Functional Genomics of PCOS. Issue 9 (September 2015)

• Record Type: Journal Article
• Authors: McAllister, Jan M.; Legro, Richard S.; Modi, Bhavi P.; Strauss, Jerome F.
• Is Part Of: Obstetrical & gynecological survey. Volume 70:Issue 9(2015)
• Publication Date: 2015-09
• Subjects: Obstetrics -- Periodicals; Gynecology -- Periodicals; Generative organs, Female -- Surgery -- Periodicals; 618
• DOI: 10.1097/01.ogx.0000471341.33429.55
• Languages: English
• ISSNs: 0029-7828

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>ABSTRACT</title> <p>Polycystic ovary syndrome (PCOS) is a common disorder affecting 5% to 7% of women of reproductive age worldwide. The syndrome is characterized by increased ovarian androgen biosynthesis, anovulation, and infertility. Its etiology is poorly understood.</p> <p>Hyperandrogenemia (hyperandrogenism) is a hallmark of the disorder and has been included as an essential element in all "consensus" diagnosis schemes. There is strong evidence for a genetic component in PCOS from familial clustering and twin studies.</p> <p>Genome-wide association studies (GWASs) in Han Chinese women identified several PCOS candidate loci in or near the genes encoding receptors for <italic>LHCGR</italic>, <italic>FSHR</italic>, <italic>DENND1A</italic>, <italic>INSR</italic>, <italic>ZNF217</italic>, <italic>YAP1</italic>, <italic>RAB5B</italic>, <italic>THADA</italic>, and <italic>C9orf3</italic>. The association of several of these loci with PCOS was confirmed in studies conducted in European populations; these loci include <italic>FSHR</italic>, <italic>LHCGR</italic>, and <italic>DENND1A</italic>, as well as <italic>RAB5B</italic> and <italic>THADA</italic>. However, there is no convincing evidence at present that the variants identified in these genes are functionally significant and contribute to the PCOS phenotype.</p> <p>This review examined the functional roles of strong candidate PCOS loci identified in the GWASs and subsequently replicated in other populations, with primary focus on <italic>FHSR</italic>, <italic>LHCGR</italic>, <italic>INSR</italic>, and <italic>DENND1A</italic>. Previous studies have shown that ovarian theca cells are the primary source of high levels of androgens in women with PCOS and that a variant of DENND1A, called <italic>DENND1A.</italic>V2, may play a major role in PCOS. This variant of <italic>DENND1A</italic> is a new diagnostic and therapeutic target for PCOS. Forced overexpression of <italic>DENND1A.V2</italic> in cultured theca cells from women without PCOS increases androgen production converting them to a PCOS phenotype, whereas blocking V2 expression in PCOS theca cells markedly reduces androgen secretion.</p> <p>The authors propose that these GWAS candidate genes comprise a hierarchical signaling network by which <italic>DENND1A</italic>, <italic>LHCGR</italic>, <italic>INSR</italic>, <italic>RAB5B</italic>, adapter proteins, and their associated downstream signaling cascades converge to regulate theca cell expression and androgen biosynthesis.</p> <p>These findings may lead to new diagnostic and therapeutic approaches for women with PCOS. <italic>DENND1A.V2</italic> is present in the urine, and its increased urinary excretion could be a diagnostic biomarker for PCOS. Having such a molecular marker may identify a population of young girls who develop the disorder at adrenarche or pubarche and allow earlier intervention. Future studies should investigate the possibility that <italic>DENND1A.V2</italic> is a biomarker for PCOS and examine its role in predicting response to common treatments for women with PCOS.</p> </sec> </abstract>