Genome-wide association analysis identifies ancestry-specific genetic variation associated with medication response in the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH)

Background: Characterization of genetic variation that influences response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes (T2D). SUGAR-MGH examined the acute response to two anti-diabetes medications in order to understand the functional relevance of known T2D- and glycemic trait-associated genetic loci. Methods: 1,000 participants at risk for T2D from diverse ancestries underwent sequential glipizide and metformin challenges. A genome-wide association study was performed using the Illumina Multi-Ethnic Genotyping Array. Imputation was performed with the TOPMed reference panel. Multiple linear regression using an additive model tested for association between variants and primary endpoints of drug response. We evaluated the influence of 804 unique T2D and glycemic trait-associated variants on SUGAR-MGH outcomes and performed colocalization analyses to identify shared genetic signals. Findings: Five genome-wide significant variants were associated with metformin or glipizide response. The strongest association was between an African ancestry-specific variant (minor allele frequency=0.026) at rs149403252 and lower fasting glucose following metformin, adjusted for baseline glucose (p=1.9x10-9), with a 0.94 mmol/L larger decrease in fasting glucose after metformin. We identified associations between T2D-associated variants and glycemic response, including the T2D-protective C allele of rs703972 near ZMIZ1 and increased levels of active GLP-1 (p=1.6x10-5), supporting the role of alterations in incretin levels in T2D pathophysiology. Interpretation: We present a well phenotyped, densely genotyped, multi-ancestry resource to study gene-drug interactions, uncover novel variation associated with response to common anti-diabetes medications, and provide insight into mechanisms of action of T2D-related variation.