Synergism between the N-acetyltransferase 2 gene and oxidant exposure increases the risk of idiopathic male infertility

N-acetyltransferase (NAT2) is a phase-II xenobiotic-metabolizing enzyme participating in the detoxification of toxic arylamines, aromatic amines and hydrazines. The present study was designed to investigate whether two common single-nucleotide polymorphisms (SNP) of the NAT2 gene (481C>T, rs1799929; 590G>A, rs1799930) are associated with susceptibility to idiopathic male infertility and to assess if the risk is modified by oxidant and antioxidant exposures. A total 430 DNA samples (203 infertile patients and 227 fertile men) were genotyped for the polymorphisms by PCR and restriction fragment length polymorphism. No association was found between the NAT2 polymorphisms and idiopathic male infertilit

The Flavin-Containing Monooxygenase 3 Gene and Essential Hypertension: The Joint Effect of Polymorphism E158K and Cigarette Smoking on Disease Susceptibility

Gene encoding flavin-containing monooxygenase 3 (FMO3), a microsomal antioxidant defense enzyme, has been suggested to contribute to essential hypertension (EH). The present study was designed to investigate whether common functional polymorphism E158K (rs2266782) of the FMO3 gene is associated with EH susceptibility in a Russian population. A total of 2 995 unrelated subjects from Kursk (1 362 EH patients and 843 healthy controls) and Belgorod (357 EH patients and 422 population controls) regions of Central Russia were recruited for this study. DNA samples from all study participants were genotyped for the FMO3 gene polymorphism through PCR followed by RFLP analysis. We found that the polymorphism E158K is associated with increased risk of essential hypertension in both discovery population from Kursk region (OR 1.36 95% CI 1.09–1.69, P=0.01) and replication population from Belgorod region (OR 1.54 95% CI 1.07–1.89, P=0.02) after adjustment for gender and age using logistic regression analysis. Further analysis showed that the increased hypertension risk in carriers of genotype 158KK gene occurred in cigarette smokers, whereas nonsmoker carriers of this genotype did not show the disease risk. This is the first study reporting the association of the FMO3 gene polymorphism and the risk of essential hypertension

Lipid-Associated GWAS Loci Predict Antiatherogenic Effects of Rosuvastatin in Patients with Coronary Artery Disease

We have shown that lipid-associated loci discovered by genome-wide association studies (GWAS) have pleiotropic effects on lipid metabolism, carotid intima-media thickness (CIMT), and CAD risk. Here, we investigated the impact of lipid-associated GWAS loci on the efficacy of rosuvastatin therapy in terms of changes in plasma lipid levels and CIMT. The study comprised 116 CAD patients with hypercholesterolemia. CIMT, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) were measured at baseline and after 6 and 12 months of follow-up, respectively. Genotyping of fifteen lipid-associated GWAS loci was performed by the MassArray-4 System. Linear regression analysis adjusted for sex, age, body mass index, and rosuvastatin dose was used to estimate the phenotypic effects of polymorphisms, and p-values were calculated through adaptive permutation tests by the PLINK software, v1.9. Over one-year rosuvastatin therapy, a decrease in CIMT was linked to rs1689800, rs4846914, rs12328675, rs55730499, rs9987289, rs11220463, rs16942887, and rs881844 polymorphisms (Pperm < 0.05). TC change was associated with rs55730499, rs11220463, and rs6065906; LDL-C change was linked to the rs55730499, rs1689800, and rs16942887 polymorphisms; and TG change was linked to polymorphisms rs838880 and rs1883025 (Pperm < 0.05). In conclusion, polymorphisms rs1689800, rs55730499, rs11220463, and rs16942887 were found to be predictive markers for multiple antiatherogenic effects of rosuvastatin in CAD patients

Polymorphisms of the <i>GCLC</i> Gene Are Novel Genetic Markers for Susceptibility to Psoriasis Associated with Alcohol Abuse and Cigarette Smoking

The aim of this pilot study was to investigate whether single nucleotide polymorphisms (SNP) in the gene encoding the catalytic subunit of glutamate cysteine ligase (GCLC) are associated with the risk and clinical features of psoriasis. A total of 944 unrelated individuals, including 474 patients with a diagnosis of psoriasis and 470 healthy controls, were recruited for the study. Six common SNPs in the GCLC gene were genotyped using the MassArray-4 system. Polymorphisms rs648595 (OR = 0.56, 95% CI 0.35–0.90; Pperm = 0.017) and rs2397147 (OR = 0.54, 95% CI 0.30–0.98; Pperm = 0.05) were associated with susceptibility to psoriasis in males. In the male group, diplotype rs2397147-C/C × rs17883901-G/G was associated with a decreased risk of psoriasis (FDR-adjusted p = 0.014), whereas diplotype rs6933870-G/G × rs17883901-G/G (FDR-adjusted p = 0.045) showed an association with an increased disease risk in females. The joint effects of SNPs with tobacco smoking (rs648595 and rs17883901) and alcohol abuse (rs648595 and rs542914) on psoriasis risk were observed (Pperm ≤ 0.05). We also found multiple sex-independent associations between GCLC gene polymorphisms and various clinical features such as earlier disease onset, the psoriatic triad, and specific localizations of skin lesions. The present study is the first to show that polymorphisms of the GCLC gene are significantly associated with the risk of psoriasis and related to its clinical features

Antioxidant Defense Enzyme Genes and Asthma Susceptibility: Gender-Specific Effects and Heterogeneity in Gene-Gene Interactions between Pathogenetic Variants of the Disease

Oxidative stress resulting from an increased amount of reactive oxygen species and an imbalance between oxidants and antioxidants plays an important role in the pathogenesis of asthma. The present study tested the hypothesis that genetic susceptibility to allergic and nonallergic variants of asthma is determined by complex interactions between genes encoding antioxidant defense enzymes (ADE). We carried out a comprehensive analysis of the associations between adult asthma and 46 single nucleotide polymorphisms of 34 ADE genes and 12 other candidate genes of asthma in Russian population using set association analysis and multifactor dimensionality reduction approaches. We found for the first time epistatic interactions between ADE genes underlying asthma susceptibility and the genetic heterogeneity between allergic and nonallergic variants of the disease. We identified GSR (glutathione reductase) and PON2 (paraoxonase 2) as novel candidate genes for asthma susceptibility. We observed gender-specific effects of ADE genes on the risk of asthma. The results of the study demonstrate complexity and diversity of interactions between genes involved in oxidative stress underlying susceptibility to allergic and nonallergic asthma

The Impact of Genetic Polymorphisms in Glutamate-Cysteine Ligase, a Key Enzyme of Glutathione Biosynthesis, on Ischemic Stroke Risk and Brain Infarct Size

The purpose of this pilot study was to explore whether polymorphisms in genes encoding the catalytic (GCLC) and modifier (GCLM) subunits of glutamate-cysteine ligase, a rate-limiting enzyme in glutathione synthesis, play a role in the development of ischemic stroke (IS) and the extent of brain damage. A total of 1288 unrelated Russians, including 600 IS patients and 688 age- and sex-matched healthy subjects, were enrolled for the study. Nine common single nucleotide polymorphisms (SNPs) of the GCLC and GCLM genes were genotyped using the MassArray-4 system. SNP rs2301022 of GCLM was strongly associated with a decreased risk of ischemic stroke regardless of sex and age (OR = 0.39, 95%CI 0.24–0.62, p GCLM possessed protective effects against ischemic stroke risk (p GCLC. The mbmdr method enabled identifying epistatic interactions of GCLC and GCLM gene polymorphisms with known IS susceptibility genes that, along with environmental risk factors, jointly contribute to the disease risk and brain infarct size. Understanding the impact of genes and environmental factors on glutathione metabolism will allow the development of effective strategies for the treatment of ischemic stroke and disease prevention

A Novel Polymorphism in the Promoter of the CYP4A11 Gene Is Associated with Susceptibility to Coronary Artery Disease

Enzymes CYP4A11 and CYP4F2 are involved in biosynthesis of vasoactive 20-hydroxyeicosatetraenoic acid and may contribute to pathogenesis of coronary artery disease (CAD). We investigated whether polymorphisms of the CYP4A11 and CYP4F2 genes are associated with the risk of CAD in Russian population. DNA samples from 1323 unrelated subjects (637 angiographically confirmed CAD patients and 686 age- and sex-matched healthy individuals) were genotyped for polymorphisms rs3890011, rs9332978, and rs9333029 of CYP4A11 and rs3093098 and rs1558139 of CYP4F2 by using the Mass-ARRAY 4 system. SNPs rs3890011 and rs9332978 of CYP4A11 were associated with increased risk of CAD in women: OR = 1.26, 95% CI: 1.02–1.57, P=0.004, and Q=0.01 and OR = 1.45, 95% CI: 1.13–1.87, P=0.004, and Q=0.01, respectively. Haplotype G-C-A of CYP4A11 was associated with increased risk of CAD (adjusted OR = 1.41, 95% CI: 1.12–1.78, and P=0.0036). Epistatic interactions were found between rs9332978 of CYP4A11 and rs1558139 of CYP4F2 (Pinteraction=0.025). In silico analysis allowed identifying that SNP rs9332978 is located at a binding site for multiple transcription factors; many of them are known to regulate the pathways involved in the pathogenesis of CAD. This is the first study in Europeans that reported association between polymorphism rs9332978 of CYP4A11 and susceptibility to coronary artery disease

Polymorphisms of CYP2C8, CYP2C9 and CYP2C19 and risk of coronary heart disease in Russian population

Epoxyeicosatrienoic acids (EETs) are important vasoactive products of arachidonic acid metabolism with a wide range of biological actions in the cardiovascular system. The present study investigated whether single nucleotide polymorphisms (SNP) of genes coding cytochrome P450 2C subfamily, enzymes involved in biosynthesis of EETs, are associated with the risk of coronary heart disease (CHD). A total of 1255 unrelated Russian subjects comprising 561 patients with angiographically diagnosed CHD and 694 age- and sex-matched healthy subjects were included in the study. DNA samples from all study participants were genotyped for six common SNPs rs7909236, rs1934953 of CYP2C8, rs9332242, rs4918758 and rs61886769 of CYP2C9 and rs4244285 of CYP2C19 using by the Mass-ARRAY 4 system. SNP rs4918758 of CYP2C9 was associated with decreased risk of CHD (codominant model) at a borderline significance with odds ratio adjusted for sex and age 0.61 (95% CI: 0.41–0.92, P = 0.038, Q = 0.20). SNP rs9332242 of CYP2C9 showed a trend towards association with increased CHD risk in cigarette smokers (P = 0.049, Q = 0.29). Log-likelihood ratio test (LRT) pointed out epistatic interactions between rs9332242 and rs61886769 of CYP2C9 (codominant model, Pinteraction = 0.02), however, this P-value did not survive after correction for multiple tests. Bioinformatic analysis revealed a regulatory potential for a majority of the investigated SNPs. Our preliminary results demonstrate that polymorphisms of genes encoding CYP2C subfamily represent potential genetic markers of CHD susceptibility. Further studies are required to substantiate the contribution of these genes to the disease risk

Polymorphisms of CYP2C8, CYP2C9 and CYP2C19 and risk of coronary heart disease in Russian population

Epoxyeicosatrienoic acids (EETs) are important vasoactive products of arachidonic acid metabolism with a wide range of biological actions in the cardiovascular system. The present study investigated whether single nucleotide polymorphisms (SNP) of genes coding cytochrome P450 2C subfamily, enzymes involved in biosynthesis of EETs, are associated with the risk of coronary heart disease (CHD). A total of 1255 unrelated Russian subjects comprising 561 patients with angiographically diagnosed CHD and 694 age- and sex-matched healthy subjects were included in the study. DNA samples from all study participants were genotyped for six common SNPs rs7909236, rs1934953 of CYP2C8, rs9332242, rs4918758 and rs61886769 of CYP2C9 and rs4244285 of CYP2C19 using by the Mass-ARRAY 4 system. SNP rs4918758 of CYP2C9 was associated with decreased risk of CHD (codominant model) at a borderline significance with odds ratio adjusted for sex and age 0.61 (95% CI: 0.41–0.92, P = 0.038, Q = 0.20). SNP rs9332242 of CYP2C9 showed a trend towards association with increased CHD risk in cigarette smokers (P = 0.049, Q = 0.29). Log-likelihood ratio test (LRT) pointed out epistatic interactions between rs9332242 and rs61886769 of CYP2C9 (codominant model, Pinteraction = 0.02), however, this P-value did not survive after correction for multiple tests. Bioinformatic analysis revealed a regulatory potential for a majority of the investigated SNPs. Our preliminary results demonstrate that polymorphisms of genes encoding CYP2C subfamily represent potential genetic markers of CHD susceptibility. Further studies are required to substantiate the contribution of these genes to the disease risk