27-OR: Genome-Wide Association Analysis Identifies Ancestry-Specific Genetic Variation Associated with Medication Response in the Study to Understand the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH)

Abstract

SUGAR-MGH is a pharmacogenetic resource for characterizing genetic influences on pharmacological perturbations relevant to type 2 diabetes (T2D). 1,000 participants who were naïve to T2D treatment received 5 mg glipizide, followed by 4 doses of 500 mg metformin and a 75-g oral glucose tolerance test (OGTT) a week later. Glucose and insulin were measured at pre-specified endpoints after glipizide and during the OGTT. Incretin levels were measured in a subset. We calculated physiologic endpoints reflecting insulin secretion, insulin sensitivity, and incretin secretion. The mean age was 47 years, 54% were women, >35% were non-white, and the mean BMI was 30.2 kg/m2. 890 participants underwent genome-wide genotyping using the Illumina Multi-Ethnic Genotyping Array, and high-quality imputation was performed with the TOPMed reference panel. Multiple linear regression using an additive model tested for association between genetic variants and endpoints. We identified 21 genome-wide significant variants, of which 3 met experiment-wide significance (P<8.3×10-9 for 2 drugs × 3 physiological hypotheses tested). The most significant 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=1.9×10-9). We tested the influence of 429 known T2D-associated variants and found that the protective C allele of rs703972 near ZMIZ1 was associated with increased secretion of active GLP-1 in response to metformin (P=1.6×10-5), suggesting that an enhanced incretin response may be a mechanism by which this variant decreases T2D risk. We illustrate that a genome-wide approach in a multi-ethnic human perturbation study can uncover new variation associated with drug response and provide insight into mechanisms of action of known T2D genetic variation. Disclosure J. H. Li: None. V. Kaur: None. L. Brenner: Research Support; Self; Apple. J. M. Mercader: None. J. C. Florez: Consultant; Self; Goldfinch Bio, Inc., Other Relationship; Self; Novo Nordisk. Funding National Institutes of Health (R01DK088214, R03DK077675, P30DK036836, M01RR01066, 1UL1RR025758-04, 8UL1TR000170-05, T32DK007028)