The mineralocorticoid receptor gene (NR3C2) is linked to and associated with polycystic ovarian syndrome in Italian families.

OBJECTIVE: Polycystic ovarian syndrome (PCOS) is a complex heterogeneous disorder characterized by hyperandrogenism, irregular menses, and subfertility and often accompanied by other related comorbid disorders such as insulin resistance, obesity, and type 2 diabetes. Several genetic risk factors predispose to PCOS, but most are still unknown. Up to 30% of women with PCOS may have hyperaldosteronism. Blood pressure and the ratio of blood levels of aldosterone to renin are higher in women with PCOS compared to healthy controls, even if still in the normal range; and the aldosterone antagonist spironolactone has been used as therapy for PCOS, mainly due to its antiandrogenic activity. Thus, we aimed to investigate the potential pathogenetic role of the mineralocorticoid receptor gene (NR3C2) as the encoded NR3C2 product binds aldosterone and plays a role in folliculogenesis, fat metabolism, and insulin resistance.

SUBJECTS AND METHODS: Within 212 Italian families with T2D and phenotyped for PCOS, we analyzed 91 single nucleotide polymorphisms in the NR3C2 gene. We tested the NR3C2 variants for linkage and linkage disequilibrium to the PCOS phenotype by using parametric analysis.

RESULTS: We found 18 novel risk variants significantly linked to and/or associated with the risk of PCOS.

CONCLUSIONS: We are the first to report NR3C2 as a risk gene in PCOS. However, our findings need to be replicated in other ethnic groups in order to reach more solid conclusions.