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Polycystic ovary syndrome (PCOS) is now recognized not only as a cosmetic and reproductive disorder, but also as a metabolic disorder with important consequences. The balance of the literature suggests that PCOS increases the risk of future type 2 diabetes (T2D); however, whether PCOS increases the risk of coronary heart disease (CHD) and/or stroke is more controversial. Despite a high burden of cardiovascular risk factors (which suggests a high risk of events), the mostly small and retrospective cohort studies have yielded conflicting results. Meta-analyses of these studies suggested at best a 1.4 to 2-fold increased risk of CHD and stroke, which attenuated to 1.2-1.6 when accounting for body mass index (BMI) (1,2). Given that observational studies may be biased by confounders between the risk factor and outcome (in this case, elevated BMI often present in PCOS), we performed Mendelian randomization (MR) analyses to examine the possible causal effect of polycystic ovary syndrome (PCOS) with T2D, CHD and stroke. MR uses genetic variants as instruments to represent exposures of interest to assess causality between exposures and outcomes (3). It is increasingly being used because it overcomes confounding and reverse causation, which often plague observational studies. The instrument variables for PCOS were constructed based on 14 SNPs derived from a published GWAS meta-analysis for PCOS conducted in European cohorts (10,074 cases and 103,164 controls) (4). The SNP to outcomes estimates were obtained from the DIAMANTE T2D GWAS (74,124 T2D cases and 824,006 controls) (5), the CHD GWAS meta-analysis of the UK Biobank plus CARDIoGRAMplusC4D (122,733 cases and 424,528 controls) (6) and the MEGASTROKE consortium GWAS (67,162 cases and 454,450 controls) (7). MR analyses were conducted using three methods: inverse variance weighted (IVW) (primary method), weighted median and MR Egger (sensitivity analyses). In our study, no significant association of genetically predicted PCOS with T2D (OR 0.97, CI 0.91-1.02), CHD (OR 0.99, CI 0.95-1.03) or stroke (OR 0.98, CI 0.93-1.02) was observed. Our findings suggest that PCOS is not a causal risk factor for T2D, CHD or stroke. The observed associations of PCOS with these three diseases from observational studies are likely due to confounding factors and small sample sizes. Given that MR has found that increasing BMI is causal for PCOS as well as T2D and CHD, overweight/obesity is the likely confounding variable. These results suggest a critical revision of how we counsel and manage women with PCOS. Reference: 1. Zhou Y, et al. Gynecol Endocrinol 2017; 33:904-910 2. De Groot PC, et al. Hum Reprod Update 2011; 17:495-500 3. Davey Smith G, et al. Hum Mol Genet. 2014; 23:R89-R98. 4. Day F, et al. PLoS Genet. 2018;14(12). 5. Mahajan A, et al. Nat Genet. 2018;50(11):1505-1513. 6. van der Harst P, et al. Circ Res. 2018;122(3):433-443. 7. Malik R, et al. Nat Genet. 2018;50(4):524-537.

journal of the endocrine society

SUN-016 Mendelian Randomization Reveals That Polycystic Ovary Syndrome Is Not a Causal Risk Factor for Type 2 Diabetes, Coronary Heart Disease, or Stroke