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.

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, 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.

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

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 (рperm = 0.005). In total 12 two-, three-, and four-locus models of gene-gene interactions were determined as contributing to AAM (pperm ≤ 0.006). Nine of the 14 AAM-associated SNPs are also associated with height and BMI (pperm ≤ 0.003). Among 14 AAM-associated SNPs (a priori all having regulatory significance), the highest regulatory potential was determined for rs4633 COMT, rs2164808 POMC, rs2252673INSR, rs6438424 3q13.32, and rs10769908 STK33. Eleven loci are cis-eQTL and affect expression of 14 genes in various tissues and organs (FDR < 0.05). The neuropeptide-encoding genes were overrepresented among the AAM-associated genes (pbonf = 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.