Han Chinese Polycystic Ovary Syndrome Risk Variants in Women of European Ancestry: Relationship to FSH Levels and Glucose Tolerance EDITORIAL COMMENT

摘要

Polycystic ovary syndrome (PCOS) affects 7% to 10% of reproductive-age women. The etiology of the syndrome is poorly understood. Twin studies suggest that the pathogenesis of PCOS in more than 70% of cases can be explained by genetic influences. Risk loci for genetic variants associated with the syndrome have been identified in women of Han Chinese ethnicity. Two genome-wide association studies in Han Chinese women identified risk loci for 11 genetic variants. Three of these 11 variants were also associated with PCOS in at least 1 European population when corrected for multiple testing, including DENND1A, THADA, and YAP1. The PCOS variants identified require additional replication in Greek and US women to establish the importance of these variants and to determine their relationship to PCOS phenotypic traits. This case-control study was designed to investigate whether PCOS risk variants identified in women of Han Chinese ethnicity were also associated with risk of PCOS or its phenotypic features in European and US women. The discovery cohort was composed of women with PCOS (n = 485) and control subjects (n = 407) from Boston (Boston 1). Susceptibility variants were examined in replicate populations in Greece (cases n = 884 and control subjects n = 311), and a second cohort from Boston identified through the electronic medical record (EMR), n = 350 cases and n = 1258 control subjects). Women in Boston 1 and Greece (n = 783) had PCOS defined by the National Institutes of Health criteria (irregular menses and clinical or biochemical hyperandrogenism [n = 527]), with additional subjects fulfilling the Rotterdam criteria (clinical or biochemical hyperandrogenism, polycystic ovary morphology, and regular menstrual cycles [n = 101]). Control subjects in Boston and Greece had regular menses and no hyperandrogenism. The second Boston cohort was defined using the EMR and natural language processing. Allele frequencies for PCOS risk variants identified in Han Chinese women were examined in PCOS cases and control subjects, along with the relationship to quantitative traits. One variant, rs2268361-T, in the intron of follicle-stimulating hormone receptor (FSHR) was associated with PCOS; the combined odds ratio was 0.84 (95% confidence interval, 0.76-0.93; P = 0.002). This variant was associated with lower follicle-stimulating hormone (FSH) levels (-0.15 0.05; P = 0.0029). Another variant, rs705702-G, near the RAB5B and SUOX genes, was associated with lower insulin (-0.16 0.05; P = 0.0029) and glucose levels (-0.20 0.05; P = 0.0002) 120 minutes after an oral glucose test, suggesting better insulin sensitivity. Although the study was large and contained replication cohorts, the findings were limited by a small number of control subjects in the Greek cohort and a small number of cases in the second Boston cohort. Moreover, it was possible that the second Boston cohort identified with EMR review could contribute to the observed differences; this cohort, however, was validated for the cardinal features of PCOS. These findings show that a PCOS risk variant present in Han Chinese women in the region of FSHR is also associated with PCOS in women of European ethnicity. This cross-ethnic PCOS risk locus, rs2268361-T, may influence FSH receptor responsiveness as suggested by the associated change in FSH levels and suggest that disrupting FSH stimulation of follicle development is a key etiologic feature of PCOS.