghua; Liu, Jie-Wei; Chen, Chuansheng; Luo, Xiong-Jian; Dong, Qi; Hashimoto, Ryota; Su, Bing

2014-12-01

Hippocampal volume is a key brain structure for learning ability and memory process, and hippocampal atrophy is a recognized biological marker of Alzheimer's disease. However, the genetic bases of hippocampal volume are still unclear although it is a heritable trait. Genome-wide association studies (GWASs) on hippocampal volume have implicated several significantly associated genetic variants in Europeans. Here, to test the contributions of these GWASs identified genetic variants to hippocampal volume in different ethnic populations, we screened the GWAS-identified candidate single-nucleotide polymorphisms in 3 independent healthy Asian brain imaging samples (a total of 990 subjects). The results showed that none of these single-nucleotide polymorphisms were associated with hippocampal volume in either individual or combined Asian samples. The replication results suggested a complexity of genetic architecture for hippocampal volume and potential genetic heterogeneity between different ethnic populations. Copyright © 2014 Elsevier Inc. All rights reserved.

Genetic Polymorphism of Inosine Triphosphate Pyrophosphatase Is a Determinant of Mercaptopurine Metabolism and Toxicity During Treatment for Acute Lymphoblastic Leukemia

PubMed Central

Stocco, G; Cheok, MH; Crews, KR; Dervieux, T; French, D; Pei, D; Yang, W; Cheng, C; Pui, C-H; Relling, MV; Evans, WE

2009-01-01

The influence of genetic polymorphism in inosine triphosphate pyrophosphatase (ITPA) on thiopurine-induced adverse events has not been investigated in the context of combination chemotherapy for acute lymphoblastic leukemia (ALL). This study investigated the effects of a common ITPA variant allele (rs41320251) on mercaptopurine metabolism and toxicity during treatment of children with ALL. Significantly higher concentrations of methyl mercaptopurine nucleotides were found in patients with the nonfunctional ITPA allele. Moreover, there was a significantly higher probability of severe febrile neutropenia in patients with a variant ITPA allele among patients whose dose of mercaptopurine had been adjusted for TPMT genotype. In a cohort of patients whose mercaptopurine dose was not adjusted for TPMT phenotype, the TPMT genotype had a greater effect than the ITPA genotype. In conclusion, genetic polymorphism of ITPA is a significant determinant of mercaptopurine metabolism and of severe febrile neutropenia, after combination chemotherapy for ALL in which mercaptopurine doses are individualized on the basis of TPMT genotype. PMID:18685564

Genetic polymorphism of inosine triphosphate pyrophosphatase is a determinant of mercaptopurine metabolism and toxicity during treatment for acute lymphoblastic leukemia.

PubMed

Stocco, G; Cheok, M H; Crews, K R; Dervieux, T; French, D; Pei, D; Yang, W; Cheng, C; Pui, C-H; Relling, M V; Evans, W E

2009-02-01

The influence of genetic polymorphism in inosine triphosphate pyrophosphatase (ITPA) on thiopurine-induced adverse events has not been investigated in the context of combination chemotherapy for acute lymphoblastic leukemia (ALL). This study investigated the effects of a common ITPA variant allele (rs41320251) on mercaptopurine metabolism and toxicity during treatment of children with ALL. Significantly higher concentrations of methyl mercaptopurine nucleotides were found in patients with the nonfunctional ITPA allele. Moreover, there was a significantly higher probability of severe febrile neutropenia in patients with a variant ITPA allele among patients whose dose of mercaptopurine had been adjusted for TPMT genotype. In a cohort of patients whose mercaptopurine dose was not adjusted for TPMT phenotype, the TPMT genotype had a greater effect than the ITPA genotype. In conclusion, genetic polymorphism of ITPA is a significant determinant of mercaptopurine metabolism and of severe febrile neutropenia, after combination chemotherapy for ALL in which mercaptopurine doses are individualized on the basis of TPMT genotype.

[ROLE OF SLC2A9 AND ABCG2 GENE POLYMORPHISMS IN ORIGIN OF HYPERURICEMIA AND GOUT].

PubMed

Fadieieva, A; Prystupa, L; Pogorelova, O; Kirichenko, N; Dudchenko, I

2016-03-01

The polymorphisms V253I, Q126X, Q141K of SLC2A9 and ABCG2 genes were characterized. GCA и GTC haplotypes of Q126X and Q141K variants can be predictors of gout. The relationship of these polymorphisms with hyperuricaemia according to gender, metabolic syndrome components, with the response to allopurinol was analyzed. It has been established that Q141K polymorphism can directly modulate BCRP-mediated allopurinol and oxypurinol efflux, the K allele is associated with a lower reduction in serum uric acid in response to allopurinol treatment.

Association between FTO gene polymorphisms and type 2 diabetes mellitus, serum levels of apelin and androgen hormones among Iranian obese women.

PubMed

Ghafarian-Alipour, Farzaneh; Ziaee, Shayan; Ashoori, Mohamad Reza; Zakeri, Mir Saeid; Boroumand, Mohammad Ali; Aghamohammadzadeh, Naser; Abbasi-Majdi, Maryam; Shool, Fatemeh; Asbaghi, Navid Sarakhs; Mohammadi, Abolghasem; Zarghami, Nosratollah

2018-01-30

Recent studies show that FTO single nucleotide polymorphisms (SNPs) are associated with obesity and type 2 diabetes mellitus (T2DM). On the other hand, many animal models and clinical studies have demonstrated that apelin, an adipocytokine, is related to the obesity and T2DM. Additionally, obese women are at risk of Hyperandrogenemia. So, the aim of this study was to investigate the relationship between FTO variants (rs763967273, rs759031579, rs141115189, rs9926289, rs76804286 and rs9939609) with T2DM, serum apelin and androgenic hormones in Iranian obese women. 197 obese women (123 women with T2DM and 74 women as healthy control) were participated in this study. Anthropometrical and biochemical characteristics were measured. Serum apelin and androgen hormones levels were determined in 66 subjects consisting of 33 cases and 33 controls. PCR were carried out and subsequently, the PCR production was genotyped by Sanger sequencing assay. Our observations showed that all SNPs are related to T2DM. The rs9926289 FTO variant had a strong association with serum apelin and dehydroepiandrosterone-sulfate levels (P=0.04 and P=0.03, respectively) among SNPs. In addition, apelin and androgenic hormones were correlated with T2DM. Two polymorphisms including rs9939609 and rs9926289 had a strong Linkage disequilibrium (r 2 =1). FTO variants not only were associated with T2DM, but also some variants had a strong association with apelin and androgenic hormones profile. Copyright © 2017 Elsevier B.V. All rights reserved.

Genetic Influences on Response to Alcohol and Response to Pharmacotherapies for Alcoholism

PubMed Central

Enoch, Mary-Anne

2014-01-01

Although very many individuals drink alcohol at safe levels, a significant proportion escalates their consumption with addiction as the end result. Alcoholism is a common, moderately heritable, psychiatric disorder that is accompanied by considerable morbidity and mortality. Variation in clinical presentation suggests inter-individual variation in mechanisms of vulnerability including genetic risk factors. The development of addiction is likely to involve numerous functional genetic variants of small effects. The first part of this review will focus on genetic factors underlying inter-individual variability in response to alcohol consumption, including variants in alcohol metabolizing genes that produce an aversive response (the flushing syndrome) and variants that predict the level of subjective and physiological response to alcohol. The second part of this review will report on genetic variants that identify subgroups of alcoholics who are more likely to respond to pharmacotherapy to reduce levels of drinking or maintain abstinence. Genetic analyses of the level of response to alcohol, particularly of the functional OPRM1 A118G polymorphism and 5′ and 3′ functional polymorphisms in SLC6A4, are beginning to provide insights into the etiology of alcoholism and also genotype-stratified subgroup responses to naltrexone and SSRIs / ondansetron respectively. Because of large inter-ethnic variation in allele frequencies, the relevance of these functional polymorphisms will vary between ethnic groups. However there are relatively few published studies in this field, particularly with large sample sizes in pharmacogenetic studies, therefore it is premature to draw any conclusions at this stage. PMID:24220019

Leishmania isoenzyme polymorphisms in Ecuador: Relationships with geographic distribution and clinical presentation

PubMed Central

Calvopina, Manuel; Armijos, Rodrigo X; Marco, Jorge D; Uezato, Hiroshi; Kato, Hirotomo; Gomez, Eduardo A; Korenaga, Masataka; Barroso, Paola A; Mimori, Tatsuyuki; Cooper, Philip J; Nonaka, Shigeo; Hashiguchi, Yoshihisa

2006-01-01

Background Determinants of the clinical presentation of the leishmaniases are poorly understood but Leishmania species and strain differences are important. To examine the relationship between clinical presentation, species and isoenzyme polymorphisms, 56 Leishmania isolates from distinct presentations of American tegumentary leishmaniasis (ATL) from Ecuador were analyzed. Methods Isolates were characterized by multilocus enzyme electrophoresis for polymorphisms of 11 isoenzymes. Patients were infected in four different ecologic regions: highland and lowland jungle of the Pacific coast, Amazonian lowlands and Andean highlands. Results Six Leishmania species constituting 21 zymodemes were identified: L. (Viannia) panamensis (21 isolates, 7 zymodemes), L. (V.) guyanensis (7 isolates, 4 zymodemes), L. (V.) braziliensis (5 isolates, 3 zymodemes), L. (Leishmania) mexicana (11 isolates, 4 zymodemes), L. (L.) amazonensis (10 isolates, 2 zymodemes) and L. (L.) major (2 isolates, 1 zymodeme). L. panamensis was the species most frequently identified in the Pacific region and was associated with several clinical variants of cutaneous disease (CL); eight cases of leishmaniasis recidiva cutis (LRC) found in the Pacific highlands were associated with 3 zymodemes of this species. Mucocutaneous leishmaniasis found only in the Amazonian focus was associated with 3 zymodemes of L. braziliensis. The papular variant of CL, Uta, found in the Andean highlands was related predominantly with a single zymodeme of L. mexicana. Conclusion Our data show a high degree of phenotypic variation within species, and some evidence for associations between specific variants of ATL (i.e. Uta and LRC) and specific Leishmania zymodemes. This study further defines the geographic distribution of Leishmania species and clinical variants of ATL in Ecuador. PMID:16968553

Association of polymorphic variants of PTPN22, TNF and VDR genes in children with lupus nephritis: A study in Colombian family triads.

PubMed

Garavito, Gloria; Egea, Eduardo; Fang, Luis; Malagón, Clara; Olmos, Carlos; González, Luz; Guarnizo, Pilar; Aroca, Gustavo; López, Guillermo; Iglesias, Antonio

2017-06-01

Systemic lupus erythematosus is an autoimmune disease in which the severity varies according to race, sex and age of onset. This variation is also observed in the genetic markers associated with the disease, including PTPN22, VDR and TNF genes. The genetic stratification in different populations worldwide can influence the variability. To analyze the heritability of PTPN22, VDR and TNF genetic variants and their association with pediatric lupus nephritis in Colombian families. We conducted a family-based study including 46 triads (case, father and mother). The variants rs2476601 of PTPN22; rs361525 and rs1800629 of TNF, and TaqI [rs731236], ApaI [rs7975232], BsmI [rs1544410] and FokI [rs2228570] of VDR were genotyped by qPCR. The effects of overtransmission of the risk allele from parents to children and linkage disequilibrium at the VDR and TNF loci were estimated. We found that allele A of rs2476601 in PTPN22 was distributed among 8.69 % (n=16) of the parents and 19.5 % (n=18) of the cases; this allele was overtransmitted from parents to children 17 times more often than the G allele (p=0.028). TNF and VDR polymorphisms did not exhibit transmission disequilibrium. VDR TaqI, ApaI and BsmI variants exhibited linkage disequilibrium. These findings showed an association between the PTPN22 rs2476601 polymorphism and pediatric lupus nephritis due to its overtransmission in the group of families studied.

Genetic influences on response to alcohol and response to pharmacotherapies for alcoholism.

PubMed

Enoch, Mary-Anne

2014-08-01

Although very many individuals drink alcohol at safe levels, a significant proportion escalates their consumption with addiction as the end result. Alcoholism is a common, moderately heritable, psychiatric disorder that is accompanied by considerable morbidity and mortality. Variation in clinical presentation suggests inter-individual variation in mechanisms of vulnerability including genetic risk factors. The development of addiction is likely to involve numerous functional genetic variants of small effects. The first part of this review will focus on genetic factors underlying inter-individual variability in response to alcohol consumption, including variants in alcohol metabolizing genes that produce an aversive response (the flushing syndrome) and variants that predict the level of subjective and physiological response to alcohol. The second part of this review will report on genetic variants that identify subgroups of alcoholics who are more likely to respond to pharmacotherapy to reduce levels of drinking or maintain abstinence. Genetic analyses of the level of response to alcohol, particularly of the functional OPRM1 A118G polymorphism and 5' and 3' functional polymorphisms in SLC6A4, are beginning to provide insights into the etiology of alcoholism and also genotype-stratified subgroup responses to naltrexone and SSRIs/ondansetron respectively. Because of large inter-ethnic variation in allele frequencies, the relevance of these functional polymorphisms will vary between ethnic groups. However there are relatively few published studies in this field, particularly with large sample sizes in pharmacogenetic studies, therefore it is premature to draw any conclusions at this stage. Published by Elsevier Inc.

CUTS FOR MTR EXCAVATION ILLUSTRATE SEDIMENTARY MANTLE OF SOIL AND ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

CUTS FOR MTR EXCAVATION ILLUSTRATE SEDIMENTARY MANTLE OF SOIL AND GRAVEL OVERLAYING LAVA ROCK FIFTY FEET BELOW. SAGEBRUSH HAS BEEN SCOURED FROM REST OF SITE. CAMERA PROBABLY FACES SOUTHWEST. INL NEGATIVE NO. 67. Unknown Photographer, 6/4/1950 - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

SOUTH WING, MTR661. INTERIOR DETAIL INSIDE LAB ROOM 131. CAMERA ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

SOUTH WING, MTR-661. INTERIOR DETAIL INSIDE LAB ROOM 131. CAMERA FACING NORTHEAST. NOTE CONCRETE BLOCK WALLS. SAFETY SHOWER AND EYE WASHER AT REAR WALL. INL NEGATIVE NO. HD46-7-2. Mike Crane, Photographer, 2/2005. - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

CANAL EMERGES FROM EAST SIDE OF MTR BUILDING. "EXTRA" LENGTH ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

CANAL EMERGES FROM EAST SIDE OF MTR BUILDING. "EXTRA" LENGTH WAS TO STORE SPENT FUEL THAT WOULD ACCUMULATE BEFORE THE CHEMICAL PROCESSING PLANT WAS READY TO PROCESS IT. INL NEGATIVE NO. 1659. Unknown Photographer, 3/9/1951 - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

MTR WING A, TRA604, INTERIOR. MAIN FLOOR. DETAIL VIEW INSIDE ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

MTR WING A, TRA-604, INTERIOR. MAIN FLOOR. DETAIL VIEW INSIDE LABORATORY 114. CAMERA FACING NORTH. DISPOSAL OF RADIOACTIVE MATERIALS IS UNDERWAY. INL NEGATIVE NO. HD46-12-4. Mike Crane, Photographer, 2/2005 - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

Serial Magnetization Transfer Imaging in Acute Optic Neuritis

ERIC Educational Resources Information Center

Hickman, S. J.; Toosy, A. T.; Jones, S. J.; Altmann, D. R.; Miszkiel, K. A.; MacManus, D. G.; Barker, G. J.; Plant, G. T.; Thompson, A. J.; Miller, D.H.

2004-01-01

In serial studies of multiple sclerosis lesions, reductions in magnetization transfer ratio (MTR) are thought to be due to demyelination and axonal loss, with later rises due to remyelination. This study followed serial changes in MTR in acute optic neuritis in combination with clinical and electrophysiological measurements to determine if the MTR…

FAST CHOPPER BUILDING, TRA665. CONTEXTUAL VIEW: CHOPPER BUILDING IN CENTER. ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

FAST CHOPPER BUILDING, TRA-665. CONTEXTUAL VIEW: CHOPPER BUILDING IN CENTER. MTR REACTOR SERVICES BUILDING,TRA-635, TO LEFT; MTR BUILDING TO RIGHT. CAMERA FACING WEST. INL NEGATIVE NO. HD42-1. Mike Crane, Photographer, 3/2004 - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

Thermodynamics of Electron Flow in the Bacterial Deca-heme Cytochrome MtrF

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

Breuer, Marian; Zarzycki, Piotr P.; Blumberger, Jochen

2012-07-01

Electron transporting multiheme cytochromes are essential to the metabolism of microbes that inhabit soils and carry out important biogeochemical processes. Recently the first crystal structure of a prototype bacterial deca-heme cytochrome (MtrF) has been resolved and its electrochemistry characterized. However, the molecular details of electron conductance along heme chains in the cytochrome are difficult to access via experiment due to the nearly identical chemical nature of the heme cofactors. Here we employ large-scale molecular dynamics simulations to compute the reduction potentials of the ten hemes of MtrF in aqueous solution. We find that as a whole they fall within amore » range of about 0.3 V in agreement with experiment. Individual reduction potentials give rise to a free energy profile for electron conduction that is approximately symmetric with respect to the center of the protein. Our calculations indicate that there is no significant potential bias along the orthogonal octa- and tetra-heme chains suggesting that under aqueous conditions MtrF is a nearly reversible two-dimensional conductor.« less

Genetic variants of the DNA repair genes from Exome Aggregation Consortium (EXAC) database: significance in cancer.

PubMed

Das, Raima; Ghosh, Sankar Kumar

2017-04-01

DNA repair pathway is a primary defense system that eliminates wide varieties of DNA damage. Any deficiencies in them are likely to cause the chromosomal instability that leads to cell malfunctioning and tumorigenesis. Genetic polymorphisms in DNA repair genes have demonstrated a significant association with cancer risk. Our study attempts to give a glimpse of the overall scenario of the germline polymorphisms in the DNA repair genes by taking into account of the Exome Aggregation Consortium (ExAC) database as well as the Human Gene Mutation Database (HGMD) for evaluating the disease link, particularly in cancer. It has been found that ExAC DNA repair dataset (which consists of 228 DNA repair genes) comprises 30.4% missense, 12.5% dbSNP reported and 3.2% ClinVar significant variants. 27% of all the missense variants has the deleterious SIFT score of 0.00 and 6% variants carrying the most damaging Polyphen-2 score of 1.00, thus affecting the protein structure and function. However, as per HGMD, only a fraction (1.2%) of ExAC DNA repair variants was found to be cancer-related, indicating remaining variants reported in both the databases to be further analyzed. This, in turn, may provide an increased spectrum of the reported cancer linked variants in the DNA repair genes present in ExAC database. Moreover, further in silico functional assay of the identified vital cancer-associated variants, which is essential to get their actual biological significance, may shed some lights in the field of targeted drug development in near future. Copyright © 2017. Published by Elsevier B.V.

Complement factor H gene (CFH) polymorphisms C-257T, G257A and haplotypes are associated with protection against severe dengue phenotype, possible related with high CFH expression.

PubMed

Pastor, André F; Rodrigues Moura, Laís; Neto, José W D; Nascimento, Eduardo J M; Calzavara-Silva, Carlos E; Gomes, Ana Lisa V; Silva, Ana Maria da; Cordeiro, Marli T; Braga-Neto, Ulisses; Crovella, Sergio; Gil, Laura H V G; Marques, Ernesto T A; Acioli-Santos, Bartolomeu

2013-09-01

Four genetic polymorphisms located at the promoter (C-257T) and coding regions of CFH gene (exon 2 G257A, exon 14 A2089G and exon 19 G2881T) were investigated in 121 dengue patients (DENV-3) in order to assess the relationship between allele/haplotypes variants and clinical outcomes. A statistical value was found between the CFH-257T allele (TT/TC genotypes) and reduced susceptibility to severe dengue (SD). Statistical associations indicate that individuals bearing a T allele presented significantly higher protein levels in plasma. The -257T variant is located within a NF-κB binding site, suggesting that this variant might have effect on the ability of the CFH gene to respond to signals via the NF-κB pathway. The G257A allelic variant showed significant protection against severe dengue. When CFH haplotypes effect was considered, the ancestral CG/CG promoter-exon 2 SNP genotype showed significant risk to SD either in a general comparison (ancestral × all variant genotypes), as well as in individual genotypes comparison (ancestral × each variant genotype), where the most prevalent effect was observed in the CG/CG × CA/TG comparison. These findings support the involvement of -257T, 257A allele variants and haplotypes on severe dengue phenotype protection, related with high basal CFH expression. Copyright © 2013 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Investigation of Outbreaks of Salmonella enterica Serovar Typhimurium and Its Monophasic Variants Using Whole-Genome Sequencing, Denmark

PubMed Central

Gymoese, Pernille; Sørensen, Gitte; Litrup, Eva; Olsen, John Elmerdal; Nielsen, Eva Møller

2017-01-01

Whole-genome sequencing is rapidly replacing current molecular typing methods for surveillance purposes. Our study evaluates core-genome single-nucleotide polymorphism analysis for outbreak detection and linking of sources of Salmonella enterica serovar Typhimurium and its monophasic variants during a 7-month surveillance period in Denmark. We reanalyzed and defined 8 previously characterized outbreaks from the phylogenetic relatedness of the isolates, epidemiologic data, and food traceback investigations. All outbreaks were identified, and we were able to exclude unrelated and include additional related human cases. We were furthermore able to link possible food and veterinary sources to the outbreaks. Isolates clustered according to sequence types (STs) 19, 34, and 36. Our study shows that core-genome single-nucleotide polymorphism analysis is suitable for surveillance and outbreak investigation for Salmonella Typhimurium (ST19 and ST36), but whole genome–wide analysis may be required for the tight genetic clone of monophasic variants (ST34). PMID:28930002

Picosecond-resolved FRET on non-amplified DNA for identifying individuals genetically susceptible to type-1 diabetes

NASA Astrophysics Data System (ADS)

Nardo, Luca; Tosi, Giovanna; Bondani, Maria; Accolla, Roberto; Andreoni, Alessandra

2012-06-01

By tens-of-picosecond resolved fluorescence detection we study Förster resonance energy transfer between a donor and a black-hole-quencher bound at the 5'- and 3'-positions of an oligonucleotide probe matching the highly polymorphic region between codons 51 and 58 of the human leukocyte antigen DQB1 0201 allele, conferring susceptibility to type-1 diabetes. The probe is annealed with non-amplified genomic DNAs carrying either the 0201 sequence or other DQB1 allelic variants. We detect the longest-lived donor fluorescence in the case of hybridization with the 0201 allele and definitely faster and distinct decays for the other allelic variants, some of which are single-nucleotide polymorphic.

Genome-wide copy number variant analysis in Holstein cattle reveals variants associated with 10 production traits including residual feed intake and dry matter intake

USDA-ARS?s Scientific Manuscript database

Copy number variation (CNV) is an important type of genetic variation contributing to phenotypic differences among mammals and may serve as an alternative molecular marker to single nucleotide polymorphism (SNP) for genome-wide association study (GWAS). Recently, GWAS analysis using CNV has been app...

The involvement of serotonin polymorphisms in autistic spectrum symptomatology.

PubMed

Hervás, Amaia; Toma, Claudio; Romarís, Patricia; Ribasés, Marta; Salgado, Marta; Bayes, Mònica; Balmaña, Noemí; Cormand, Bru; Maristany, Marta; Guijarro, Silvina; Arranz, María J

2014-08-01

Autism spectrum disorders (ASD) are highly inherited developmental syndromes, resulting from a complex interaction between environmental and genetic factors. To date, only a limited number of genetic variants have been discovered with respect to autism, and their contribution to the development of the disorder has not been clearly determined. Investigation of specific autistic symptomatology may improve the chances of identifying related genes and may help to better understand these disorders. We investigated the contribution of 80 genetic variants in 15 serotonin genes to ASD phenotypes [intelligence quotation (IQ), intellectual disability (ID) and language onset delay (LD)] in a cohort of 141 children and young adults (121 male patients and 20 female patients, average age 14.5±5.1 years). Two polymorphisms in the HTR2B gene, rs10194776 and rs16827801, were associated with IQ (P=0.0004 and 0.003, respectively), ID (P=0.02 and 0.03) and LD (P=0.04 and 0.004). Nominal associations were also detected between the ASD phenotypes investigated and 5-HT2A, 5-HT4 and 5-HT6 genetic variants. Our study provides evidence of the contribution of serotonergic variants to IQ, ID and LD in ASD patients.

Quantitative trait nucleotide analysis using Bayesian model selection.

PubMed

Blangero, John; Goring, Harald H H; Kent, Jack W; Williams, Jeff T; Peterson, Charles P; Almasy, Laura; Dyer, Thomas D

2005-10-01

Although much attention has been given to statistical genetic methods for the initial localization and fine mapping of quantitative trait loci (QTLs), little methodological work has been done to date on the problem of statistically identifying the most likely functional polymorphisms using sequence data. In this paper we provide a general statistical genetic framework, called Bayesian quantitative trait nucleotide (BQTN) analysis, for assessing the likely functional status of genetic variants. The approach requires the initial enumeration of all genetic variants in a set of resequenced individuals. These polymorphisms are then typed in a large number of individuals (potentially in families), and marker variation is related to quantitative phenotypic variation using Bayesian model selection and averaging. For each sequence variant a posterior probability of effect is obtained and can be used to prioritize additional molecular functional experiments. An example of this quantitative nucleotide analysis is provided using the GAW12 simulated data. The results show that the BQTN method may be useful for choosing the most likely functional variants within a gene (or set of genes). We also include instructions on how to use our computer program, SOLAR, for association analysis and BQTN analysis.

A Cajal body-independent pathway for telomerase trafficking in mice

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

Tomlinson, Rebecca L.; Li, Jian; Culp, Bradley R.

2010-10-15

The intranuclear trafficking of human telomerase involves a dynamic interplay between multiple nuclear sites, most notably Cajal bodies and telomeres. Cajal bodies are proposed to serve as sites of telomerase maturation, storage, and assembly, as well as to function in the cell cycle-regulated delivery of telomerase to telomeres in human cells. Here, we find that telomerase RNA does not localize to Cajal bodies in mouse cells, and instead resides in separate nuclear foci throughout much of the cell cycle. However, as in humans, mouse telomerase RNA (mTR) localizes to subsets of telomeres specifically during S phase. The localization of mTRmore » to telomeres in mouse cells does not require coilin-containing Cajal bodies, as mTR is found at telomeres at similar frequencies in cells from wild-type and coilin knockout mice. At the same time, we find that human TR localizes to Cajal bodies (as well as telomeres) in mouse cells, indicating that the distinct trafficking of mTR is attributable to an intrinsic property of the RNA (rather than a difference in the mouse cell environment such as the properties of mouse Cajal bodies). We also find that during S phase, mTR foci coalesce into short chains, with at least one of the conjoined mTR foci co-localizing with a telomere. These findings point to a novel, Cajal body-independent pathway for telomerase biogenesis and trafficking in mice.« less

Physiological and transcriptional approaches reveal connection between nitrogen and manganese cycles in Shewanella algae C6G3.

PubMed

Aigle, Axel; Bonin, Patricia; Iobbi-Nivol, Chantal; Méjean, Vincent; Michotey, Valérie

2017-03-20

To explain anaerobic nitrite/nitrate production at the expense of ammonium mediated by manganese oxide (Mn(IV)) in sediment, nitrate and manganese respirations were investigated in a strain (Shewanella algae C6G3) presenting these features. In contrast to S. oneidensis MR-1, a biotic transitory nitrite accumulation at the expense of ammonium was observed in S. algae during anaerobic growth with Mn(IV) under condition of limiting electron acceptor, concomitantly, with a higher electron donor stoichiometry than expected. This low and reproducible transitory accumulation is the result of production and consumption since the strain is able to dissimilative reduce nitrate into ammonium. Nitrite production in Mn(IV) condition is strengthened by comparative expression of the nitrate/nitrite reductase genes (napA, nrfA, nrfA-2), and rates of the nitrate/nitrite reductase activities under Mn(IV), nitrate or fumarate conditions. Compared with S. oneidensis MR-1, S. algae contains additional genes that encode nitrate and nitrite reductases (napA-α and nrfA-2) and an Outer Membrane Cytochrome (OMC)(mtrH). Different patterns of expression of the OMC genes (omcA, mtrF, mtrH and mtrC) were observed depending on the electron acceptor and growth phase. Only gene mtrF-2 (SO1659 homolog) was specifically expressed under the Mn(IV) condition. Nitrate and Mn(IV) respirations seem connected at the physiological and transcriptional levels.

Physiological and transcriptional approaches reveal connection between nitrogen and manganese cycles in Shewanella algae C6G3

NASA Astrophysics Data System (ADS)

Aigle, Axel; Bonin, Patricia; Iobbi-Nivol, Chantal; Méjean, Vincent; Michotey, Valérie

2017-03-01

To explain anaerobic nitrite/nitrate production at the expense of ammonium mediated by manganese oxide (Mn(IV)) in sediment, nitrate and manganese respirations were investigated in a strain (Shewanella algae C6G3) presenting these features. In contrast to S. oneidensis MR-1, a biotic transitory nitrite accumulation at the expense of ammonium was observed in S. algae during anaerobic growth with Mn(IV) under condition of limiting electron acceptor, concomitantly, with a higher electron donor stoichiometry than expected. This low and reproducible transitory accumulation is the result of production and consumption since the strain is able to dissimilative reduce nitrate into ammonium. Nitrite production in Mn(IV) condition is strengthened by comparative expression of the nitrate/nitrite reductase genes (napA, nrfA, nrfA-2), and rates of the nitrate/nitrite reductase activities under Mn(IV), nitrate or fumarate conditions. Compared with S. oneidensis MR-1, S. algae contains additional genes that encode nitrate and nitrite reductases (napA-α and nrfA-2) and an Outer Membrane Cytochrome (OMC)(mtrH). Different patterns of expression of the OMC genes (omcA, mtrF, mtrH and mtrC) were observed depending on the electron acceptor and growth phase. Only gene mtrF-2 (SO1659 homolog) was specifically expressed under the Mn(IV) condition. Nitrate and Mn(IV) respirations seem connected at the physiological and transcriptional levels.

Structure of MRDI Explains its Dual Function as a Metabolic Enzyme and a Mediator of Cell Invasion

PubMed Central

Templeton, Paul D.; Litman, Elizabeth S.; Metzner, Sandra I.; Ahn, Natalie G.; Sousa, Marcelo C.

2013-01-01

Metastatic melanoma is among the most intractable cancers to treat, where patients show resistance to therapy and limited survival time. A critical step in the development of metastatic melanoma is the acquisition of invasion and transition from thin to thick tumors on the skin, followed by invasion to lymph nodes. Prior studies have shown that metastatic melanoma is associated with dysregulation of RhoA and enhanced expression of a protein named “mediator of RhoA-dependent invasion (MRDI)”. Importantly, MRDI is a “moonlighting” enzyme, with two distinct functions in melanoma cells. First, MRDI acts as a methylthioribose-1-phosphate (MTR-1-P) isomerase, catalyzing a critical step in methionine salvage. Second, MRDI promotes and is necessary for melanoma cell invasion, independent of its catalytic activity. Here, we demonstrate that MtnA, a bacterial MTR-1-P isomerase, rescues the methionine salvage function of MRDI, but is unable to rescue its role in invasion. We then solve the crystal structure of MRDI to a resolution of 2.5 Å, in order to identify structural elements important for its invasion activity. We present this structure and its comparison with other MTR-1-P isomerases, and identify mutations within a region separate from the MTR-1-P binding site which interfere with invasion. Thus, structural elements in MRDI distal from the MTR-1-P catalytic site are responsible for the invasion phenotype. PMID:23859498

Quantitative Ultrasound Using Texture Analysis of Myofascial Pain Syndrome in the Trapezius.

PubMed

Kumbhare, Dinesh A; Ahmed, Sara; Behr, Michael G; Noseworthy, Michael D

2018-01-01

Objective-The objective of this study is to assess the discriminative ability of textural analyses to assist in the differentiation of the myofascial trigger point (MTrP) region from normal regions of skeletal muscle. Also, to measure the ability to reliably differentiate between three clinically relevant groups: healthy asymptomatic, latent MTrPs, and active MTrP. Methods-18 and 19 patients were identified with having active and latent MTrPs in the trapezius muscle, respectively. We included 24 healthy volunteers. Images were obtained by research personnel, who were blinded with respect to the clinical status of the study participant. Histograms provided first-order parameters associated with image grayscale. Haralick, Galloway, and histogram-related features were used in texture analysis. Blob analysis was conducted on the regions of interest (ROIs). Principal component analysis (PCA) was performed followed by multivariate analysis of variance (MANOVA) to determine the statistical significance of the features. Results-92 texture features were analyzed for factorability using Bartlett's test of sphericity, which was significant. The Kaiser-Meyer-Olkin measure of sampling adequacy was 0.94. PCA demonstrated rotated eigenvalues of the first eight components (each comprised of multiple texture features) explained 94.92% of the cumulative variance in the ultrasound image characteristics. The 24 features identified by PCA were included in the MANOVA as dependent variables, and the presence of a latent or active MTrP or healthy muscle were independent variables. Conclusion-Texture analysis techniques can discriminate between the three clinically relevant groups.

Physiological and transcriptional approaches reveal connection between nitrogen and manganese cycles in Shewanella algae C6G3

PubMed Central

Aigle, Axel; Bonin, Patricia; Iobbi-Nivol, Chantal; Méjean, Vincent; Michotey, Valérie

2017-01-01

To explain anaerobic nitrite/nitrate production at the expense of ammonium mediated by manganese oxide (Mn(IV)) in sediment, nitrate and manganese respirations were investigated in a strain (Shewanella algae C6G3) presenting these features. In contrast to S. oneidensis MR-1, a biotic transitory nitrite accumulation at the expense of ammonium was observed in S. algae during anaerobic growth with Mn(IV) under condition of limiting electron acceptor, concomitantly, with a higher electron donor stoichiometry than expected. This low and reproducible transitory accumulation is the result of production and consumption since the strain is able to dissimilative reduce nitrate into ammonium. Nitrite production in Mn(IV) condition is strengthened by comparative expression of the nitrate/nitrite reductase genes (napA, nrfA, nrfA-2), and rates of the nitrate/nitrite reductase activities under Mn(IV), nitrate or fumarate conditions. Compared with S. oneidensis MR-1, S. algae contains additional genes that encode nitrate and nitrite reductases (napA-α and nrfA-2) and an Outer Membrane Cytochrome (OMC)(mtrH). Different patterns of expression of the OMC genes (omcA, mtrF, mtrH and mtrC) were observed depending on the electron acceptor and growth phase. Only gene mtrF-2 (SO1659 homolog) was specifically expressed under the Mn(IV) condition. Nitrate and Mn(IV) respirations seem connected at the physiological and transcriptional levels. PMID:28317859

Factor VII deficiency: a novel missense variant and genotype-phenotype correlation in patients from Southern Italy.

PubMed

Tiscia, Giovanni; Favuzzi, Giovanni; Chinni, Elena; Colaizzo, Donatella; Fischetti, Lucia; Intrieri, Mariano; Margaglione, Maurizio; Grandone, Elvira

2017-01-01

This study aimed at attempting to correlate genotype and phenotype in factor VII deficiency. Here, we present molecular and clinical findings of 10 patients with factor VII deficiency. From 2013 to 2016, 10 subjects were referred to our center because of a prolonged prothrombin time identified during routine or presurgery examinations or after a laboratory assessment of a bleeding episode. Mutation characterization was performed using the bioinformatics applications PROMO, SIFT, and Polyphen-2. Structural changes in the factor VII protein were analyzed using the SPDB viewer tool. Of the 10 variants we identified, 1 was responsible for a novel missense change (c.1199G>C, p.Cys400Ser); in 2 cases we identified the c.-54G>A and c.509G>A (p.Arg170His) polymorphic variants in the 5'-upstream region of the factor VII gene and exon 6, respectively. To our knowledge, neither of these polymorphic variants has been described previously in factor VII-deficient patients. In silico predictions showed differences in binding sites for transcription factors caused by the c.-54G>A variant and a probable damaging effect of the p.Cys400Ser missense change on factor VII active conformation, leading to breaking of the Cys400-Cys428 disulfide bridge. Our findings further suggest that, independently of factor VII levels and of variants potentially affecting factor VII levels, environmental factors, e.g., trauma, could heavily influence the clinical phenotype of factor VII-deficient patients.

In Vitro Activity of Delafloxacin against Clinical Neisseria gonorrhoeae Isolates and Selection of Gonococcal Delafloxacin Resistance.

PubMed

Soge, Olusegun O; Salipante, Stephen J; No, David; Duffy, Erin; Roberts, Marilyn C

2016-05-01

We evaluated the in vitro activity of delafloxacin against a panel of 117 Neisseria gonorrhoeae strains, including 110 clinical isolates collected from 2012 to 2015 and seven reference strains, compared with the activities of seven antimicrobials currently or previously recommended for treatment of gonorrhea. We examined the potential for delafloxacin to select for resistant mutants in ciprofloxacin-susceptible and ciprofloxacin-resistant N. gonorrhoeae We characterized mutations in the gyrA, gyrB, parC, and parE genes and the multidrug-resistant efflux pumps (MtrC-MtrD-MtrE and NorM) by PCR and sequencing and by whole-genome sequencing. The MIC50, MIC90, and MIC ranges of delafloxacin were 0.06 μg/ml, 0.125 μg/ml, and ≤0.001 to 0.25 μg/ml, respectively. The frequency of spontaneous mutation ranged from 10(-7) to <10(-9) The multistep delafloxacin resistance selection of 30 daily passages resulted in stable resistant mutants. There was no obvious cross-resistance to nonfluoroquinolone comparator antimicrobials. A mutant with reduced susceptibility to ciprofloxacin (MIC, 0.25 μg/ml) obtained from the ciprofloxacin-susceptible parental strain had a novel Ser91Tyr alteration in the gyrA gene. We also identified new mutations in the gyrA and/or parC and parE genes and the multidrug-resistant efflux pumps (MtrC-MtrD-MtrE and NorM) of two mutant strains with elevated delafloxacin MICs of 1 μg/ml. Although delafloxacin exhibited potent in vitro activity against N. gonorrhoeae isolates and reference strains with diverse antimicrobial resistance profiles and demonstrated a low tendency to select for spontaneous mutants, it is important to establish the correlation between these excellent in vitro data and treatment outcomes through appropriate randomized controlled clinical trials. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

In Vitro Activity of Delafloxacin against Clinical Neisseria gonorrhoeae Isolates and Selection of Gonococcal Delafloxacin Resistance

PubMed Central

Salipante, Stephen J.; No, David; Duffy, Erin; Roberts, Marilyn C.

2016-01-01

We evaluated the in vitro activity of delafloxacin against a panel of 117 Neisseria gonorrhoeae strains, including 110 clinical isolates collected from 2012 to 2015 and seven reference strains, compared with the activities of seven antimicrobials currently or previously recommended for treatment of gonorrhea. We examined the potential for delafloxacin to select for resistant mutants in ciprofloxacin-susceptible and ciprofloxacin-resistant N. gonorrhoeae. We characterized mutations in the gyrA, gyrB, parC, and parE genes and the multidrug-resistant efflux pumps (MtrC-MtrD-MtrE and NorM) by PCR and sequencing and by whole-genome sequencing. The MIC50, MIC90, and MIC ranges of delafloxacin were 0.06 μg/ml, 0.125 μg/ml, and ≤0.001 to 0.25 μg/ml, respectively. The frequency of spontaneous mutation ranged from 10−7 to <10−9. The multistep delafloxacin resistance selection of 30 daily passages resulted in stable resistant mutants. There was no obvious cross-resistance to nonfluoroquinolone comparator antimicrobials. A mutant with reduced susceptibility to ciprofloxacin (MIC, 0.25 μg/ml) obtained from the ciprofloxacin-susceptible parental strain had a novel Ser91Tyr alteration in the gyrA gene. We also identified new mutations in the gyrA and/or parC and parE genes and the multidrug-resistant efflux pumps (MtrC-MtrD-MtrE and NorM) of two mutant strains with elevated delafloxacin MICs of 1 μg/ml. Although delafloxacin exhibited potent in vitro activity against N. gonorrhoeae isolates and reference strains with diverse antimicrobial resistance profiles and demonstrated a low tendency to select for spontaneous mutants, it is important to establish the correlation between these excellent in vitro data and treatment outcomes through appropriate randomized controlled clinical trials. PMID:26976873

Serotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder.

PubMed

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

2002-01-01

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

Serotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder

PubMed Central

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

2002-01-01

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

[Effect of mitochondrial DNA 5178 C/A polymorphism on risks for type 2 diabetes mellitus and its complications].

PubMed

Yang, Xunjun; Zhang, Yuning; Ma, Yin; Zhao, Qiongya; Lyu, Jianxin

2015-12-01

To explore the role of mitochondrial DNA 5178 C/A (Mt5178) polymorphism of NADH-dehydrogenase subunit 2 (ND2) gene in type-2 diabetes mellitus (T2DM) among ethnic Han Chinese through a case-control study. The Mt5178C/A polymorphism was determined by sequencing 1103 T2DM patients and 791 healthy controls. Logistic regression analysis was conducted to estimate odds ratios (OR) and 95% confidence intervals (CI). To confirm the results, a meta-analysis was conducted based on published literature on the association of Mt5178 variant with T2DM. No significant association was found between the Mt5178C/A variant and T2DM either by our study or the meta-analysis which included eight published studies. Nevertheless, it was found that the T2DM patients with 5178C genotype were at a higher risk for nephropathy complication (OR=1.49, 95%CI: 1.005-2.197, P<0.05) and at significantly lower risk for hypertension complication (OR=0.744, 95%CI: 0.556-0.996, P<0.05) compared with those carrying a 5178A genotype. No association was found between the Mt5178C/A polymorphism of mitochondrial ND2 gene with the increased risk of T2DM. However, the polymorphism may affect the development of nephropathy and hypertension complications among T2DM patients.

Impacts of CA9 gene polymorphisms on urothelial cell carcinoma susceptibility and clinicopathologic characteristics in Taiwan.

PubMed

Wang, Shian-Shiang; Liu, Yu-Fan; Ou, Yen-Chuan; Chen, Chuan-Shu; Li, Jian-Ri; Yang, Shun-Fa

2013-01-01

Carbonic anhydrase 9 (CA9) is reportedly overexpressed in several types of carcinomas and is generally considered a marker of malignancy. The current study explored the effect of CA9 gene polymorphisms on the susceptibility of developing urothelial cell carcinoma (UCC) and the clinicopathological status. A total of 442 participants, including 221 healthy people and 221 patients with UCC, were recruited for this study. Four single-nucleotide polymorphisms (SNPs) of the CA9 gene were assessed by a real-time PCR with the TaqMan assay. After adjusting for other co-variants, the individuals carrying at least one A allele at CA9 rs1048638 had a 2.303-fold risk of developing UCC than did wild-type (CC) carriers. Furthermore, UCC patients who carried at least one A allele at rs1048638 had a higher invasive stage risk (p< 0.05) than did patients carrying the wild-type allele. Moreover, among the UCC patients with smoker, people with at least one A allele of CA9 polymorphisms (rs1048638) had a 4.75-fold (95% CI = 1.204-18.746) increased risk of invasive cancer. The rs1048638 polymorphic genotypes of CA9 might contribute to the prediction of susceptibility to and pathological development of UCC. This is the first study to provide insight into risk factors associated with CA9 variants in carcinogenesis of UCC in Taiwan.

Methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms in chronic myeloid leukemia: an Egyptian study.

PubMed

Khorshied, Mervat Mamdooh; Shaheen, Iman Abdel Mohsen; Abu Khalil, Reham E; Sheir, Rania Elsayed

2014-01-01

Methylenetetrahydrofolate reductase (MTHFR) gene plays a pivotal role in folate metabolism. Several genetic variations in MTHFR gene as MTHFR-C677T and MTHFR-A1298C result in decreased MTHFR activity, which could influence efficient DNA methylation and explain susceptibility to different cancers. The etiology of chronic myeloid leukemia (CML) is obscure and little is known about individual's susceptibility to CML. In order to assess the influence of these genetic polymorphisms on the susceptibility to CML and its effect on the course of the disease among Egyptians, we performed an age-gender-ethnic matched case-control study. The study included 97 CML patients and 130 healthy controls. Genotyping of MTHFR-C677T and -A1298C was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The results showed no statistical difference in the distribution of MTHFR-C677T and -A1298C polymorphic genotypes between CML patients and controls. The frequency of MTHFR 677-TT homozygous variant was significantly higher in patients with accelerated/blastic transformation phase when compared to those in the chronic phase of the disease. In conclusion, our study revealed that MTHFR-C677T and -A1298C polymorphisms could not be considered as genetic risk factors for CML in Egyptians. However, MTHFR 677-TT homozygous variant might be considered as a molecular predictor for disease progression.

Methylenetetrahydrofolate reductase C677T polymorphism predicts response and time to progression to gemcitabine-based chemotherapy for advanced non-small cell lung cancer in a Chinese Han population*

PubMed Central

Hong, Wei; Wang, Kai; Zhang, Yi-ping; Kou, Jun-yan; Hong, Dan; Su, Dan; Mao, Wei-min; Yu, Xin-min; Xie, Fa-jun; Wang, Xiao-jian

2013-01-01

Objective: The aim of this study was to evaluate the association between the methylenetetrahydrofolate reductase (MTHFR) C677T excision repair cross-complementation group 1 (ERCC1) genetic polymorphisms and the clinical efficacy of gemcitabine-based chemotherapy in advanced non-small cell lung cancer (NSCLC). Methods: A total of 135 chemonaive patients with unresectable advanced NSCLC were treated with gemcitabine/platinum regimens. The polymorphisms of MTHFR C677T, ERCC1 C8092A, and ERCC1 C118T were genotyped using the TaqMan methods. Results: The overall response rate was 28.9%. Patients with MTHFR CC genotype had a higher rate of objective response than patients with variant genotype (TT or CT) (41.2% versus 19.1%, P=0.01). Median time to progression (TTP) of patients with MTHFR CC genotype was longer than that of patients with variant genotype (7.6 months versus 5.0 months, P=0.003). No significant associations were obtained between ERCC1 C118T and C8092A polymorphisms and both response and survival. Conclusions: Our data suggest the value of MTHFR C677T polymorphism as a possible predictive marker of response and TTP in advanced NSCLC patients treated with gemcitabine/platinum. PMID:23463763

Assessment of the patellofemoral cartilage: Correlation of knee pain score with magnetic resonance cartilage grading and magnetization transfer ratio asymmetry of glycosaminoglycan chemical exchange saturation transfer.

PubMed

Lee, Young Han; Yang, Jaemoon; Jeong, Ha-Kyu; Suh, Jin-Suck

2017-01-01

Biochemical imaging of glycosaminoglycan chemical exchange saturation transfer (gagCEST) could predict the depletion of glycosaminoglycans (GAG) in early osteoarthritis. The purpose of this study was to evaluate the relationship between the magnetization transfer ratio asymmetry (MTR asym ) of gagCEST images and visual analog scale (VAS) pain scores in the knee joint. This retrospective study was approved by the institutional review board. A phantom study was performed using hyaluronic acid to validate the MTR asym values of gagCEST images. Knee magnetic resonance (MR) images of 22 patients (male, 9; female, 13; mean age, 50.3years; age range; 25-79years) with knee pain were included in this study. The MR imaging (MRI) protocol involved standard knee MRI as well as gagCEST imaging, which allowed region-of-interest analyses of the patellar facet and femoral trochlea. The MTR asym at 1.0ppm was calculated at each region. The cartilages of the patellar facets and femoral trochlea were graded according to the Outerbridge classification system. Data regarding the VAS scores of knee pain were collected from the electronic medical records of the patients. Statistical analysis was performed using Spearman's correlation. The results of the phantom study revealed excellent correlation between the MTR asym values and the concentration of GAGs (r=0.961; p=0.003). The cartilage grades on the MR images showed significant negative correlation with the MTR asym values in the patellar facet and femoral trochlea (r=-0.460; p=0.031 and r=-0.543; p=0.009, respectively). The VAS pain scores showed significant negative correlation with the MTR asym values in the patellar facet and femoral trochlea (r=-0.435; p=0.043 and r=-0.671; p=0.001, respectively). The pain scores were associated with the morphological and biochemical changes in articular cartilages visualized on knee MR images. The biochemical changes, visualized in terms of the MTR asym values of the gagCEST images, exhibited greater correlation with the pain scores than the morphological changes visualized on conventional MR images; these results provide evidence supporting the theory regarding the association of patellofemoral osteoarthritis with knee pain scores. Copyright © 2016 Elsevier Inc. All rights reserved.

Susceptibility to endometrial cancer: influence of allelism at p53, glutathione S-transferase (GSTM1 and GSTT1) and cytochrome P-450 (CYP1A1) loci.

PubMed Central

Esteller, M.; García, A.; Martínez-Palones, J. M.; Xercavins, J.; Reventós, J.

1997-01-01

A case-control study was designed to identify associations between polymorphisms at p53, cytochrome P-450 (CYP1A1) and glutathione-S-transferases and endometrial cancer susceptibility. Among all polymorphisms analysed, an insertional variant in p53 (P53PIN3) and two polymorphisms in the 3'-end and exon 7 of CYP1A1 showed significant association with enhanced endometrial cancer risk. Images Figure 1 Figure 2 PMID:9155064

Triglyceride associated polymorphisms of the APOA5 gene have very different allele frequencies in Pune, India compared to Europeans

PubMed Central

Chandak, Giriraj R; Ward, Kirsten J; Yajnik, Chittaranjan S; Pandit, Anand N; Bavdekar, Ashish; Joglekar, Charu V; Fall, Caroline HD; Mohankrishna, P; Wilkin, Terence J; Metcalf, Bradley S; Weedon, Michael N; Frayling, Timothy M; Hattersley, Andrew T

2006-01-01

Background The APOA5 gene variants, -1131T>C and S19W, are associated with altered triglyceride concentrations in studies of subjects of Caucasian and East Asian descent. There are few studies of these variants in South Asians. We investigated whether the two APOA5 variants also show similar association with various lipid parameters in Indian population as in the UK white subjects. Methods We genotyped 557 Indian adults from Pune, India, and 237 UK white adults for -1131T>C and S19W variants in the APOA5 gene, compared their allelic and genotype frequency and determined their association with fasting serum triglycerides, total cholesterol, HDL and LDL cholesterol levels using univariate general linear analysis. APOC3 SstI polymorphism was also analyzed in 175 Pune Indian subjects for analysis of linkage disequilibrium with the APOA5 variants. Results The APOA5 -1131C allele was more prevalent in Indians from Pune (Pune Indians) compared to UK white subjects (allele frequency 20% vs. 4%, p = 0.00001), whereas the 19W allele was less prevalent (3% vs. 6% p = 0.0015). Patterns of linkage disequilibrium between the two variants were similar between the two populations and confirmed that they occur on two different haplotypes. In Pune Indians, the presence of -1131C allele and the 19W allele was associated with a 19% and 15% increase respectively in triglyceride concentrations although only -1131C was significant (p = 0.0003). This effect size was similar to that seen in the UK white subjects. Analysis of the APOC3 SstI polymorphism in 175 Pune Indian subjects showed that this variant is not in appreciable linkage disequilibrium with the APOA5 -1131T>C variant (r2 = 0.07). Conclusion This is the first study to look at the role of APOA5 in Asian Indian subjects that reside in India. The -1131C allele is more prevalent and the 19W allele is less prevalent in Pune Indians compared to UK Caucasians. We confirm that the APOA5 variants are associated with triglyceride levels independent of ethnicity and that this association is similar in magnitude in Asian Indians and Caucasians. The -1131C allele is present in 36% of the Pune Indian population making it a powerful marker for looking at the role of elevated triglycerides in important conditions such as pancreatitis, diabetes and coronary heart disease. PMID:17032446

Prion protein testis specific (PRNT) gene polymorphisms and transcript level in ovine spermatozoa: Implications in freezability, fertilization and embryo production.

PubMed

Pereira, R M; Mesquita, P; Pires, V M R; Baptista, M C; Barbas, J P; Pimenta, J; Horta, A E M; Prates, J A M; Marques, C C

2018-07-15

An essential role of prion protein testis specific (PRNT) and prion protein 2 dublet (PRND) genes in the male reproductive function has been highlighted, although a deeper knowledge for the mechanisms involved is still lacking. Our goal was to determine the importance of the PRNT haplotypic variants and mRNA expression levels in ovine spermatozoa freezability and ability for fertilization and embryo developmental processes. Their association with the PRND gene polymorphisms was also analyzed. DNA from rams belonging to three Portuguese sheep breeds (n = 28) was screened by single-strand conformation polymorphism (SSCP) analysis to identify the PRNT and PRND polymorphisms. Semen collected from these rams was cryopreserved and fertility traits evaluated. The SSCP analyses revealed polymorphisms in the codons 6, 38, 43 and 48 of the PRNT coding region - respectively c.17C > T (p.Ser6Phe, which disrupts a consensus arginine-X-X serine/threonine motif); c.112G > C (p.Gly38 > Arg); and synonymous c.129T > C and c.144A > G. The polymorphisms in codons 6, 38 and 48 occur simultaneously while the one in codon 43 occurs independently. Six haplotypes were identified in the PRNT coding region, resulting in three different amino acid polymorphic variants (6S-38G-43C-48V, S6F-G38R-43C-48V and 6F-38R-43C-48V). The PRNT gene mRNA transcript level in spermatozoa was related to the identified haplotypic variants, either considering the codons 6-38-48 (P ≤ 0.0001) or the codon 43 alone (P ≤ 0.0001) or altogether (P ≤ 0.0001). An interaction between PRNT haplotypes and PRND genotypes on PRNT transcript level was also identified (P = 0.0003). Rams carrying the 17C-112G-144A PRNT haplotype had sperm with the highest post-thawed individual motility (P ≤ 0.03). Combined PRNT and PRND polymorphic variation influenced the post-thawed individual motility (P = 0.01). The male PRNT haplotypic, either considering the codons 6-38-48 and 43 altogether or the codon 43 alone, interfered (P ≤ 0.04) in embryo production rates. In conclusion, our data confirm that the PRNT gene is highly polymorphic in sheep and that the PRNT and PRND genotypes are associated. The identified polymorphisms of PRNT coding region seems to interfere on the ram spermatozoa mRNA transcript level and on male fertility, specifically in sperm freezability and ability for embryo development. Copyright © 2018. Published by Elsevier Inc.

Patatin-like phospholipase domain containing-3 gene I148M polymorphism, steatosis, and liver damage in hereditary hemochromatosis

PubMed Central

Valenti, Luca; Maggioni, Paolo; Piperno, Alberto; Rametta, Raffaela; Pelucchi, Sara; Mariani, Raffaella; Dongiovanni, Paola; Fracanzani, Anna Ludovica; Fargion, Silvia

2012-01-01

AIM: To investigate whether the patatin-like phospholipase domain containing-3 gene (PNPLA3) I148M polymorphism is associated with steatosis, fibrosis stage, and cirrhosis in hereditary hemochromatosis (HH). METHODS: We studied 174 consecutive unrelated homozygous for the C282Y HFE mutation of HH (C282Y+/+ HH) patients from Northern Italy, for whom the presence of cirrhosis could be determined based on histological or clinical criteria, without excessive alcohol intake (< 30/20 g/d in males or females) or hepatitis B virus and hepatitis C virus viral hepatitis. Steatosis was evaluated in 123 patients by histology (n = 100) or ultrasound (n = 23). The PNPLA3 rs738409 single nucleotide polymorphism, encoding for the p.148M protein variant, was genotyped by a Taqman assay (assay on demand, Applied Biosystems). The association of the PNPLA3 I148M protein variant (p.I148M) with steatosis, fibrosis stage, and cirrhosis was evaluated by logistic regression analysis. RESULTS: PNPLA3 genotype was not associated with metabolic parameters, including body mass index (BMI), the presence of diabetes, and lipid levels, but the presence of the p.148M variant at risk was independently associated with steatosis [odds ratio (OR) 1.84 per p.148M allele, 95% confidence interval (CI): 1.05-3.31; P = 0.037], independently of BMI and alanine aminotransaminase (ALT) levels. The p.148M variant was also associated with higher aspartate aminotransferase (P = 0.0014) and ALT levels (P = 0.017) at diagnosis, independently of BMI and the severity of iron overload. In patients with liver biopsy, the 148M variant was independently associated with the severity (stage) of fibrosis (estimated coefficient 0.56 ± 0.27, P = 0.041). In the overall series of patients, the p.148M variant was associated with cirrhosis in lean (P = 0.049), but not in overweight patients (P = not significant). At logistic regression analysis, cirrhosis was associated with BMI ≥ 25 (OR 1.82, 95% CI: 1.02-3.55), ferritin > 1000 ng/mL at diagnosis (OR 19.3, 95% CI: 5.3-125), and with the G allele in patients with BMI < 25 (OR 3.26, 95% CI: 1.3-10.3). CONCLUSION: The PNPLA3 I148M polymorphism may represent a permissive factor for fibrosis progression in patients with C282Y+/+ HH. PMID:22719190

The variant call format and VCFtools.

PubMed

Danecek, Petr; Auton, Adam; Abecasis, Goncalo; Albers, Cornelis A; Banks, Eric; DePristo, Mark A; Handsaker, Robert E; Lunter, Gerton; Marth, Gabor T; Sherry, Stephen T; McVean, Gilean; Durbin, Richard

2011-08-01

The variant call format (VCF) is a generic format for storing DNA polymorphism data such as SNPs, insertions, deletions and structural variants, together with rich annotations. VCF is usually stored in a compressed manner and can be indexed for fast data retrieval of variants from a range of positions on the reference genome. The format was developed for the 1000 Genomes Project, and has also been adopted by other projects such as UK10K, dbSNP and the NHLBI Exome Project. VCFtools is a software suite that implements various utilities for processing VCF files, including validation, merging, comparing and also provides a general Perl API. http://vcftools.sourceforge.net

Interactive effects of the ACE DD polymorphism with the NOS III homozygous G849T (Glu298-->Asp) variant in determining endothelial function in coronary artery disease.

PubMed

Schmidt, Michael A; Chakrabarti, Anjan K; Kehrer, Chris; Pfeninnger, Dana; Brook, Robert D; Kaciroti, Niko; Duvernoy, Claire; Killeen, Anthony A; Rajagopalan, Sanjay

2003-01-01

The products of nitric oxide synthase (NOS) and angiotensin-converting enzyme (ACE) play a critical role in determining vessel wall structure and function. Polymorphisms in both genes have been independently demonstrated to influence propensity to cardiovascular events. The purpose of this study was to determine the influence of the homozygous G849T (Glu298-->Asp) polymorphism in NOS III on peripheral conduit artery endothelial function and to elucidate the modifier role, if any, of a common ACE polymorphism. Three hundred and ninety-seven consecutive subjects presenting to the cardiac catheterization laboratory of the University of Michigan over a period of 18 months were recruited. DNA was extracted and polymerase chain reaction (PCR) analysis for ACE and NOS polymorphisms performed. Patients with homozygosity for G849T at both loci (TT) who belong to DD and II ACE genotype (groups 1 and 2) and those who are negative for this polymorphism (GG) and belong to either DD or II genotype (groups 3 and 4) were identified. The four groups then underwent determination of conduit endothelial function. Heterozygosity of Glu298-Asp or the ID variant of the ACE were not studied. Median FMD value in the TT-DD group was 0.20 (-3.17, 2.01) compared with 2.23% (-0.29, 4.17) in the GG-II group. Median values in the TT-II and the GG-DD groups were 3.04 (-1.16, 6.61) and 2.46% (-1.83, 6.52) respectively. These values were not statistically significant (p > 0.05 by one-way ANOVA). Median nitroglycerin-mediated dilation in the four groups did not differ between the four groups (p = NS by ANOVA). Atherosclerosis burdens as assessed by angiography were not different across the groups. In conclusion, the homozygous NOS III variant (GG) status does not seem to interact additively with the ACE homozygous DD genotype in determining flow-mediated vasodilation in individuals with established atherosclerosis and pre-existent endothelial dysfunction.

Subsets of Inflammatory Cytokine Gene Polymorphisms are Associated with Risk of Carcinogenic Liver Fluke Opisthorchis viverrini-Associated Advanced Periductal Fibrosis and Cholangiocarcinoma.

PubMed

Surapaitoon, Arpa; Suttiprapa, Sutas; Mairiang, Eimorn; Khuntikeo, Narong; Pairojkul, Chawalit; Bethony, Jeffrey; Brindley, Paul J; Sripa, Banchob

2017-06-01

Opisthorchis viverrini infection induces chronic inflammation, and a minor proportion of infected individuals develop advanced periductal fibrosis (APF) and cholangiocarcinoma (CCA). Inflammatory cytokines and/or their gene polymorphisms may link to these biliary pathologies. We therefore investigated associations among cytokine gene polymorphisms and cytokine production in 510 Thai cases infected with O. viverrini who presented with APF+ or APF-, as established by abdominal ultrasonography as well as in patients diagnosed with CCA. Levels of pro-inflammatory and anti-inflammatory cytokines were determined in culture supernatants after stimulation of peripheral blood mononuclear cells (PBMCs) with O. viverrini excretory-secretory (ES) products. Pro-inflammatory cytokines, IL-1β, IL-6, IFN-γ, LT-α, and TNF-α were significantly increased in CCA patients compared with non-CCA (APF- and APF+) cases. Polymorphisms in genes encoding IL-1β-511C/T, IL-6-174G/C, IFN-γ +874T/A, LT-α +252A/G, and TNF-α -308G/A were then investigated by using PCR-RFLP or allele specific-PCR (AS-PCR) analyses. In the CCA cases, LT-α +252A/G and TNF-α -308G/A heterozygous and homozygous variants showed significantly higher levels of these cytokines than the wild type. By contrast, levels of cytokines in wild type of IFN-γ +874T/A were significantly higher than the variants in CCA cases. IFN-γ +874T/A polymorphisms were associated with advanced periductal fibrosis, whereas IL-6 -174G/C polymorphisms were associated with CCA. To our knowledge, these findings provide the first demonstration that O. viverrini infected individuals carrying several specific cytokine gene polymorphisms are susceptible to develop fibrosis and CCA.

Subsets of Inflammatory Cytokine Gene Polymorphisms are Associated with Risk of Carcinogenic Liver Fluke Opisthorchis viverrini-Associated Advanced Periductal Fibrosis and Cholangiocarcinoma

PubMed Central

Surapaitoon, Arpa; Suttiprapa, Sutas; Mairiang, Eimorn; Khuntikeo, Narong; Pairojkul, Chawalit; Bethony, Jeffrey; Brindley, Paul J.; Sripa, Banchob

2017-01-01

Opisthorchis viverrini infection induces chronic inflammation, and a minor proportion of infected individuals develop advanced periductal fibrosis (APF) and cholangiocarcinoma (CCA). Inflammatory cytokines and/or their gene polymorphisms may link to these biliary pathologies. We therefore investigated associations among cytokine gene polymorphisms and cytokine production in 510 Thai cases infected with O. viverrini who presented with APF+ or APF−, as established by abdominal ultrasonography as well as in patients diagnosed with CCA. Levels of pro-inflammatory and anti-inflammatory cytokines were determined in culture supernatants after stimulation of peripheral blood mononuclear cells (PBMCs) with O. viverrini excretory-secretory (ES) products. Pro-inflammatory cytokines, IL-1β, IL-6, IFN-γ, LT-α, and TNF-α were significantly increased in CCA patients compared with non-CCA (APF− and APF+) cases. Polymorphisms in genes encoding IL-1β-511C/T, IL-6-174G/C, IFN-γ +874T/A, LT-α +252A/G, and TNF-α −308G/A were then investigated by using PCR-RFLP or allele specific-PCR (AS-PCR) analyses. In the CCA cases, LT-α +252A/G and TNF-α −308G/A heterozygous and homozygous variants showed significantly higher levels of these cytokines than the wild type. By contrast, levels of cytokines in wild type of IFN-γ +874T/A were significantly higher than the variants in CCA cases. IFN-γ +874T/A polymorphisms were associated with advanced periductal fibrosis, whereas IL-6 −174G/C polymorphisms were associated with CCA. To our knowledge, these findings provide the first demonstration that O. viverrini infected individuals carrying several specific cytokine gene polymorphisms are susceptible to develop fibrosis and CCA. PMID:28719954

Association of Common Genetic Variants in Pre-microRNAs and Neuroblastoma Susceptibility: A Two-Center Study in Chinese Children.

PubMed

He, Jing; Zou, Yan; Liu, Xiaodan; Zhu, Jinhong; Zhang, Jiao; Zhang, Ruizhong; Yang, Tianyou; Xia, Huimin

2018-06-01

Neuroblastoma is a commonly occurring extracranial pediatric solid tumor without defined etiology. Polymorphisms in pre-miRNAs have been demonstrated to associate with the risk of several cancers. So far, no such polymorphism has been investigated in neuroblastoma. With this in mind, we performed a two-center case-control study to assess the association of genetic variants in pre-miRNAs and neuroblastoma susceptibility in Chinese children, including 393 cases and 812 controls. We found that miR-34b/c rs4938723 T > C polymorphism was significantly associated with decreased neuroblastoma risk (TC versus TT: adjusted odds ratio [OR] = 0.51, 95% confidence interval [CI] = 0.39-0.67; TC/CC versus TT: adjusted OR = 0.62, 95% CI = 0.48-0.79). We also observed the significant association between the miR-218 rs11134527 A > G polymorphism and decreased neuroblastoma risk (AG versus AA: adjusted OR = 0.73, 95% CI = 0.56-0.96). Stratified analysis further demonstrated that the protective effect of the rs4938723 T > C polymorphism remained prominent in the subgroups, regardless of age, gender, and clinical stages. In term of sites of origin, this polymorphism significantly reduced the risk of tumors originating from the adrenal gland. We further validated the significant results using false-positive report probability analyses. Overall, the miR-34b/c rs4938723 T > C and miR-218 rs11134527 A > G polymorphisms displayed a protective role from neuroblastoma. These findings need further validation. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Association between BIM deletion polymorphism and clinical outcome of EGFR-mutated NSCLC patient with EGFR-TKI therapy: A meta-analysis.

PubMed

Ma, Ji-Yong; Yan, Hai-Jun; Gu, Wei

2015-01-01

BIM deletion polymorphism was deemed to be associated with downregulation of BIM, resulting in a decreased apoptosis induced by epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in EGFR mutation-positive non-small cell lung cancer (NSCLC). However, accumulating evidences concerning the association between BIM deletion polymorphism and efficacy of EGFR-TKI and survival in EGFR-mutation-driven NSCLC patient reported contradictory results. A meta-analysis was conducted by combing six original eligible studies including 871 NSCLC patients. Our study showed that BIM deletion polymorphism was significantly associated with poor response to EGFR-TKI therapy in mutant EGFRNSCLC patients (P(h) = 0.309, P(z) = 0.001, OR = 0.39, 95% confidence interval (CI) = 0.23-0.67). Disease control rate (DCR) in mutant EGFRNSCLC patient with treatment of EGFR-TKI was significantly decreased in patients with BIM deletion polymorphism comparing to patients harbored BIM wild variant (P(h) = 0.583, P(Z) = 0.007, OR = 0.46, 95%CI = 0.25-0.85). EGFR mutation-derived NSCLC patient carrying BIM deletion polymorphism had a shorter progression-free survival (PFS; P(h) < 0.001, P(z) < 0.001, hazard ratio (HR) = 1.37, 95%CI = 1.09-1.71) and overall survival (OS; P(h) = 0.90, P(z) = 0.003, HR = 1.25, 95%CI = 1.08-1.45), than those harbored BIM wild variant. These results suggested that BIM deletion polymorphism might be a cause that contributes to primary EGFR-TKI resistance, and it could be used as a genetic predictor for EGFR-TKI outcome and an independent prognostic factor of EGFR mutation-driven NSCLC patient.

Genetics in endocrinology: genetic variation in deiodinases: a systematic review of potential clinical effects in humans.

PubMed

Verloop, Herman; Dekkers, Olaf M; Peeters, Robin P; Schoones, Jan W; Smit, Johannes W A

2014-09-01

Iodothyronine deiodinases represent a family of selenoproteins involved in peripheral and local homeostasis of thyroid hormone action. Deiodinases are expressed in multiple organs and thyroid hormone affects numerous biological systems, thus genetic variation in deiodinases may affect multiple clinical endpoints. Interest in clinical effects of genetic variation in deiodinases has clearly increased. We aimed to provide an overview for the role of deiodinase polymorphisms in human physiology and morbidity. In this systematic review, studies evaluating the relationship between deiodinase polymorphisms and clinical parameters in humans were eligible. No restrictions on publication date were imposed. The following databases were searched up to August 2013: Pubmed, EMBASE (OVID-version), Web of Science, COCHRANE Library, CINAHL (EbscoHOST-version), Academic Search Premier (EbscoHOST-version), and ScienceDirect. Deiodinase physiology at molecular and tissue level is described, and finally the role of these polymorphisms in pathophysiological conditions is reviewed. Deiodinase type 1 (D1) polymorphisms particularly show moderate-to-strong relationships with thyroid hormone parameters, IGF1 production, and risk for depression. D2 variants correlate with thyroid hormone levels, insulin resistance, bipolar mood disorder, psychological well-being, mental retardation, hypertension, and risk for osteoarthritis. D3 polymorphisms showed no relationship with inter-individual variation in serum thyroid hormone parameters. One D3 polymorphism was associated with risk for osteoarthritis. Genetic deiodinase profiles only explain a small proportion of inter-individual variations in serum thyroid hormone levels. Evidence suggests a role of genetic deiodinase variants in certain pathophysiological conditions. The value for determination of deiodinase polymorphism in clinical practice needs further investigation. © 2014 European Society of Endocrinology.

Evaluation of Glutathione-S-Transferase P1 Polymorphism and its Relation to Bone Mineral Density in Egyptian Children and Adolescents with Beta-Thalassemia Major

PubMed Central

Ragab, Seham M.; Badr, Eman A.; Ibrahim, Ahmed S.

2016-01-01

Background Osteoporosis is a major complication of beta thalassemia major (TM). Increased oxidative stress and its controlling genes were linked to osteoporosis. Ile105 Val variant is a functional polymorphism of Glutathione S-transferase P1 (GSTP1), with reduced anti-oxidative property. No data are available about this variant or its association with osteoporosis among thalassemia patients yet. Objectives To investigate Ile105Val polymorphism and its possible association with bone mineral density (BMD) values in a group of TM children. Methods Thirty five TM children and 30 age and sex matched healthy controls were included. Liver and renal functions, serum ferritin, calcium, phosphorous, alkaline phosphatase and osteocalcin were assayed. BMD was determined by DXA with calculation of Z-scores at lumbar spine (LS) and femoral neck (FN). Height for age Z- score (HAZ) adjusted BMD Z-scores were calculated. GSTP1 Ile105Val polymorphism was studied by polymerase chain reaction-restriction fragment length polymorphism. Results The relative frequency of 105 Val allele was significantly higher in TM patients than the controls (p<0.0001). Significant association between genotype subgroups and BMD parameters was detected. Compared to wild homozygotes, polymorphic homozygotes had lower LS-BMD (p =0.029), LS-BMD Z –score (p=0.008 ), LS- BMD haz - Z-score (p=0.011), FN- BMD (p= 0.001), FN- BMD Z –score (p=0.02) and FN-BMD haz - Z-score (p=0.001). They exhibited higher osteocalcin levels compared to heterozygotes and wild homozygotes (p=0.012, p=0.013, respectively). Conclusion Ile105Val polymorphism was frequent among TM patients and could increase their susceptibility to reduced BMD. Large sample studies are required to confirm these findings. PMID:26740865

Methylenetetrahydrofolate reductase gene polymorphism and risk of chronic myelogenous leukemia: a meta-analysis.

PubMed

Li, Chen; Yichao, Jin; Jiaxin, Lin; Yueting, Zhang; Qin, Lu; Tonghua, Yang

2015-01-01

Reported evidence supports a role for methylenetetrahydrofolate reductase (MTHFR) in the risk of chronic myelogenous leykemia (CML). However, these reports arrived at non-conclusive and even conflicting results regarding the association between two common MTHFR polymorphisms (C677T and A1298C) and CML risk. Thus, a meta-analysis was carried out to clarify a more precise association between these two polymorphisms and the CML risk by updating the available publications. Pooled odds ratios (OR) with corresponding 95% confidence interval (95% CI) and stratification analysis were performed to estimate the relationship between MTHFR polymorphisms and the risk of CML under different genetic comparison models. Data from the meta-analysis showed no significant association between MTHFR C677T polymorphism and CML risk. However, significant associations were found between MTHFR A1298C variants and CML risk under homozygous comparison model (CC vs AA, OR=1.62, 95% CI=1.11-2.36, p=0.01) and dominant comparison model (CC+AC vs AA, OR=1.68, 95% CI=1.17-2.43, p=0.005) in overall population; especially more obvious impacts were noticed for Asian populations in subgroup analysis for homozygous model (CC vs AA, OR=2.00, 95% CI=1.25-3.21, p=0.004) and dominant model (CC+AC vs AA, OR=2.49, 95% CI=1.42-4.36, p=0.001), but this did not apply in Caucasian populations. The results of this meta-analysis suggested no significant association between MTHFR C677T polymorphism and CML risk, while an increased CML risk was noticed for 1298C variant carriers, especially in Asian populations but not in Caucasian populations, which suggested ethnicity differences between MTHFR A1298C polymorphisms and risk of CML.

GSTP1 Polymorphisms and their Association with Glutathione Transferase and Peroxidase Activities in Patients with Motor Neuron Disease.

PubMed

Gajewska, Beata; Kaźmierczak, Beata; Kuźma-Kozakiewicz, Magdalena; Jamrozik, Zygmunt; Barańczyk-Kuźma, Anna

2015-01-01

Glutathione S-transferase pi (GSTP1) is a crucial enzyme in detoxification of electrophilic compounds and organic peroxides. Together with Se-dependent glutathione peroxidase (Se-GSHPx) it protects cells against oxidative stress which may be a primary factor implicated in motor neuron disease (MND) pathogenesis. We investigated GSTP1 polymorphisms and their relationship with GST and Se-GSTPx activities in a cohort of Polish patients with MND. Results were correlated with clinical phenotypes. The frequency of genetic variants for GSTP1 exon 5 (I105V) and exon 6 (A114V) was studied in 104 patients and 100 healthy controls using real-time polymerase chain reaction. GST transferase activity was determined in serum with 1-chloro-2,4-dinitrobenzene, its peroxidase activity with cumene hydroperoxide, and Se-GSHPx activity with hydrogen peroxide. There were no differences in the prevalence of GSTP1 polymorphism I105V and A114V between MND and controls, however the occurrence of CT variant in codon 114 was associated with a higher risk for MND. GSTP1 polymorphisms were less frequent in classic ALS than in progressive bulbar palsy. In classic ALS C* (heterozygous I /V and A /V) all studied activities were significantly lower than in classic ALS A* (homozygous I /I and A/A). GST peroxidase activity and Se-GSHPx activity were lower in classic ALS C* than in control C*, but in classic ALS A* Se-GSHPx activity was significantly higher than in control A*. It can be concluded that the presence of GSTP1 A114V but not I105V variant increases the risk of MND, and combined GSTP1 polymorphisms in codon 105 and 114 may result in lower protection of MND patients against the toxicity of electrophilic compounds, organic and inorganic hydroperoxides.

Association of the Serotonin Receptor 3E Gene as a Functional Variant in the MicroRNA-510 Target Site with Diarrhea Predominant Irritable Bowel Syndrome in Chinese Women.

PubMed

Zhang, Yu; Li, Yaoyao; Hao, Zhenfeng; Li, Xiangming; Bo, Ping; Gong, Weijuan

2016-04-30

The functional variant (rs56109847) in the 3'-untranslated regions (3'-UTR) of the serotonin receptor 3E (HTR3E) gene is associated with female diarrhea predominant irritable bowel syndrome (IBS-D) in British populations. However, the relationship of the polymorphism both to HTR3E expression in the intestine and to the occurrence of Chinese functional gastrointestinal disorders has yet to be examined. Polymerase chain reaction amplification and restriction fragment length polymorphism analyses were employed to detect polymorphisms among Chinese Han women, particularly 107 patients with IBS-D, 99 patients with functional dyspepsia (FD), 115 patients with mixed IBS and 69 patients with IBS-D + FD. We also assessed microRNA-510 (miR-510) and HTR3Eexpression in human colonic mucosal tissues with immunohistochemistry and other methods. Dual-luciferase reporter assays were conducted to examine the binding ability of miR-510 and HTR3E 3'-UTR. Genotyping data showed the variant rs56109847 was significantly associated with IBS-D, but not with FD, mixed-IBS, or FD + IBS-D. HTR3E was abundantly expressed around the colonic mucosal glands but less expressed in the stroma. miR-510 expression decreased, whereas HTR3E expression increased in the colonic mucosal tissue of patients with IBS-D compared with those in controls. HTR3E expression was significantly higher in patients with the GA genotype than that in patients with the GG genotype. The single-nucleotide polymorphisms disrupted the binding site of miR-510 and significantly upregulated luciferase expression in HEK293 and HT-29 cells. The single-nucleotide polymorphisms rs56109847 led to reduced microRNA binding and overexpression of the target gene in intestinal cells, thereby increasing IBS-D risk in the Chinese Han population. The decreased expression of miR-510 might contribute to IBS-D.

Polymorphisms in Plasmodium vivax Circumsporozoite Protein (CSP) Influence Parasite Burden and Cytokine Balance in a Pre-Amazon Endemic Area from Brazil

PubMed Central

Ribeiro, Bruno de Paulo; Cassiano, Gustavo Capatti; de Souza, Rodrigo Medeiros; Cysne, Dalila Nunes; Grisotto, Marcos Augusto Grigolin; de Azevedo dos Santos, Ana Paula Silva; Marinho, Cláudio Romero Farias; Machado, Ricardo Luiz Dantas; Nascimento, Flávia Raquel Fernandes

2016-01-01

Mechanisms involved in severe P. vivax malaria remain unclear. Parasite polymorphisms, parasite load and host cytokine profile may influence the course of infection. In this study, we investigated the influence of circumsporozoite protein (CSP) polymorphisms on parasite load and cytokine profile in patients with vivax malaria. A cross-sectional study was carried out in three cities: São Luís, Cedral and Buriticupu, Maranhão state, Brazil, areas of high prevalence of P. vivax. Interleukin (IL)-2, IL-4, IL-10, IL-6, IL-17, tumor necrosis factor alpha (TNF-α, interferon gamma (IFN-γ and transforming growth factor beta (TGF-β were quantified in blood plasma of patients and in supernatants from peripheral blood mononuclear cell (PBMC) cultures. Furthermore, the levels of cytokines and parasite load were correlated with VK210, VK247 and P. vivax-like CSP variants. Patients infected with P. vivax showed increased IL-10 and IL-6 levels, which correlated with the parasite load, however, in multiple comparisons, only IL-10 kept this association. A regulatory cytokine profile prevailed in plasma, while an inflammatory profile prevailed in PBMC culture supernatants and these patterns were related to CSP polymorphisms. VK247 infected patients showed higher parasitaemia and IL-6 concentrations, which were not associated to IL-10 anti-inflammatory effect. By contrast, in VK210 patients, these two cytokines showed a strong positive correlation and the parasite load was lower. Patients with the VK210 variant showed a regulatory cytokine profile in plasma, while those infected with the VK247 variant have a predominantly inflammatory cytokine profile and higher parasite loads, which altogether may result in more complications in infection. In conclusion, we propose that CSP polymorphisms is associated to the increase of non-regulated inflammatory immune responses, which in turn may be associated with the outcome of infection. PMID:26943639

Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults

PubMed Central

Skibola, Christine F.; Smith, Martyn T.; Kane, Eleanor; Roman, Eve; Rollinson, Sara; Cartwright, Raymond A.; Morgan, Gareth

1999-01-01

Reduction of 5,10-methylenetetrahydrofolate (methyleneTHF), a donor for methylating dUMP to dTMP in DNA synthesis, to 5-methyltetrahydrofolate (methylTHF), the primary methyl donor for methionine synthesis, is catalyzed by 5,10-methylenetetrahydrofolate reductase (MTHFR). A common 677 C → T polymorphism in the MTHFR gene results in thermolability and reduced MTHFR activity that decreases the pool of methylTHF and increases the pool of methyleneTHF. Recently, another polymorphism in MTHFR (1298 A → C) has been identified that also results in diminished enzyme activity. We tested whether carriers of these variant alleles are protected from adult acute leukemia. We analyzed DNA from a case–control study in the United Kingdom of 308 adult acute leukemia patients and 491 age- and sex-matched controls. MTHFR variant alleles were determined by a PCR-restriction fragment length polymorphism assay. The MTHFR 677TT genotype was lower among 71 acute lymphocytic leukemia (ALL) cases compared with 114 controls, conferring a 4.3-fold decrease in risk of ALL [odds ratio (OR = 0.23; 95% CI = 0.06–0.81]. We observed a 3-fold reduction in risk of ALL in individuals with the MTHFR 1298AC polymorphism (OR = 0.33; 95% CI = 0.15–0.73) and a 14-fold decreased risk of ALL in those with the MTHFR 1298CC variant allele (OR = 0.07; 95% CI = 0.00–1.77). In acute myeloid leukemia, no significant difference in MTHFR 677 and 1298 genotype frequencies was observed between 237 cases and 377 controls. Individuals with the MTHFR 677TT, 1298AC, and 1298CC genotypes have a decreased risk of adult ALL, but not acute myeloid leukemia, which suggests that folate inadequacy may play a key role in the development of ALL. PMID:10536004

DNA repair gene XRCC1 polymorphisms, smoking, and bladder cancer risk.

PubMed

Stern, M C; Umbach, D M; van Gils, C H; Lunn, R M; Taylor, J A

2001-02-01

Bladder cancer is the sixth most common cancer in the United States. The main identified risk factor is cigarette smoking, which is estimated to contribute to up to 50% of new cases in men and 20% in women. Besides containing other carcinogens, cigarette smoke is a rich source of reactive oxygen species (ROS) that can induce a variety of DNA damage, some of which is repaired by the base excision repair (BER) pathway. The XRCC1 gene protein plays an important role in BER by serving as a scaffold for other repair enzymes and by recognizing single-strand DNA breaks. Three polymorphisms that induce amino acid changes have been found in codon 194 (exon 6), codon 280 (exon 9), and codon 399 (exon 10) of this gene. We tested whether polymorphisms in XRCC1 were associated with bladder cancer risk and whether this association was modified by cigarette smoking. Therefore, we genotyped for the three polymorphisms in 235 bladder cancer cases and 213 controls who had been frequency matched to cases on age, sex, and ethnicity. We found no evidence of an association between the codon 280 variant and bladder cancer risk [odds ratio (OR), 1.2; 95% confidence interval (CI), 0.6-2.6]. We found some evidence of a protective effect for subjects that carried at least one copy of the codon 194 variant allele relative to those homozygous for the common allele (OR, 0.59; 95% CI, 0.3-1.0). The combined analysis with smoking history suggested a possible gene-exposure interaction; however, the results were not statistically significant. Similarly, for the codon 399 polymorphism, our data suggested a protective effect of the homozygous variant genotype relative to carriers of either one or two copies of the common allele (OR, 0.70; 95% CI, 0.4-1.3), and provided limited evidence, albeit not statistically significant, for a gene-smoking interaction.

Polymorphisms in the interleukin-6 receptor gene are associated with bone mineral density and body mass index in Spanish postmenopausal women.

PubMed

Bustamante, M; Nogués, X; Mellibovsky, L; Agueda, L; Jurado, S; Cáceres, E; Blanch, J; Carreras, R; Díez-Pérez, A; Grinberg, D; Balcells, S

2007-11-01

Osteoporosis and obesity are complex diseases with a strong genetic component. Bone mineral density (BMD) and body mass index (BMI) linkage studies identified a locus at 1q21-23, where the interleukin-6 receptor (IL6R) gene is located. The IL6R and the gp130 receptors are the mediators of IL6 action. Serum levels of IL6 and sIL6R (the soluble form of IL6R) are higher in several diseases such as osteoporosis or obesity. Variants at IL6R have been associated with BMI and obesity. However, IL6R is an as-yet-unexplored osteoporosis candidate gene. In the present study we analysed two polymorphisms in the IL6R promoter, -1435 C/T (rs3887104) and -208 G/A (rs4845617), and the Asp358Ala polymorphism (rs8192284), in relation to both BMD and BMI in a cohort of 559 postmenopausal Spanish women. The promoter polymorphisms, -1435 C/T and -208 G/A were associated with femoral neck (FN) BMD (P=0.011 and P=0.025 respectively). The C-A and T-G promoter haplotypes were also associated with FN BMD. Additionally, the Asp358Ala variant was associated with lumbar spine BMD (P=0.038). Finally, the -208 G/A polymorphism and the C-G and C-A haplotypes were associated with BMI and obesity, where GG was the risk genotype (P=0.033 for BMI; P=0.010 for obesity). These data suggest that variants in the IL6R gene are not only involved in the determination of BMI but also relevant for the determination of BMD. The IL6R gene may belong to the growing list of genes known to be involved in both phenotypes.

Polymorphisms of drug-metabolizing enzymes (GST, CYP2B6 and CYP3A) affect the pharmacokinetics of thiotepa and tepa

PubMed Central

Ekhart, Corine; Doodeman, Valerie D; Rodenhuis, Sjoerd; Smits, Paul H M; Beijnen, Jos H; Huitema, Alwin D R

2009-01-01

AIMS Thiotepa is widely used in high-dose chemotherapy. Previous studies have shown relations between exposure and severe organ toxicity. Thiotepa is metabolized by cytochrome P450 and glutathione S-transferase enzymes. Polymorphisms of these enzymes may affect elimination of thiotepa and tepa, its main metabolite. The purpose of this study was to evaluate effects of known allelic variants in CYP2B6, CYP3A4, CYP3A5, GSTA1 and GSTP1 genes on pharmacokinetics of thiotepa and tepa. METHODS White patients (n = 124) received a high-dose regimen consisting of cyclophosphamide, thiotepa and carboplatin as intravenous infusions. Genomic DNA was analysed using polymerase chain reaction and sequencing. Plasma concentrations of thiotepa and tepa were determined using validated GC and LC-MS/MS methods. Relations between allelic variants and elimination pharmacokinetic parameters were evaluated using nonlinear mixed effects modelling (nonmem). RESULTS The polymorphisms CYP2B6 C1459T, CYP3A4*1B, CYP3A5*3, GSTA1 (C-69T, G-52A) and GSTP1 C341T had a significant effect on clearance of thiotepa or tepa. Although significant, most effects were generally not large. Clearance of thiotepa and tepa was predominantly affected by GSTP1 C341T polymorphism, which had a frequency of 9.3%. This polymorphism increased non-inducible thiotepa clearance by 52% [95% confidence interval (CI) 41, 64, P < 0.001] and decreased tepa clearance by 32% (95% CI 29, 35, P < 0.001) in heterozygous patients, which resulted in an increase in combined exposure to thiotepa and tepa of 45% in homozygous patients. CONCLUSIONS This study indicates that the presently evaluated variant alleles explain only a small part of the substantial interindividual variability in thiotepa and tepa pharmacokinetics. Patients homozygous for the GSTP1 C341T allele may have enhanced exposure to thiotepa and tepa. PMID:19076156

Insertion and deletion polymorphisms of the ancient AluS family in the human genome.

PubMed

Kryatova, Maria S; Steranka, Jared P; Burns, Kathleen H; Payer, Lindsay M

2017-01-01

Polymorphic Alu elements account for 17% of structural variants in the human genome. The majority of these belong to the youngest AluY subfamilies, and most structural variant discovery efforts have focused on identifying Alu polymorphisms from these currently retrotranspositionally active subfamilies. In this report we analyze polymorphisms from the evolutionarily older AluS subfamily, whose peak activity was tens of millions of years ago. We annotate the AluS polymorphisms, assess their likely mechanism of origin, and evaluate their contribution to structural variation in the human genome. Of 52 previously reported polymorphic AluS elements ascertained for this study, 48 were confirmed to belong to the AluS subfamily using high stringency subfamily classification criteria. Of these, the majority (77%, 37/48) appear to be deletion polymorphisms. Two polymorphic AluS elements (4%) have features of non-classical Alu insertions and one polymorphic AluS element (2%) likely inserted by a mechanism involving internal priming. Seven AluS polymorphisms (15%) appear to have arisen by the classical target-primed reverse transcription (TPRT) retrotransposition mechanism. These seven TPRT products are 3' intact with 3' poly-A tails, and are flanked by target site duplications; L1 ORF2p endonuclease cleavage sites were also observed, providing additional evidence that these are L1 ORF2p endonuclease-mediated TPRT insertions. Further sequence analysis showed strong conservation of both the RNA polymerase III promoter and SRP9/14 binding sites, important for mediating transcription and interaction with retrotransposition machinery, respectively. This conservation of functional features implies that some of these are fairly recent insertions since they have not diverged significantly from their respective retrotranspositionally competent source elements. Of the polymorphic AluS elements evaluated in this report, 15% (7/48) have features consistent with TPRT-mediated insertion, thus suggesting that some AluS elements have been more active recently than previously thought, or that fixation of AluS insertion alleles remains incomplete. These data expand the potential significance of polymorphic AluS elements in contributing to structural variation in the human genome. Future discovery efforts focusing on polymorphic AluS elements are likely to identify more such polymorphisms, and approaches tailored to identify deletion alleles may be warranted.

Association of five SNPs with human hair colour in the Polish population.

PubMed

Siewierska-Górska, A; Sitek, A; Żądzińska, E; Bartosz, G; Strapagiel, D

2017-03-01

Twenty-two variants (single nucleotide polymorphisms - SNPs) of the genes involved in hair pigmentation (OCA2, HERC2, MC1R, SLC24A5, SLC45A2, TPCN2, TYR, TYRP1) were genotyped in a group of 186 Polish participants, representing a range of hair colours (45 red, 64 blond, 77 dark). A genotype-phenotype association analysis was performed. Using z-statistics we identified three variants highly associated with different hair colour categories (rs12913832:A>G in HERC2, rs1805007:T>C and rs1805008:C>T in MC1R). Two variants: rs1800401:C>T in OCA2 and rs16891982:C>G in SLC45A2 showed a high probability of a relation with hair colour, although that probability did not exceed the threshold of statistical significance after applying the Bonferroni correction. We created and validated mathematical logistic regression models in order to test the usefulness of the sets of polymorphisms for hair colour prediction in the Polish population. We subjected four models to stratified cross-validation. The first model consisted of three polymorphisms that proved to be important in the associative analysis. The second model included, apart from the mentioned polymorphisms, additionally rs16891982:C>G in SLC45A. The third model included, apart from the variants relevant in the associating analysis, rs1800401:C>T in OCA. The fourth model consisted of the set of polymorphisms from the first model supplemented with rs16891982:C>G in SLC45A and rs1800401:C>T in OCA. The validation of our models has shown that the inclusion of rs16891982:C>G in SLC45A and rs1800401:C>T in OCA increases the prediction of red hair in comparison with the algorithm including only rs12913832:A>G in HERC2, rs1805007:T>C and rs1805008:C>T in MC1R. The model consisting of all the five above-mentioned genetic variants has shown good prediction accuracies, expressed by the area under the curve (AUC) of the receiver operating characteristics: 0.84 for the red-haired, 0.82 for the dark-haired and 0.71 for the blond-haired. A genotype-phenotype association analysis brought results similar to those in other studies and confirmed the role of rs16891982:C>G, rs12913832:A>G, rs1805007:T>C and rs1805008:C>T in hair colour determination in the Polish population. Our study demonstrated for the first time the possibility of a share of the rs1800401:C>T SNP in the OCA2 gene in hair colour determination. Including this single nucleotide polymorphism in the actual hair colour predicting models would improve their predictive accuracy. Copyright © 2017 Elsevier GmbH. All rights reserved.

Structural and functional characteristics of natural and constructed channels draining a reclaimed mountaintop removal and valley fill coal mine

EPA Science Inventory

Mountaintop removal and valley fill (MTR/VF) coal mining has altered the landscape of the Central Appalachian region in the United States. The goals of this study were to 1) compare the structure and function of natural and constructed stream channels in forested and MTR/VF catch...

MTR WING A, TRA604. SOUTH SIDE. CAMERA FACING NORTH. THIS ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

MTR WING A, TRA-604. SOUTH SIDE. CAMERA FACING NORTH. THIS VIEW TYPIFIES TENDENCY FOR EXPANSIONS TO TAKE THE FORM OF PROJECTIONS AND INFILL USING AVAILABLE YARD SPACES. INL NEGATIVE NO. HD47-44-3. Mike Crane, Photographer, 4/2005 - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

MTR, TRA603. CONTROL ROOM DETAILS. ACOUSTIC PLASTER CEILING, USHAPED CONSOLE, ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

MTR, TRA-603. CONTROL ROOM DETAILS. ACOUSTIC PLASTER CEILING, U-SHAPED CONSOLE, INSTRUMENT PANELS, GLASS DOOR, ASPHALT TILE FLOOR AND COLORS. BLAW-KNOX 3150-803-11, 10/1950. INL INDEX NO. 531-0603-00-098-100570, REV. 3. - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

Export of detritus and invertebrate from headwater streams: linking mountaintop removal and valley fill coal mining to downstream receiving waters

EPA Science Inventory

Mountaintop removal and valley fill (MTR/VF) coal mining has resulted in large scale alteration of the topography, reduced forest productivity, and burial of headwater streams in the U.S. Central Appalachians. Although MTR/VF coal mining has occurred for several decades and the ...

MTR WING, TRA604. BASEMENT FLOOR PLAN. FIREPROOF RECORD ROOM BELOW ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

MTR WING, TRA-604. BASEMENT FLOOR PLAN. FIRE-PROOF RECORD ROOM BELOW COUNTING ROOM. HEATING AND COOLING EQUIPMENT. UNSPECIFIED EXPANSION AREA ALONG WEST WALL. BLAW-KNOX 3150-4-1, 7/1950. INL INDEX NO. 531-0604-00-098-100007, REV. 1. - Idaho National Engineering Laboratory, Test Reactor Area, Materials & Engineering Test Reactors, Scoville, Butte County, ID

Dopamine D{sub 3} receptor gene: Organization transcript variants, and polymorphism associated with schizophrenia

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

Griffon, N.; Pilon, C.; Martres, M.P.

1996-02-16

DNA fragments from a genomic library were used to establish the partial structure of the human dopamine D{sub 3} receptor gene (DRD3). Its coding sequence contains 6 exons and stretches over 40,000 base pairs. The complete DRD3 transcript and three shorter variants, in which the second and/or third exon are deleted, were detected in similar proportions in brains from four controls and three psychiatric patients. The Msp I polymorphism was localized in the fifth intron of the gene, 40,000 base pairs downstream the Bal I polymorphism and a PCR-based method was developed for genotyping this polymorphism. The distributions of themore » Msp I and Bal I genotypes were not independent in 297 individuals ({chi}{sup 2} = 10.5, df = 4, P = 0.03), but only a weak association was found between allele 1 of the Bal I polymorphism and allele 2 of the Msp I polymorphism ({chi}{sup 2} = 3.99, df = 1, P = 0.04). The previously reported association between homozygosity at both alleles of the Bal I polymorphism and schizophrenia was presently maintained in an extended sample, comprising 119 DSM-III-R chronic schizophrenics and 85 controls ({chi}{sup 2}= 5.3, df = 1, P = 0.02) and found more important in males than in females. The presence of the Bal I allele 2 is associated with an early age at onset, particularly in males (df = 35, t value = 2.6, P = 0.014). In the same sample, allelic frequencies, genotype counts, and proportion of homozygotes for the Msp I polymorphism did not differ between schizophrenics and controls ({chi}{sup 2}= 0.06, df = 1, P = 0.80, {chi}{sup 2} = 0.22, df = 1, P = 0.90 and {chi}{sup 2} = 0.16, df = 1, P = 0.69, respectively). The large distance of the Msp I polymorphism from the Bal I polymorphism and its localization in the 3{prime} part of the gene may explain the discrepant results obtained with the two polymorphisms. 36 refs., 2 figs., 4 tabs.« less

A polymorphism of the MAOA gene is associated with emotional brain markers and personality traits on an antisocial index.

PubMed

Williams, Leanne M; Gatt, Justine M; Kuan, Stacey A; Dobson-Stone, Carol; Palmer, Donna M; Paul, Robert H; Song, Le; Costa, Paul T; Schofield, Peter R; Gordon, Evian

2009-06-01

Association studies suggest that the low activity variant of the monoamine oxidase A (MAOA)-uVNTR polymorphism confers risk for emotional disturbances associated with antisocial traits, particularly in males. Here, we assessed the low (MAOA-L) activity variant in relation to both brain function and a behavioral index of antisocial traits. From an initial sample of 290 healthy participants, 210 had low (MAOA-L) or high (MAOA-H) activity variants. Participants underwent a brief assessment of personality traits and event-related potential (ERP) recording during an emotion-processing task. Genotype differences in ERPs were localized using LORETA. The MAOA-L genotype was distinguished by elevated scores on the index of antisocial traits. These traits were related to altered ERPs elicited 120-280ms post-stimulus, particularly for negative emotion. Altered neural processing of anger in MAOA-L genotypes was localized to medial frontal, parietal, and superior temporo-occipital regions in males, but only to the superior occipital cortex in females. The MAOA low activity variant may increase susceptibility to antisocial traits through alterations to the neural systems for processing threat-related emotion, especially for males. Monoamines such as noradrenalin and serotonin may modulate these relationships, given that their metabolism varies according to MAOA variants, and that they modulate both emotional brain systems and antisocial aggression.

Genetic polymorphisms in carnitine palmitoyltransferase 1A gene are associated with variation in body composition and fasting lipid traits in Yup'ik Eskimos[S

PubMed Central

Lemas, Dominick J.; Wiener, Howard W.; O'Brien, Diane M.; Hopkins, Scarlett; Stanhope, Kimber L.; Havel, Peter J.; Allison, David B.; Fernandez, Jose R.; Tiwari, Hemant K.; Boyer, Bert B.

2012-01-01

Variants of carnitine palmitoyltransferase 1A (CPT1A), a key hepatic lipid oxidation enzyme, may influence how fatty acid oxidation contributes to obesity and metabolic outcomes. CPT1A is regulated by diet, suggesting interactions between gene variants and diet may influence outcomes. The objective of this study was to test the association of CPT1A variants with body composition and lipids, mediated by consumption of polyunsaturated fatty acids (PUFA). Obesity phenotypes and fasting lipids were measured in a cross-sectional sample of Yup'ik Eskimo individuals (n = 1141) from the Center of Alaska Native Health Research (CANHR) study. Twenty-eight tagging CPT1A SNPs were evaluated with outcomes of interest in regression models accounting for family structure. Several CPT1A polymorphisms were associated with HDL-cholesterol and obesity phenotypes. The P479L (rs80356779) variant was associated with all obesity-related traits and fasting HDL-cholesterol. Interestingly, the association of P479L with HDL-cholesterol was still significant after correcting for body mass index (BMI), percentage body fat (PBF), or waist circumference (WC). Our findings are consistent with the hypothesis that the L479 allele of the CPT1A P479L variant confers a selective advantage that is both cardioprotective (through increased HDL-cholesterol) and associated with reduced adiposity. PMID:22045927

VKOR variant and sex are the main influencing factors on bromadiolone tolerance of the house mouse (Mus musculus L.).

PubMed

Šćepović, Tanja; Jokić, Goran; Esther, Alexandra; Kataranovski, Dragan; Vukša, Petar; Đedović, Suzana; Vukša, Marina

2016-03-01

After reports of management problems in practice, a survey was conducted to determine the presence of bromadiolone-resistant animals in different house mouse (Mus musculus L.) populations in Serbia. A 21 day no-choice feeding test was carried out to examine the resistance of house mice to bromadiolone. Eighty house mice collected from four locations (ten males and ten females per location) were tested for bromadiolone tolerance. Surviving animals and their F1 offspring were screened for mutations. The influence of VKOR variant, zygosity and sex on bromadiolone tolerance was analysed. Bait intake and changes in body weight revealed different animal responses regarding susceptibility or resistance. Leu128Ser, Tyr139Cys and a new Ala21Thr polymorphism were detected in wild-born survivors and their F1 generation. However, not every individual with the polymorphisms Leu128Ser and Tyr139Cys survived the feeding test. VKOR variants and sex caused variations in bromadiolone tolerance. For the first time it was shown that the VKOR variant, along with sex, is responsible for bromadiolone tolerance in house mice. Other factors influencing bromadiolone tolerance, including sex-specific factors, cannot be excluded. The tolerance levels of VKOR variants should be determined in further studies in order to evaluate the effectiveness of bromadiolone in sustainable management. © 2015 Society of Chemical Industry.

A New Single Nucleotide Polymorphism Database for Rainbow Trout Generated Through Whole Genome Resequencing.

PubMed

Gao, Guangtu; Nome, Torfinn; Pearse, Devon E; Moen, Thomas; Naish, Kerry A; Thorgaard, Gary H; Lien, Sigbjørn; Palti, Yniv

2018-01-01

Single-nucleotide polymorphisms (SNPs) are highly abundant markers, which are broadly distributed in animal genomes. For rainbow trout ( Oncorhynchus mykiss ), SNP discovery has been previously done through sequencing of restriction-site associated DNA (RAD) libraries, reduced representation libraries (RRL) and RNA sequencing. Recently we have performed high coverage whole genome resequencing with 61 unrelated samples, representing a wide range of rainbow trout and steelhead populations, with 49 new samples added to 12 aquaculture samples from AquaGen (Norway) that we previously used for SNP discovery. Of the 49 new samples, 11 were double-haploid lines from Washington State University (WSU) and 38 represented wild and hatchery populations from a wide range of geographic distribution and with divergent migratory phenotypes. We then mapped the sequences to the new rainbow trout reference genome assembly (GCA_002163495.1) which is based on the Swanson YY doubled haploid line. Variant calling was conducted with FreeBayes and SAMtools mpileup , followed by filtering of SNPs based on quality score, sequence complexity, read depth on the locus, and number of genotyped samples. Results from the two variant calling programs were compared and genotypes of the double haploid samples were used for detecting and filtering putative paralogous sequence variants (PSVs) and multi-sequence variants (MSVs). Overall, 30,302,087 SNPs were identified on the rainbow trout genome 29 chromosomes and 1,139,018 on unplaced scaffolds, with 4,042,723 SNPs having high minor allele frequency (MAF > 0.25). The average SNP density on the chromosomes was one SNP per 64 bp, or 15.6 SNPs per 1 kb. Results from the phylogenetic analysis that we conducted indicate that the SNP markers contain enough population-specific polymorphisms for recovering population relationships despite the small sample size used. Intra-Population polymorphism assessment revealed high level of polymorphism and heterozygosity within each population. We also provide functional annotation based on the genome position of each SNP and evaluate the use of clonal lines for filtering of PSVs and MSVs. These SNPs form a new database, which provides an important resource for a new high density SNP array design and for other SNP genotyping platforms used for genetic and genomics studies of this iconic salmonid fish species.

Toward optimal set of single nucleotide polymorphism investigation before IVF.

PubMed

Ivanov, A V; Dedul, A G; Fedotov, Y N; Komlichenko, E V

2016-10-01

At present, the patient preparation for IVF needs to undergo a series of planned tests, including the genotyping of single nucleotide polymorphism (SNP) alleles of some genes. In former USSR countries, such investigation was not included in overwhelming majority of health insurance programs and paid by patient. In common, there are prerequisites to the study of more than 50 polymorphisms. An important faced task is to determine the optimal panel for SNP genotyping in terms of price/number of SNP. During 2009-2015 in the University Hospital of St. Petersburg State University, blood samples were analyzed from 550 women with different reproductive system disorders preparing for IVF and 46 healthy women in control group. In total, 28 SNP were analyzed in the genes of thrombophilia factors, folic acid cycle, detoxification system, and the renin-angiotensin system. The method used was real-time PCR. A significant increase in the frequency of pathological alleles of some polymorphisms in patients with habitual failure of IVF was shown, compared with the control group. As a result, two options defined panels for optimal typing SNP before IVF were composed. Standard panel includes 8 SNP, 5 in thromborhilic factors, and 3 in folic acid cycle genes. They are 20210 G > A of FII gene, R506Q G > A of FV gene (mutation Leiden), -675 5G > 4G of PAI-I gene, L33P T > C of ITGB3 gene, -455 G > A of FGB gene, 667 C > T of MTHFR gene, 2756 A > G of MTR gene, and 66 A > G of MTRR gene. Extended panel of 15 SNP also includes 807 C > T of ITGA2 gene, T154M C > T of GP1BA gene, second polymorphism 1298 A > C in MTHFR gene, polymorphisms of the renin-angiotensin gene AGT M235T T > C and -1166 A > C of AGTR1 gene, polymorphisms I105V A > G and A114V C > T of detoxification system gene GSTP. The results of SNP genotyping can be adjusted for treatment tactics and IVF, and also medical support getting pregnant. The success rate of IVF is increased as the result, especially in the group with the usual failure of IVF.

Association of transforming growth-factor alpha gene polymorphisms with nonsyndromic cleft palate only (CPO)

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

Shiang, R.; Lidral, A.C.; Ardinger, H.H.

1993-10-01

Genetic analysis and tissue-specific expression studies support a role for transforming growth-factor alpha (TGFA) in craniofacial development. Previous studies have confirmed an association of alleles for TGFA with nonsyndromic cleft lip with or without cleft palate (CL/P) in humans. The authors carried out a retrospective association study to determine whether specific allelic variants of the TGFA gene are also associated with cleft palate only (CPO). The PCR products from 12 overlapping sets of primers to the TGFA cDNA were examined by using single-strand conformational polymorphism analysis. Four DNA polymorphic sites for TGFA were identified in the 3[prime] untranslated region ofmore » the TGFA gene. These variants, as well as previously identified RFLPs for TGFA, were characterized in case and control populations for CPO by using X[sup 2] analysis. A significant association between alleles of TGFA and CPO was identified which further supports a role for this gene as one of the genetic determinants of craniofacial development. Sequence analysis of the variants disclosed a cluster of three variable sites within 30 bp of each other in the 3[prime] untranslated region previously associated with an antisense transcript. These studies extend the role for TGFA in craniofacial morphogenesis and support an interrelated mechanism underlying nonsyndromic forms of CL/P. 46 refs., 3 figs., 3 tabs.« less

A single nucleotide polymorphism -1131T>C in the apolipoprotein A5 gene is associated with an increased risk of coronary artery disease and alters triglyceride metabolism in Chinese.

PubMed

Bi, Nan; Yan, Sheng-kai; Li, Guo-ping; Yin, Zhi-nong; Chen, Bao-sheng

2004-11-01

The disorder of triglyceride (TG) metabolism leading to hypertriglyceridemia is an independent risk factor for coronary artery disease (CAD). Variants in the newly identified apolipoprotein APOA5 gene were found to be strongly associated with elevated TG levels in different racial groups. In this study, we investigated the phenotypic effects of two polymorphisms (APOA5-1131T>C and APOC3-482C>T) on susceptibility to CAD in 312 Chinese CAD patients diagnosed by angiography. The frequency of the APOA5-1131C allele in these patients was significantly higher than that of the control group (39.9 vs. 33.3%, P=0.02). Compared with the wild type TT, CC homozygotes had a significantly increased CAD risk (OR=1.93 and OR=1.80 using unadjusted and adjusted logistic regression models, respectively). This association still existed after adjustment for the APOC3-482 variant. The APOA5-1131C allele also showed a correlation with increasing plasma TG levels (P<0.001). These data suggest that the APOA5-1131T>C polymorphism might contribute to an increased risk of CAD among Chinese as a result of its effect on TG metabolism; this effect was found to be independent of the APOC3-482C>T variant.

Significance of common variants on human chromosome 8q24 in relation to the risk of prostate cancer in native Japanese men

PubMed Central

Liu, Miao; Kurosaki, Takayuki; Suzuki, Motofumi; Enomoto, Yutaka; Nishimatsu, Hiroaki; Arai, Tomio; Sawabe, Motoji; Hosoi, Takayuki; Homma, Yukio; Kitamura, Tadaichi

2009-01-01

Background Common variants on human chromosome 8q24, rs1447295 (C/A) and rs6983267 (T/G), have been recently linked to the prevalence of prostate cancer in European and American populations. Here, we evaluated whether the single-nucleotide polymorphisms rs1447295 and rs6983267 were associated with the risk of sporadic prostate cancer as well as latent prostate cancer in a native Japanese population. Results We analyzed genomic DNA samples from 391 sporadic prostate cancer patients, 323 controls who had died from causes unrelated to cancer and 112 Japanese men who were diagnosed as having latent prostate cancer based on autopsy results. The polymorphisms were determined by allelic discrimination using a fluorescent-based TaqMan assay. The A allele of rs1447295 was significantly associated with the risk of sporadic prostate cancer (p = 0.04; age-adjusted OR, 1.34), while the G allele of rs6983267 showed a trend towards being a high-risk allele (p = 0.06; age-adjusted OR, 1.27). No significant difference between these two polymorphisms and the risk of latent prostate cancer was observed in the present Japanese population. Conclusion Known variants on human chromosome 8q24 may be risk factors for sporadic prostate cancer in native Japanese men. PMID:19602258

Evaluation of the association between the TAS1R2 and TAS1R3 variants and food intake and nutritional status in children

PubMed Central

Melo, Silvia V.; Agnes, Grasiela; Vitolo, Márcia R.; Mattevi, Vanessa S.; Campagnolo, Paula D.B.; Almeida, Silvana

2017-01-01

Abstract Taste perception plays a key role in determining individual food preferences and dietary habits and may influence nutritional status. This study aimed to investigate the association of TAS1R2 (Ile191Val - rs35874116) and TAS1R3 (-1266 C/T - rs35744813) variants with food intake and nutritional status in children followed from birth until 7.7 years old. The nutritional status and food intake data of 312 children were collected at three developmental stages (1, 3.9 and 7.7 years old). DNA was extracted from blood samples and the polymorphisms were analyzed by real-time polymerase chain reactions (qPCR) using hydrolysis probes as the detection method. Food intake and nutritional status were compared among individuals with different single nucleotide polymorphism (SNP) genotypes. At 3.9 years old, children homozygous (Val/Val) for the TAS1R2 Ile191Val polymorphism ingested less sugar and sugar-dense foods than children who were *Ile carriers. This finding demonstrated that a genetic variant of the T1R2 taste receptor is associated with the intake of different amounts of high sugar-content foods in childhood. This association may provide new perspectives for studying dietary patterns and nutritional status in childhood. PMID:28497839

Drug & Gene Interaction Risk Analysis With & Without Genetic Testing Among Patients Undergoing MTM

ClinicalTrials.gov

2017-02-22

Cytochrome P450 CYP2D6 Enzyme Deficiency; Poor Metabolizer Due to Cytochrome P450 CYP2D6 Variant; Ultrarapid Metabolizer Due to Cytochrome P450 CYP2D6 Variant; Extensive Metabolizer Due to Cytochrome P450 CYP2D6 Variant; Cytochrome P450 CYP2C9 Enzyme Deficiency; Cytochrome P450 CYP2C19 Enzyme Deficiency; Drug Metabolism, Poor, CYP2D6-RELATED; Drug Metabolism, Poor, CYP2C19-RELATED; CYP2D6 Polymorphism

Behavioral and Neural Manifestations of Reward Memory in Carriers of Low-Expressing versus High-Expressing Genetic Variants of the Dopamine D2 Receptor

PubMed Central

Richter, Anni; Barman, Adriana; Wüstenberg, Torsten; Soch, Joram; Schanze, Denny; Deibele, Anna; Behnisch, Gusalija; Assmann, Anne; Klein, Marieke; Zenker, Martin; Seidenbecher, Constanze; Schott, Björn H.

2017-01-01

Dopamine is critically important in the neural manifestation of motivated behavior, and alterations in the human dopaminergic system have been implicated in the etiology of motivation-related psychiatric disorders, most prominently addiction. Patients with chronic addiction exhibit reduced dopamine D2 receptor (DRD2) availability in the striatum, and the DRD2 TaqIA (rs1800497) and C957T (rs6277) genetic polymorphisms have previously been linked to individual differences in striatal dopamine metabolism and clinical risk for alcohol and nicotine dependence. Here, we investigated the hypothesis that the variants of these polymorphisms would show increased reward-related memory formation, which has previously been shown to jointly engage the mesolimbic dopaminergic system and the hippocampus, as a potential intermediate phenotype for addiction memory. To this end, we performed functional magnetic resonance imaging (fMRI) in 62 young, healthy individuals genotyped for DRD2 TaqIA and C957T variants. Participants performed an incentive delay task, followed by a recognition memory task 24 h later. We observed effects of both genotypes on the overall recognition performance with carriers of low-expressing variants, namely TaqIA A1 carriers and C957T C homozygotes, showing better performance than the other genotype groups. In addition to the better memory performance, C957T C homozygotes also exhibited a response bias for cues predicting monetary reward. At the neural level, the C957T polymorphism was associated with a genotype-related modulation of right hippocampal and striatal fMRI responses predictive of subsequent recognition confidence for reward-predicting items. Our results indicate that genetic variations associated with DRD2 expression affect explicit memory, specifically for rewarded stimuli. We suggest that the relatively better memory for rewarded stimuli in carriers of low-expressing DRD2 variants may reflect an intermediate phenotype of addiction memory. PMID:28507526

Sibling-based association study of the PPARgamma2 Pro12Ala polymorphism and metabolic variables in Chinese and Japanese hypertension families: a SAPPHIRe study. Stanford Asian-Pacific Program in Hypertension and Insulin Resistance.

PubMed

Chuang, L M; Hsiung, C A; Chen, Y D; Ho, L T; Sheu, W H; Pei, D; Nakatsuka, C H; Cox, D; Pratt, R E; Lei, H H; Tai, T Y

2001-11-01

The peroxisome proliferator activated receptor (PPAR) gamma2 is a transcription factor that has been shown to be involved in adipocyte differentiation, adipogenesis, and insulin sensitivity. To address the role of PPARgamma2 in glucose homeostasis and insulin sensitivity, among many other objectives, we conducted a sibling-controlled association study in a multicenter program - the Stanford Asian-Pacific Program in Hypertension and Insulin Resistance (SAPPHIRe). Approximately 2525 subjects in 734 Chinese and Japanese families have been recruited from six field centers for SAPPHIRe. In total, 1702 subjects including parents and siblings from 449 families have been genotyped for PPARgamma2, of which 328 families were Chinese and 121 Japanese. Only 88 subjects of the 1525 siblings screened for the P12A polymorphism were found to be carriers of the A variant, the most common variant of the PPARgamma2 gene. A variant frequencies of the siblings were 4.27% in Chinese and 2.72% in Japanese. A sibling-controlled association study was performed through genetically discordant sibships (i.e., P/P genotype vs. P/A + A/A genotypes). Specifically, we examined whether there were differences in metabolic variables between the discordant siblings within families. In total, 88 subjects carrying either 1 or 2 A alleles had at least one sibling who was discordant for the P12A polymorphism, yielding a total of 180 individuals from 47 families for analyses, among which 92 siblings were homozygous for wild-type P allele. Siblings with the A variant tended to have lower levels of fasting plasma glucose (OG-10), and lower glucose levels at 60 min following oral glucose loading after adjusting for age, gender, and body mass index. Using a mixed model treating family as a random effect, we found that P12A polymorphism of the PPARgamma2 gene contributes significantly to the variance in fasting plasma glucose, glucose level at 60 min, and insulin-resistance homeostasis model assessment. Our results suggest that within families siblings with the A variant in the PPARgamma2 gene may be more likely to have better glucose tolerance and insulin sensitivity independent of obesity in Chinese and Japanese populations.

Physical activity modifies the associations between genetic variants and blood pressure in European adolescents.

PubMed

de Moraes, Augusto César Ferreira; Fernández-Alvira, Juan Miguel; Carvalho, Heráclito Barbosa; Meirhaeghe, Aline; Dallongeville, Jean; Kafatos, Anthony; Marcos, Ascensión; Molnar, Dénes; Manios, Yannis; Ruiz, Jonatan R; Labayen, Idoia; Widhalm, Kurt; Breidenassel, Christina; Gonzalez-Gróss, Marcela; Moreno, Luis A

2014-11-01

We hypothesized that physical activity and sedentary behavior could modify the associations between known genetic variants blood pressure-associated genes in European adolescents. Meeting current physical activity recommendations (≥ 60 minutes/day) was able attenuate the deleterious effect of the NOS3 rs3918227 polymorphism on systolic blood pressure in European adolescents. Copyright © 2014 Elsevier Inc. All rights reserved.

Polymorphisms in ghrelin and neuropeptide Y genes are associated with non-Hodgkin lymphoma.

PubMed

Skibola, Danica R; Smith, Martyn T; Bracci, Paige M; Hubbard, Alan E; Agana, Luz; Chi, Shawn; Holly, Elizabeth A

2005-05-01

We previously reported a positive association among body mass index, single nucleotide polymorphisms (SNP) in the leptin and leptin receptor genes that are involved in body weight regulation, and non-Hodgkin lymphoma (NHL). Polymorphisms in the ghrelin (GHRL) and neuropeptide Y (NPY) genes were examined in the same population-based case-control study of NHL to further explore the role of genes involved in energy homeostasis and obesity in susceptibility to NHL. Ghrelin is an orexigenic hormone that induces NPY release and inhibits proinflammatory cytokines via its antagonistic relationship with leptin. NPY is a potent appetite stimulator controlled by ghrelin and leptin and also acts as a mediator of immune function. DNA from 458 cases and 812 controls was genotyped. Among genotyped GHRL SNPs, the variant allele for GHRL -4427G>A was inversely associated with all NHL [odds ratios (OR), 0.78; 95% confidence interval (95% CI), 0.59-1.0] and more specifically with diffuse large cell lymphoma (DLCL; homozygous variant: OR, 0.31; 95% CI, 0.13-0.74). Another SNP, GHRL 5179A>G, decreased the risk of DLCL (homozygous variant: OR, 0.35; 95% CI, 0.10-1.2). NPY -485T>C, 1258G>A, and 5671C>T were in total linkage disequilibrium (D' = 0.99) and the homozygous variants were associated with an increased risk of NHL in NPY SNPs -485T>C (OR, 1.7; 95% CI, 1.1-2.5), 1258G>A (OR, 1.7; 95% CI, 1.1-2.5), and 5671C>T (OR, 1.9; 95% CI, 1.3-2.8). When stratified by subtype, the variant allele for NPY 1128T>C was positively associated with follicular lymphoma (OR, 2.3; 95% CI, 1.1-4.9) as were homozygous variants for NPY SNPs -485T>C (OR, 2.4; 95% CI, 1.3-4.4), 1258G>A (OR, 2.0; 95% CI, 1.1-3.5), and 5671C>T (OR, 1.8; 95% CI, 1.1-3.0). These results add further support for the hypothesis that SNPs in energy-regulating genes affect risk of NHL.

Association between cytochrome CYP17A1, CYP3A4, and CYP3A43 polymorphisms and prostate cancer risk and aggressiveness in a Korean study population

PubMed Central

Han, Jun Hyun; Lee, Yong Seong; Kim, Hae Jong; Lee, Shin Young; Myung, Soon Chul

2015-01-01

In this study, we evaluated genetic variants of the androgen metabolism genes CYP17A1, CYP3A4, and CYP3A43 to determine whether they play a role in the development of prostate cancer (PCa) in Korean men. The study population included 240 pathologically diagnosed cases of PCa and 223 age-matched controls. Among the 789 single-nucleotide polymorphism (SNP) database variants detected, 129 were reported in two Asian groups (Han Chinese and Japanese) in the HapMap database. Only 21 polymorphisms of CYP17A1, CYP3A4, and CYP3A43 were selected based on linkage disequilibrium in Asians (r2 = 1), locations (SNPs in exons were preferred), and amino acid changes and were assessed. In addition, we performed haplotype analysis for the 21 SNPs in CYP17A1, CYP3A4, and CYP3A43 genes. To determine the association between genotype and haplotype distributions of patients and controls, logistic analyses were carried out, controlling for age. Twelve sequence variants and five major haplotypes were identified in CYP17A1. Five sequence variants and two major haplotypes were identified in CYP3A4. Four sequence variants and four major haplotypes were observed in CYP3A43. CYP17A1 haplotype-2 (Ht-2) (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.04–2.18) was associated with PCa susceptibility. CYP3A4 Ht-2 (OR: 1.87; 95% CI: 1.02–3.43) was associated with PCa metastatic potential according to tumor stage. rs17115149 (OR: 1.96; 95% CI: 1.04–3.68) and CYP17A1 Ht-4 (OR: 2.01; 95% CI: 1.07–4.11) showed a significant association with histologic aggressiveness according to Gleason score. Genetic variants of CYP17A1 and CYP3A4 may play a role in the development of PCa in Korean men. PMID:25337833

Association between cytochrome CYP17A1, CYP3A4, and CYP3A43 polymorphisms and prostate cancer risk and aggressiveness in a Korean study population.

PubMed

Han, Jun Hyun; Lee, Yong Seong; Kim, Hae Jong; Lee, Shin Young; Myung, Soon Chul

2015-01-01

In this study, we evaluated genetic variants of the androgen metabolism genes CYP17A1, CYP3A4, and CYP3A43 to determine whether they play a role in the development of prostate cancer (PCa) in Korean men. The study population included 240 pathologically diagnosed cases of PCa and 223 age-matched controls. Among the 789 single-nucleotide polymorphism (SNP) database variants detected, 129 were reported in two Asian groups (Han Chinese and Japanese) in the HapMap database. Only 21 polymorphisms of CYP17A1, CYP3A4, and CYP3A43 were selected based on linkage disequilibrium in Asians (r2 = 1), locations (SNPs in exons were preferred), and amino acid changes and were assessed. In addition, we performed haplotype analysis for the 21 SNPs in CYP17A1, CYP3A4, and CYP3A43 genes. To determine the association between genotype and haplotype distributions of patients and controls, logistic analyses were carried out, controlling for age. Twelve sequence variants and five major haplotypes were identified in CYP17A1. Five sequence variants and two major haplotypes were identified in CYP3A4. Four sequence variants and four major haplotypes were observed in CYP3A43. CYP17A1 haplotype-2 (Ht-2) (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.04-2.18) was associated with PCa susceptibility. CYP3A4 Ht-2 (OR: 1.87; 95% CI: 1.02-3.43) was associated with PCa metastatic potential according to tumor stage. rs17115149 (OR: 1.96; 95% CI: 1.04-3.68) and CYP17A1 Ht-4 (OR: 2.01; 95% CI: 1.07-4.11) showed a significant association with histologic aggressiveness according to Gleason score. Genetic variants of CYP17A1 and CYP3A4 may play a role in the development of PCa in Korean men.

Demonstration of Protein-Based Human Identification Using the Hair Shaft Proteome

PubMed Central

Leppert, Tami; Anex, Deon S.; Hilmer, Jonathan K.; Matsunami, Nori; Baird, Lisa; Stevens, Jeffery; Parsawar, Krishna; Durbin-Johnson, Blythe P.; Rocke, David M.; Nelson, Chad; Fairbanks, Daniel J.; Wilson, Andrew S.; Rice, Robert H.; Woodward, Scott R.; Bothner, Brian; Hart, Bradley R.; Leppert, Mark

2016-01-01

Human identification from biological material is largely dependent on the ability to characterize genetic polymorphisms in DNA. Unfortunately, DNA can degrade in the environment, sometimes below the level at which it can be amplified by PCR. Protein however is chemically more robust than DNA and can persist for longer periods. Protein also contains genetic variation in the form of single amino acid polymorphisms. These can be used to infer the status of non-synonymous single nucleotide polymorphism alleles. To demonstrate this, we used mass spectrometry-based shotgun proteomics to characterize hair shaft proteins in 66 European-American subjects. A total of 596 single nucleotide polymorphism alleles were correctly imputed in 32 loci from 22 genes of subjects’ DNA and directly validated using Sanger sequencing. Estimates of the probability of resulting individual non-synonymous single nucleotide polymorphism allelic profiles in the European population, using the product rule, resulted in a maximum power of discrimination of 1 in 12,500. Imputed non-synonymous single nucleotide polymorphism profiles from European–American subjects were considerably less frequent in the African population (maximum likelihood ratio = 11,000). The converse was true for hair shafts collected from an additional 10 subjects with African ancestry, where some profiles were more frequent in the African population. Genetically variant peptides were also identified in hair shaft datasets from six archaeological skeletal remains (up to 260 years old). This study demonstrates that quantifiable measures of identity discrimination and biogeographic background can be obtained from detecting genetically variant peptides in hair shaft protein, including hair from bioarchaeological contexts. PMID:27603779

PvuII and XbaI polymorphisms of estrogen receptor-α and the results of estroprogestagen therapy in girls with functional hypothalamic amenorrhea – preliminary study

PubMed Central

Syrenicz, Anhelli; Friebe, Zbigniew; Jarząbek-Bielecka, Grażyna; Chełstowski, Kornel

2012-01-01

Introduction The aim of this study was the long-term prospective evaluation of the effects of estroprogestagen (EP) therapy on the bone mineral density (BMD) of girls with functional hypothalamic amenorrhea (FHA) carrying various PvuII and XbaI polymorphisms of ER-α. Material and methods Prospective observation included 84 FHA girls and 50 controls. The FHA patients were subjected to 4-year sequential therapy with 17β estradiol (2 mg from the 2nd to 25th day of the menstrual cycle) and dydrogesterone (10 mg from the 16th to the 25th day). Hormonal parameters, serum concentration of the bone fraction of alkaline phosphatase (BALP), urine concentration of cross-linked n-telopeptide of type I collagen (Ntx) and BMD were determined before and after the treatment. Results Six-month treatment resulted in a marked increase in estradiol (p = 0.001), testosterone and prolactin levels (p = 0.01 both) and a significant decrease in BALP and Ntx (p = 0.001 both). Patients with the PP polymorphism had significantly lower baseline BMD compared to carriers of other polymorphic variants of PvuII (p = 0.003). A significant increase in BMD was observed throughout the entire therapy period, with no significant differences in the yearly dynamics of BMD changes observed amongst various polymorphic variants and haplotypes of ER-α. Conclusions The EP therapy is effective in the treatment of BMD disorders associated with FHA, and treatment results do not depend on PvuII and XbaI polymorphisms of ER-α. PMID:23185193

PvuII and XbaI polymorphisms of estrogen receptor-α and the results of estroprogestagen therapy in girls with functional hypothalamic amenorrhea - preliminary study.

PubMed

Sowińska-Przepiera, Elżbieta; Syrenicz, Anhelli; Friebe, Zbigniew; Jarząbek-Bielecka, Grażyna; Chełstowski, Kornel

2012-11-09

The aim of this study was the long-term prospective evaluation of the effects of estroprogestagen (EP) therapy on the bone mineral density (BMD) of girls with functional hypothalamic amenorrhea (FHA) carrying various PvuII and XbaI polymorphisms of ER-α. Prospective observation included 84 FHA girls and 50 controls. The FHA patients were subjected to 4-year sequential therapy with 17β estradiol (2 mg from the 2(nd) to 25(th) day of the menstrual cycle) and dydrogesterone (10 mg from the 16(th) to the 25(th) day). Hormonal parameters, serum concentration of the bone fraction of alkaline phosphatase (BALP), urine concentration of cross-linked n-telopeptide of type I collagen (Ntx) and BMD were determined before and after the treatment. Six-month treatment resulted in a marked increase in estradiol (p = 0.001), testosterone and prolactin levels (p = 0.01 both) and a significant decrease in BALP and Ntx (p = 0.001 both). Patients with the PP polymorphism had significantly lower baseline BMD compared to carriers of other polymorphic variants of PvuII (p = 0.003). A significant increase in BMD was observed throughout the entire therapy period, with no significant differences in the yearly dynamics of BMD changes observed amongst various polymorphic variants and haplotypes of ER-α. The EP therapy is effective in the treatment of BMD disorders associated with FHA, and treatment results do not depend on PvuII and XbaI polymorphisms of ER-α.

Genetic polymorphisms of Th2 interleukins, history of asthma or eczema and childhood acute lymphoid leukaemia: Findings from the ESCALE study (SFCE).

PubMed

Bonaventure, A; Orsi, L; Rudant, J; Goujon-Bellec, S; Leverger, G; Baruchel, A; Bertrand, Y; Nelken, B; Pasquet, M; Michel, G; Sirvent, N; Chastagner, P; Ducassou, S; Thomas, C; Besse, C; Hémon, D; Clavel, J

2018-06-05

Previous studies on the putative role of allergy in the aetiology of childhood leukaemia have reported contradictory results. The present study aimed to analyse the relation between a medical history of asthma or eczema and childhood acute lymphoid leukaemia (ALL) in light of potential candidate gene-environment interactions. Analyses were based on a subset of 434 cases of ALL and 442 controls successfully genotyped and of European ancestry children enrolled in a French population-based case-control study conducted in 2003-2004. Information about medical history was obtained during a standardized interview with the mothers. Candidate polymorphisms in genes of the Th2 cytokines IL4, IL10, IL13 and IL4-receptor, were genotyped or imputed. None of the variant alleles were directly associated with childhood acute lymphoid leukaemia. A medical history of asthma or eczema was reported more often in the control group (OR = 0.7 [0.5-1.0]). This association was mostly seen in the group of children not carrying the IL13-rs20541 variant allele (Interaction Odds Ratio IOR 1.9, p-interaction = 0.07) and in those carrying the IL10 triple variant haplotype (IOR 0.5, p-interaction = 0.04). No interaction was observed with the candidate polymorphisms in IL4 and IL4R. This study provides a new insight into the relationship between allergic symptoms and childhood acute lymphoid leukaemia, by suggesting this inverse association could be limited to children carrying certain genetic polymorphisms. If confirmed, these results could help better understand the biological mechanisms involved in the development of childhood acute lymphoid leukaemia. Copyright © 2018. Published by Elsevier Ltd.

Functional variability of glutathione S-transferases in Basque populations.

PubMed

Iorio, Andrea; Piacentini, Sara; Polimanti, Renato; De Angelis, Flavio; Calderon, Rosario; Fuciarelli, Maria

2014-01-01

Glutathione S-transferases (GSTs) are enzymes involved in Phase II reactions. They play a key role in cellular detoxification. Various studies have shown that genes coding for the GST are highly polymorphic and some of these variants are directly associated with a decrease of enzyme activity making individuals more susceptible to different clinical phenotypes. The aim of this study is to investigate the genetic variability of GST genes among human populations. We have focused our attention on the polymorphic variants of the GSTA1, GSTM1, GSTO1, GSTO2, GSTP1, GSTT1, and GSTT2B genes. These polymorphisms were analyzed in a whole sample of 151 individuals: 112 autochthonous Navarrese Basques, and 39 non-autochthonous Navarrese Basques. DNA extraction from plasma was performed by using the phenol:chloroform:isoamylic alcohol method. Genotyping of the gene polymorphisms was performed by PCR Multiplex and the PCR-RFLP method. We applied correspondence analysis and built frequency-maps to compare the genetic structure in worldwide populations. Our results were compared with data available on the Human Genome Diversity Project (HGDP) and on the 1,000 Genomes Project to obtain information on the functional variability of GSTs in Basques. Our data indicated that Basque communities showed a higher differentiation of certain functional GST variants (i.e., GSTM1-positive/null genotype, GSTP1*I105V, and GSTT2B*1/0) than other European and Mediterranean populations. This might account for epidemiological differences in the predisposition to diseases and drug response among Basques and could be used to design and interpret genetic association studies for this particular population. Copyright © 2014 Wiley Periodicals, Inc.

A meta-analysis of Th2 pathway genetic variants and risk for allergic rhinitis.

PubMed

Bunyavanich, Supinda; Shargorodsky, Josef; Celedón, Juan C

2011-06-01

There is a significant genetic contribution to allergic rhinitis (AR). Genetic association studies for AR have been performed, but varying results make it challenging to decipher the overall potential effect of specific variants. The Th2 pathway plays an important role in the immunological development of AR. We performed meta-analyses of genetic association studies of variants in Th2 pathway genes and AR. PubMed and Phenopedia were searched by double extraction for original studies on Th2 pathway-related genetic polymorphisms and their associations with AR. A meta-analysis was conducted on each genetic polymorphism with data meeting our predetermined selection criteria. Analyses were performed using both fixed and random effects models, with stratification by age group, ethnicity, and AR definition where appropriate. Heterogeneity and publication bias were assessed. Six independent studies analyzing three candidate polymorphisms and involving a total of 1596 cases and 2892 controls met our inclusion criteria. Overall, the A allele of IL13 single nucleotide polymorphism (SNP) rs20541 was associated with increased odds of AR (estimated OR=1.2; 95% CI 1.1-1.3, p-value 0.004 in fixed effects model, 95% CI 1.0-1.5, p-value 0.056 in random effects model). The A allele of rs20541 was associated with increased odds of AR in mixed age groups using both fixed effects and random effects modeling. IL13 SNP rs1800925 and IL4R SNP 1801275 did not demonstrate overall associations with AR. We conclude that there is evidence for an overall association between IL13 SNP rs20541 and increased risk of AR, especially in mixed-age populations. © 2011 John Wiley & Sons A/S.

Cytochrome P450 2C9 gene polymorphism and warfarin maintenance dosage in pediatric patients: A systematic review and meta-analysis.

PubMed

Zhang, Jinhua; Tian, Lihong; Huang, Jinlong; Huang, Sihan; Chai, Tingting; Shen, Jianzhen

2017-02-01

To assess the effect of Cytochrome P450 2C9 (CYP2C9) gene polymorphism on pediatric warfarin maintenance dosage requirement. A previously developed search strategy was conducted in PubMed, EMBASE, and the Cochrane Library. Eligible studies published prior to January 27, 2016, were identified and compared against strict inclusion/exclusion criteria. Required data were extracted, and researchers were consulted for additional data if needed. Review Manager version 5.2.3 software was used to analyze the relationship between CYP2C9 polymorphisms and warfarin maintenance doses in pediatric patients. Eight articles with a combined total of 507 pediatric patients were included in the meta-analysis. Maintenance warfarin doses in patients with CYP2C9 *1/*2 genotype, CYP2C9 *1/*3 genotype, and CYP2C9 variant carriers which contain at least one variant allele (*2 or *3) were from 15% to 41% lower than doses in patients with the wild-type allele (CYP2C9 *1/*1): All differences were significant with P-values <.05. The Fontan procedure as a medical indication for anticoagulation was also associated with a lower warfarin maintenance dose; however, target INR range was not. We found that CYP2C9 gene polymorphism (referring to the presence of *1/*2, *1/*3, and variant genotypes in the population in addition to the wild type) was significantly associated with decreased warfarin maintenance dose requirements. Additionally, a specific indication for warfarin, the Fontan procedure, was associated with a lower daily warfarin dose. However, the results of our study require confirmation from more research with larger numbers of pediatric patients. © 2016 John Wiley & Sons Ltd.

Comparative polymorphism of BAT-26 between healthy individuals and cancer patients and its cancer risk implication for local Chinese.

PubMed

Zheng, Yanying; Liu, Li; Sun, Yi; Chen, Jie; Wang, Jianrong; Zhu, Changle; Lai, Rensheng; Xie, Ling

2016-07-30

BAT-26 is one of the representative markers for microsatellite instability evaluation and presents different polymorphisms in different ethnic populations. The current knowledge of its comparative polymorphism between healthy individuals and cancer patients in the Chinese population is insufficient. This study aims to analyze germline polymorphic variations of BAT-26 between healthy individuals and cancer patients in Chinese from Jiangsu province and the associated cancer risk implications. The various BAT-26 alleles and their percentages in cervical cells from 500 healthy women were assessed by direct sequencing. Twenty of these samples were also analyzed by fragment analysis. BAT-26 of blood DNA from 24 healthy individuals and 247 cancer patients was analyzed by fragment analysis. Compared with the sequencing results, 122.6-122.9 bp, 123.4-123.8 bp and 124.1-124.8 bp corresponded to the A25, A26 and A27 alleles, respectively. The 524 healthy individuals showed 4.58%, 92.18% and 3.24% of A25, A26 and A27, respectively. The variant alleles A18, A24, A28, A29 and A32 were only found in cancer patients, accounting for 0.81%, 0.40%, 0.40%, 0.40% and 0.40%, respectively; the A25, A26 and A27 alleles in cancer patients accounted for 6.48%, 77.33% and 13.77%. Healthy individuals had a stable BAT-26 profile within the quasimonomorphic variation range (QMVR), but cancer patients harbored variant alleles outside QMVR and showed a trend from quasimonomorph to polymonomorph, suggesting that variant alleles of BAT-26 in germline cells may be regarded as a potential marker of higher cancer risk in the Chinese population from Jiangsu province.

Role of treatment-modifying MTHFR677C>T and 1298A>C polymorphisms in metformin-treated Puerto Rican patients with type-2 diabetes mellitus and peripheral neuropathy.

PubMed

Jiménez-Ramírez, Francisco J; Castro, Liza M; Ortiz, Clarymar; Concepción, Jennifer; Renta, Jessicca Y; Morales-Borges, Raúl H; Miranda-Massari, Jorge R; Duconge, Jorge

2017-03-01

The study was conducted to investigate potential association between MTHFR genotypes and diabetic peripheral neuropathy (DPN) in Puerto Ricans with type-2 diabetes mellitus (T2DM) treated with metformin. The prevalence of major MTHFR polymorphisms in this cohort was also ascertained. DNAs from 89 metformin-treated patients with T2DM and DPN were genotyped using the PCR-based RFLP assay for MTHFR677C>T and 1298A>C polymorphisms. Frequency distributions of these variants in the study cohort were compared to those reported for three reference populations (HapMap project) and controls (400 newborn specimens). Chi-square (or Fischer's exact) tests and odds ratios (OR) were used to assess association with DPN susceptibility risk (patients vs. controls) and biochemical markers (wild types vs. carriers). Sixty-seven percent (67%) of participants carry at least one of these MTHFR polymorphisms. No deviations from Hardy-Weinberg equilibrium were detected. The genotype and allele frequencies showed statistically significant differences between participants and controls (p<0.0001 and p=0.03, respectively). Results suggest that 1298A>C but not 677C>T is associated with DPN susceptibility in this cohort (p=0.018). Different patterns of allelic dissimilarities are observed when comparing our cohort vs. the three parental ancestries. After sorting individuals by their carrier status, no significant associations were observed between these genetic variants (independently or combined) and any of the biochemical markers (HbA1c, folate, vitamin B12, homocysteine). Prevalence of major MTHFR variants in Puerto Rican patients with T2DM is first time ever reported. The study provides further evidence on the use of this genetic marker as an independent risk factor for DPN.

Genetic variant in the IGF2BP2 gene may interact with fetal malnutrition to affect glucose metabolism.

PubMed

van Hoek, Mandy; Langendonk, Janneke G; de Rooij, Susanne R; Sijbrands, Eric J G; Roseboom, Tessa J

2009-06-01

Fetal malnutrition may predispose to type 2 diabetes through gene programming and developmental changes. Previous studies showed that these effects may be modulated by genetic variation. Genome-wide association studies discovered and replicated a number of type 2 diabetes-associated genes. We investigated the effects of such well-studied polymorphisms and their interactions with fetal malnutrition on type 2 diabetes risk and related phenotypes in the Dutch Famine Birth Cohort. The rs7754840 (CDKAL1), rs10811661 (CDKN2AB), rs1111875 (HHEX), rs4402960 (IGF2BP2), rs5219 (KCNJ11), rs13266634 (SLC30A8), and rs7903146 (TCF7L2) polymorphisms were genotyped in 772 participants of the Dutch Famine Birth Cohort Study (n = 328 exposed, n = 444 unexposed). Logistic and linear regression models served to analyze their interactions with prenatal exposure to famine on type 2 diabetes, impaired glucose tolerance (IGT), and area under the curves (AUCs) for glucose and insulin during oral glucose tolerance testing (OGTT). In the total population, the TCF7L2 and IGF2BP2 variants most strongly associated with increased risk for type 2 diabetes/IGT and increased AUC for glucose, while the CDKAL1 polymorphism associated with decreased AUC for insulin. The IGF2BP2 polymorphism showed an interaction with prenatal exposure to famine on AUC for glucose (beta = -9.2 [95% CI -16.2 to -2.1], P = 0.009). The IGF2BP2 variant showed a nominal interaction with exposure to famine in utero, decreasing OGTT AUCs for glucose. This may provide a clue that modulation of the consequences of fetal environment depends on an individual's genetic background.

Genetic Variant in the IGF2BP2 Gene May Interact With Fetal Malnutrition to Affect Glucose Metabolism

PubMed Central

van Hoek, Mandy; Langendonk, Janneke G.; de Rooij, Susanne R.; Sijbrands, Eric J.G.; Roseboom, Tessa J.

2009-01-01

OBJECTIVE Fetal malnutrition may predispose to type 2 diabetes through gene programming and developmental changes. Previous studies showed that these effects may be modulated by genetic variation. Genome-wide association studies discovered and replicated a number of type 2 diabetes–associated genes. We investigated the effects of such well-studied polymorphisms and their interactions with fetal malnutrition on type 2 diabetes risk and related phenotypes in the Dutch Famine Birth Cohort. RESEARCH DESIGN AND METHODS The rs7754840 (CDKAL1), rs10811661 (CDKN2AB), rs1111875 (HHEX), rs4402960 (IGF2BP2), rs5219 (KCNJ11), rs13266634 (SLC30A8), and rs7903146 (TCF7L2) polymorphisms were genotyped in 772 participants of the Dutch Famine Birth Cohort Study (n = 328 exposed, n = 444 unexposed). Logistic and linear regression models served to analyze their interactions with prenatal exposure to famine on type 2 diabetes, impaired glucose tolerance (IGT), and area under the curves (AUCs) for glucose and insulin during oral glucose tolerance testing (OGTT). RESULTS In the total population, the TCF7L2 and IGF2BP2 variants most strongly associated with increased risk for type 2 diabetes/IGT and increased AUC for glucose, while the CDKAL1 polymorphism associated with decreased AUC for insulin. The IGF2BP2 polymorphism showed an interaction with prenatal exposure to famine on AUC for glucose (β = −9.2 [95% CI −16.2 to −2.1], P = 0.009). CONCLUSIONS The IGF2BP2 variant showed a nominal interaction with exposure to famine in utero, decreasing OGTT AUCs for glucose. This may provide a clue that modulation of the consequences of fetal environment depends on an individual's genetic background. PMID:19258437

Polymorphisms in the type I deiodinase gene and frontal function in recurrent depressive disorder.

PubMed

Gałecka, Elżbieta; Talarowska, Monika; Orzechowska, Agata; Górski, Paweł; Szemraj, Janusz

2016-09-01

Significant impairment of some psychological functions, including cognitive functioning, has been characteristically found in depressed patients. Memory disturbances may be related to the levels of thyroid hormones (TH) that are under the influence of different mechanisms and molecules, including deiodinase type 1(D1) - an important determinant of circulating triiodothyronine (T3). We investigated the relationship between two functionally known polymorphisms within the DIO1 gene, i.e. DIO1a-C/T and DIO1b-A/G, and cognitive functioning in patients diagnosed with recurrent depressive disorder (rDD). In the planned analysis we mainly concentrated on the frontal function: working memory, executive functions and verbal fluency. Genetic variants were genotyped in 128 patients using a method based on polymerase chain reaction (PCR). Cognitive functions were assessed by the Trail Making Test, the Stroop Test and the Verbal Fluency Test (VFT). No significant associations were found between DIO1 polymorphisms and cognitive functioning in rDD. Only the CT and TT genotypes of the DIO1a variant were significantly related to verbal fluency. There were no significant differences between the distribution of the genotypes and demographic/medical variables. Based on the study, the examined polymorphisms are not an important risk or protective factor for cognitive impairment in depressive patients. Functional variants within the DIO1 gene that affect triiodothyronine (T3) levels seem not to be associated with cognitive functions. Nevertheless, considering the fact that the DIO1 gene is related to the course and management of depression, further studies on a larger sample size might be suggested. Copyright © 2016 Medical University of Bialystok. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Genome-Wide Association Study Identifies Risk Variants for Lichen Planus in Patients With Hepatitis C Virus Infection.

PubMed

Nagao, Yumiko; Nishida, Nao; Toyo-Oka, Licht; Kawaguchi, Atsushi; Amoroso, Antonio; Carrozzo, Marco; Sata, Michio; Mizokami, Masashi; Tokunaga, Katsushi; Tanaka, Yasuhito

2017-06-01

There is a close relationship between hepatitis C virus (HCV) infection and lichen planus, a chronic inflammatory mucocutaneous disease. We performed a genome-wide association study (GWAS) to identify genetic variants associated with HCV-related lichen planus. We conducted a GWAS of 261 patients with HCV infection treated at a tertiary medical center in Japan from October 2007 through January 2013; a total of 71 had lichen planus and 190 had normal oral mucosa. We validated our findings in a GWAS of 38 patients with HCV-associated lichen planus and 7 HCV-infected patients with normal oral mucosa treated at a medical center in Italy. Single-nucleotide polymorphisms in NRP2 (rs884000) and IGFBP4 (rs538399) were associated with risk of HCV-associated lichen planus (P < 1 × 10 -4 ). We also found an association between a single-nucleotide polymorphism in the HLA-DR/DQ genes (rs9461799) and susceptibility to HCV-associated lichen planus. The odds ratios for the minor alleles of rs884000, rs538399, and rs9461799 were 3.25 (95% confidence interval, 1.95-5.41), 0.40 (95% confidence interval, 0.25-0.63), and 2.15 (95% confidence interval, 1.41-3.28), respectively. In a GWAS of Japanese patients with HCV infection, we replicated associations between previously reported polymorphisms in HLA class II genes and risk for lichen planus. We also identified single-nucleotide polymorphisms in NRP2 and IGFBP4 loci that increase and reduce risk of lichen planus, respectively. These genetic variants might be used to identify patients with HCV infection who are at risk for lichen planus. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Intraspecific Polymorphism, Interspecific Divergence, and the Origins of Function-Altering Mutations in Deer Mouse Hemoglobin

PubMed Central

Natarajan, Chandrasekhar; Hoffmann, Federico G.; Lanier, Hayley C.; Wolf, Cole J.; Cheviron, Zachary A.; Spangler, Matthew L.; Weber, Roy E.; Fago, Angela; Storz, Jay F.

2015-01-01

Major challenges for illuminating the genetic basis of phenotypic evolution are to identify causative mutations, to quantify their functional effects, to trace their origins as new or preexisting variants, and to assess the manner in which segregating variation is transduced into species differences. Here, we report an experimental analysis of genetic variation in hemoglobin (Hb) function within and among species of Peromyscus mice that are native to different elevations. A multilocus survey of sequence variation in the duplicated HBA and HBB genes in Peromyscus maniculatus revealed that function-altering amino acid variants are widely shared among geographically disparate populations from different elevations, and numerous amino acid polymorphisms are also shared with closely related species. Variation in Hb-O2 affinity within and among populations of P. maniculatus is attributable to numerous amino acid mutations that have individually small effects. One especially surprising feature of the Hb polymorphism in P. maniculatus is that an appreciable fraction of functional standing variation in the two transcriptionally active HBA paralogs is attributable to recurrent gene conversion from a tandemly linked HBA pseudogene. Moreover, transpecific polymorphism in the duplicated HBA genes is not solely attributable to incomplete lineage sorting or introgressive hybridization; instead, it is mainly attributable to recurrent interparalog gene conversion that has occurred independently in different species. Partly as a result of concerted evolution between tandemly duplicated globin genes, the same amino acid changes that contribute to variation in Hb function within P. maniculatus also contribute to divergence in Hb function among different species of Peromyscus. In the case of function-altering Hb mutations in Peromyscus, there is no qualitative or quantitative distinction between segregating variants within species and fixed differences between species. PMID:25556236

A cis-phase interaction study of genetic variants within the MAOA gene in major depressive disorder.

PubMed

Zhang, JieXu; Chen, YanBo; Zhang, KeRang; Yang, Hong; Sun, Yan; Fang, Yue; Shen, Yan; Xu, Qi

2010-11-01

The genetic basis of major depressive disorder (MDD) has been explored extensively, but the mode of transmission of the disease has yet to be established. To better understand the mechanism by which the monoamine oxidase A (MAOA) gene may play a role in developing MDD, the present work examined the cis-phase interaction between genetic variants within the MAOA gene for the pathogenesis of MDD. A variable number tandem repeat (VNTR) and 19 single nucleotide polymorphisms (SNPs) within the gene were genotyped in 512 unrelated patients with MDD and 567 unrelated control subjects among a Chinese population. Quantitative real-time polymerase chain reaction analysis was applied to test the effect of genetic variants on expression of the MAOA gene in MDD. Neither the VNTR polymorphism nor seven informative SNPs showed allelic association with MDD, but the cis-acting interactions between the VNTR polymorphism and four individual SNPs were strongly associated with MDD risk, of which the VNTR-rs1465107 combination showed the strongest association (p = .000011). Quantitative real-time polymerase chain reaction analysis showed that overall relative quantity of MAOA messenger RNA was significantly higher in patients with MDD than in control subjects (fold change = 5.28, p = 1.7 × 10⁻⁷) and that in the male subjects carrying the VNTR-L, rs1465107-A, rs6323-G, rs2072743-A, or rs1137070-T alleles, expression of MAOA messenger RNA was significantly higher in the patient group than in the control group. The cis-phase interaction between the VNTR polymorphism and functional SNPs may contribute to the etiology of MDD. Copyright © 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Thyroid hormone receptor alpha gene variants increase the risk of developing obesity and show gene-diet interactions.

PubMed

Fernández-Real, J M; Corella, D; Goumidi, L; Mercader, J M; Valdés, S; Rojo Martínez, G; Ortega, F; Martinez-Larrad, M-T; Gómez-Zumaquero, J M; Salas-Salvadó, J; Martinez González, M A; Covas, M I; Botas, P; Delgado, E; Cottel, D; Ferrieres, J; Amouyel, P; Ricart, W; Ros, E; Meirhaeghe, A; Serrano-Rios, M; Soriguer, F; Estruch, R

2013-11-01

Thyroid hormone receptor-beta resistance has been associated with metabolic traits. THRA gene sequencing of an obese woman (index case) who presented as empirical thyroid hormone receptor-α (THRA) resistance, disclosed a polymorphism (rs12939700) in a critical region involved in TRα alternative processing. THRA gene variants were evaluated in three independent europid populations (i) in two population cohorts at baseline (n=3417 and n=2265), 6 years later (n=2139) and (ii) in 4734 high cardiovascular risk subjects (HCVR, PREDIMED trial). The minor allele of the index case polymorphism (rs12939700), despite having a very low frequency (4%), was significantly associated with higher body mass index (BMI) (P=0.042) in HCVR subjects. A more frequent THRA polymorphism (rs1568400) was associated with higher BMI in subjects from the population (P=0.00008 and P=0.05) after adjusting for several confounders. Rs1568400 was also strongly associated with fasting triglycerides (P dominant=3.99 × 10(-5)). In the same sample, 6 years later, age and sex-adjusted risk of developing obesity was significantly increased in GG homozygotes (odds ratio 2.93 (95% confidence interval, 1.05-6.95)). In contrast, no association between rs1568400 and BMI was observed in HCVR subjects, in whom obesity was highly prevalent. This might be explained by the presence of an interaction (P <0.001) among the rs1568400 variant, BMI and saturated fat intake. Only when saturated fat intake was high (>24.5 g d(-1)), GG carriers showed a significantly higher BMI than A carriers after controlling for energy intake and physical activity. THRA gene polymorphisms are associated with obesity development. This is a novel observation linking the THRA locus to metabolic phenotypes.