Abstract P104: Genetic Factors Influence Glycated Hemoglobin, Fasting Glucose, and Fasting Insulin Levels in the Population Architecture Using Genomics and Epidemiology Consortium

Abstract

Elevated levels of fasting glucose and fasting insulin precede the development type 2 diabetes (T2D). While T2D and cardiovascular disease share common risk factors, dysregulation of glucose metabolism is of particular concern because it can result in end-organ damage including the heart, nerves, kidneys, and eyes. The prevalence of diabetes is higher in American minority populations. Through genome-wide association studies, approximately 60 loci have been identified for fasting glucose, fasting insulin, and glycated hemoglobin. To better understand the genetic basis of glucose dysregulation, the Population Architecture using Genomics and Epidemiology (PAGE) Consortium genotyped 12,801 Hispanic/Latinos, 5,696 African Americans, 1,405 Native Hawaiians, 398 Native Americans, and 1,727 Asians without diabetes using the approximately 1.3 million variants on the Multi-Ethnic Global Array (MEGA), which is enriched for coding variation and ancestral diverse content. Through ancestry-combined single variant association testing with fasting glucose, fasting insulin, and glycated hemoglobin (HbA1c), we identified a novel potential association between decreased HbA1c and the minor A allele of rs11887523 ( p = 4.51x10 -9 , MFSD2B p.A60T, minor allele frequency (MAF) 7% in African Americans, MAF 2% in Hispanics). Other associations with HbA1c included hemoglobin genes, further highlighting the importance of considering variation in hemoglobin and red-blood cell lifespan when using HbA1c as a measure of glucose control. We also replicated several known associations including between fasting glucose and variants near G6PC2, GCKR, MTNR1B, and FOXA2 ; and between fasting insulin and the GRB14/COBLL1 locus. Further analyses including imputing the data out to 1000 Genomes phase3 and gene-based tests of rare variants are underway. These will increase power to detect associations with ancestry-specific rare variants.