Background: Hyperandrogenism is a main feature of the polycystic ovary syndrome (PCOS). Although its ovarian origin is well recognized, laboratory investigation suggested the contribution of adrenal gland, albeit of unknown mechanism.
Aim: To understand the contribution of genetic factors in adrenal hyperandrogenism (AH) we investigated genome wide SNPs in subgroups of PCOS patients stratified as function of DHEAS levels in two ethnic populations (Romanians and French).
Subjects and methods: Patients recruited during European MEDIGENE program (FP7-279171) with PCOS (n=307) of 1842 years old were stratified in two groups as function of DHEAS level greater than 95th percentiles in age-matched controls. Genotyping was performed with customized MEDISCOPE microarray chip with 759 000 SNP. Influential SNPs were determined by correlation trend (CT) test and then by genetic association in two subgroups of patients.
Results: Despite no difference in total-testosterone levels, in PCOS with AH (n=58, 18.9%) the SHBG (27.6±3.6 vs 44.5±3.3 nmol/L, P< 0.0002) was lower and FAI (14.0±2.2 vs 8.7±0.7, P< 0.002), 2-h insulin in OGTT (111.2±26.0 vs 77.3±6.9 mUI/L, P<0.044) and systolic BP (123.7±4.26 vs 114.4±1.8 mmHg, P<0.045) were higher than in PCOS without AH. SNPs corresponding to at least 15 genes were positive in CT test with DHEAS levels. Among them, INSR and CDH13 were the most significant with numerous SNPs having a P value < 1.0×10-5 after Bonferroni correction. In genetic association by logistic regression between two groups, other genes were also confirmed, the most influential being IL2RA, PTER, SORCS1, LGR4 and KSR2. For instance, LGR4 (Chr 11) was associated with P< 0.005, OR 5.6, 95%CI [1.619].
Conclusion: These data indicated that, in PCOS patients, AH may be in part explained by genetic susceptibility. Despite a full array of genes involved, the insulin-resistance appears as potential actor of AH in PCOS.
20 - 23 May 2017
European Society of Endocrinology