Publications by authors named "Alexey Polonikov"

49 Publications

DNA Hypomethylation of the MPO Gene in Peripheral Blood Leukocytes Is Associated with Cerebral Stroke in the Acute Phase.

J Mol Neurosci 2021 Apr 17. Epub 2021 Apr 17.

Research Institute of Medical Genetics, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia.

Dysregulation of the oxidant-antioxidant system contributes to the pathogenesis of cerebral stroke (CS). Epigenetic changes of redox homeostasis genes, such as glutamate-cysteine ligase (GCLM), glutathione-S-transferase-P1 (GSTP1), thioredoxin reductase 1 (TXNRD1), and myeloperoxidase (MPO), may be biomarkers of CS. In this study, we assessed the association of DNA methylation levels of these genes with CS and clinical features of CS. We quantitatively analyzed DNA methylation patterns in the promoter or regulatory regions of 4 genes (GCLM, GSTP1, TXNRD1, and MPO) in peripheral blood leukocytes of 59 patients with CS in the acute phase and in 83 relatively healthy individuals (controls) without cardiovascular and cerebrovascular diseases. We found that in both groups, the methylation level of CpG sites in genes TXNRD1 and GSTP1 was ≤ 5%. Lower methylation levels were registered at a CpG site (chr1:94,374,293, GRCh37 [hg19]) in GCLM in patients with ischemic stroke compared with the control group (9% [7%; 11.6%] (median and interquartile range) versus 14.7% [10.4%; 23%], respectively, p < 0.05). In the leukocytes of patients with CS, the methylation level of CpG sites in the analyzed region of MPO (chr17:56,356,470, GRCh3 [hg19]) on average was significantly lower (23.5% [19.3%; 26.7%]) than that in the control group (35.6% [30.4%; 42.6%], p < 0.05). We also found increased methylation of MPO in smokers with CS (27.2% [23.5%; 31.1%]) compared with nonsmokers with CS (21.7% [18.1%; 24.8%]). Thus, hypomethylation of CpG sites in GCLM and MPO in blood leukocytes is associated with CS in the acute phase.
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http://dx.doi.org/10.1007/s12031-021-01840-8DOI Listing
April 2021

Candidate Genes for Age at Menarche Are Associated With Uterine Leiomyoma.

Front Genet 2020 22;11:512940. Epub 2021 Jan 22.

Department of Medical Biological Disciplines, Belgorod State University, Belgorod, Russia.

Age at menarche (AAM) is an important marker of the pubertal development and function of the hypothalamic-pituitary-ovarian system. It was reported as a possible factor for a risk of uterine leiomyoma (UL). However, while more than 350 loci for AAM have been determined by genome-wide association studies (GWASs) to date, no studies of these loci for their association with UL have been conducted so far. In this study, we analyzed 52 candidate loci for AAM for possible association with UL in a sample of 569 patients and 981 controls. The results of the study suggested that 23 out of the 52 studied polymorphisms had association with UL. Locus rs7759938 was individually associated with the disease according to the dominant model. Twenty loci were associated with UL within 11 most significant models of intergenic interactions. Nine loci involved in 16 most significant models of interactions between single-nucleotide polymorphism (SNP), induced abortions, and chronic endometritis were associated with UL. Among the 23 loci associated with UL, 16 manifested association also with either AAM (7 SNPs) or height and/or body mass index (BMI) (13 SNPs). The above 23 SNPs and 514 SNPs linked to them have non-synonymous, regulatory, and expression quantitative trait locus (eQTL) significance for 35 genes, which play roles in the pathways related to development of the female reproductive organs and hormone-mediated signaling [false discovery rate (FDR) ≤ 0.05]. This is the first study reporting associations of candidate genes for AAM with UL.
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http://dx.doi.org/10.3389/fgene.2020.512940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863975PMC
January 2021

[Gene-environment interactions between polymorphic loci of MMPs and obesity in essential hypertension in women.]

Probl Endokrinol (Mosk) 2020 Jun 10;65(6):425-435. Epub 2020 Jun 10.

Belgorod National Research University.

Background: The prevalence of essential hypertension (ЕH) is increasing every year, both in Russia and around the world. Genetic and environmental risk factors are involved in the development of hypertension, and obesity plays an important role. Therefore, the study of gene-ecological interactions in the development of hypertension seems to be relevant.

Aims: to study the gene-environment interactions between polymorphic loci of MMP and obesity in essential hypertension in women.

Materials And Methods: The study was conducted in a case-control design. The sample included 584 subjects: 375 patients with EH and 209 women in the control group. All individuals included in the study were genotyped for eight polymorphic loci of MMPs. The study of the gene-environmental interactions during the formation of hypertension was performed using the GMDR method (Generalized Multifactor Dimensionality Reduction, http://www.ssg.uab.edu/gmdr).

Results: rs11568818 MMР7 and rs11225395 MMР8 polymorphic loci were found to be involved in the development of arterial hypertension in women without obesity (p<0.050). Fifteen three-, four-, and five-factor models of gene-environmental interactions of 8 MMPs with obesity, associated with EH (p=0.01), were found. It is shown that the analyzed SNPs are located in the DNA regions that bind to histones, marking promoters and enhancers, in the region of hypersensitivity to DNAse-1, in the binding sites of regulatory proteins and transcription factors. The loci of MMPs rs17577, rs11568818, rs1320632 and rs11225395 have cis-eQTL-value. They affecting the expression of the genes of MMP7, SNX21, SLC12A5 and RP11-817J15.3.

Conclusions: SNP rs11568818 MMP7 and rs11225395 MMP8 and gene-environmental interactions of MMPs rs1799750, rs243865, rs3025058, rs11568818, rs1320632, rs11225395, rs17577, rs652438 with obesity are involved in the development of essential hypertension in women.
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http://dx.doi.org/10.14341/probl10236DOI Listing
June 2020

Candidate genes for age at menarche are associated with endometriosis.

Reprod Biomed Online 2020 Nov 14;41(5):943-956. Epub 2020 May 14.

Department of Medical Biological Disciplines, Belgorod State University, Belgorod 308015, Russia.

Research Question: Are the candidate genes for age at menarche associated with a risk of endometriosis?

Design: Fifty-two candidate single nucleotide polymorphisms (SNP) for age at menarche, their gene-gene and gene-environment interactions were analysed for possible association with endometriosis in a sample of 395 patients and 981 controls. Association of the polymorphisms was analysed using logistic regression according to three main genetic models (additive, recessive and dominant). The gene-gene and gene-environment interactions were analysed for the second-, third- and fourth-order models with adjustment for covariates and multiple comparisons with subsequent cross-validation.

Results: Sixteen SNP for age at menarche out of the 52 studied were associated with endometriosis. Polymorphism rs6589964 BSX was associated with endometriosis according to the additive and recessive models (OR 1.27-1.47, P ≤ 0.006). Fourteen SNP were associated with the disease within 12 most significant models of gene-gene interactions (P ≤ 0.008). Twelve SNP involved in 10 most significant models of SNP-induced abortion interactions are associated with endometriosis. Fourteen of the 16 polymorphisms associated with endometriosis demonstrated pleiotropic effects: they were also associated with either age at menarche (7 SNP) or height and/or body mass index (10 SNP) in the studied sample. The 16 SNP associated with endometriosis and 316 SNP linked to them have regulatory and expression quantitative trait locus significance for 28 genes contributing to the G alpha signal pathway (fold enrichment 31.09, P = 0.001) and responses to endogenous stimuli (fold enrichment 16.01, P = 0.027).

Conclusions: Sixteen SNP for age at menarche out of the 52 studied were associated with endometriosis.
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http://dx.doi.org/10.1016/j.rbmo.2020.04.016DOI Listing
November 2020

Functionally significant polymorphisms of ESR1and PGR and risk of intrauterine growth restriction in population of Central Russia.

Eur J Obstet Gynecol Reprod Biol 2020 Oct 28;253:52-57. Epub 2020 Jul 28.

Department of Medical Biological Disciplines, Belgorod State University, 308015 Belgorod, Russia.

Objective: This study aimed to investigate the role ofESR1 and PGR gene polymorphisms in development of intrauterine growth restriction (IUGR) among Russian women in Central Russia.

Study Design: This case-control study recruited a total of 520 women in the third trimester of pregnancy, including 196 IUGR patients and 324 controls. The participants were unrelated women of self-reported Russian ethnicity. Participants were genotyped at 4 functionally significant polymorphisms of theESR1 (rs2234693, rs9340799) and the PGR (rs484389, rs1042838) genes. The association analysis was performed using logistic regression. Two polymorphisms, which were associated with IUGR, and 26 polymorphisms linked to them (r≥0.6) were analyzed for their functional significance in silico.

Results: Haplotype TG of loci rs2234693-rs9340799ESR1 (OR = 1.94, р = 0.006) was associated with an increased risk of IUGR. Allele T of rs2234693 decreases expression of ESR1 in thyroid gland, allele T of rs2234693 and allele G of rs9340799 increase affinity to eight transcription factors (AP-4, HEN1, E2A, LBP-1, RP58, LUN, Ets and Hand). The loci that are linked (r≥0.6) to the IUGR-associated SNPs, have the cis-eQTL value (expression ESR1 in thyroid gland) and showed their regulatory effects in organs and tissues related to pathogenesis of IUGR.

Conclusion: Haplotype TG defined by polymorphisms rs2234693-rs9340799 of theESR1 gene is associated with the development of IUGR in Russian women from Central Russia.
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http://dx.doi.org/10.1016/j.ejogrb.2020.07.045DOI Listing
October 2020

Genetic variants in glutamate cysteine ligase confer protection against type 2 diabetes.

Mol Biol Rep 2020 Aug 26;47(8):5793-5805. Epub 2020 Jul 26.

Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, Kursk, Russian Federation, 305041.

Oxidative stress contributes to the pathogenesis of type 2 diabetes (T2D). This study investigated whether single nucleotide polymorphisms (SNPs) at genes encoding glutamate cysteine ligase catalytic (rs12524494, rs17883901, rs606548, rs636933, rs648595, rs761142 at GCLC) and modifier (rs2301022, rs3827715, rs7517826, rs41303970 at GCLM) subunits are associated with susceptibility to type 2 diabetes. 2096 unrelated Russian subjects were enrolled for the study. Genotyping was done with the use of the MassArray System. Plasma levels of reactive oxygen species (ROS) and glutathione in the study subjects were analyzed by fluorometric and colorimetric assays, respectively.The present study found, for the first time, an association of SNP rs41303970 in the GCLM gene with a decreased risk of T2D (P = 0.034, Q = 0.17). Minor alleles such as rs12524494-G GCLC gene (P = 0.026, Q = 0.17) and rs3827715-C GCLM gene (P = 0.03, Q = 0.17) were also associated with reduced risk for T2D. Protective effects of variant alleles such as rs12524494-G at GCLC (P = 0.02, Q = 0.26) and rs41303970-A GCLM (P = 0.013, Q = 0.25) against the risk of T2D were seen solely in nonsmokers. As compared with healthy controls, diabetic patients had markedly increased levels of ROS and decreased levels of total GSH in plasma. Interestingly, fasting blood glucose level positively correlated with oxidized glutathione concentration (r = 0.208, P = 0.01). Three SNPs rs17883901, rs636933, rs648595 at GCLC and one rs2301022 at GCLM were associated with decreased levels of ROS, while SNPs rs7517826, rs41303970 at GCLM were associated with increased levels of total GSH in plasma. Single nucleotide polymorphisms in genes encoding glutamate cysteine ligase subunits confer protection against type 2 diabetes and their effects are mediated through increased levels of glutathione.
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http://dx.doi.org/10.1007/s11033-020-05647-5DOI Listing
August 2020

Candidate genes for age at menarche are associated with endometrial hyperplasia.

Gene 2020 Oct 5;757:144933. Epub 2020 Jul 5.

Department of Medical Biological Disciplines, Belgorod State University, 308015 Belgorod, Russia.

Objectives: To study associations candidate genes for age at menarche with a risk of endometrial hyperplasia (EH).

Methods: 52 candidate loci for age at menarche were analyzed for possible association with EH in a sample of 520 patients and 981 controls. Association of the polymorphisms was analyzed using the method of logistic regression. The gene-gene and gene-environment interactions were analyzed using MB-MDR. 21 polymorphisms, which were associated with EH, and 397 polymorphisms linked to them (r ≥ 0.8) were analyzed in silico for their functional significance.

Results: 21 out of the 52 studied polymorphisms had association with EH. Locus rs11031010 FSHB was individually associated with the disease according to the dominant (OR = 0.62, p = 0.001) and additive (OR = 0.67, p = 0.002) models. Haplotype GAA of loci rs555621-rs11031010-rs1782507 FSHB were associated with the EH (OR = 0.66, p = 0.007). Seventeen loci were associated with EH within 12 most significant models of intergenic interactions (p ≤ 0.001). Locus rs4374421 of the LHCGR gene appeared in the largest number of models (four models). Nine loci involved in 14 most significant models of interactions between SNP, induced abortions, and chronic endometritis were associated with EH. The polymorphisms of genes FTO (rs12324955) and FSHB (rs11031010) appeared in the largest number of the models (9 and 6, respectively). Among the 21 loci associated with EH, 16 manifested association also with either age at menarche (7 SNPs) or height and/or BMI (13 SNPs). The above 21 SNPs and 397 SNPs linked to them have non-synonymous, regulatory and eQTL significance for 25 genes, which play roles in the pathways related to development of the female reproductive organs and hormone-mediated signaling (FDR ≤ 0.05).

Conclusions: Candidate genes for age at menarche are associated with endometrial hyperplasia.
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http://dx.doi.org/10.1016/j.gene.2020.144933DOI Listing
October 2020

Dataset of allele, genotype and haplotype frequencies of five polymorphisms CDKN2B-AS1 gene in Russian patients with primary open-angle glaucoma.

Data Brief 2020 Aug 18;31:105722. Epub 2020 May 18.

Department of Medical Biological Disciplines, Belgorod State University, 308015 Belgorod, Russia.

Data on the allele, genotype and haplotype frequencies of the five single nucleotide polymorphisms (SNPs) such as rs1063192, rs7865618, rs2157719, rs944800 and rs4977756 of the gene in Russian patients with primary open-angle glaucoma (POAG) are provided. These SNPs are found to be associated with the risk of POAG by genome-wide association studies (GWAS). The frequencies of alleles, genotypes and haplotypes of gene were present separately for entire group of patients, females and males, and may be used as reference data of Russian population.
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http://dx.doi.org/10.1016/j.dib.2020.105722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265048PMC
August 2020

Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients.

Authors:
Alexey Polonikov

ACS Infect Dis 2020 07 28;6(7):1558-1562. Epub 2020 May 28.

Department of Biology, Medical Genetics and Ecology and Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russian Federation.

Higher rates of serious illness and death from coronavirus SARS-CoV-2 (COVID-19) infection among older people and those who have comorbidities suggest that age- and disease-related biological processes make such individuals more sensitive to environmental stress factors including infectious agents like coronavirus SARS-CoV-2. Specifically, impaired redox homeostasis and associated oxidative stress appear to be important biological processes that may account for increased individual susceptibility to diverse environmental insults. The aim of this Viewpoint is to justify (1) the crucial roles of glutathione in determining individual responsiveness to COVID-19 infection and disease pathogenesis and (2) the feasibility of using glutathione as a means for the treatment and prevention of COVID-19 illness. The hypothesis that glutathione deficiency is the most plausible explanation for serious manifestation and death in COVID-19 patients was proposed on the basis of an exhaustive literature analysis and observations. The hypothesis unravels the mysteries of epidemiological data on the risk factors determining serious manifestations of COVID-19 infection and the high risk of death and opens real opportunities for effective treatment and prevention of the disease.
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http://dx.doi.org/10.1021/acsinfecdis.0c00288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263077PMC
July 2020

Dataset of allele, genotype and haplotype frequencies of four polymorphisms filaggrin gene in Russian patients with atopic dermatitis.

Data Brief 2020 Apr 21;29:105307. Epub 2020 Feb 21.

Department of Medical Biological Disciplines, Belgorod State University, 308015, Belgorod, Russia.

Data on the allele, genotype and haplotype frequencies of four single nucleotide polymorphisms (SNPs) (rs3126085, rs12144049, rs471144 and rs4363385) () gene in Russian patients with atopic dermatitis are presented. Genome-wide association studies identified these SNPs could be significant genetic markers associated with atopic dermatitis. The frequencies of alleles, genotypes and haplotypes of four SNPs were calculated in 3 groups: entire sample, females and males. No significant differences in the allele, genotype and haplotype frequencies between males and females with AD patients were observed.
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http://dx.doi.org/10.1016/j.dib.2020.105307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047013PMC
April 2020

Dataset of allele and genotype frequencies of five polymorphisms candidate genes analyzed for association with body mass index in Russian women.

Data Brief 2020 Feb 9;28:104962. Epub 2019 Dec 9.

Department of Medical Biological Disciplines, Belgorod State University, 308015, Belgorod, Russia.

Data on the allele and genotype frequencies of the five single nucleotide polymorphisms (SNPs) 5 genes - rs1514175 , rs713586 RBJ, rs887912 , rs2241423 , rs12444979 in Russian women are presented. Several genome-wide association studies identified these SNPs could be significant genetic markers associated with body mass index (BMI). Standard methods were used for collecting of the anthropometric characteristics (height and weight). We calculated the frequencies of alleles and genotypes of five SNPs in 5 groups: all samples, underweight (BMI<18.50), normal weight (18.50-24.99), overweight (25.00-29.99), obese (>30.00).
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http://dx.doi.org/10.1016/j.dib.2019.104962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931107PMC
February 2020

Dataset of allele, genotype and haplotype frequencies of four gene polymorphisms analyzed for association with age at menarche in Russian women.

Data Brief 2019 Aug 30;25:104323. Epub 2019 Jul 30.

Department of Medical Biological Disciplines, Belgorod State University, 308015, Belgorod, Russia.

In this paper, we present the allele, genotype and haplotype frequencies of 4 single nucleotide polymorphisms (SNPs) in gene (rs4946651, rs7759938, rs314280, rs314276) in a sample of Russian women. These SNPs had been previously identified to be associated with age at menarche in genome-wide association studies (GWAS). The information about age at menarche was obtained using the questionnaire. The frequencies of alleles, genotypes and haplotypes of four SNPs were classified in 3 groups: the whole sample, individuals with the early age at menarche (<12 years), and those with the average age at menarche (12-14 years).
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http://dx.doi.org/10.1016/j.dib.2019.104323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698934PMC
August 2019

The VNTR polymorphism of the endothelial nitric oxide synthase gene and blood pressure in women at the end of pregnancy.

Taiwan J Obstet Gynecol 2019 May;58(3):390-395

Department of Medical Biological Disciplines, Belgorod State University, Belgorod, Russia.

Objective: Examine the association of the 4a/4b polymorphism of endothelial nitric oxide synthase (eNOS) with blood pressure in women at late pregnancy.

Materials And Methods: Blood pressure before pregnancy and at the end of gestation (37-40-week term) was measured in 588 women of the Russian ancestry. The women were divided into groups according to the body mass index and the presence of preeclampsia at late pregnancy. The 4a/4b polymorphism of the eNOS gene was genotyped using PCR with subsequent screening of amplified fragment length polymorphisms.

Results: The 4a4a eNOS genotype was associated with higher levels of diastolic blood pressure in pregnant women and with more pronounced dynamics of the diastolic and mean arterial pressure in the development of pregnancy (p = 0.02-0.03). Pregnant women with the 4a4a genotype and increased body mass index had higher systolic, diastolic, and mean arterial pressure (p = 0.001-0.009). In pregnant women with preeclampsia, the 4a4a genotype was associated with higher level of diastolic blood pressure at the end of pregnancy (p = 0.04), whereas in the women without preeclampsia this genotype was associated with more pronounced changes of blood pressure at pregnancy (p = 0.02).

Conclusion: The results of our study suggest that the genotype 4a4a of the eNOS gene is associated with higher levels of blood pressure in women at the end of pregnancy.
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http://dx.doi.org/10.1016/j.tjog.2018.11.035DOI Listing
May 2019

Matrix metalloproteinases as target genes for gene regulatory networks driving molecular and cellular pathways related to a multistep pathogenesis of cerebrovascular disease.

J Cell Biochem 2019 10 5;120(10):16467-16482. Epub 2019 May 5.

Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, Kursk, Russian Federation.

The present study investigated a joint contribution of matrix metalloproteinases (MMPs) genes to ischemic stroke (IS) development and analyzed interactions between MMP genes and genome-wide associated loci for IS. A total of 1288 unrelated Russians (600 IS patients and 688 healthy individuals) from Central Russia were recruited for the study. Genotyping of seven single nucleotide polymorphisms (SNPs) of MMP genes (rs1799750, rs243865, rs3025058, rs11225395, rs17576, rs486055, and rs2276109) and eight genome-wide associated loci for IS were done using Taq-Man-based assays and MALDI-TOF mass spectrometry iPLEX platform, respectively. Allele - 799T at rs11225395 of the MMP8 gene was significantly associated with a decreased risk of IS after adjustment for sex and age (OR = 0.82; 95%CI, 0.70-0.96; P = 0.016). The model-based multifactor dimensionality reduction method has revealed 21 two-order, 124 three-order, and 474 four-order gene-gene (G×G) interactions models meaningfully (P  < 0.05) associated with the IS risk. The bioinformatic analysis enabled establishing the studied MMP gene polymorphisms possess a clear regulatory potential and may be targeted by gene regulatory networks driving molecular and cellular pathways related to the pathogenesis of IS. In conclusion, the present study was the first to identify an association between polymorphism rs11225395 of the MMP8 gene and IS risk. The study findings also indicate that MMPs deserve special attention as a potential class of genes influencing the multistep mechanisms of cerebrovascular disease including atherosclerosis in cerebral arteries, acute cerebral artery occlusion as well as the ischemic injury of the brain and its recovery.
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http://dx.doi.org/10.1002/jcb.28815DOI Listing
October 2019

A comprehensive study revealed SNP-SNP interactions and a sex-dependent relationship between polymorphisms of the CYP2J2 gene and hypertension risk.

Hypertens Res 2019 02 5;42(2):257-272. Epub 2018 Dec 5.

Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx St., Kursk, 305041, Russian Federation.

This study investigated whether common polymorphisms of cytochrome P450 2J2 (CYP2J2), a major enzyme that controls the biosynthesis of vasoactive epoxyeicosatrienoic acids, are collectively involved in the molecular basis of essential hypertension (EH). A total of 2314 unrelated Russian subjects from the Kursk (discovery sample: 913 EH patients and 645 controls) and Belgorod (replication sample: 345 EH patients and 411 controls) regions were recruited for this study. Eight single nucleotide polymorphisms (SNPs), including rs890293, rs11572182, rs10493270, rs1155002, rs2280275, rs7515289, rs11572325, and rs10889162, of CYP2J2 were genotyped using the MassARRAY 4 system and TaqMan-based assays. Significant associations were identified among the SNPs rs890293 (OR = 2.17, 95%CI 1.30-3.65), rs2280275 (OR = 1.59, 95%CI 1.10-2.37) and rs11572325 (OR = 1.89, 95%CI 1.22-2.95) and the risk of EH in females from the Kursk population. Sixteen CYP2J2 genotype combinations only showed significant associations with EH risk only in females. A common haplotype, T-T-G-C-C-C-T-A, increased the risk of EH in females. The bioinformatic analysis enabled identification of the SNPs that possess regulatory potential and/or are located within the binding sites for multiple transcription factors that play roles in the pathways involved in hypertension pathogenesis. Moreover, the polymorphisms rs890293, rs2280275, and rs11572325 were found to be significantly associated with hypertension risk in the Belgorod population. In conclusion, the rs2280275 and rs11572325 SNPs of CYP2J2 may be considered novel genetic markers of hypertension, at least in Russian women. However, sex-specific associations between CYP2J2 gene polymorphisms and hypertension require further investigation to clarify the specific genetic and/or environmental factors that are responsible for the increased disease susceptibility of women compared to that of men.
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http://dx.doi.org/10.1038/s41440-018-0142-1DOI Listing
February 2019

Association of genetic polymorphisms with age at menarche in Russian women.

Gene 2019 Feb 16;686:228-236. Epub 2018 Nov 16.

Department of Medical Biological Disciplines, Belgorod State University, 308015 Belgorod, Russia.

Objectives: Examine the association of genetic polymorphisms with age at menarche (AAM) in Russian women.

Study Design: A total of 1613 Russian females were recruited for the study. Fifty two polymorphisms were analyzed for their association with AAM, height, and BMI. The associations were analyzed assuming the additive, dominant, and recessive models and using the log-linear regression as implemented in PLINK v. 2.050. The 2-, 3-, and 4-loci models of gene-gene interactions were analyzed using the MB-MDR method and validated by the permutation test.

Main Outcome Measures: Genetic polymorphism rs6438424 3q13.32 was independently associated with AAM in Russian women. In addition, 14 SNPs were determined as possible contributors to this trait through gene-gene interactions.

Results: The obtained results suggest that 14 out of 52 studied polymorphisms may contribute to AAM in Russian women. The rs6438424 3q13.32 polymorphism was associated with AAM according to both additive and dominant models (р = 0.005). In total 12 two-, three-, and four-locus models of gene-gene interactions were determined as contributing to AAM (p ≤ 0.006). Nine of the 14 AAM-associated SNPs are also associated with height and BMI (p ≤ 0.003). Among 14 AAM-associated SNPs (a priori all having regulatory significance), the highest regulatory potential was determined for rs4633 COMT, rs2164808 POMC, rs2252673INSR, rs6438424 3q13.32, and rs10769908 STK33. Eleven loci are cis-eQTL and affect expression of 14 genes in various tissues and organs (FDR < 0.05). The neuropeptide-encoding genes were overrepresented among the AAM-associated genes (p = 0.039).

Conclusions: The rs6438424 polymorphism is independently associated with AAM in Russian females in this study. The other 14 SNPs manifest this association through gene-gene interactions.
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http://dx.doi.org/10.1016/j.gene.2018.11.042DOI Listing
February 2019

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

Dis Markers 2018 1;2018:5812802. Epub 2018 Feb 1.

Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, Karl Marx Street 3, Kursk 305041, Russia.

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 and 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 and rs3093098 and rs1558139 of by using the Mass-ARRAY 4 system. SNPs rs3890011 and rs9332978 of were associated with increased risk of CAD in women: OR = 1.26, 95% CI: 1.02-1.57, = 0.004, and = 0.01 and OR = 1.45, 95% CI: 1.13-1.87, = 0.004, and = 0.01, respectively. Haplotype G-C-A of was associated with increased risk of CAD (adjusted OR = 1.41, 95% CI: 1.12-1.78, and = 0.0036). Epistatic interactions were found between rs9332978 of and rs1558139 of ( = 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 and susceptibility to coronary artery disease.
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http://dx.doi.org/10.1155/2018/5812802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5816861PMC
September 2018

Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks.

Nat Genet 2018 01 22;50(1):42-53. Epub 2017 Dec 22.

Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico.

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.
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http://dx.doi.org/10.1038/s41588-017-0014-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901974PMC
January 2018

Gene set enrichment analysis and expression pattern exploration implicate an involvement of neurodevelopmental processes in bipolar disorder.

J Affect Disord 2018 03 14;228:20-25. Epub 2017 Nov 14.

Max Planck Institute of Psychiatry, Munich, Germany.

Background: Bipolar disorder (BD) is a common and highly heritable disorder of mood. Genome-wide association studies (GWAS) have identified several independent susceptibility loci. In order to extract more biological information from GWAS data, multi-locus approaches represent powerful tools since they utilize knowledge about biological processes to integrate functional sets of genes at strongly to moderately associated loci.

Methods: We conducted gene set enrichment analyses (GSEA) using 2.3 million single-nucleotide polymorphisms, 397 Reactome pathways and 24,025 patients with BD and controls. RNA expression of implicated individual genes and gene sets were examined in post-mortem brains across lifespan.

Results: Two pathways showed a significant enrichment after correction for multiple comparisons in the GSEA: GRB2 events in ERBB2 signaling, for which 6 of 21 genes were BD associated (P = 0.0377), and NCAM signaling for neurite out-growth, for which 11 out of 62 genes were BD associated (P = 0.0451). Most pathway genes showed peaks of RNA co-expression during fetal development and infancy and mapped to neocortical areas and parts of the limbic system.

Limitations: Pathway associations were technically reproduced by two methods, although they were not formally replicated in independent samples. Gene expression was explored in controls but not in patients.

Conclusions: Pathway analysis in large GWAS data of BD and follow-up of gene expression patterns in healthy brains provide support for an involvement of neurodevelopmental processes in the etiology of this neuropsychiatric disease. Future studies are required to further evaluate the relevance of the implicated genes on pathway functioning and clinical aspects of BD.
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http://dx.doi.org/10.1016/j.jad.2017.11.068DOI Listing
March 2018

Glutathione S-transferase genes and the risk of type 2 diabetes mellitus: Role of sexual dimorphism, gene-gene and gene-smoking interactions in disease susceptibility.

J Diabetes 2018 May 2;10(5):398-407. Epub 2018 Jan 2.

Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, Kursk, Russian Federation.

Background: Compromised defense against reactive oxygen species (ROS) is considered important in the pathogenesis of type 2 diabetes mellitus (T2DM); therefore, genes encoding antioxidant defense enzymes may contribute to disease susceptibility. This study investigated whether polymorphisms in genes encoding glutathione S-transferase M1 (GSTM1), T1 (GSTT1), and P1 (GSTP1) jointly contribute to the risk of T2DM.

Methods: In all, 1120 unrelated Russian subjects (600 T2DM patients, 520 age- and sex-matched healthy subjects), were recruited to the study. Genotyping was performed by multiplex polymerase chain reaction (PCR; del/del polymorphisms of GSTM1 and GSTT1) and TaqMan-based PCR (polymorphisms I105V and A114V of GSTP1). Plasma ROS and glutathione levels in study subjects were analyzed by fluorometric and colorimetric assays, respectively.

Results: Genotype del/del GSTT1 was significantly associated with the risk of T2DM (odds ratio [OR] 1.60, 95% confidence interval [CI] 1.17-2.21, P = 0.003). Gender-stratified analysis showed that the deletion genotypes of GSTM1 (OR 1.99, 95% CI 1.30-3.05; P = 0.0002, Q = 0.016) and GSTT1 (OR 2.23, 95% CI 1.22-4.09; P = 0.008, Q = 0.0216), as well as genotype 114A/V of GSTP1 (OR 2.85, 95% CI 1.44-5.62; P = 0.005, Q = 0.02) were associated with an increased risk of T2DM exclusively in males. Three genotype combinations (i.e. GSTM1+ × GSTT1+, GSTM1+ × GSTP1 114A/A and GSTT1+ × GSTP1 114A/A) showed significant associations with a decreased risk of T2DM in males.

Conclusions: This study demonstrates, for the first time, that genes encoding glutathione S-transferases jointly contribute to the risk of T2DM, and that their effects on disease susceptibility are gender specific.
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http://dx.doi.org/10.1111/1753-0407.12623DOI Listing
May 2018

Genes of tumor necrosis factors and their receptors and the primary open angle glaucoma in the population of Central Russia.

Int J Ophthalmol 2017 18;10(10):1490-1494. Epub 2017 Oct 18.

Department of Medical Biological Disciplines, Belgorod State University, Belgorod 308015, Russia.

Aim: To examine the association of genetic polymorphisms (-308)G/A , (+250)A/G , (+36)A/G , (+1663)A/G 2 with the development of primary open angle glaucoma (POAG) among people in Central Russia.

Methods: The study sample included 443 individuals, of which 252 patients with POAG and 191 individuals in the control group. Genotyping of (-308)G/A , (+250)A/G , (+36)A/G , (+1663)A/G 2 was performed using polymerase chain reaction. The distribution of alleles and genotypes of the studied DNA markers in the groups was examined by 2×2 contingency tables and with the Yates's correction for continuity and odds ratios (OR) with 95% confidence intervals (CI).

Results: Allele (-308)G (=0.01, OR=1.78, 95%CI 1.12-2.85) was identified as a risk factor for POAG. Homozygotes (-308) AA are at a lowest risk for development of the disease (=0.01, OR=0.0005). The following combination of genetic variants of cytokines were associated with a reduced risk of POAG: (+1663)A and (+250)G (OR=0.34).

Conclusion: Genetic polymorphisms (-308)G/A , (+250)A/G , (+1663)A/G associated with the development of POAG in the population of Central Russia.
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http://dx.doi.org/10.18240/ijo.2017.10.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638967PMC
October 2017

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

Gene 2017 Sep 4;627:451-459. Epub 2017 Jul 4.

Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx St., Kursk 305041, Russian Federation.

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, P=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.
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http://dx.doi.org/10.1016/j.gene.2017.07.004DOI Listing
September 2017

Genetic markers for inherited thrombophilia are associated with fetal growth retardation in the population of Central Russia.

J Obstet Gynaecol Res 2017 Jul 19;43(7):1139-1144. Epub 2017 May 19.

Department of Medical Biological Disciplines, Belgorod State University, Belgorod, Russia.

Aim: The aim of this study was to examine the role of hereditary thrombophilia in the development of fetal growth retardation (FGR) in the population of Central Russia.

Methods: The case-control study sample included 497 women in the third trimester of pregnancy recruited during 2009-2013. The participants were enrolled into two groups: patients with FGR (n = 250) and controls without FGR (n = 247). The participants were genotyped for four genetic markers of hereditary thrombophilia: factor V Leiden (G > A FV, rs6025), prothrombin (G > A FII, rs1799963), factor VII (G > A FVII, rs6046), and fibrinogen (G > A FI, rs1800790).

Results: The genetic factors for an increased risk of FGR were allele G of rs6046 (odds ratio [OR] = 2.34) and genotype GG of rs6046 (OR = 2.64), whereas genotype GA of rs6046 had the protective value (OR = 0.42). A combination of alleles G of rs1799963, A of rs6046, and G of rs1800790 (OR = 0.31) reduces the risk of FGR.

Conclusion: Polymorphism rs6046 of the FVII gene is associated with the development of FGR.
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http://dx.doi.org/10.1111/jog.13329DOI Listing
July 2017

The contribution of CYP2C gene subfamily involved in epoxygenase pathway of arachidonic acids metabolism to hypertension susceptibility in Russian population.

Clin Exp Hypertens 2017 17;39(4):306-311. Epub 2017 May 17.

a Department of Biology, Medical Genetics and Ecology , Kursk State Medical University , Kursk , Russian Federation.

Numerous studies demonstrated an importance of cytochrome P-450 epoxygenase pathway of arachidonic acids metabolism for the pathogenesis of essential hypertension (EH). The present study was designed to investigate whether common single-nucleotide polymorphisms (SNP) of CYP2C gene subfamily such as CYP2C8 (rs7909236 and rs1934953), CYP2C9 (rs9332242), and CYP2C19 (rs4244285) are associated with susceptibility to EH in Russian population. A total of 816 unrelated Russian individuals comprising 425 EH patients and 391 normotensive controls were included into the study. Genotyping of SNPs was performed using the MassARRAY 4 system. SNP rs7909236 of CYP2C8 was significantly associated with increased risk of EH (OR adjusted for sex and age was 2.99 95% CI 1.39-6.44, P = 0.005). SNPs rs1934953 CYP2C8 and rs4244285 of CYP2C19 showed association with EH risk but at a borderline statistical significance (P ≤ 0.04). Combination of genotypes CYP2C8 rs7909236 TT and CYP2C19 rs4244285 GG was associated with increased EH risk (OR 3.34 95%CI 1.48-7.51, P = 0.004). Genotype-phenotype correlation analysis showed that the levels of CYP2C8 mRNA were significantly correlated with SNP rs7909236 (P = 0.01). in silico functional prediction analysis revealed the functionality of majority of investigated SNPs. Thus, genes of CYP2C subfamily are important genetic determinants of susceptibility to essential hypertension in Russians.
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http://dx.doi.org/10.1080/10641963.2016.1246562DOI Listing
February 2018

Identification of shared risk loci and pathways for bipolar disorder and schizophrenia.

PLoS One 2017 6;12(2):e0171595. Epub 2017 Feb 6.

Institute of Human Genetics, University of Bonn, Bonn, Germany.

Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. BD shows substantial clinical and genetic overlap with other psychiatric disorders, in particular schizophrenia (SCZ). The genes underlying this etiological overlap remain largely unknown. A recent SCZ genome wide association study (GWAS) by the Psychiatric Genomics Consortium identified 128 independent genome-wide significant single nucleotide polymorphisms (SNPs). The present study investigated whether these SCZ-associated SNPs also contribute to BD development through the performance of association testing in a large BD GWAS dataset (9747 patients, 14278 controls). After re-imputation and correction for sample overlap, 22 of 107 investigated SCZ SNPs showed nominal association with BD. The number of shared SCZ-BD SNPs was significantly higher than expected (p = 1.46x10-8). This provides further evidence that SCZ-associated loci contribute to the development of BD. Two SNPs remained significant after Bonferroni correction. The most strongly associated SNP was located near TRANK1, which is a reported genome-wide significant risk gene for BD. Pathway analyses for all shared SCZ-BD SNPs revealed 25 nominally enriched gene-sets, which showed partial overlap in terms of the underlying genes. The enriched gene-sets included calcium- and glutamate signaling, neuropathic pain signaling in dorsal horn neurons, and calmodulin binding. The present data provide further insights into shared risk loci and disease-associated pathways for BD and SCZ. This may suggest new research directions for the treatment and prevention of these two major psychiatric disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0171595PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5293228PMC
August 2017

A comprehensive contribution of genes for aryl hydrocarbon receptor signaling pathway to hypertension susceptibility.

Pharmacogenet Genomics 2017 02;27(2):57-69

aDepartment of Biology, Medical Genetics and Ecology bLaboratory of Statistical Genetics and Bioinformatics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, Kursk cPopulation Genetics Laboratory, Research Institute for Medical Genetics, Tomsk dDepartment of Medical Biological Disciplines, Belgorod State University, Belgorod, Russian Federation.

Objective: The present study was designed to investigate whether genetic polymorphisms of the aryl hydrocarbon receptor (AHR) signaling pathway are involved in the molecular basis of essential hypertension (EH).

Methods: A total of 2160 unrelated Russian individuals comprising 1341 EH patients and 819 healthy controls were recruited into the study. Seven common AHR pathway single-nucleotide polymorphisms (SNPs) such as rs2066853, rs2292596, rs2228099, rs1048943, rs762551, rs1056836, and rs1800566 were genotyped by TaqMan-based allele discrimination assays.

Results: We found that SNP rs2228099 of ARNT is associated with an increased risk of EH (odds ratio=1.20 95% confidence interval: 1.01-1.44, P=0.043) in a dominant genetic model, whereas polymorphism rs762551 of CYP1A2 showed an association with a decreased risk of disease in a recessive genetic model (odds ratio=0.68, 95% confidence interval: 0.52-0.89, P=0.006). A log-likelihood ratio test enabled identification of epistatic interaction effects on EH susceptibility for all SNPs. MB-MDR analysis showed that cigarette smoking, rs1048943, rs762551, rs1056836, and rs2228099 were significant contributing factors in 19, 18, 13, 13, and 11 interaction models, respectively. The best MDR model associated with EH risk included rs1048943, rs762551, rs1056836, and cigarette smoking (cross-validation consistency 100%, prediction error 45.7%, Ppermutation<0.0001). The mRNA expression and in-silico function prediction analyses have confirmed a regulatory potential for a majority of SNPs associated with EH susceptibility.

Conclusion: Our pilot study was the first to show that gene-gene and gene-environment interactions in the AHR signaling pathway represent important determinants for the development of EH, and the pathway may become an attractive target for a pharmacological intervention in hypertensive patients in the future.
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http://dx.doi.org/10.1097/FPC.0000000000000261DOI Listing
February 2017

Alcohol Consumption and Cigarette Smoking are Important Modifiers of the Association Between Acute Pancreatitis and the PRSS1-PRSS2 Locus in Men.

Pancreas 2017 02;46(2):230-236

From the *Department of Biology, Medical Genetics and Ecology, †Research Institute for Genetic and Molecular Epidemiology, ‡Department of Surgical Diseases №2, Kursk State Medical University, Kursk, Russian Federation; and §Laboratory of Genetics, Kursk State University, Kursk, Russian Federation.

Objectives: The present study was designed to investigate whether the susceptibility to acute pancreatitis (AP) attributable to polymorphism rs10273639 at the PRSS1-PRSS2 locus is dependent on alcohol consumption and cigarette smoking.

Methods: A total of 603 unrelated Russian individuals including 304 patients with physician-diagnosed AP and 299 sex- and age-matched healthy controls have been recruited for the study. A polymorphism rs10273639 (-408C>T) of PRSS1-PRSS2 was genotyped by TaqMan-based assay.

Results: A variant allele -408T (P = 0.003) and genotypes -408CT plus TT (P = 0.002) were associated with decreased AP risk only in men. The odds ratios for AP in the CC homozygotes versus the variant genotypes were 1.95 [95% confidence interval (CI), 0.65-5.85; P = 0.23], 1.72 (95% CI, 0.93-3.20; P = 0.08), and 2.37 (95% CI, 1.09-5.13; P = 0.03) for men who consumed up to 28, 29 to 59, and more than 60 alcohol drinks a week, respectively. Cigarette smokers with the -408CC genotype had an increased risk of AP (odds ratio, 2.07; 95% CI, 1.25-3.42; P = 0.004), whereas nonsmoker carriers did not have a disease risk (odds ratio, 1.48; 95% CI, 0.58-3.82; P = 0.42).

Conclusions: We confirmed a robust association of polymorphism rs10273639 at PRSS1-PRSS2 with AP in the Russian population. The present study is the first to show that relationship between the locus and disease is significantly modified by alcohol consumption and cigarette smoking.
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http://dx.doi.org/10.1097/MPA.0000000000000729DOI Listing
February 2017

Gender-specific protective effect of the -463G>A polymorphism of myeloperoxidase gene against the risk of essential hypertension in Russians.

J Am Soc Hypertens 2015 Nov 21;9(11):902-6. Epub 2015 Aug 21.

Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, Kursk, Russian Federation.

The purpose of this study was to investigate whether a common polymorphism -463G>A (rs2333227) in the promoter of myeloperoxidase (MPO) gene, an oxidant enzyme producing hypohalogenic radicals, is associated with the risk of essential hypertension (EH) in Russian population. A total of 2044 unrelated subjects including 1256 EH patients and 788 normotensive controls were recruited for this study. Genotyping of the MPO gene polymorphism was done using TaqMan-based assay. A genotype -463GA was associated with decreased risk of EH (odds ratio = 0.82; 95% confidence interval: 0.68-1.00) at a borderline significance level (P = .05). The gender-stratified analysis showed that a carriage of the -463GA and -463AA genotypes is associated with decreased EH risk only in females (odds ratio = 0.74, 95% confidence interval: 0.56-0.96; P = .02). To the best of our knowledge, this is the first study reporting a negative association between the -463G>A polymorphism of the MPO gene and EH risk. Molecular mechanisms by which MPO gene is involved in the pathogenesis of EH are discussed.
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http://dx.doi.org/10.1016/j.jash.2015.08.006DOI Listing
November 2015

Altered erythrocyte membrane protein composition mirrors pleiotropic effects of hypertension susceptibility genes and disease pathogenesis.

J Hypertens 2015 Nov;33(11):2265-77

aDepartment of Biology, Medical Genetics and Ecology, Kursk State Medical University bDivision of Cardiology, Kursk Regional Clinical Hospital, Kursk cDepartment of Medical Biological Disciplines, Belgorod State University, Belgorod dPopulation Genetics Laboratory, Research Institute for Medical Genetics, Tomsk, Russian Federation eDepartment of Physiology, Pathophysiology and Medical Biology, Sumy State University, Sumy, Ukraine.

Objective: The study was designed to assess the effects of polymorphisms in genes associated with essential hypertension on the variation of erythrocyte membrane proteins (EMPs) in hypertensive patients.

Methods: Major EMPs content was analyzed in blood from 1162 unrelated Russians (235 hypertensive patients, 176 healthy controls, and 751 random individuals from the Central Russia population). Essential hypertension patients were genotyped for 11 polymorphisms of essential hypertension susceptibility genes including ADD1 (rs4961), GNB3 (rs5443, rs16932941), NOS3 (rs1799983, rs2070744), ACE (rs5186), AGTR1 (rs5186), AGT (rs699, rs4762), MR (rs5534), and TGFB1 (rs1800471). EMP contents and their relationship with the genetic loci were analyzed using various statistical tests.

Results: Sex-specific differences in EMP contents between the cases and controls were observed. Regardless of sex, hypertensives exhibited mainly decreased levels of alpha (SPTA1) and beta-spectrin (SPTB) and increased levels of glucose transporter (GLUT1) as compared with healthy subjects (P ≤ 0.001). EMP correlated differently in essential hypertension patients and controls. Almost 70% of the joint variation in the EMP levels is explained by five gender-specific principal components. The essential hypertension susceptibility genes showed considerable effects on the levels of spectrins and glucose transporter. A joint variation of the genes explained about half the total polygenic variance in the GLUT1, SPTA1, and SPTB levels in hypertensives.

Conclusions: The study showed that essential hypertension susceptibility genes are the important factors of the inherited EMP variation, and their pleitropic effects may be mirrored in the altered expression of genes encoding cytoskeletal proteins and those related to intracellular glucose metabolism.
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http://dx.doi.org/10.1097/HJH.0000000000000699DOI Listing
November 2015

Antioxidant-related gene polymorphisms associated with the cardio-ankle vascular index in young Russians.

Cardiol Young 2016 Apr 17;26(4):677-82. Epub 2015 Jun 17.

3Department of Biology, Medical Genetics and Ecology,Kursk State Medical University,Kursk,Russia.

The cardio-ankle vascular index is a measure of arterial stiffness, whereas oxidative stress underlies arterial pathology. This study aimed to investigate the association between the cardio-ankle vascular index and antioxidant-related gene polymorphisms in young Russians. A total of 89 patients (mean age, 21.6 years) were examined by the cardio-ankle vascular index and for 15 gene polymorphisms related to antioxidant enzymes including FMO3 (flavin-containing monooxygenase 3), GPX1 (glutathione peroxidase 1), and GPX4 (glutathione peroxidase 4). A higher cardio-ankle vascular index level was detected in carriers with the KK-genotype of FMO3 polymorphism rs2266782 than in those without (mean levels: 6.2 versus 5.6, respectively, p<0.05). Similarly, a higher cardio-ankle vascular index level was seen in carriers with the CC-genotype of GPX4 polymorphism rs713041 than in those without (6.0 versus 5.5, respectively, p<0.05). We did not observe significant associations between the cardio-ankle vascular index levels and the other gene polymorphisms. Although carriers with the LL-genotype of GPX1 polymorphism rs1050450 showed a higher diastolic blood pressure level than those without, the polymorphism did not affect the cardio-ankle vascular index level. This study showed a significant association between rs2266782 and rs713041 polymorphisms and arterial stiffness, as measured by the cardio-ankle vascular index, in young Russians. The pathways utilised by antioxidant enzymes may be responsible for early arterial stiffening in the Russian population.
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http://dx.doi.org/10.1017/S104795111500102XDOI Listing
April 2016