Genome-Wide Association Analysis Identifies Ancestry-Specific Genetic Variation Associated With Acute Response to Metformin and Glipizide in SUGAR-MGH

Authors

Josephine H Li
Laura N Brenner
Varinderpal Kaur
Katherine Figueroa
Philip Schroeder
Alicia Huerta-Chagoya
Miriam S Udler
Aaron Leong
Josep M Mercader
Jose C Florez

Publication Date

7-1-2023

Journal

Diabetologia

Abstract

AIMS/HYPOTHESIS: Characterisation of genetic variation that influences the response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) examined the acute response to metformin and glipizide in order to identify new pharmacogenetic associations for the response to common glucose-lowering medications in individuals at risk of type 2 diabetes.

METHODS: One thousand participants at risk for type 2 diabetes 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 genetic variants and primary endpoints of drug response. In a more focused analysis, we evaluated the influence of 804 unique type 2 diabetes- and glycaemic trait-associated variants on SUGAR-MGH outcomes and performed colocalisation analyses to identify shared genetic signals.

RESULTS: 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 [MAF

CONCLUSIONS/INTERPRETATION: We present a well-phenotyped, densely genotyped, multi-ancestry resource to study gene-drug interactions, uncover novel variation associated with response to common glucose-lowering medications and provide insight into mechanisms of action of type 2 diabetes-related variation.

DATA AVAILABILITY: The complete summary statistics from this study are available at the Common Metabolic Diseases Knowledge Portal ( https://hugeamp.org ) and the GWAS Catalog ( www.ebi.ac.uk/gwas/ , accession IDs: GCST90269867 to GCST90269899).

Keywords

Humans, Metformin, Glipizide, Diabetes Mellitus, Type 2, Genome-Wide Association Study, Blood Glucose, Glucose, Genetic Variation, Hypoglycemic Agents