LAUSR

Objective: Discover loci associated with triglyceride (TG) levels in the context of type 2 diabetes (T2D). Research Design and Methods: Genome-wide association study (GWAS) was performed in 424,120 genotyped participants of the UK Biobank (UKB) with T2D status and TG levels. Association analyses of TG levels were performed stratified by T2D status for genetic variants with minor allele count (MAC) at least 20 in each stratum. Effect differences of genetic variants by T2D status were determined by Cochrans Q-test implemented in METAL (p-value<5x10-8). Validation of significant variants was pursued in 25,137 participants of the Mass General Brigham Biobank (MGBB). Results: Among 21,176 T2D and 402,944 non-T2D samples, stratified GWAS identified 19 and 315 genomic risk loci significantly associated with TG levels, respectively. Only chr6p21.32 exhibited genome-wide significant heterogeneity (I2=98.4%; pheterogeneity=2.1x10-15), with log(TG) effect estimates of -0.066 (95%CI: -0.082, -0.050) and 0.002 (95%CI: -0.002, 0.006) for T2D and non-T2D, respectively. The lead variant rs9274619:A (allele frequency 0.095) is located 2Kb upstream of the HLA-DQB1 gene. We replicated this finding among 25,137 participants (6,951 T2D cases) of MGBB (pheterogeneity=9.5x10-3). Phenome-wide interaction association analyses showed that the lead variant was strongly associated with a concomitant diagnosis of type 1 diabetes (T1D) as well as diabetes-associated complications. Conclusion: An intergenic variant near HLA-DQB1 significantly associates with decreased triglycerides only among those with T2D and highlights an immune overlap with T1D.