239-OR: Genome-Wide Association Study (GWAS) of Hypoglycemia in the Million Veteran Program (MVP)

Hypoglycemia is a preventable adverse effect of treatment in diabetes patients, but actionable pharmacogenetic evidence to minimize hypoglycemia risk is lacking. We used the MVP biospecimen and clinical biobank to perform a case/control GWAS of hypoglycemia in 96,406 diabetes patients receiving care in the U.S. Veterans Health Administration. Cases had an outpatient random plasma glucose (RPG) <70 mg/dL or an emergency room visit for hypoglycemia; controls had an RPG or clinic visit annually during follow-up but did not meet the case criteria. Genotypes were based on a custom MVP Affymetrix array, imputed with ancestry-specific HRC reference panels and limited to variants with minor allele frequency (MAF) >1%. GWAS were conducted in 72,244 participants (22,045 cases) of European ancestry [EUR] and 24,162 (10,441 cases) of African ancestry [AFR]), adjusted for age at MVP enrollment, sex, and 10 genetic principal components. We identified a single locus associated with hypoglycemia in EUR individuals (rs1064173, HLA-DQB1 locus, odds ratio [OR] 1.15, p=5.6E-19, MAF 0.20) and in AFR individuals (rs12712928, SIX3 locus, OR 0.87, p=2.7E-8, MAF 0.17). In a phenomewide association study (PheWAS) in MVP EUR diabetes patients, rs1064173 was associated with type 1 diabetes (T1D, OR 1.41, p=7.8E-25) and diabetes complications (retinopathy, OR 1.24, p=9E-24; neuropathy, OR 1.16, p=1.3E-5). To address the known association of the HLA locus with T1D, we performed a sensitivity analysis excluding patients with any use of T1D diagnosis codes. In this sample enriched for type 2 diabetes, rs1064173 remained nominally associated with hypoglycemia (OR 1.23, p=0.02) and retinopathy (OR 1.10, p=0.003). Rs12712928 - previously associated with glucose and hemoglobin A1c in an East Asian sample - was not associated with any diagnoses in a PheWAS of MVP AFR diabetes patients.

In conclusion, a GWAS of hypoglycemia in a clinical biobank found ancestry-specific genetic associations that may have treatment implications.