RF10 | PMON217 Replication of PCOS Reproductive and Metabolic Subtypes in Diverse Cohorts – Towards a Rationale Approach to PCOS Classification

PCOS diagnosed by NIH or non-NIH Rotterdam criteria or by self-report is generally genetically similar. Using Hierarchical Clustering (HC), we have previously identified discrete, stable PCOS subtypes, which we designated reproductive (higher LH, FSH, SHBG) and metabolic (higher BMI, insulin, glucose), in a United States (US) cohort of ∼900 PCOS diagnosed by NIH criteria (Dapas et al. PLoS Med, 2020). The subtypes appeared to capture biologically meaningful differences because they were associated with distinct and novel genome-wide significant loci. In this study, we tested the hypothesis that the subtypes are a common feature of PCOS in regionally and ethnically diverse cohorts. All PCOS cases were ages 13-45 years, at least 2-years postmenarche and fulfilled NIH diagnostic criteria: 1) US European ancestry (EA), 1449; 2) Netherlands (NL) EA, 1067; 3) Greece (GR) EA, 568; 4) South Korea (KR) East Asian ancestry, 418. BMI, testosterone, SHBG, DHEAS, LH, FSH, fasting insulin, and fasting glucose levels were used for clustering. Trait Z-scores were compared among the cohorts. HC was adjusted for age and assay method. Both median BMI and BMI categories (nonobese, overweight, obese) defined by ancestry-specific cut points for EA and Asians differed (US>NL>GR>KR, all P<0.01). The prevalence of Class 2 (35.0-39.9) and Class 3 (≥ 40.0) was highest in US (P<0.001). The remaining traits were similar between cohorts prior to HC. Reproductive and metabolic subtypes were present in the 4 cohorts with similar Jaccard coefficients indicating cluster stability. The percent of cases was: reproductive subtype US 26%; NL 19%; GR, 62%; KR 20%; metabolic subtype US 53%; NL 61%; GR 22%; KR 31%. These differences were significant, except for the reproductive subtype in NL and KR. There was a 3-fold higher prevalence of the reproductive subtype in GR. BMI could not completely account for the metabolic subtype differences since KR had a higher prevalence of the metabolic subtype than GR, despite being significantly less obese. Remaining cases in each cohort who did not have a distinct pattern of trait distribution were designated "indeterminate" (US 21%; NL 20%; GR 16%; KR 49%). Reproductive and metabolic subtypes of PCOS diagnosed by NIH criteria are present in both regionally (US, Northern and Southern Europe) and ethnically (European and East Asian) diverse cohorts. Despite similar trait values, except for BMI, the prevalence of these subtypes varied among cohorts. Compared to other European and East Asian ancestry cohorts, the GR cohort had a strikingly higher prevalence of the reproductive and lower prevalence of the metabolic subtype. The reasons for these differences are being investigated but may reflect population-specific genetic variation. Nevertheless, our findings suggest that clustering algorithms capture biologically discrete subtypes in diverse PCOS populations diagnosed by NIH criteria. Presentation: Saturday, June 11, 2022 1:54 p.m. - 1:59 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.