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Introduction: The study was designed to assess the effects of hypertension (HT) susceptibility genes polymorphisms in the development of preeclampsia (PE) in Caucasians from Central Russia.Methods: PE patients (n = 452) and women control group (n = 498) were genotyped for 10 polymorphisms of HT/blood pressure (BP) susceptibility genes (according to the previously published GWAS in Caucasian populations) including AC026703.1 (rs1173771), HFE (rs1799945), BAG6 (rs805303), PLCE1 (rs932764), OBFC1 (rs4387287), ARHGAP42 (rs633185), CERS5 (rs7302981), ATP2B1 (rs2681472), TBX2 (rs8068318) and RGL3 (rs167479). A logistic regression method was applied to search for associations between SNPs and PE. The relationship between SNP-SNP interactions and PE risk was analyzed by performing MB-MDR.Results: The rs1799945 gene in HFE significantly independently increased the risk of developing PE (OR = 2.24) and rs805303 in BAG6 was associated with a reduced risk in the occurrence of PE (OR = 0.55-0.78). Among the 10 SNPs examined, nine SNPs were associated with PEs within the 10 most significant SNP-SNP interaction models. Loci rs7302981 CERS5, rs805303 BAG6 and rs932764 PLCE1 contributed to the largest number of epistatic models (50% or more).Discussion: The present study is the first to report an association between polymorphisms of HT/BP susceptibility genes important for GWAS and the risk of PE in Caucasians from Central Russia. Our pathway-based functional annotation of the PE risk variants highlights the potential regulatory function (epigenetic/eQTL/sQTL/non-synonymous) that nine genetic risk markers and their 115 highly correlated variants exert on 155 genes. The study shows that these genes may function cooperatively in key signaling pathways in PE biology. [ABSTRACT FROM AUTHOR]

Are the candidate genes for age at menarche associated with a risk of endometriosis? 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. 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). Sixteen SNP for age at menarche out of the 52 studied were associated with endometriosis. [ABSTRACT FROM AUTHOR]

Abstract 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 perm = 0.005). In total 12 two-, three-, and four-locus models of gene-gene interactions were determined as contributing to AAM (p perm ≤ 0.006). Nine of the 14 AAM-associated SNPs are also associated with height and BMI (p perm ≤ 0.003). Among 14 AAM-associated SNPs (a priori all having regulatory significance), the highest regulatory potential was determined for rs4633 COMT, rs2164808 POMC , rs2252673 INSR , 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 bonf = 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. Highlights • The rs6438424 3q13.32 was associated with age at menarche in Russian women. • The 14 SNPs manifest this association through gene-gene interactions. • Nine of the 14 AAM-associated SNPs are also associated with height and BMI. • The highest regulatory potential was determined for 5 SNPs and 11 SNPs are cis- eQTL. • The neuropeptide-encoding genes were overrepresented among the AAM-associated genes. [ABSTRACT FROM AUTHOR]

• Locus rs11031010 FSHB was associated with endometrial hyperplasia (EH). • Haplotype GAA of loci rs555621-rs11031010-rs1782507 FSHB were associated with EH. • 17 SNPs were associated with EH within 12 models of intergenic interactions. • 9 loci involved in 14 models of gene-environment interactions were EH-associated. • EH-associated SNPs play roles in the pathways related to hormone-mediated signaling. To study associations candidate genes for age at menarche with a risk of endometrial hyperplasia (EH). 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 (r2 ≥ 0.8) were analyzed in silico for their functional significance. 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 perm = 0.001) and additive (OR = 0.67, p perm = 0.002) models. Haplotype GAA of loci rs555621-rs11031010-rs1782507 FSHB were associated with the EH (OR = 0.66, p perm = 0.007). Seventeen loci were associated with EH within 12 most significant models of intergenic interactions (p perm ≤ 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). Candidate genes for age at menarche are associated with endometrial hyperplasia. [ABSTRACT FROM AUTHOR]

• Alleles A rs3126085 and C rs12144049 FLG were associated with a higher risk of AD. • Nine SNPs of the FLG gene were associated with AD within 30 haplotypes. • Seven SNPs showed interlocus interaction effects for AD within ten epistatic models. • AD risk variants and their proxies may produce functional effects on 38 genes. • The AD candidate genes are involved in more than twenty pathways. 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. [ABSTRACT FROM AUTHOR]

Abstract: Chronic glomerulonephritis (CGN) is one of the most severe kidney diseases. Genes of vascular reactivity are thought to play an important role in development and progression of CGN. In this study, we analyzed association of genes of vascular homeostasis with hypertension and renal survival of CGN patients. The study sample included 238 patients with CGN and 304 healthy subjects of population control. Ten polymorphisms of ten genes of vascular homeostasis were genotyped through polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP) analysis and TaqMan assays. Association of the genotypes with renal survival was analyzed by the Kaplan–Meier estimator. Genotypes 311SC and 311SS of the PON2 gene, (−1166)AC and (−1166)CC of the AGTR1 gene, (+46)AA of the ADRB2 gene, and 198KK and 198KN of the EDN1 gene were associated with decreased rate of renal survival of the patients. Polymorphisms S311C PON2, (−1166)A/C AGTR1, (+46)G/A ADRB2, and K198N EDN1 were associated with the accelerated decline in kidney function in the CGN patients. [Copyright &y& Elsevier]