1339-P: Multiancestry Genome-Wide Association Study of Diabetic Ketoacidosis

Diabetic ketoacidosis (DKA) is a life-threatening complication disproportionately affecting people with African (AFR) and Hispanic (HIS) more than European (EUR) ancestry. To examine genetic susceptibility to DKA, we performed multi-ancestry meta-analysis of genome-wide association studies (GWAS) of DKA, and phenome-wide association studies (PheWAS) of significant loci, in VA Million Veteran Program (MVP) participants with diabetes, with vs. without DKA, and adjusted for age, sex and top ten principal components. Among 5,036 DKA cases (2,843 EUR; 1,733 AFR; 460 HIS) and 152,119 controls (105,504 EUR; 33,037 AFR; 13,578 HIS), both had mean BMI 31 kg/m² and were 94% male, but cases were younger than controls (60 vs. 65 yr). Of five genome-wide significant loci identified, four had similar effects across all ancestry groups: increased DKA risk associated with a chromosome (chr) 3 locus (rs1716165575, nearest gene SLC2A2, OR 1.2, 95% CI 1.2-1.3, p=1.25E-18) and two loci on chr 6 (rs3130396, HCG17, OR 1.1 [1.1-1.2], p=1.34E-08; and rs539981616, HLA-DQA1, OR 1.7 [1.6-1.8], p=7.82E-43), and decreased DKA risk with a chr 11 locus (rs3842752, INS-IGF2, OR 0.8 [0.8-0.9], p=8.74E-10). In contrast, for a chr 17 locus (rs113748381, SLC16A11, OR 1.5 [1.3-1.8], p=3.16E-20), HIS and AFR, but not EUR (p>0.05), individuals had higher risk for DKA (OR 1.7 [1.4-1.7] in HIS; OR 1.5 [1.4-1.6] in AFR), and higher effect allele frequencies (HIS 19% and AA 8%, vs. EUR 0.81%). In PheWAS analyses, all genetic loci, except chr 6 HCG17, were significantly associated with DKA (for both type 1 and type 2 diabetes), where SLC2A2, HLADQA1, and SLC16A11 were associated with increased risk of both, and INS-IGF2 was associated with decreased risk.

Conclusion: Both HLA and non-HLA chromosomal regions were associated with increased risk of DKA in a large multi-ancestry cohort. Variants at SLC16A11 were much more common in HIS and AFR compared to EUR individuals and might underlie racial/ethnic differences in the clinical presentation of DKA.