Sex-Hormone-Binding Globulin Gene Polymorphisms and Breast Cancer Risk in Caucasian Women of Russia.

In our work, the associations of GWAS (genome-wide associative studies) impact for sex-hormone-binding globulin (SHBG)-level SNPs with the risk of breast cancer (BC) in the cohort of Caucasian women of Russia were assessed. The work was performed on a sample of 1498 women (358 BC patients and 1140 control (non BC) subjects). SHBG correlated in previously GWAS nine polymorphisms such as rs780093 GCKR, rs17496332 PRMT6, rs3779195 BAIAP2L1, rs10454142 PPP1R21, rs7910927 JMJD1C, rs4149056 SLCO1B1, rs440837 ZBTB10, rs12150660 SHBG, and rs8023580 NR2F2 have been genotyped. BC risk effects of allelic and non-allelic SHBG-linked gene SNPs interactions were detected by regression analysis. The risk genetic factor for BC developing is an SHBG-lowering allele variant C rs10454142 PPP1R21 ([additive genetic model] OR = 1.31; 95%CI = 1.08-1.65; pperm = 0.024; power = 85.26%), which determines 0.32% of the cancer variance. Eight of the nine studied SHBG-related SNPs have been involved in cancer susceptibility as part of nine different non-allelic gene interaction models, the greatest contribution to which is made by rs10454142 PPP1R21 (included in all nine models, 100%) and four more SNPs-rs7910927 JMJD1C (five models, 55.56%), rs17496332 PRMT6 (four models, 44.44%), rs780093 GCKR (four models, 44.44%), and rs440837 ZBTB10 (four models, 44.44%). For SHBG-related loci, pronounced functionality in the organism (including breast, liver, fibroblasts, etc.) was predicted in silico, having a direct relationship through many pathways with cancer pathophysiology. In conclusion, our results demonstrated the involvement of SHBG-correlated genes polymorphisms in BC risk in Caucasian women in Russia.

Maternal Age at Menarche Genes Determines Fetal Growth Restriction Risk.

We aimed to explore the potential link of maternal age at menarche (mAAM) gene polymorphisms with risk of the fetal growth restriction (FGR). This case (FGR)-control (FGR free) study included 904 women (273 FGR and 631 control) in the third trimester of gestation examined/treated in the Departments of Obstetrics. For single nucleotide polymorphism (SNP) multiplex genotyping, 50 candidate loci of mAAM were chosen. The relationship of mAAM SNPs and FGR was appreciated by regression procedures (logistic/model-based multifactor dimensionality reduction [MB-MDR]) with subsequent in silico assessment of the assumed functionality pithy of FGR-related loci. Three mAAM-appertain loci were FGR-linked to genes such as KISS1 (rs7538038) (effect allele G-odds ratio (OR)allelic = 0.63/pperm = 0.0003; ORadditive = 0.61/pperm = 0.001; ORdominant = 0.56/pperm = 0.001), NKX2-1 (rs999460) (effect allele A-ORallelic = 1.37/pperm = 0.003; ORadditive = 1.45/pperm = 0.002; ORrecessive = 2.41/pperm = 0.0002), GPRC5B (rs12444979) (effect allele T-ORallelic = 1.67/pperm = 0.0003; ORdominant = 1.59/pperm = 0.011; ORadditive = 1.56/pperm = 0.009). The haplotype ACA FSHB gene (rs555621*rs11031010*rs1782507) was FRG-correlated (OR = 0.71/pperm = 0.05). Ten FGR-implicated interworking models were founded for 13 SNPs (pperm ≤ 0.001). The rs999460 NKX2-1 and rs12444979 GPRC5B interplays significantly influenced the FGR risk (these SNPs were present in 50% of models). FGR-related mAAM-appertain 15 polymorphic variants and 350 linked SNPs were functionally momentous in relation to 39 genes participating in the regulation of hormone levels, the ovulation cycle process, male gonad development and vitamin D metabolism. Thus, this study showed, for the first time, that the mAAM-appertain genes determine FGR risk.

Risk Effects of rs1799945 Polymorphism of the HFE Gene and Intergenic Interactions of GWAS-Significant Loci for Arterial Hypertension in the Caucasian Population of Central Russia.

The aim of this case-control replicative study was to investigate the link between GWAS-impact for arterial hypertension (AH) and/or blood pressure (BP) gene polymorphisms and AH risk in Russian subjects (Caucasian population of Central Russia). AH (n = 939) and control (n = 466) cohorts were examined for ten GWAS AH/BP risk loci. The genotypes/alleles of these SNP and their combinations (SNP-SNP interactions) were tested for their association with the AH development using a logistic regression statistical procedure. The genotype GG of the SNP rs1799945 (C/G) HFE was strongly linked with an increased AH risk (ORrecGG = 2.53; 95%CIrecGG1.03-6.23; ppermGG = 0.045). The seven SNPs such as rs1173771 (G/A) AC026703.1, rs1799945 (C/G) HFE, rs805303 (G/A) BAG6, rs932764 (A/G) PLCE1, rs4387287 (C/A) OBFC1, rs7302981 (G/A) CERS5, rs167479 (T/G) RGL3, out of ten regarded loci, were related with AH within eight SNP-SNP interaction models (<0.001 ≤ pperm-interaction ≤ 0.047). Three polymorphisms such as rs8068318 (T/C) TBX2, rs633185 (C/G) ARHGAP42, and rs2681472 (A/G) ATP2B1 were not linked with AH. The pairwise rs805303 (G/A) BAG6-rs7302981 (G/A) CERS5 combination was a priority in determining the susceptibility to AH (included in six out of eight SNP-SNP interaction models [75%] and described 0.82% AH entropy). AH-associated variants are conjecturally functional for 101 genes involved in processes related to the immune system (major histocompatibility complex protein, processing/presentation of antigens, immune system process regulation, etc.). In conclusion, the rs1799945 polymorphism of the HFE gene and intergenic interactions of BAG6, CERS5, AC026703.1, HFE, PLCE1, OBFC1, RGL3 have been linked with AH risky in the Caucasian population of Central Russia.

Sex-Specific Features of the Correlation between GWAS-Noticeable Polymorphisms and Hypertension in Europeans of Russia.

The aim of the study was directed at studying the sex-specific features of the correlation between genome-wide association studies (GWAS)-noticeable polymorphisms and hypertension (HTN). In two groups of European subjects of Russia (n = 1405 in total), such as men (n = 821 in total: n = 564 HTN, n = 257 control) and women (n = 584 in total: n = 375 HTN, n = 209 control), the distribution of ten specially selected polymorphisms (they have confirmed associations of GWAS level with blood pressure (BP) parameters and/or HTN in Europeans) has been considered. The list of studied loci was as follows: (PLCE1) rs932764 A > G, (AC026703.1) rs1173771 G > A, (CERS5) rs7302981 G > A, (HFE) rs1799945 C > G, (OBFC1) rs4387287 C > A, (BAG6) rs805303 G > A, (RGL3) rs167479 T > G, (ARHGAP42) rs633185 C > G, (TBX2) rs8068318 T > C, and (ATP2B1) rs2681472 A > G. The contribution of individual loci and their inter-locus interactions to the HTN susceptibility with bioinformatic interpretation of associative links was evaluated separately in men's and women's cohorts. The men-women differences in involvement in the disease of the BP/HTN-associated GWAS SNPs were detected. Among women, the HTN risk has been associated with HFE rs1799945 C > G (genotype GG was risky; ORGG = 11.15 ppermGG = 0.014) and inter-locus interactions of all 10 examined SNPs as part of 26 intergenic interactions models. In men, the polymorphism BAG6 rs805303 G > A (genotype AA was protective; ORAA = 0.30 ppermAA = 0.0008) and inter-SNPs interactions of eight loci in only seven models have been founded as HTN-correlated. HTN-linked loci and strongly linked SNPs were characterized by pronounced polyvector functionality in both men and women, but at the same time, signaling pathways of HTN-linked genes/SNPs in women and men were similar and were represented mainly by immune mechanisms. As a result, the present study has demonstrated a more pronounced contribution of BP/HTN-associated GWAS SNPs to the HTN susceptibility (due to weightier intergenic interactions) in European women than in men.

Sex Hormone Candidate Gene Polymorphisms Are Associated with Endometriosis.

The present study was designed to examine whether sex hormone polymorphisms proven by GWAS are associated with endometriosis risk. Unrelated female participants totaling 1376 in number (395 endometriosis patients and 981 controls) were recruited into the study. Nine single-nucleotide polymorphisms (SNPs) which GWAS correlated with circulating levels of sex hormones were genotyped using a TaqMan allelic discrimination assay. FSH-lowering, and LH- and testosterone-heightening polymorphisms of the FSHB promoter (allelic variants A rs11031002 and C rs11031005) exhibit a protective effect for endometriosis (OR = 0.60-0.68). By contrast, the TT haplotype loci that were GWAS correlated with higher FSH levels and lower LH and testosterone concentrations determined an increased risk for endometriosis (OR = 2.03). Endometriosis-involved epistatic interactions were found between eight loci of sex hormone genes (without rs148982377 ZNF789) within twelve genetic simulation models. In silico examination established that 8 disorder-related loci and 80 proxy SNPs are genome variants affecting the expression, splicing, epigenetic and amino acid conformation of the 34 genes which enrich the organic anion transport and secondary carrier transporter pathways. In conclusion, the present study showed that sex hormone polymorphisms proven by GWAS are associated with endometriosis risk and involved in the molecular pathophysiology of the disease due to their functionality.

Matrix Metalloproteinase Gene Polymorphisms Are Associated with Breast Cancer in the Caucasian Women of Russia.

We conducted this study to explore the association between matrix metalloproteinase (MMP) gene polymorphisms and breast cancer (BC) risk in the Caucasian women of Russia. In total, 358 affected (BC) and 746 unaffected (cancer-free) women were included in this case-control retrospective study. From BC-related genes in previous studies, ten single nucleotide polymorphisms (SNPs) in five MMP genes (MMP1, 2, 3, 8, 9) were genotyped. The BC risk was calculated by logistic regression (to evaluate the SNPs' independent effects) and model-based multifactor dimensionality reduction (MB-MDR) (to identify SNP−SNP interactions) methods. The allelic variants' distribution of c.836 A > G (rs17576) and c. 1721 C > G (rs2250889) MMP9 was significantly different between BC and cancer-free women: for G minor alleles, these SNPs manifested disorder protective effects (OR 0.82 and OR 0.67−0.71, respectively, pperm ≤ 0.035). Eleven haplotypes of six SNPs MMP9 were involved in BC risk (nine haplotypes) and protective (two haplotypes) effects. All 10 SNPs of the MMP genes examined were associated with BC within the 13 SNP−SNP interaction simulated models, with a pivotal role of the two-locus (rs17577 × rs3918242) MMP9 epistatic interaction (defined as 1.81% BC entropy within more than 60% of the genetic models). Under in silico bioinformatics, BC susceptibility MMP polymorphic loci are located in functionally active genome regions and impact genes expression and splicing "regulators" in the mammary gland. The biological pathways of BC MMP candidate genes are mainly realized due to metalloendopeptidase activity and extracellular matrix organization (structure, disassembly, metabolic process, etc.). In conclusion, our data show that MMP gene polymorphisms are related to BC susceptibility in the Caucasian women of Russia.

LOXL1 gene polymorphism candidates for exfoliation glaucoma are also associated with a risk for primary open-angle glaucoma in a Caucasian population from central Russia.

Purpose: This study was aimed to replicate the previously reported associations of the three LOXL1 gene polymorphisms with exfoliation glaucoma (XFG) and to analyze these genetic variants for their possible contribution to primary open-angle glaucoma (POAG) in Caucasians from central Russia. Methods: In total, 932 participants were recruited for the study, including 328 patients with XFG, 208 patients with POAG, and 396 controls. The participants were of Russian ethnicity (self-reported) and born in Central Russia. They were genotyped at three single nucleotide polymorphisms (SNPs) of the LOXL1 gene (rs2165241, rs4886776, and rs893818). The association was analyzed using logistic regression. Results: Allele C of rs2165241 was associated with a decreased risk of XFG (odds ratio [OR] =0.27-0.45, pperm ≤5*10-6) and POAG (OR=0.35-0.47, рperm≤0.001), and allele A of rs4886776 and rs893818 were associated with a lower risk of XFG (OR=0.53-0.57, рperm≤0.001). Haplotype TGG of loci rs2165241-rs4886776-rs893818 was associated with an elevated risk of XFG (OR=2.23, рperm=0.001) and POAG (OR=2.01, рperm=0.001), haplotype CGG was also associated with a decreased risk of XFG (OR=0.45, рperm=0.001) and POAG (OR=0.35, рperm=0.001). Haplotype CAA was associated with a decreased risk of XFG only (OR=0.50, рperm=0.001). Conclusions: Polymorphisms rs2165241, rs4886776, and rs893818 of the LOXL1 gene showed association with XFG and POAG in a Caucasian sample from central Russia.

Novel Data about Association of the Functionally Significant Polymorphisms of the MMP9 Gene with Exfoliation Glaucoma in the Caucasian Population of Central Russia.

AIM: This study aimed to investigate the role of functionally significant polymorphisms of the MMP1, MMP3, and MMP9 genes in the development of exfoliation glaucoma (XFG) in the Caucasian population of Central Russia. METHODS: The study sample consisted of 724 participants, including 328 patients with XFG and 396 individuals in the control group. The participants were of Russian ethnicity (self-reported) born in Central Russia. The participants were genotyped at 8 functionally significant polymorphisms of the MMP genes (rs3918242, rs3918249, rs17576, rs3787268, rs2250889, rs17577 MMP9, rs679620 MMP3, and rs1799750 MMP1). The association analysis was performed using logistic regression. Two polymorphisms, which were associated with XFG, and 12 polymorphisms linked to them (r2 ≥ 0.8) were analyzed for their functional significance in silico. RESULTS: Allele C of rs3918249 MMP9 was associated with XFG according to the additive model (OR = 0.75, 95% CI: 0.56-0.93, pperm = 0.015), and allele G of the rs2250889 MMP9 locus was associated with XFG according to the additive (OR = 1.59, 95% CI: 1.10-2.29, pperm = 0.013) and dominant (OR = 1.68, 95% CI: 1.11-2.56, pperm = 0.016) models. Two XFG-associated loci of the MMP9 gene and 12 SNPs linked to them had a significant regulatory potential (they are located in the evolutionarily conserved regions, promoter and enhancer histone marks, the DNAase-hypersensitivity regions, a region binding to regulatory protein, and a region of regulatory motifs) and may influence the expression of 13 genes and alternative splicing of 4 genes in various tissues and organs related to the pathogenesis of XFG. CONCLUSION: Allele C rs3918249 MMP9 decreased risk for XFG (OR = 0.75), and allele G of the rs2250889 MMP9 locus increased risk for XFG (OR = 1.59-1.68) in the Caucasian population of Central Russia.

Candidate genes for age at menarche are associated with endometriosis.

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, Pperm ≤ 0.006). Fourteen SNP were associated with the disease within 12 most significant models of gene-gene interactions (Pperm ≤ 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, PFDR = 0.001) and responses to endogenous stimuli (fold enrichment 16.01, PFDR = 0.027). CONCLUSIONS: Sixteen SNP for age at menarche out of the 52 studied were associated with endometriosis.

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

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.

Obesity-Dependent Association of the rs10454142 PPP1R21 with Breast Cancer.

The purpose of this work was to find a link between the breast cancer (BC)-risk effects of sex hormone-binding globulin (SHBG)-associated polymorphisms and obesity. The study was conducted on a sample of 1498 women (358 BC; 1140 controls) who, depending on the presence/absence of obesity, were divided into two groups: obese (119 BC; 253 controls) and non-obese (239 BC; 887 controls). Genotyping of nine SHBG-associated single nucleotide polymorphisms (SNP)-rs17496332 PRMT6, rs780093 GCKR, rs10454142 PPP1R21, rs3779195 BAIAP2L1, rs440837 ZBTB10, rs7910927 JMJD1C, rs4149056 SLCO1B1, rs8023580 NR2F2, and rs12150660 SHBG-was executed, and the BC-risk impact of these loci was analyzed by logistic regression separately in each group of obese/non-obese women. We found that the BC-risk effect correlated by GWAS with the SHBG-level polymorphism rs10454142 PPP1R21 depends on the presence/absence of obesity. The SHBG-lowering allele C rs10454142 PPP1R21 has a risk value for BC in obese women (allelic model: CvsT, OR = 1.52, 95%CI = 1.10-2.11, and pperm = 0.013; additive model: CCvsTCvsTT, OR = 1.71, 95%CI = 1.15-2.62, and pperm = 0.011; dominant model: CC + TCvsTT, OR = 1.95, 95%CI = 1.13-3.37, and pperm = 0.017) and is not associated with the disease in women without obesity. SNP rs10454142 PPP1R21 and 10 proxy SNPs have adipose-specific regulatory effects (epigenetic modifications of promoters/enhancers, DNA interaction with 51 transcription factors, eQTL/sQTL effects on five genes (PPP1R21, RP11-460M2.1, GTF2A1L, STON1-GTF2A1L, and STON1), etc.), can be "likely cancer driver" SNPs, and are involved in cancer-significant pathways. In conclusion, our study detected an obesity-dependent association of the rs10454142 PPP1R21 with BC in women.

Polymorphism rs143384 GDF5 reduces the risk of knee osteoarthritis development in obese individuals and increases the disease risk in non-obese population.

BACKGROUND: We investigated the effect of obesity on the association of genome-wide associative studies (GWAS)-significant genes with the risk of knee osteoarthritis (KOA). METHODS: All study participants (n = 1,100) were divided into 2 groups in terms of body mass index (BMI): BMI ≥ 30 (255 KOA patients and 167 controls) and BMI < 30 (245 KOA and 433 controls). The eight GWAS-significant KOA single nucleotide polymorphisms (SNP) of six candidate genes, such as LYPLAL1 (rs2820436, rs2820443), SBNO1 (rs1060105, rs56116847), WWP2 (rs34195470), NFAT5 (rs6499244), TGFA (rs3771501), GDF5 (rs143384), were genotyped. Logistic regression analysis (gPLINK online program) was used for SNPs associations study with the risk of developing KOA into 2 groups (BMI ≥ 30 and BMI < 30) separately. The functional effects of KOA risk loci were evaluated using in silico bioinformatic analysis. RESULTS: Multidirectional relationships of the rs143384 GDF5 with KOA in BMI-different groups were found: This SNP was KOA protective locus among individuals with BMI ≥ 30 (OR 0.41 [95%CI 0.20-0.94] recessive model) and was disorder risk locus among individuals with BMI < 30 (OR 1.32 [95%CI 1.05-1.65] allele model, OR 1.44 [95%CI 1.10-1.86] additive model, OR 1.67 [95%CI 1.10-2.52] dominant model). Polymorphism rs143384 GDF5 manifested its regulatory effects in relation to nine genes (GDF5, CPNE1, EDEM2, ERGIC3, GDF5OS, PROCR, RBM39, RPL36P4, UQCC1) in adipose tissue, which were involved in the regulation of pathways of apoptosis of striated muscle cells. CONCLUSIONS: In summary, the effect of obesity on the association of the rs143384 GDF5 with KOA was shown: the "protective" value of this polymorphism in the BMI ≥ 30 group and the "risk" meaning in BMI < 30 cohort.

Maternal Age at Menarche Gene Polymorphisms Are Associated with Offspring Birth Weight.

In this study, the association between maternal age at menarche (AAM)-related polymorphisms and offspring birth weight (BW) was studied. The work was performed on a sample of 716 pregnant women and their newborns. All pregnant women underwent genotyping of 50 SNPs of AAM candidate genes. Regression methods (linear and Model-Based Multifactor Dimensionality Reduction (MB-MDR)) with permutation procedures (the indicator pperm was calculated) were used to identify the correlation between SNPs and newborn weight (transformed BW values were analyzed) and in silico bioinformatic examination was applied to assess the intended functionality of BW-associated loci. Four AAM-related genetic variants were BW-associated including genes such as POMC (rs7589318) (ßadditive = 0.202/pperm = 0.015), KDM3B (rs757647) (ßrecessive = 0.323/pperm = 0.005), INHBA (rs1079866) (ßadditive = 0.110/pperm = 0.014) and NKX2-1 (rs999460) (ßrecessive = -0.176/pperm = 0.015). Ten BW-significant models of interSNPs interactions (pperm ≤ 0.001) were identified for 20 polymorphisms. SNPs rs7538038 KISS1, rs713586 RBJ, rs12324955 FTO and rs713586 RBJ-rs12324955 FTO two-locus interaction were included in the largest number of BW-associated models (30% models each). BW-associated AAM-linked 22 SNPs and 350 proxy loci were functionally related to 49 genes relevant to pathways such as the hormone biosynthesis/process and female/male gonad development. In conclusion, maternal AMM-related genes polymorphism is associated with the offspring BW.

Functionally significant polymorphisms of the MMP9 gene are associated with primary open-angle glaucoma in the population of Russia.

PURPOSE: The aim of this study was to investigate the role of functionally significant loci of the matrix metalloproteinases genes 1, 3, 9 (MMP1, MMP3, and MMP9) in the development of primary open-angle glaucoma (POAG) in Caucasians of the Central region of Russia. METHODS: In total 604 participants were recruited for the study, including 208 patients with POAG and 396 healthy controls. They were genotyped at eight single nucleotide polymorphisms (SNPs) of the three MMP genes. The association was analyzed using logistic and log-linear regression. POAG-associated loci and their proxies were in silico assessed for their functional prediction. RESULTS: Variant allele G*rs2250889 of MMP9 was significantly associated with higher risk of POAG (ORcov = 1.57-1.71). Haplotype CCA [rs3918242-rs3918249-rs17576] of the MMP9 gene was associated with lower risk of POAG (ORcov = 0.33). Allele А*rs3787268 of MMP9 was associated with the low intraocular pressure in the POAG patients (ßcov = -0.176 - -0.272), and so were haplotypes AA [rs17576-rs3787268] (ßcov = -0.577) and AAC [rs17576-rs3787268- rs2250889] (ßcov = -0.742) of the same gene, whereas allele 2G*rs1799750 of MMP1 was associated with the earlier onset of the disease (ßcov = -0.112 - -0.218). In silico analysis of the polymorphisms suggested the functionality of POAG-associated SNPs and their proxies (epigenetic potential, expression and alternative splicing effects for several genes). CONCLUSIONS: The MMP9 gene polymorphisms are associated with POAG and intraocular pressure in POAG patients; rs1799750 of MMP1 was associated with the earlier age of manifestation of the disease symptoms.

Polymorphisms of the filaggrin gene are associated with atopic dermatitis in the Caucasian population of Central Russia.

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, pperm = 0.002 and 1.45, pperm = 0.011 respectively), additive (ORs being 1.69, pperm = 0.004 and 1.47, pperm = 0.011 respectively) and dominant (ORs being 1.79, pperm = 0.004 and 1.63, pperm = 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 (pperm = 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.

Polymorphisms of hypertension susceptibility genes as a risk factors of preeclampsia in the Caucasian population of central Russia.

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.

Effects of Pre-Pregnancy Overweight/Obesity on the Pattern of Association of Hypertension Susceptibility Genes with Preeclampsia.

The aim of this study was to explore the effects of pre-pregnancy overweight/obesity on the pattern of association of hypertension susceptibility genes with preeclampsia (PE). Ten single-nucleotide polymorphisms (SNPs) of the 10 genome-wide association studies (GWAS)-significant hypertension/blood pressure (BP) candidate genes were genotyped in 950 pregnant women divided into two cohorts according to their pre-pregnancy body mass index (preBMI): preBMI ≥ 25 (162 with PE and 159 control) and preBMI < 25 (290 with PE and 339 control). The PLINK software package was utilized to study the association (analyzed four genetic models using logistic regression). The functionality of PE-correlated loci was analyzed by performing an in silico database analysis. Two SNP hypertension/BP genes, rs805303 BAG6 (OR: 0.36−0.66) and rs167479 RGL3 (OR: 1.86), in subjects with preBMI ≥ 25 were associated with PE. No association between the studied SNPs and PE in the preBMI < 25 group was determined. Further analysis showed that two PE-associated SNPs are functional (have weighty eQTL, sQTL, regulatory, and missense values) and could be potentially implicated in PE development. In conclusion, this study was the first to discover the modifying influence of overweight/obesity on the pattern of association of GWAS-significant hypertension/BP susceptibility genes with PE: these genes are linked with PE in preBMI ≥ 25 pregnant women and are not PE-involved in the preBMI < 25 group.

The Modifying Effect of Obesity on the Association of Matrix Metalloproteinase Gene Polymorphisms with Breast Cancer Risk.

Objective: We investigated the possible modifying effect of obesity on the association of matrix metalloproteinase (MMP) gene polymorphisms with breast cancer (BC) risk. Methods: A total of 1104 women divided into two groups according to their body mass index (BMI): BMI ≥ 30 (119 BC, and 190 control) and BMI < 30 (239 BC, and 556 control) were genotyped for specially selected (according to their association with BC in the previous study) 10 single-nucleotide polymorphisms (SNP) of MMP1, 2, 3, 8, and 9 genes. Logistic regression association analysis was performed in each studied group of women (with/without obesity). Functional annotation of BC-correlated MMP polymorphic variants was analyzed by in silico bioinformatics. Results: We observed significant differences in the involvement of MMP SNPs in BC in obese and non-obese women. Polymorphic loci MMP9 (c.836 A > G (rs17576) and c. 1721 C > G (rs2250889)) were BC-protective factors in obese women (OR 0.71, allelic model, and OR 0.55, additive model, respectively). Genotypes TT MMP2 (c.-1306 C > T,rs243865) and AA MMP9 (c. 1331-163 G > A,rs3787268) determined BC susceptibility in non-obese women (OR 0.31, and OR 2.36, respectively). We found in silico substantial multidirectional influences on gene expression in adipose tissue BC-related polymorphic loci: BC risk allele A-rs3787268 in non-obese women is associated with low expression NEURL2, PLTP, RP3-337O18.9, SPATA25, and ZSWIM1, whereas BC risk allele A-rs17576 in obese women is associated with high expression in the same genes in visceral and/or subcutaneous adipose. Conclusions: our study indicated that obesity has a significant modifying effect on the association of MMP genes with BC risk in postmenopausal women.

Maternal polymorphic loci of rs1979277 serine hydroxymethyl transferase and rs1805087 5-methylenetetrahydrofolate are correlated with the development of fetal growth restriction: A case-control study.

BACKGROUND: Key reactions in folate-mediated single-carbon metabolism are regulated by folate cycle enzymes. Violations of the folate cycle may be associated with the occurrence of fetal growth restriction (FGR) in pregnant women. OBJECTIVE: To study the relationship between polymorphisms of folate cycle genes in the mother with the development of FGR. MATERIALS AND METHODS: In this case-control study, 122 pregnant women with FGR and 243 pregnant women with normal newborn weight were enrolled. The polymorphic loci of folate cycle genes including rs1805087 5-methylenetetrahydrofolate (MTR) and rs1979277 serine hydroxymethyl transferase (SHMT1) were examined. The study of polymorphisms was carried out through the TaqMan probe detection method using polymerase chain reaction. Logistic regression was used to analyze the associations of the polymorphisms. RESULTS: It was established that the T allele rs1979277 of the SHMT1 gene was correlated with the development of FGR within the framework of the allelic (OR = 1.67, 95% CI 1.20-2.33, p perm < 0.01), additive (OR = 1.69, 95% CI 1.20-2.37, p perm < 0.01), dominant (OR = 1.81, 95% CI 1.15-2.87, p perm = 0.01) and recessive (OR = 2.34, 95% CI 1.15-4.73, p perm = 0.01) models. The association of the G rs1805087 allele of the MTR gene with the occurrence of FGR was also identified following the recessive model (OR = 3.01, 95% CI 1.05-8.68, p perm = 0.04). CONCLUSION: Our results indicated that maternal polymorphic loci rs1979277 SHMT1 and rs1805087 MTR may be associated with the development of FGR.

Association of the functionally significant polymorphisms of the MMP9 gene with H. pylori-positive gastric ulcer in the Caucasian population of Central Russia.

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.