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Background: This pilot study aimed to investigate the association between the single nucleotide polymorphism (SNP) rs3918226 in the promoter of the nitric oxide synthase (NOS3) gene and the risk of peripheral artery disease (PAD)., Methods: DNA samples from 1,263 unrelated subjects of Slavic origin, including 620 patients with PAD and 643 controls, were genotyped for the SNP rs3918226 using the MassArray-4 system., Results: The rs3918226 polymorphism was found to be strongly associated with an increased risk of PAD regardless of coronary artery disease, hypertension, or cigarette smoking (odds ratio [OR] = 2.86; 95% confidence interval [CI] 1.89-4.32; P perm < 0.0001). The SNP-PAD association was almost 3 times stronger in females (OR = 8.31; 95% CI 3.07-22.48) than in males (OR = 1.79; 95% CI 1.10-2.93). SNP rs3918226 was correlated with ankle-brachial index and total plasma cholesterol in patients with PAD (Р perm < 0.05). The NOS3 polymorphism was closely associated with SNPs rs7692387 and rs13139571 in guanylate cyclase soluble subunit alpha-3 (GUCY1A3) to determine the risk of PAD, suggesting that the rs3918226 polymorphism may disrupt signaling in the NO-soluble guanylyl cyclase pathway. Diplotypes with wild-type alleles, such as NOS3 rs3918226-C/C×GUCY1A1 rs7692387G/G and NOS3 rs3918226-C/C×GUCY1A1 rs13139571C/C, showed strong protection against disease risk (false discovery rate ≤ 0.001). Functional SNP annotation revealed that the allele rs3918226-T was associated with decreased expression of NOS3, most strongly in the tibial arteries than in the coronary artery or aorta., Conclusions: The present study is the first to show that the rs3918226 polymorphism of NOS3 is a novel susceptibility marker for PAD. Further research in independent populations is necessary to reproduce the association between polymorphism rs3918226 and disease risk., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: Increased plasma gamma-glutamyl transferase (GGT1) has been identified as a robust and independent risk factor for ischemic stroke (IS), but the molecular mechanisms of the enzyme-disease association are unclear. The present study investigated whether polymorphisms in the GGT1 gene contribute to IS susceptibility., Materials and Methods: DNA samples obtained from 1288 unrelated individuals (600 IS patients and 688 controls) were genotyped for common single nucleotide polymorphisms of GGT1 using the MassArray-4 platform., Results: The rs5751909 polymorphism was significantly associated with decreased risk of ischemic stroke regardless sex and age (P perm ≤ 0.01, dominant genetic model). The haplotype rs4820599A-rs5760489A-rs5751909A showed strong protection against ischemic stroke (OR 0.53, 95 %CI 0.36 - 0.77, P perm ≤ 0.0001). The protective effect of SNP rs5751909 in the stroke phenotype was successfully replicated in the UK Biobank, SiGN, and ISGC cohorts (P ≤ 0.01). GGT1 polymorphisms showed joint (epistatic) effects on the risk of ischemic stroke, with some known IS-associated GWAS loci (e.g., rs4322086 and rs12646447) investigated in our population. In addition, SNP rs5751909 was found to be strongly associated with a decreased risk of ischemic stroke in non-smokers (OR 0.54 95 %CI 0.39-0.75, P perm = 0.0002) and non-alcohol abusers (OR 0.43 95 %CI 0.30-0.61, P perm = 2.0 × 10 -6 ), whereas no protective effects of this SNP against disease risk were observed in smokers and alcohol abusers (P perm < 0.05)., Conclusions: We propose mechanisms underlying the observed associations between GGT1 polymorphisms and ischemic stroke risk. This pilot study is the first to demonstrate that GGT1 is a novel susceptibility gene for ischemic stroke and provides additional evidence of the genetic contribution to impaired redox homeostasis underlying disease pathogenesis., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Studying mechanisms of development and the causes of various human diseases continues to be the focus of attention of various researchers [...].

Association of the filaggrin (FLG) gene with atopic dermatitis (AD) in Caucasians from Central Russia was studied in the sample of 700 patients and 612 controls. In total ten SNPs of the gene (rs61816761, rs12130219, rs77199844, rs558269137, rs4363385, rs12144049, rs471144, rs6661961, rs10888499, rs3126085), their haplotypes and interlocus interactions were analyzed using logistic regression. The functional effects of the AD risk candidate loci and their proxies (136 SNPs) were evaluated by in silico analysis. All analyzed SNPs were associated with AD: two SNPs (rs3126085 and rs12144049) manifested the independent association, nine SNPs were associated within 30 haplotypes, and seven SNPs showed interlocus interaction effects within ten most significant epistatic models. Alleles A rs3126085 and C rs12144049 were associated with a higher risk of AD according to the allelic (ORs being 1.75, p perm  = 0.002 and 1.45, p perm  = 0.011 respectively), additive (ORs being 1.69, p perm  = 0.004 and 1.47, p perm  = 0.011 respectively) and dominant (ORs being 1.79, p perm  = 0.004 and 1.63, p perm  = 0.005 respectively) genetic models. Three haplotypes, GT[rs3126085-rs12144049] (OR = 0.60), GGT[rs61816761-rs3126085-rs12144049] (OR = 0.59), and AWGGT[rs12130219-rs558269137-rs61816761-rs3126085-rs12144049] (OR = 0.63) demonstrated the protective effect (p perm  = 0.001). The in silico analysis suggested that the AD risk variants and their proxies apparently produce various effects on 38 genes in various tissue/organs (including 20 genes in the skin). The biological process enrichment analyses suggest that the target AD candidate genes influence the formation of the cornified envelope, keratinization and cornification, and more than twenty other pathways related to skin development, programmed cell death, and regulation of water loss via skin., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Purpose: This study aimed to analyze the gender-specific association of the filaggrin (FLG) gene polymorphisms with atopic dermatitis (AD) in Caucasians from the central region of Russia., Methods: The study sample consisted of 906 female (including 474 patients with AD and 432 controls) and 406 male (such as 226 patients with AD and 180 controls) participants. Genotyping of ten polymorphisms of the FLG gene was done. The logistic regression was used to analyze the associations. A total of 125 SNPs (seven AD-associated SNPs and 118 proxy SNPs, r2≥0.8) FLG gene were used for the in silico functional annotation analysis in the females., Results: Significant associations were identified between seven SNPs of the FLG gene (rs12130219, rs61816761, rs558269137, rs12144049, rs3126085, rs471144, rs6661961) and AD in females: rs12144049 was associated independent individually (for allele C OR = 1.71, 95%Сl 1.19-2.46, рperm = 0.004 and OR = 1.76, 95%Сl 1.18-2.63, рperm = 0.006 according to the additive and dominant genetic models, respectively) and seven SNPs of the FLG gene within 14 haplotypes. Haplotype GGT [rs61816761-rs3126085-rs12144049] showed the strongest association (OR = 0.55, рperm = 0.001). No association between the analyzed SNPs and AD was determined in the male group. The subsequent bioinformatic analysis predicted the SNPs of the FLG gene that possessed epigenetic and non-synonymous effects, were involved in the control of gene expression and alternative splicing of genes that contribute to AD pathophysiology., Conclusion: Polymorphisms of the FLG gene are associated with AD in females but not in males in the Caucasian population of Central Russia., Competing Interests: The authors have declared that no competing interests exist.

Background and Purpose: The study analyzed the association of functionally significant polymorphisms of matrix metalloproteinases (MMPs) genes with the development of gastric ulcer (GU) in Caucasians from Central Russia., Methods: The 781 participants, including 434 patients with GU (196 Helicobacter pylori (H. pylori)-positive and 238 H. pylori-negative) and 347 controls (all H. pylori-negative) were recruited for the study. Ten SNPs of the MMP1 (rs1799750), MMP2 (rs243865), MMP3 (rs679620), MMP8 (rs1940475), and MMP9 (rs3918242, rs3918249, rs3787268, rs17576, rs17577, and rs2250889) genes were considered for association with GU using multiple logistic regression. The SNPs associated with GU and loci linked (r2≥0.8) to them were analyzed in silico for their functional assignments., Results: The SNPs of the MMP9 gene were associated with H. pylori-positive GU: alleles C of rs3918249 (OR = 2.02, pperm = 0.008) and A of rs3787268 (OR = 1.60-1.82, pperm ≤ 0.016), and eight haplotypes of all studied MMP9 gene SNPs (OR = 1.85-2.04, pperm ≤ 0.016) increased risk for H. pylori-positive GU. None of the analyzed SNPs was independently associated with GU and H. pylori-negative GU. Two haplotypes of the MMP9 gene (contributed by rs3918242, rs3918249, rs17576, and rs3787268) increased risk for GU (OR = 1.62-1.65, pperm ≤ 0.006). Six loci of the MMP9 gene, which are associated with H. pylori-positive GU, and 65 SNPs linked to them manifest significant epigenetic effects, have pronounced eQTL (17 genes) and sQTL (6 genes) values., Conclusion: SNPs of the MMP9 were associated with H. pylori-positive GU but not with H. pylori-negative GU in Caucasians of Central Russia., Competing Interests: The authors have declared that no competing interests exist.

This study aimed to determine possible association of eight polymorphisms of seven MMP genes with essential hypertension (EH) in a Caucasian population of Central Russia. Eight SNPs of the MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, and MMP12 genes and their gene-gene (epistatic) interactions were analyzed for association with EH in a cohort of 939 patients and 466 controls using logistic regression and assuming additive, recessive, and dominant genetic models. The functional significance of the polymorphisms associated with EH and 114 variants linked to them (r 2  ≥ 0.8) was analyzed in silico. Allele G of rs11568818 MMP7 was associated with EH according to all three genetic models (OR = 0.58-0.70, p perm  = 0.01-0.03). The above eight SNPs were associated with the disorder within 12 most significant epistatic models (OR = 1.49-1.93, p perm  < 0.02). Loci rs1320632 MMP8 and rs11568818 MMP7 contributed to the largest number of the models (12 and 10, respectively). The EH-associated loci and 114 SNPs linked to them had non-synonymous, regulatory, and eQTL significance for 15 genes, which contributed to the pathways related to metalloendopeptidase activity, collagen degradation, and extracellular matrix disassembly. In summary, eight studied SNPs of MMPs genes were associated with EH in the Caucasian population of Central 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 perm  ≤ 0.006). Fourteen SNP were associated with the disease within 12 most significant models of gene-gene interactions (P perm  ≤ 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 FDR  = 0.001) and responses to endogenous stimuli (fold enrichment 16.01, P FDR  = 0.027)., Conclusions: Sixteen SNP for age at menarche out of the 52 studied were associated with endometriosis., (Copyright © 2020 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

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 2 ≥0.6) were analyzed for their functional significance in silico., Results: Haplotype TG of loci rs2234693-rs9340799ESR1 (OR = 1.94, р perm = 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 2 ≥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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships which have, or could be perceived to have, influenced the work reported in this article., (Copyright © 2020 Elsevier B.V. All rights reserved.)

To study the interaction of polymorphic markers of matrix metalloproteinases (MMP) and chronic stress in the development of stroke associated with hypertension. MATERIAL AND METHODS: A total of 830 patients, including 303 patients with ischemic stroke associated with essential hypertension (EH) and 527 patients with EH without stroke, were examined. The study of metalloproteinases SNP was carried out using real-time PCR. The functional significance and influence of polymorphic loci on gene expression was studied using of HaploReg (v4.1) (http://archive.broadinstitute.org) and GTEx-portal (http://www.gtexportal.org). RESULTS AND CONCLUSION: An association of the genotype GG (rs11568818) of MMP7 with a high risk of stroke in patients exposed to regular stress (OR=1.71) was observed. It was found that allele 5A and genotype 5A/5A (rs3025058) of MMP3 had a protective effect on the development of stroke in patients without regular stress in the anamnesis (OR=0.73 and OR=0.60, respectively). Those SNPs are localized in the region of histone proteins H3K4me1 and H3K4me3, in the region of hypersensitivity to DNase-1, in the region of binding of regulatory proteins and transcription factors. The polymorphic locus rs11568818 is associated with the expression level of MMP7.

It has been proposed that the Delta32 mutation in the chemokine receptor gene, inducing resistance to HIV-1 and, probably, to other virus infections, has undergone selection in historical times. The frequency of this mutant allele has changed rapidly both in time (during the last two millennia) and in space (across Eurasia). We compiled a global database on Delta32 allele frequencies in 300 populations. Nearly 10 percent of them are our data on 35 East European populations analyzed here for the first time. A detailed map of Delta32 frequency distribution was constructed and statistically analysed. We found a linearly decreasing trend with a maximum in areas surrounding the Baltic and White seas. Significant correlations with ground surface temperature were revealed. However, compared with our previous results, these correlations diminished, indicating that the influence of climate on Delta32 distribution was, if anything at all, indirect. The proposed scenario includes: i) arise and initial spread of the mutation among Uralic-speaking populations; ii) a frequency increase in northeastern Europe as a result of selection and/or genetic drift; iii) secondary spread (with selection continued) due to gene flow and the migrations of northern Europeans across the globe.