Abstract 10660: Genome-Wide Scan Identifies Variants Increasing Triglycerides Only Among Diabetics

Abstract

Introduction: Increased triglycerides (TG) frequently accompanies type 2 diabetes (T2D) mellitus and poor glycemic control. The extent to which genetics influences triglycerides differently in individuals with T2D is not well understood. Methods: We conducted a genome-wide association study (GWAS) of log(TG) stratified by T2D using imputed UKB genotypes with minor allele count>20. We used linear regression model with a leave-one-out cross-validation using REGENIE adjusted for PC1-10, age, age 2 , gender, array-type, and race. We assessed the heterogeneity (I 2 ) between the effects of TG in T2D and non-T2D individuals. We sought replication in the Mass General Brigham Biobank (MGBB). Results: Among 21,176 T2D and 402,944 non-T2D samples, stratified GWAS identified 17 and 45 loci significantly associated with TG levels, respectively. Only one loci exhibited significant genome-wide heterogeneity (I 2 =98.4%; p heterogeneity =2x10 -15 ). The most significantly heterogenous variant was an intronic variant of the HLA-DQB1 gene, where the major allele (frequency 91.3%) was associated with increased TGs among those with T2D but not non-T2D (T2D group: beta=0.066, p-value=3.9x10 -15 ; non-T2D group: beta=-0.002, p-value=0.21). Among 25,136 participants (6,951 T2D cases) of MGBB, we replicated this finding (p heterogeneity =0.01). Conclusions: An intronic variant at HLA-DQB1 significantly associates with increased TGs only in those with T2D.