Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of young women, affecting ~ 7 % of reproductive age women in western societies. It is characterized by hyperandrogenemia and menstrual irregularities. In addition to these reproductive phenotypes, PCOS is also associated with obesity, insulin resistance, and an increased risk of developing type 2 diabetes mellitus (T2DM). PCOS is heritable and shares many features in common with insulin resistance, diabetes and obesity, suggesting that the genetic underpinnings of PCOS and T2DM may be related or even identical. It is becoming increasingly clear that members of the inflammatory response are important in the etiology of phenotypes of the metabolic syndrome including diabetes and obesity. Given the above we will address the hypothesis that genetic variation in the inflammatory response genes contributes to the etiology of PCOS. We propose to test this hypothesis by characterizing variation in ~30 inflammatory response genes in a cohort of PCOS cases and controls. Our analysis will be divided into three Specific Aims. The initial analysis will consist of an association study in which we test for association between single nucleotide polymorphisms (SNPs) within ~43 candidate genes and ~1000 women with PCOS and ~1000 BMI and ethnicity matched control women. The SNPs will cover the coding region and 20 kb upstream and downstream of each gene and will be selected from the HAPMAP project for maximum informativeness.
In Aim 2 promising genes/regions will be analyzed in greater detail by identifying potentially functional variants using deep sequencing of promising haplotype blocks and further association studies.
Aim 3 will test the hypothesis that the expression pattern of the genes identified in Aims 1 + 2 is altered in PCOS. These studies will be critical in identifying genes that contribute to the etiology of PCOS and the primary biological pathways that are perturbed in the syndrome. Moreover, women with PCOS are at a seven-fold increased risk for developing T2DM making PCOS potentially the major risk factor for developing T2DM in women. Therefore, elucidating the role of these genes in the etiology of PCOS should also provide insight into the genetics and etiology of T2DM that can be tested in other populations.

Public Health Relevance

Polycystic ovary syndrome (PCOS) is common endocrine disorder characterized by elevated male sex hormones and menstrual irregularities and is also associated with obesity, insulin resistance, and a 7 fold increased risk of developing type 2 diabetes mellitus (T2DM). Since the inflammatory response is important in disorders related to PCOS like the metabolic syndrome, diabetes and obesity, we hypothesize that genes in the inflammatory response pathway also contribute to PCOS and propose to test the role of ~43 inflammatory response genes in PCOS. These studies will be critical in identifying genes that contribute to the etiology of PCOS, the primary biological pathways that are perturbed in this syndrome, and potentially also provide insight into the genetics and etiology of T2DM, an increasingly common disorder in western societies.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Taymans, Susan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northwestern University at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Gorsic, Lidija K; Kosova, Gulum; Werstein, Brian et al. (2017) Pathogenic Anti-Müllerian Hormone Variants in Polycystic Ovary Syndrome. J Clin Endocrinol Metab 102:2862-2872
Hayes, M Geoffrey; Urbanek, Margrit; Ehrmann, David A et al. (2015) Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nat Commun 6:7502
Bhatt, Surabhi; Mutharasan, Priscilla; Garcia, Obed A et al. (2014) The inflammatory gene pathway is not a major contributor to polycystic ovary snydrome. J Clin Endocrinol Metab 99:E567-71
Raja-Khan, Nazia; Urbanek, Margrit; Rodgers, Raymond J et al. (2014) The role of TGF-? in polycystic ovary syndrome. Reprod Sci 21:20-31
Mutharasan, Priscilla; Galdones, Eugene; Peñalver Bernabé, Beatriz et al. (2013) Evidence for chromosome 2p16.3 polycystic ovary syndrome susceptibility locus in affected women of European ancestry. J Clin Endocrinol Metab 98:E185-90
Kosova, Gülüm; Urbanek, Margrit (2013) Genetics of the polycystic ovary syndrome. Mol Cell Endocrinol 373:29-38
El Muayed, Malek; Raja, Meera R; Zhang, Xiaomin et al. (2012) Accumulation of cadmium in insulin-producing ? cells. Islets 4:405-16
Urbanek, Margrit; Hayes, M Geoffrey; Lee, Hoon et al. (2012) The role of inflammatory pathway genetic variation on maternal metabolic phenotypes during pregnancy. PLoS One 7:e32958
Strauss 3rd, Jerome F; McAllister, Jan M; Urbanek, Margrit (2012) Persistence pays off for PCOS gene prospectors. J Clin Endocrinol Metab 97:2286-8
Goodarzi, Mark O; Jones, Michelle R; Li, Xiaohui et al. (2012) Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts. J Med Genet 49:90-5

Showing the most recent 10 out of 14 publications