1477-P: Polygenic Risk Score (PRS) Derived from Common Variants of Monogenic Diabetes Genes (MDG) Predicts Young Onset Diabetes (YOD) and Cardiovascular(CV)-Kidney Complications

Introduction & Objectives: Monogenic diabetes are caused by rare mutations in genes usually implicated in β-cell reserve/function. Whether their common variants could jointly influence risk of YOD diagnosed before 40 years and CV-kidney events is underexplored. We hypothesized a positive association of a weighted PRS derived from common variants of MDG with these outcomes. Methods: We constructed three weighted PRS with common variants (minor allele frequency>0.01) of 34 MDG based on three r2 thresholds (0.2, 0.4, 0.6) of linkage disequilibrium (LD), from a discovery cohort of adults with [n=453, median age (interquartile range) = 40.0 (35.0-47.0)] and without [n=405, age=56.7 (50.3-61.0)] YOD who had whole exome sequencing data followed by validation in an independent cohort with array-based genotyping. We further tested association of the best performer with incident CV-kidney events in a cohort of type 2 diabetes (T2D). Results: 135 single nucleotide polymorphisms were used to construct the PRS based on LD r2 threshold 0.2 which performed the best at validation in an independent cohort (920 YOD + 4909 non-YOD) where per standard deviation (SD) rise in PRS was associated with 8% increased risk of YOD after adjusting sex and BMI (OR 1.08, p=0.047). In an independent cohort of T2D free of CV-kidney events at baseline [n=2313, age = 53.4 (45.4-61.7), disease duration = 4.0 (1.0-9.0)], per SD rise in PRS was associated with 16%, 9% and 10% increased risk of incident CV (HR 1.16, p