Genotype–phenotype correlations of PCOS susceptibility SNPs identified by GWAS in a large cohort of Han Chinese women

• Published in: Human reproduction (Oxford) Vol. 28; no. 2; pp. 538 - 544
• Main Authors: Cui, Linlin, Zhao, Han, Zhang, Bo, Qu, Zhongyu, Liu, Jiayin, Liang, Xiaoyan, Zhao, Xiaoming, Zhao, Junli, Sun, Yingpu, Wang, Peng, Li, Tao, Shi, Yuhua, Chen, Zi-Jiang
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.02.2013
• Subjects: Adult; China - ethnology; Cohort Studies; Death Domain Receptor Signaling Adaptor Proteins - genetics; Female; Gene Frequency; Genetic Predisposition to Disease; Genome-Wide Association Study; Guanine Nucleotide Exchange Factors; Humans; Neoplasm Proteins - genetics; Polycystic Ovary Syndrome - genetics; Polymorphism, Single Nucleotide; Receptors, LH - genetics; China; phenotype; PCOS; THADA; DENND1A
• ISSN: 0268-1161; 1460-2350; 1460-2350
• DOI: 10.1093/humrep/des424

STUDY QUESTION Are there any correlations between the phenotypes of polycystic ovary syndrome (PCOS) and the genotypes of the PCOS susceptibility single nucleotide polymorphisms (SNPs) in THADA, DENND1A and LHCGR? SUMMARY ANSWER The PCOS susceptibility genes, THADA and DENND1A, carry risk alleles that are associated with endocrine and metabolic disturbances in patients with PCOS. WHAT IS KNOWN ALREADY PCOS is a heterogeneous endocrinopathy characterized by oligo-anovulation, hyperandrogenism and polycystic ovaries. In a previous genome-wide association study, the SNP variants rs13429458, rs12478601, rs2479106, rs10818854 and rs13405728 in the THADA, DENND1A and LHCGR genes were identified as being independently associated with PCOS. The aim of this study was to identify any additional correlations between the phenotypes of PCOS and genotypes of the five SNPs described in the previous study. STUDY DESIGN, SIZE, DURATION In the present cross-sectional study, a total of 1731 PCOS patients and 4964 controls were enrolled. PARTICIPANTS/MATERIALS, SETTING, METHODS Patients were diagnosed according to Rotterdam criteria. Clinical information was collected from the patients and controls. Endocrine and metabolic parameters were evaluated for phenotype–genotype correlation analyses. MAIN RESULTS AND THE ROLE OF CHANCE Using a recessive model, the AA group for rs13429458 in THADA was associated with increased luteinizing hormone (LH) (P < 0.01) and testosterone (T) (P = 0.02) levels in subjects with PCOS; the LH/follicle-stimulating hormone ratio was also higher in the AA group (P < 0.01). Also using a recessive model, the CC genotype of rs12478601, also in THADA, was associated with increased levels of low-density lipoprotein (P = 0.02). Using a dominant model, the GG + AG group for rs2479106 in DENND1A was associated with elevated serum insulin levels 2 h after a glucose load in the patients with PCOS (P = 0.02). All of the comparisons were adjusted for age and BMI. LIMITATIONS, REASONS FOR CAUTION The relatively younger age of the participants may represent a considerable bias when evaluating metabolic alterations as a function of different genotypes, as significant metabolic disturbances may emerge later in life. Furthermore, the sample sizes of several sub-genotype groups were relatively small; to some extent this limited the statistical power of the analysis. WIDER IMPLICATIONS OF THE FINDINGS The PCOS susceptibility genes, THADA and DENND1A, carry risk alleles that are associated with endocrine and metabolic disturbances in PCOS patients of Han Chinese descent. The findings have shown genuine heterogeneity, stratified on the basis of both clinical findings and genotypes. Replication of these results is expected in other ethnic groups. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by the National Basic Research Program of China (973 program) (2010CB945002, 2012CB944700), the National Natural Science Foundation of China (81000238, 81070461, 81000236, 30973170), the Graduate Independent Innovation Foundation of Shandong University (GIIFSDU) (21300070613242, 21300070613246), the Science Research Foundation item of no-earnings health vocation (201002013) and the National Key Technology Research and Development Program (2011BAI17B00). There are no competing interests.