137-OR: A Genetic Approach to Detangling the Heterogeneity of Fasting Insulin Levels

Fasting insulin (FI) is a heterogeneous trait with high variability between individuals and populations. Increased FI is associated with an increased risk of type 2 diabetes (T2D) and its complications, including coronary artery disease (CAD) and hypertension (HTN) . We hypothesize that we could use a genetic approach to cluster FI-associated variants, characterize the clusters in terms of insulin processes within the Mexican American Cardiovascular Disease Study (MACAD; N=821) , and test for association of polygenic scores (PS) created from these clusters with T2D, CAD and HTN in three cohorts: Mass General Brigham Biobank (MGBB; N=18,127) , Aspirin in Reducing Events in the Elderly (ASPREE; N=13,349) , and Framingham Heart Study (FHS; N=7,145) . We identified six clusters using a soft clustering approach with 446 FI-increasing genetic alleles and 27 FI-related traits. Associations in two of the clusters, allowed us to characterize them and show their impact on T2D and T2D-associated complications. The first cluster had alleles associated with increased subcutaneous and visceral adiposity and was characterized by reduced insulin sensitivity (from euglycemic clamp; P=0.02) , increased insulin secretion (from oral glucose tolerance test [OGTT]; P=0.04) , and increased insulin clearance (from euglycemic clamp; P=0.02) in MACAD. This cluster’s PS was associated with HTN (MGBB Odds ratio (OR) = 1.04, P=0.013) , T2D (MGBB OR = 1.04, P =0.001) and CAD (MGB OR=1.07, P =0.008; ASPREE OR=1.04, P =0.036) The second cluster had alleles associated with a lipodystrophy phenotype and was characterized by increased insulin secretion (from OGTT P =0.019) in MACAD. We observed associations of the PS with T2D (MGBB OR= 1.13, P =2.3x10^-10) and HTN (MGBB OR = 1.06, P =0.001) which were replicated in ASPREE and FHS. Our results suggest the presence of two different FI-associated genetic domains and elucidate the deleterious mechanisms by which increased FI is associated with T2D and T2D complications.