Genome-wide association analysis identifies ancestry-specific genetic variation associated with acute response to metformin and glipizide in SUGAR-MGH

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_Afr]=0.0283) at rs149403252 and lower fasting glucose at Visit 2 following metformin (p=1.9×10^-9); carriers were found to have a 0.94 mmol/l larger decrease in fasting glucose. rs111770298, another African ancestry-specific variant (MAF_Afr=0.0536), was associated with a reduced response to metformin (p=2.4×10^-8), where carriers had a 0.29 mmol/l increase in fasting glucose compared with non-carriers, who experienced a 0.15 mmol/l decrease. This finding was validated in the Diabetes Prevention Program, where rs111770298 was associated with a worse glycaemic response to metformin: heterozygous carriers had an increase in HbA_1c of 0.08% and non-carriers had an HbA_1c increase of 0.01% after 1 year of treatment (p=3.3×10^-3). We also identified associations between type 2 diabetes-associated variants and glycaemic response, including the type 2 diabetes-protective C allele of rs703972 near ZMIZ1 and increased levels of active glucagon-like peptide 1 (GLP-1) (p=1.6×10^-5), supporting the role of alterations in incretin levels in type 2 diabetes pathophysiology.

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: Genetics; Genome-wide association study; Glipizide; Incretin; Metformin; Multi-ancestry; Pathophysiology; Pharmacogenetics; Sulfonylurea; Type 2 diabetes.

Fig. 1

Study schema. (a) We recruited 1000 individuals at risk of developing type 2 diabetes. (b) At V1, participants had their vital signs monitored, provided whole blood for DNA and underwent fasting measurements. Individuals with a fasting blood sugar >4.4 mmol/l received a dose of 5 mg of glipizide orally, followed by additional measurements. (c) After a 5 day wash-out period, participants received three doses of metformin of 500 mg. (d) At V2, participants returned for the final (fourth) dose of metformin and a 75 mg OGTT. (e) We performed genome-wide genotyping, constructed phenotypes of drug response and performed a GWAS, in order to (f) identify genotypes associated with outcomes of drug response. MTF, metformin; SU, sulfonylurea

Fig. 2

(a) Regional association plot of rs111770298. (b) Box plot illustrating mean change in fasting glucose (V2 minus V1) by rs111770298 genotype

Fig. 3

(a) Colocalisation plot showing that rs703972 near ZMIZ1 colocalises with active GLP-1 and type 2 diabetes risk. (b, c) LocusZoom plots of association of rs703972 with (b) type 2 diabetes and (c) active GLP-1. (d) Change in total and (e) active GLP-1 by rs703972 at V2 during OGTT. abf, approximate Bayes factor; T2D_DIAMANTE_EUR, GWAS results in European population from Diabetes, Meta-Analysis Trans-Ethnic Consortium