Abstract 18535: Rare Variants Identified With Whole Exome Chip Genotyping Are Associated With Insulin Resistance and Glycemic Control

Abstract

Background: Insulin resistance (IR) and type 2 diabetes mellitus (DM) are heritable. Application of genome mapping for these traits, primarily with common variants, has incompletely characterized the genetic architecture. We hypothesized that rare coding variants are associated with IR in individuals without DM, and with glycemic control in individuals with DM. Methods: Extracted DNA from 611 Caucasian individuals enrolled in the CATHGEN cardiovascular biorepository at Duke University was genotyped on the Illumina Infinium HumanExome BeadChip (241465 single nucleotide variants [SNVs]). Linear regression was used to test each variant for association with glycated albumin (GA) measured in frozen, fasting plasma (a surrogate for hemoglobin A1c and thus a marker of glycemic control in individuals with DM and of IR in individuals without DM), adjusting for age, sex, batch, and principal component-derived ethnicity. Results: In individuals without DM, one SNV in an uncharacterized protein ( KIAA1614 , p=3.1x10 -8 ) met genomewide significance (p<10 -7 ). Other lesser significant SNVs included genes reporting on ribosomal function ( MRPL44 p=5.5x10 -5 , LACTB p=1.7x10 -4 ), cellular processes ( CENPP p=2.6x10 -5 ; MEGF6 p=1.6x10 -4 ), ion channels ( KCNT1 p=2.0x10 -5 ), protein degradation ( ASB10 p=8.1x10 -5 ), and in insulin receptor ( INSR p=9.4x10 -5 ) and carbonyl reductase ( CBR1 p=6.6x10 -5 ). In individuals with DM, several SNVs met genomewide significance: WDR27 (p=8.1x10 -12 ), HELQ (p=2.0x10 -9 ), genes involved in cell cycle processes ( NUP214 p=9.8x10 -9 , PTPRJ p=1.6x10 -8 ), cell-cell interactions ( CHST9 p=2.6x10-8, multiple protocadherin [ PCDHG ] genes, p=3.3x10 -8 ), ion channels ( CACAN1A , p=4.2x10 -8 ), MMP13 (p=4.7x10 -8 ), and FBLN5 (p=9.1x10 -8 ), involved in vascular development and remodeling. Conclusions: We have identified several rare variants in biologically plausible genes reporting on diverse cellular processes that are associated with IR in individuals without DM, and with glycemic control in individuals with DM, that would not have been identified using traditional genomewide association (GWAS) screens. These may serve as novel biomarkers and identify novel pathways of IR and DM pathogenesis.