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.

Filaggrin gene polymorphisms are associated with atopic dermatitis in women but not in men in the Caucasian population of Central Russia.

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.

Significant interpopulation differentiation at candidate loci may underlie ethnic disparities in the prevalence of uterine fibroids.

Uterine fibroids (UF) are a significant health problem bearing a substantial economic burden. The prevalence of the disease is disparate in populations of different ethnic ancestry being the highest in Africans. This study analysed worldwide population differentiation at the genomewide association study (GWAS)-significant UF-associated loci to test a hypothesis that population structure at risk loci might underlie the observed interethnic disparities in the prevalence. In total, 28 single-nucleotide polymorphism (SNP) with the GWAS significance for European Caucasians were analysed in female cohorts of the European, admixed American, African, east Asian, and South Asian populations retrieved from the 1000 Genomes Project data. Common population genetic structure estimators, polygenic risk score (unweighted and weighted) were computed. According to the Fisher's exact test, the populations were significantly differentiated (P<< 10-5) at the UF risk loci. The polygenic risk scores did not differ significantly when calculated across all loci. However, they differed when only loci with risk alleles showing the enrichment/depletion patterns correlating with the documented ethnicity-specific risk of the disease were included in the calculation. The population genetic structure at the UF risk loci is apparently a significant factor underlying the observed between-ethnic disparities in the disease prevalence.

Polymorphisms of the TNF, LTA, and TNFRSF1B genes are associated with onsets of menarche and menopause in US women of European ancestry.

BACKGROUND: The TNF, LTA and TNFRSF1B genes have been implicated in various traits related to menarche and menopause. AIM: To analyse the TNF, LTA and TNFRSF1B genes for their association with ages at menarche (AM) and natural menopause (ANM). SUBJECTS AND METHODS: The study sample consisted of 314 unrelated females of European ancestry. Twenty SNPs located in and near the genes were analysed using various statistical methods. In addition, the functional significance of the loci associated with AM and ANM was analysed in silico. RESULTS: Locus rs2229094 of the LTA gene was associated with AM according to the additive (ß = -0.295, pperm = 0.016) and recessive (ß = -0.940, pperm = 0.016) genetic models. Haplotype GG rs1148459-rs590368 of the TNFRSF1B gene was associated with AM (ß = 0.307, pperm = 0.023). Haplotype GCA rs2844484-rs2229094-rs1799964 was associated with ANM after adjustment for covariates (ß = -1.020, pperm = 0.035). All studied loci were associated with ANM after adjustment for breastfeeding (raw p < 0.05). In addition, eight of the most significant models of interlocus interactions were associated with AM and five with ANM. CONCLUSION: The results of the present study suggest that the TNF, LTA and TNFRSF1B genes are associated with AM and ANM.

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.

The haplotype of the CDKN2B-AS1 gene is associated with primary open-angle glaucoma and pseudoexfoliation glaucoma in the Caucasian population of Central Russia.

PURPOSE: To replicate the finding of the association of five CDKN2B-AS1 gene polymorphisms (rs7865618, rs1063192, rs944800, rs2157719, and rs4977756) with primary open-angle glaucoma (POAG) and to analyze them for possible association with pseudoexfoliation glaucoma (PXFG) in a Caucasian population of Central Russia. METHODS: A total of 932 participants of Russian ethnicity (self-reported), including 328 patients with PXFG, 208 patients with POAG (high-tension glaucoma), and 396 controls, were enrolled in the study. The SNPs were analyzed for possible associations using logistic regression. RESULTS: Several haplotypes based on the studied SNPs were associated with POAG (three haplotypes) and PXFG (six haplotypes). Haplotype AAAGG of loci rs1063192-rs7865618-rs2157719-rs944800-rs4977756 conferred the highest risk for both POAG (OR = 3.99, рperm = 0.001) and PXFG (OR = 2.84, рperm = 0.001). CONCLUSIONS: The CDKN2B-AS1 gene was associated with an increased risk of both POAG and PXFG in Caucasians of Central Russia. The gene may be related to the development of various types of glaucoma.

Functionally significant polymorphisms of the MMP-9 gene are associated with peptic ulcer disease in the Caucasian population of Central Russia.

This study analyzed the association of functionally significant SNPs of matrix metalloproteinase (MMP) genes in the development of peptic ulcer disease (PUD) in Caucasians from Central Russia. Ten SNPs of the MMP-1, MMP-2, MMP-3, MMP-8, and MMP-9 genes were analyzed for association with PUD in a cohort of 798 patients with PUD (including 404 H. pylori-positive and 394 H. pylori-negative) and 347 H. pylori-negative controls using logistic regression and assuming the additive, recessive, and dominant genetic models. The variants of MMP-1, MMP-2, MMP-3, and MMP-8 did not manifest any significant associations with the diseases. Five SNPs of the MMP-9 gene demonstrated such association. Allele G of the rs17576 MMP-9 locus conferred a higher risk for PUD (ORadj = 1.31, pperm = 0.016), haplotype AACG of loci rs17576-rs3787268-rs2250889-rs17577 of the MMP-9 gene decreased risk for PUD (ORadj = 0.17, pperm = 0.003). Also, allele C of rs3918249, allele G of rs17576 and haplotype CG of rs3918249-rs17576 of the MMP-9 gene increased risk for H. pylori-positive PUD (ORadj = 1.82, pperm = 0.002; ORadj = 1.53-1.95 pperm = 0.001-0.013 and ORadj = 1.49 pperm = 0.009 respectively). The above loci and 50 linked to them possess significant regulatory effects and may affect the alternative splicing of four genes and the expression of 17 genes in various organs and tissues related to the PUD pathogenesis.

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.

Evolution of kaiA, a key circadian gene of cyanobacteria.

The circadian system of cyanobacteria is built upon a central oscillator consisting of three genes, kaiA, kaiB, and kaiC. The KaiA protein plays a key role in phosphorylation/dephosphorylation cycles of KaiC, which occur over the 24-h period. We conducted a comprehensive evolutionary analysis of the kaiA genes across cyanobacteria. The results show that, in contrast to the previous reports, kaiA has an ancient origin and is as old as cyanobacteria. The kaiA homologs are present in nearly all analyzed cyanobacteria, except Gloeobacter, and have varying domain architecture. Some Prochlorococcales, which were previously reported to lack the kaiA gene, possess a drastically truncated homolog. The existence of the diverse kaiA homologs suggests significant variation of the circadian mechanism, which was described for the model cyanobacterium, Synechococcus elongatus PCC7942. The major structural modifications in the kaiA genes (duplications, acquisition and loss of domains) have apparently been induced by global environmental changes in the different geological periods.

Polymorphisms of the matrix metalloproteinase genes are associated with essential hypertension in a Caucasian population of Central Russia.

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 (r2 ≥ 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, pperm = 0.01-0.03). The above eight SNPs were associated with the disorder within 12 most significant epistatic models (OR = 1.49-1.93, pperm < 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.

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.

Functionally significant polymorphisms of ESR1and PGR and risk of intrauterine growth restriction in population of Central 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 (r2≥0.6) were analyzed for their functional significance in silico. RESULTS: Haplotype TG of loci rs2234693-rs9340799ESR1 (OR = 1.94, рperm = 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 (r2≥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.

Dataset of allele and genotype frequencies of the three functionally significant polymorphisms of the MMP genes in Russian patients with primary open-angle glaucoma, essential hypertension and peptic ulcer.

Data on the allele and genotype frequencies of the three functionally significant single nucleotide polymorphisms (SNPs) of the matrix metalloproteinases (MMP) genes (rs1799750 MMP1, rs3918242 and rs17576 MMP9) in Russian patients with primary open-angle glaucoma (POAG), essential hypertension (EH) and peptic ulcer (PU) are presented. Association studies identified these SNPs as possible significant markers associated with many multifactorial disorders, including POAG, EH, and PU. The frequencies of alleles and genotypes of the three SNPs in Russian patients with POAG, EH, and PU were presented separately for the entire study sample, females, and males, respectively. The data can be used as a reference for the Russian population.

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

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 (r2 ≥ 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, pperm = 0.001) and additive (OR = 0.67, pperm = 0.002) models. Haplotype GAA of loci rs555621-rs11031010-rs1782507 FSHB were associated with the EH (OR = 0.66, pperm = 0.007). Seventeen loci were associated with EH within 12 most significant models of intergenic interactions (pperm ≤ 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.

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

Data on the allele and genotype frequencies of the five single nucleotide polymorphisms (SNPs) 5 genes - rs1514175 TNNI3K, rs713586 RBJ, rs887912 FANCL, rs2241423 MAP2K5, rs12444979 GPRC5B 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).

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

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 LIN28B 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.

Dataset of allele, genotype and haplotype frequencies of four LIN28B gene polymorphisms analyzed for association with age at menarche in Russian women.

In this paper, we present the allele, genotype and haplotype frequencies of 4 single nucleotide polymorphisms (SNPs) in LIN28B 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).

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

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.