Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity

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Polycystic ovary syndrome (PCOS) is the most common hormonal disturbance in reproductive age women and features high levels of male sex hormones, such as testosterone, and infrequent ovulation. Twin studies have demonstrated that inheritance plays a significant role in PCOS, and recent genome wide association studies (GWAS) have implicated 11 susceptibility regions. The mechanism by which these genetic loci cause PCOS has yet to be determined. We looked at DNA methylation and gene expression levels in these 11 loci in fat biopsies from women with and without PCOS. We identified differences in the expression of two receptors that bind hormones known to contribute to the pathogenesis of PCOS–the receptors for luteinizing hormone (LH) and insulin. We found increased expression of the LH receptor in non-obese PCOS women, while in the obese women with PCOS the insulin receptor was underexpressed. Both excess LH stimulation and elevated insulin levels, due to decreased receptor levels and resulting insulin resistance, can cause increased androgen production from the ovary. Our findings suggest the primary mechanism for elevated androgen levels in PCOS may differ between non-obese and obese women with PCOS and that the clinical heterogeneity seen in PCOS may have genetic underpinnings.

Vyšlo v časopise: Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity. PLoS Genet 11(8): e32767. doi:10.1371/journal.pgen.1005455
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005455

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