Metabolic and cardiovascular genes in polycystic ovary syndrome: A candidate-wide association study (CWAS)

Abstract

The role of metabolic disturbance in polycystic ovary syndrome (PCOS) has been well established, with insulin resistance and the resulting compensatory hyperinsulinemia thought to promote hyperandrogenemia. Genome-wide association studies (GWAS) have established a large number of loci for metabolic conditions such as type 2 diabetes and obesity. A subset of these loci has been investigated for a role in PCOS; these studies generally have not revealed a confirmed role for these loci in PCOS risk. However, a large scale investigation of genes related to these pathways has not previously been performed. We conducted a two stage case control association study of 121,715 single nucleotide polymorphisms (SNPs) selected to represent susceptibility loci associated with traits such as type 2 diabetes, obesity measures, lipid levels and cardiovascular function using the Cardio-Metabochip in 847 PCOS cases and 845 controls. Several hypothesis-generating associations with PCOS were observed (top SNP rs2129107, P = 3.8 × 10−6). We did not find any loci definitively associated with PCOS after strict correction for multiple testing, suggesting that cardio-metabolic loci are not major risk factors underlying the susceptibility to PCOS.

Leutinizing hormone/choriogonadotropin receptor and follicle stimulating hormone receptor gene variants in polycystic ovary syndrome

“…Previous studies that evaluated the association of LHCGR variants with PCOS focused on rs13405728, but with conflicting outcomes, and a racial influence was evident. In our study, rs13405728 was not associated with PCOS among Bahraini Arab subjects, which was in agreement with recent studies on Dutch [19], and USA women of European ancestry [18,20], but in sharp contrast to two independent Chinese studies, which confirmed its strong association with PCOS in Chinese [6] and in Han Chinese [17] subjects. In addition to rs13405728, rs2293275 was not associated with PCOS among Bahraini Arab (this study) and Dutch [25] subjects, with comparable case:control MAF recorded for Bahraini Arab (0.34:0.34) and Dutch (0.40:0.42) cases and controls.…”

“…We analyzed the association of PCOS with 11 SNPs from LHCGR and FSHR previously tested for their association with PCOS in European [18][19][20]25], and non-European [17,[26][27][28][29] populations. This case-control sample included 203 women with PCOS and 211 age-and ethnically-matched (Bahraini Arab) control women.…”

“…For example, the LHCGR rs13405728 variant, independently shown to be associated with PCOS in the Chinese [6,17], is not informative in European-derived population [18][19][20]. As such, the search of specific PCOS-predisposing loci is influenced by racial background, PCOS phenotype and diagnostic criteria, along with variable fertility of PCOS cases.…”

Adipose tissue dysfunction, adipokines, and low-grade chronic inflammation in polycystic ovary syndrome

“…The prevalence of PCOS is high, ranging from 9% according to NIH criteria to 18% according to Rotterdam criteria (Rotterdam ESHRE/ ASRM-Sponsored PCOS Consensus Workshop Group 2004, March et al 2010). Current evidence indicates that PCOS is a multifactorial disease, and that individual susceptibility is determined by genetic and environmental risk factors (Jones et al 2012).…”

Genome-wide association study identifies GYS2 as a novel genetic factor for polycystic ovary syndrome through obesity-related condition

“…[7][8][9] Although a recent genome-wide association study (GWAS) has contributed to susceptibility genes or loci discovery for PCOS, 10 identifying a major determinants underlying variation in primary metabolism would be more valuable. [11][12][13] PCOS and T2D are obesity-related conditions that share epidemiological and pathophysiological factors. [14][15][16] A large number of women with PCOS are considered to be overweight or obese, implicating BMI (body mass index) as an important determinant in the manifestation of the syndrome.…”