In-Silico Investigation of Effects of Single-Nucleotide Polymorphisms in PCOS-Associated CYP11A1 Gene on Mutated Proteins (original) (raw)
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Korean Journal of Clinical Laboratory Science
Polycystic ovary syndrome (PCOS) is a complex endocrinopathy in women of reproductive age. The genetics of PCOS is heterogeneous with the involvement of number of genes in the steroid synthesis pathway. The CYP11B2 encodes aldosterone synthase and the genetic variants might increase aldosterone secretion in PCOS cases. CYP1A1 is known to enhance the intraovarian catechol estrogen production and thus the propensity for PCOS. The present case-control study analyzed a total of 619 females for CYP11B2 (rs1799998) and CYP1A1 (rs4646903) polymorphisms. Obesity was examined according to body mass index (BMI) and waist hip ratio (WHR) categorization. Biochemical (lipid profile) analysis was performed in PCOS females. BMI (P=0.0001) and WHR (P=0.0001) revealed a statistically significant difference between PCOS cases and controls. The overall levels of triglycerides were higher in PCOS females. The genotype frequency distribution of CYP11B2 (rs1799998) polymorphism revealed statistically significant difference between PCOS cases and controls (P=0.017). However, CYP1A1 (rs4646903) polymorphism did not showed any association with PCOS. The present case-control association analysis is first from our region for CYP1A1 and CYP11B2 polymorphisms and is suggestive of genetic predisposition of steroidogenic genes among PCOS patients in the North-Indian Punjabi females.
JOURNAL OF REPRODUCTION AND INFERTILITY, 2023
Background:Genetic factors are significantly have important role in the etiology of the polycystic ovary syndrome (PCOS). This study examined the possible relation of rs1484215 and rs6495096 polymorphisms of CYP11A1 gene in Iranian women with PCOS.Methods:The population of the case-control research included 100 women presenting with PCOS and 100 women as a control group who were referred to Infertility Center in Qom, Iran. The genotypes of rs1484215 and rs6495096 polymorphisms in CYP11A1 gene were detected with the tetra-ARMS PCR method. The independent segregation of alleles was tested for the Hardy–Weinberg equilibrium (HWE). Differences in quantitative traits were assessed between each group with a single PCOS feature and control group using Mann–Whitney U test for categorical variables and student’s t-test for continuous variables. Statistical analysis of allele and genotype frequencies between women with PCOS and control was performed using the chi-square test. Significance level was defined as p<0.05.Results:There was a significant association of C with G alleles in rs6495096 polymorphism and susceptibility to PCOS (p=0.001), but no significant relation was found between C and T alleles in rs1484215 polymorphism and susceptibility to PCOS. Also, GG genotype of rs6495096 was significantly associated with the waist-to-hip ratio (WHR) and infertility duration compared to CG and CC (p<0.01). However, rs1484215 showed no association with these variables.Conclusion:The results from the research indicated that rs6495096 polymorphism of CYP11A1 gene is related to the PCOS risk in Iranians women.
PLoS ONE, 2014
Single nucleotide polymorphisms (SNPs) are the most common type of genetic variations in humans and play a major role in the genetics of human phenotype variation and the genetic basis of human complex diseases. Recently, there is considerable interest in understanding the possible role of the CYP11B2 gene with corticosterone methyl oxidase deficiency, primary aldosteronism, and cardio-cerebro-vascular diseases. Hence, the elucidation of the function and molecular dynamic behavior of CYP11B2 mutations is crucial in current genomics. In this study, we investigated the pathogenic effect of 51 nsSNPs and 26 UTR SNPs in the CYP11B2 gene through computational platforms. Using a combination of SIFT, PolyPhen, I-Mutant Suite, and ConSurf server, four nsSNPs (F487V, V129M, T498A, and V403E) were identified to potentially affect the structure, function, and activity of the CYP11B2 protein. Furthermore, molecular dynamics simulation and structure analyses also confirmed the impact of these nsSNPs on the stability and secondary properties of the CYP11B2 protein. Additionally, utilizing the UTRscan, MirSNP, PolymiRTS and miRNASNP, three SNPs in the 39UTR region were predicted to exhibit a pattern change in the upstream open reading frames (uORF), and eight microRNA binding sites were found to be highly affected due to 39UTR SNPs. This cataloguing of deleterious SNPs is essential for narrowing down the number of CYP11B2 mutations to be screened in genetic association studies and for a better understanding of the functional and structural aspects of the CYP11B2 protein.
Research Journal of Applied Biotechnology, 2016
Several studies have reported the association of the SNP rs4077582 in the CYP11 gene with hyperandrogenism, which is one of the clinical manifestations of polycystic ovary syndrome (PCOS). These studies suggest that SNP rs4077582 may be involved in the etiopathogenisis of PCOS. To investigate whether the CYP11 gene SNP rs4077582 polymorphism is associated with the susceptibility to PCOS, we designed a case-controlled association study including 104 individuals. A case-controlled association study including 106 individuals (53 PCOS patients and 53 controls) was performed to assess the association of SNP rs4077582 with PCOS. Genotyping of SNP rs4077582 was conducted by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method that was performed on genomic DNA isolated from blood leucocytes. Results were analyzed in respect to clinical test results. The genotypic distributions of rs4077582 (CC, CT, TT) in the CYP11 gene in women with PCOS (CC, 29 (55.8%); CT, 20 (33.5%); and TT, 3 (5.8%). respectively) were significantly different from that in controls (CC, 44 (84.6%); CT, 6 (11.6%); and TT, 2 (3.8%) respectively) (P = 0.001). The allele frequencies in the PCOs women were: C, 78 (75%); and T, 26 (25%). This also was significantly different from the distribution in non-PCOs women: C, 94 (90.4%); and T, 10 (9.6%) (Table 2). In addition, rs4077582 C > T showed a association with PCOs by logistic regression analysis controlling for confounding factors. Our data suggest that SNP rs4077582 in the CYP11 gene is associated with susceptibility to PCOS.
CYP1A1 gene polymorphism and polycystic ovary syndrome
Reproductive Biomedicine Online, 2008
The aim of this study was to assess the rates of variant alleles of cytochrome P4501A1 (CYP1A1) in patients with polycystic ovary syndrome (PCOS). It was designed as a case–control study in Hacettepe University, Faculty of Medicine, Department of Obstetrics and Gynecology and Genetics. Forty-eight patients with PCOS served as the study group. Ninety-six regularly cycling women with no clinical and biochemical evidence of hyperandrogenism and polycystic ovary appearance served as the controls. The CYP1A1 variant alleles of all patients were determined via polymerase chain reaction. The rate of the CYP1A1 isoleucine (Ile)/valine (Val) allele was significantly higher in patients with PCOS than in the controls (OR: 7.8, 95% CI: 3.45–17.52, P < 0.001). However, there was no statistically significant difference in the distribution of Val/Val genotype (OR: 4.0, 95% CI: 0.60–26.73). The rate of any Val genotype (Ile/Val or Val/Val) was significantly higher in patients with PCOS compared with the control group (OR: 7.4, 95% CI: 3.33–16.46, P < 0.001). In conclusion, the patients with PCOS had a 7.8-fold higher frequency of CYP1A1 Ile/Val genotype and a 7.4-fold higher frequency of CYP1A1 of any Val genotype (Ile/Val or Val/Val).
International Journal of Molecular Medicine, 1998
Women with polycystic ovary syndrome (PCOS) are characterized by excess androgen secretion and anovulatory infertility as a cause of follicular maturation arrest, and they are also associated with insulin resistance and obesity. Recently, it was suggested that one of the etiologies for PCOS is an abnormality of steroid hormones, and excessive secretion of androgen. The endoplasmic reticular cytochrome P450, 17α-hydroxylase (CYP17A), plays a key role in the mechanism of steroid hormones such as adrenal and gonadal steroid biosynthesis. Therefore, we studied the association between single nucleotide polymorphisms (SNPs) of the A1 allelic variant of the CYP17 gene and PCOS in a Korean population. The study recruited 134 Korean women with PCOS and 100 healthy women as controls. Using the HapAnalyzer, the genotype of the CYP17A1 polymorphism in PCOS and control patients were analyzed. We considered a p-value lower than 0.05 to be statistically significant. After genotypic analysis, we found seven SNPs of the CYP17A1 gene in a large population of subjects. The frequency of seven SNPs had no significant association with PCOS. However, one haplotype (ht3) had a p-value of p=0.001, suggesting that it may be associated with the pathogenesis of PCOS in a Korean population.
In-Silico Analysis of nsSNPs Associated with CYP11B2 Gene
CYP11B2 gene is located over the upper layer of the kidney. It produces aldosterone synthase enzyme and thereby has an essential role to balance salt and mineral level in the body. A mutation in this gene can deregulate the production of aldosterone hormone in the body which may lead to many diseases including hypertension and cardiac diseases. To control the excess production of this aldosterone an inhibitor “Fadrozole” is being used which is associated with an active site cavity of CYP11B2. This study has been divided into two parts. In the first part, the four computational tools (SIFT, Polyphen-2, I-Mutant, ConSurf) were used to identify 29 deleterious SNPs out of 1600 CYP11B2 SNPs. In the second part, five residues (R448G, R141P, W260R, F130S, and F445S) were identified in the active site cavity (out of 29 deleterious CYP11B2 SNPs) at the distance of 5Ao. Binding free energy calculation as well as Dynamics simulation techniques were applied to determine the effect of these muta...
Fertility and Sterility, 2009
To analyze promoter regions of CYP11A1 and CYP17 for putative variations in a defined group of women with polycystic ovary syndrome (PCOS) and to study their association with androgen levels. Retrospective study. A secondary referral center for infertility at National Institute for Research in Reproductive Health, Mumbai, India. One hundred women whose condition was diagnosed on the basis of the Rotterdam consensus were compared against 100 age-matched controls. A single sample of blood was collected after overnight fast on day 3 of the menstrual cycle. Plasma levels of T, androstenedione, 17alpha-hydroxyprogesterone, and DHEAS and nucleotide sequence of promoter regions of CYP11A1 and CYP17 genes. Polymorphisms in promoter regions of the two key androgen-regulating genes, CYP11A1 and CYP17, were found to be significantly associated with T levels in the cohort of well-characterized PCOS cases as compared with controls. The significance was greater in the PCOS cases with both the polymorphisms. Our study carried out in a defined group of Indian women with PCOS suggests for the first time an individual, as well as combined, association of polymorphisms in CYP11A1 and CYP17 promoters with T levels.
Research Square (Research Square), 2023
Objectives: The main objective of the study was to evaluate the association of CYP11A1 gene (rs4077582), VEGF (rs1570360), CYP21 gene (rs13405728), FTO (rs9939609), THADA (rs13429458) in PCOS patients. The reason behind the study of selected SNPs was that previously in Pakistan no work on these SNPs has been published yet. Methods: Blood samples of 600 persons including 300 PCOS patients and 300 controls were collected from different hospitals of Sargodha. DNA was extracted from whole blood samples. To study polymorphism, speci c region of DNA was ampli ed with the help of polymerase chain reaction (PCR). Polymorphic analysis was performed on genes CYP11A1 (rs4077582), VEGF (rs1570360), CYP21 (rs13405728), FTO(rs9939609), THADA (rs13429458) to determine the possible association of with PCOS. Results: The genotypic association of SNP rs9939609 of FTO, rs13429458 of THADA, rs1570360 VEGF, rs13405728of CYP21 and rs40077582 of CYP11A1 were given in Table 4.2. The heterozygous TA of FTO SNP (rs9939609) show signi cant association with decreased risk of polycystic ovarian syndrome (OR=0.50; 95% CI= 0.31-0.80; P=0.0038). The mutant AA of the same SNP (rs9939609) did not show any signi cant association with PCOS (OR=1.23; 95%CI=0.73-2.08; P =0.4261). Combined dominant genotype model (TA+AA) of rs9939609 again show signi cant association with decreased risk of PCOS (OR=0.42;95%CI=0.23-0.78;P=0.0060) while combined recessive genotype model (TA+TT) did not show any signi cant association with PCOS (OR= 0..80;95%CI= 0.48-1.36; P=0.4261). In case of gene THADA polymorphism, heterozygous genotype (AC) of showed a signi cant association with decreased risk of PCOS (OR =0.43; 95%CI= 0.25-0.75; p=0.0027) while homozygous mutant (CC) of same SNP did not show any-signi cant association (OR=1.26; 95%Cl=0.78-2.04; p=0.3299). Joint genotype model for dominant and recessive did not show any signi cant association with PCOS(OR=0.78 (95 % CI 0.48-1.27; p=0.3299; OR=0.65; 95 %CI=0.41-1.04; p=0.0781 respectively). The genotypic frequencies of rs1570360 of VEGF gene heterozygote (GA) showed a signi cant association with increased risk of PCOS by almost 3-folds (OR =2.89, 95%Ci=1.77-4.72; p=0.0001). Same is the case with mutant (AA) which showed highly signi cant association but with decreased risk of PCOS (OR=0.476; 95%Cl=0.28-0.80; p=0.0051). When the association of Joint genotype model for dominant showed signi cant association with increased risk of PCOS (OR=2.09; 95%CI=1.24-3.52; p=0.0051) while Joint genotype model for recessive did not show any signi cant association with PCOS (OR=1.507; 95%CI=0.93-2.42; p=0.0916). Genotypic frequencies of SNPs rs13405728 of CYP21 (LHCGR) gene, heterozygous (CT) showed signi cant association increase the risk of PCOS by 4-fold (OR=4.10; 95%CI=2.47-6.80; p=0.0001). Situation is same for mutant (TT) which showed signi cant association with PCOS but with decreased risk (OR=0.27; 95%CI=0.16-0.45; p=0.0001). Joint genotype model for recessive (CT+TT) of this SNP did not show any signi cant association with PCOS (OR=1.14; 95% CI=0.68-1.92; p=0.59) while Joint genotype model for dominant showed signi cant association with increased risk of PCOS by 3-folds (OR=3.59; 95% CI=2.52-5.12; p=0.0001). In case of rs4077582 SNP of CYP11A1gene,heterozygous (CT) shows signi cant association with PCOS with increased risk of 1 fold. The homozygous mutant (TT) of the same SNP did not show Page 3/28 any association with the disease (OR=1.377; 95% CI=0.85-2.2; p=0.1855). The combined genotype model for dominant (CT +CC) of the same SNP did not show any signi cant association with polycystic ovarian syndrome (OR=0.72; 95% CI=0.51-1.01; p=0.06) while combined genotype model for recessive (CT +TT) showed signi cant association with increased risk of PCOS by 2-folds (OR=2.19; 95% CI=1.35-3.53; p=0.0014). Conclusion: On the basis of results it is concluded that the hypothesis is accepted. The polymorphism CYP11A1 gene (rs4077582), VEGF (rs1570360), CYP21 gene (rs13405728), FTO (rs9939609), THADA (rs13429458) is associated with PCOS. Allele and some genotypic frequencies in patients and controls are non-signi cantly associated with PCOS. Our results of the rs13429458 polymorphism shows increasing association between smoking and PCOS. To conclude PCOS is a combination of complex heredity disorders and previous studies have investigated have many genes for their role as possible loci. By investigating the useful role of this SNP in Pakistani women and building up more information on the genetic basis for PCOS; the establishment of disease in the individuals at risk can be delayed by changing the lifestyle.