Association between TCF7L2

Previous studies showed associations between variants in TCF7L2 gene and the therapeutic response to sulfonylureas. All sulfonylureas stimulate insulin secretion by the closure of ATP-sensitive potassium (KATP) channel. The aim of the present study was to compare TCF7L2 genotype specific effect of gliclazide binding to KATP channel A-site (Group 1) with sulfonylureas binding to AB-site (Group 2). A total of 101 patients were treated with sulfonylureas for 6 months as an add-on therapy to the previous metformin treatment. TCF7L2 rs7903146 C/T genotype was identified by real-time PCR with subsequent melting curve analysis. Analyses using the dominant genetic model showed significantly higher effect of gliclazide in the CC genotype group in comparison with combined CT + TT genotype group (1.32±0.15% versus 0.73±0.11%, Padj=0.005). No significant difference in ΔHbA1c between the patients with CC genotype and the T-allele carriers was observed in Group 2. In the multivariate analysis, only the TCF7L2 genotype (P=0.006) and the baseline HbA1c (P<0.001) were significant predictors of ΔHbA1c. After introducing an interaction term between the TCF7L2 genotype and the sulfonylurea type into multivariate model, the interaction became a significant predictor (P=0.023) of ΔHbA1c. The results indicate significantly higher difference in ΔHbA1c among the TCF7L2 genotypes in patients treated with gliclazide than in patients treated with glimepiride, glibenclamide, or glipizide

Association of JAG1 gene polymorphism with systemic blood pressure in patients with obstructive sleep apnea: a prospective cohort study

Aim To assess the effects of single nucleotide polymorphisms (SNPs) on blood pressure control in patients with obstructive sleep apnea (OSA). Methods This prospective observational cohort study, conducted between 2004 and 2014, examined the associations of SNPs of JAG1, GUCY1A3-GUCY1B3, SH2B3, and NPR3-C5orf23 genes with systolic and diastolic blood pressure (SBP, DBP) in 1179 adults evaluated for OSA with overnight polysomnography. Genotyping was performed by unlabeled probe melting analysis.Results The patients were predominantly male (69.6%, mean age 52 ± 11 years, apnea-hypopnea index 34 ± 31 episodes/h). Only JAG1 genotype was associated with SBP and DBP: compared with AA homozygotes, G allele carriers (pooled GG and AG genotype) had significantly higher morning SBP (132 ± 19 vs 129 ± 18 mm Hg; P = 0.009) and morning and evening DBP (85 ± 11 vs 83 ± 10 mm Hg, P = 0.004; 86 ± 10 vs 84 ± 10 mm Hg, P = 0.012, respectively); the differences remained significant after the correction for multiple SNPs testing. In multivariate analyses, oxygen desaturation index and JAG1 genotype independently predicted morning SBP (P = 0.001, P = 0.003, respectively) and DBP (P < 0.001, P = 0.005, respectively), and evening SBP (P = 0.019, P = 0.048, respectively) and DBP (P = 0.018, P = 0.018, respectively). Conclusion This is the first replication study of the SNPs recently linked to arterial hypertension in general population by genome-wide association studies. Our findings suggest that JAG1 genotype is related to blood pressure control in OSA: G allele was associated with higher morning and evening SBP and DBP

Glutathione S-transferase and Microsomal Epoxide Hydrolase Gene Polymorphisms and Risk of Chronic Obstructive Pulmonary Disease in Slovak Population

Cilj Odrediti rizik kronične opstruktivne bolesti pluća (COPD) povezan s polimorfizmima na genima glutation S-transferaze (GST) M1, GST T1 i mikrosomalne epoksid hidrolaze (EPHX1) u kohorti Slovačke populacije. Postupci U istraživanje je uključeno 217 bolesnika s dijagnozom COPD-a i 160 kontrolnih ispitanika. Od svih su ispitanika prikupljeni uzorci krvi, a DNA iz limfocita u perifernoj krvi rabljena je za genotipizaciju s pomoću lančane reakcije polimerazom i analize polimorfizma duljine restrikcijskih ulomaka. Rezultati U statistički kontroliranom modelu, povećan rizik od COPD-a primjećen je u ispitanika s genotipom EPHX1 His113-His113 (omjer izgleda [OR], 2,32; 95% raspon pouzdanosti [CI], 1,20-4,69; P=0,008), u usporedbi s nositeljima alela Tyr113. Ipak, nakon statističke kontrole za dob, spol i pušenje, nije pronađen značajni rizk (kontrolirani OR, 1,79; 95% CI, 0,91-3,53; P=0,093). U kombiniranoj analizi genskih polimorfizama, kombinacija genotipova EPHX1 His113-His113/GSTM1 nula bila je značajno povezana s višim rizikom obolijevanja od COPD-a i u kontroliranom (OR, 5,08; 95% CI, 1,70-20,43; P=0,001) i u nekontroliranom modelu (OR, 4,87; 95% CI, 1,57-15.13; P=0,006). Zaključak Iako ni jedan od proučavanih genskih polimorfizama nije sam bio značajano povezan s povećanim rizikom obolijevanja od COPD-a, homozigotni 3. ekson mutantne varijante gena EPHX1, u kombinaciji a genotipom GSTM1 nula, bio je značajan prediktor povećanog rizika obolijevanja od COPD-a u Slovačkoj populaciji. Naša studija naglašava detoksifikacijske i antioksidativne puteve u patogenezi COPD-a. 1Aim To determine the risk of chronic obstructive pulmonary disease (COPD) associated with polymorphisms in the glutathione S-transferase (GST) M1, GST T1, and microsomal epoxide hydrolase (EPHX1) genes in a cohort of Slovak population. Methods Two hundred and seventeen patients with the diagnosis of COPD and 160 control subjects were enrolled in the study. Blood samples were collected from all subjects and the DNA from peripheral blood lymphocytes was used for subsequent genotyping assays, using polymerase chain reaction and restriction fragment-length polymorphism methods. Results In an unadjusted model, an increased risk for COPD was observed in subjects with EPHX1 His113-His113 genotype (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.20-4.69; P = 0.008), compared with the carriers of the Tyr113 allele. However, after the adjustments for age, sex, and smoking status, the risk was not significant (adjusted OR, 1.79; 95% CI, 0.91-3.53; P = 0.093). In a combined analysis of gene polymorphisms, the genotype combination EPHX1 His113- His113/GSTM1 null significantly increased the risk of COPD in both, unadjusted (OR, 5.08; 95% CI, 1.70-20.43; P = 0.001) and adjusted model (OR, 4.87; 95% CI, 1.57-15.13; P = 0.006). Conclusion Although none of the tested gene polymorphisms was significantly related to an increased risk of COPD alone, our results suggest that the homozygous exon 3 mutant variant of EPHX1 gene in the combination with GSTM1 null genotype is a significant predictor of increased susceptibility to COPD in the Slovak population. The findings of the present study emphasize the importance of detoxifying and antioxidant pathways in the pathogenesis of COPD

Single nucleotide polymorphisms in the intergenic region between metformin transporter OCT2 and OCT3 coding genes are associated with short-Term response to metformin monotherapy in type 2 diabetes mellitus patients

Publisher Copyright: © 2016 The authors Published by Bioscientifica Ltd. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.Objective(s): High variability in clinical response to metformin is often observed in type 2 diabetes (T2D) patients, and it highlights the need for identification of genetic components affecting the efficiency of metformin therapy. Aim of this observational study is to evaluate the role of tagSNPs (tagging single nucleotide polymorphisms) from genomic regions coding for six metformin transporter genes with respect to the short-Term efficiency. Design: 102 tagSNPs in 6 genes coding for metformin transporters were genotyped in the group of 102 T2D patients treated with metformin for 3 months. Methods: Most significant hits were analyzed in the group of 131 T2D patients from Slovakia. Pharmacokinetic study in 25 healthy nondiabetic volunteers was conducted to investigate the effects of identified polymorphisms. Results: In the discovery group of 102 patients, minor alleles of rs3119309, rs7757336 and rs2481030 were significantly nominally associated with metformin inefficiency (P = 1.9 × 106 to 8.1 × 106). Effects of rs2481030 and rs7757336 did not replicate in the group of 131 T2DM patients from Slovakia alone, whereas rs7757336 was significantly associated with a reduced metformin response in combined group. In pharmacokinetic study, group of individuals harboring risk alleles of rs7757336 and rs2481030 displayed significantly reduced AUC∞ of metformin in plasma. Conclusions: For the first time, we have identified an association between the lack of metformin response and SNPs rs3119309 and rs7757336 located in the 5 flanking region of the genes coding for Organic cation transporter 2 and rs2481030 located in the 5 flanking region of Organic cation transporter 3 that was supported by the results of a pharmacokinetic study on 25 healthy volunteers.publishersversionPeer reviewe

Variation in the Glucose Transporter gene <i>SLC2A2 </i>is associated with glycaemic response to metformin

Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear1. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10−14) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine

Glutathione S-transferase and Microsomal Epoxide Hydrolase Gene Polymorphisms and Risk of Chronic Obstructive Pulmonary Disease in Slovak Population

Cilj Odrediti rizik kronične opstruktivne bolesti pluća (COPD) povezan s polimorfizmima na genima glutation S-transferaze (GST) M1, GST T1 i mikrosomalne epoksid hidrolaze (EPHX1) u kohorti Slovačke populacije. Postupci U istraživanje je uključeno 217 bolesnika s dijagnozom COPD-a i 160 kontrolnih ispitanika. Od svih su ispitanika prikupljeni uzorci krvi, a DNA iz limfocita u perifernoj krvi rabljena je za genotipizaciju s pomoću lančane reakcije polimerazom i analize polimorfizma duljine restrikcijskih ulomaka. Rezultati U statistički kontroliranom modelu, povećan rizik od COPD-a primjećen je u ispitanika s genotipom EPHX1 His113-His113 (omjer izgleda [OR], 2,32; 95% raspon pouzdanosti [CI], 1,20-4,69; P=0,008), u usporedbi s nositeljima alela Tyr113. Ipak, nakon statističke kontrole za dob, spol i pušenje, nije pronađen značajni rizk (kontrolirani OR, 1,79; 95% CI, 0,91-3,53; P=0,093). U kombiniranoj analizi genskih polimorfizama, kombinacija genotipova EPHX1 His113-His113/GSTM1 nula bila je značajno povezana s višim rizikom obolijevanja od COPD-a i u kontroliranom (OR, 5,08; 95% CI, 1,70-20,43; P=0,001) i u nekontroliranom modelu (OR, 4,87; 95% CI, 1,57-15.13; P=0,006). Zaključak Iako ni jedan od proučavanih genskih polimorfizama nije sam bio značajano povezan s povećanim rizikom obolijevanja od COPD-a, homozigotni 3. ekson mutantne varijante gena EPHX1, u kombinaciji a genotipom GSTM1 nula, bio je značajan prediktor povećanog rizika obolijevanja od COPD-a u Slovačkoj populaciji. Naša studija naglašava detoksifikacijske i antioksidativne puteve u patogenezi COPD-a. 1Aim To determine the risk of chronic obstructive pulmonary disease (COPD) associated with polymorphisms in the glutathione S-transferase (GST) M1, GST T1, and microsomal epoxide hydrolase (EPHX1) genes in a cohort of Slovak population. Methods Two hundred and seventeen patients with the diagnosis of COPD and 160 control subjects were enrolled in the study. Blood samples were collected from all subjects and the DNA from peripheral blood lymphocytes was used for subsequent genotyping assays, using polymerase chain reaction and restriction fragment-length polymorphism methods. Results In an unadjusted model, an increased risk for COPD was observed in subjects with EPHX1 His113-His113 genotype (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.20-4.69; P = 0.008), compared with the carriers of the Tyr113 allele. However, after the adjustments for age, sex, and smoking status, the risk was not significant (adjusted OR, 1.79; 95% CI, 0.91-3.53; P = 0.093). In a combined analysis of gene polymorphisms, the genotype combination EPHX1 His113- His113/GSTM1 null significantly increased the risk of COPD in both, unadjusted (OR, 5.08; 95% CI, 1.70-20.43; P = 0.001) and adjusted model (OR, 4.87; 95% CI, 1.57-15.13; P = 0.006). Conclusion Although none of the tested gene polymorphisms was significantly related to an increased risk of COPD alone, our results suggest that the homozygous exon 3 mutant variant of EPHX1 gene in the combination with GSTM1 null genotype is a significant predictor of increased susceptibility to COPD in the Slovak population. The findings of the present study emphasize the importance of detoxifying and antioxidant pathways in the pathogenesis of COPD

Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin

Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10(-14)) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine