Association Study Between Polycystic Ovary Syndrome And The Genetic Variations Of Gene TCF7L2 And CDKAL1

Background Polycystic ovary syndrome (PCOS) is a highly heterogeneous endocrine disorder of women that always results in infertility. It is characterized by oligomenorrhea or amenorrhea, hyperandrogenism, insulin resistance, infertility, acne, obesity and multiple small subcapsular cystic follicles in the ovary on ultrasonography. It affects about 5%-10%of women of reproductive age. Recently, it was demonstrated that PCOS was also a metabolic disorder. The etiopathogenisis of PCOS is still unknown. PCOS displays evident familial aggregation. The interaction between genetic susceptibility and environmental factors plays a possible role in the pathogenesis of PCOS.PCOS and type 2 diabetes mellitus are both diseases of multifactorial inheritance. The genetic backgrounds of these two disorders are complex. They share many common features in both clinical metabolism manifestations and epidemiology characters. Insulin resistance and hyperinsulinemia is the link between PCOS and type 2 diabetes. The risk of developing type 2 diabetes is significantly higher in women with PCOS than in women without PCOS. Therefore, the known susceptibility genes for type 2 diabetes are reasonable candidates for investigation of the genetic basis of PCOS.A number of studies had shown the powerful association between the common variants, rs7903146 (T) and rs 12255372 (T), in the gene encoding transcription factor 7-like 2 (TCF7L2) and type 2 diabetes in European ancestry populations. However, rs7903146 and rs12255372 were not associated with type 2 diabetes in Han Chinese population. Since the risk alleles of the two loci were rare and the statistical power was inadequate in Chinese. Two studies identified that another two SNPs (rs290487 [C] and rs11196218 [G]) in gene TCF7L2 were associated with type 2 diabetes in Han Chinese populations.Recently, a genome-wide association study identified a novel risk locus, single nucleotide polymorphism (SNP) rs7756992 (G) in the cyclin-dependent kinase 5 (CDK5) regulatory subunit associated protein 1-like 1 (CDKALI) gene (with an allelic specific odds ratio [OR] of 1.20,95%confidence interval [95%CI] of 1.13-1.27), for type 2 diabetes in several case-control cohorts of European ancestry. The association between rs7756992 and type 2 diabetes in individuals from Hong Kong Han Chinese was also identified (OR [95%CI] =1.25[1.11-1.40]).We hypothesize that these three novel risk loci for type 2 diabetes, rs7756992 in gene CDKAL1, rs290487 and rs11196218 in gene TCF7L2, may also contribute to the risk for PCOS in Han Chinese women. In this study, we performed a case-control study to test our hypothesis.Objective To test whether the SNPs rs290487 and rs11196218 in gene TCF7L2 and rs7756992 in gene CDKAL1 associated with PCOS. To analyze the associations between the genotype distribution of these three SNPs and the clinical features of PCOS patients.MethodsSubjects A total of 826 women with PCOS were recruited from the outpatient clinic of Shandong Provincial Hospital. Recruitment was based on the revised Rotterdam diagnostic criteria. We recruited 620 healthy nondiabetic women with regular menstrual cycles as a control group. None of the controls had hyperandrogenism or other endocrine disorders related to PCOS. All patients and controls were Han Chinese women and were recruited from the same area. After undergoing a physical examination, including measurement of abdominal and hip circumferences and the measurement of hormone, an oral glucose tolerance test (OGTT) was performed in PCOS patients. Body mass index (BMI) was used to evaluate obesity. Insulin sensitivity in the fasting state was estimated by the homeostasis model assessment of insulin resistance (HOMA-IR).Genotyping Peripheral blood from participants was collected and the genomic DNA was isolated. Genotypes were identified by TaqMan genotyping technologies. Both the PCR reaction and the analysis were performed on the ABI 7500 real-time PCR system.Statistical analysis The Hardy-Weinberg equilibrium test was performed using the chi-square test.Genotype and allele frequencies for the case and control groups were compared using the chi-square test. Analysis of covariance (ANCOVA) was used to analyze the associations between the genotype of these three SNPs and the clinical features of PCOS patients in PCOS group, introducing BMI as the covariate. P<0.05 was considered statistically significant.Results1. There are no significant differences of the T, FSH, LH and PRL between the PCOS patient with or without insulin resistance. The serum glucose and plasma insulin level of patients with insulin resistance in OGTT are significant higher than that of patients without insulin resistance.2. There are no significant differences of the T, FSH, LH and PRL between the PCOS patient with or without obesity. The serum glucose and plasma insulin level of patients with obesity in OGTT are significant higher than that of patients without obesity, except the serum glucose level at the time point of 180 min.3. There is a positive correlation between the HOMA-IR and BMI of PCOS patient.4. No significant differences in genotypes of these three SNPs and allele frequencies were found between PCOS patients and healthy controls. 5. No significant differences in genotype and allele frequencies of these three SNPs were found between PCOS patients with or without insulin resistance.6. No significant differences in genotype and allele frequencies of these three SNPs were found between PCOS patients with or without obesity.7. No associations were observed between genotype of these three SNPs and the quantitative clinical features of PCOS patients in PCOS group after adjustment for BMI.Conclusions The risk allele of the SNPs rs290487 and rs11196218 in gene TCF7L2 and rs7756992 in gene CDKALI have no associations with PCOS or PCOS-related clinical features.