Genome-wide association analysis identifies ancestry-specific genetic variation associated with acute response to metformin and glipizide in SUGAR-MGH
Authors' conclusion
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.
Study context
- Population
- Individuals at risk for T2D from diverse ancestries (SUGAR-MGH)
- Participants
- 1,000 individuals
- Comparison
- Carriers vs non-carriers of genetic variants for acute response to metformin and glipizide
- Outcome
- Primary endpoints of drug response to metformin and glipizide
Methodological detailsmulti-ancestry, sequential glipizide and metformin challenges, additive model, colocalisation analyses
- Multi-ancestry
- Sequential glipizide and metformin challenges
- Additive model
- Colocalisation analyses
Main finding
As reported in the abstract
Genome-wide significant variants for metformin or glipizide response
- Genome-wide significant variants associated with metformin or glipizide response
- 5
- African ancestry-specific rs149403252 (MAFAfr=0.0283): lower fasting glucose at Visit 2 after metformin; carriers 0.94 mmol/l larger decrease in fasting glucose
- p=1.9×10-9
- African ancestry-specific rs111770298 (MAFAfr=0.0536): reduced metformin response; carriers 0.29 mmol/l increase in fasting glucose vs 0.15 mmol/l decrease in non-carriers
- p=2.4×10-8
Further findings
Validation of rs111770298 in the Diabetes Prevention Program: HbA1c change · 1 year of treatment
- Worse glycaemic response to metformin; HbA1c increase 0.08% in heterozygous carriers vs 0.01% in non-carriers
- P = 3.3×10-3
T2D-associated variants: rs703972 near ZMIZ1 (T2D-protective C allele) and active GLP-1
- C allele of rs703972 associated with increased active GLP-1 levels
- P = 1.6×10-5
- 804 unique T2D- and glycaemic trait-associated variants evaluated
Original publication
Genome-wide association analysis identifies ancestry-specific genetic variation associated with acute response to metformin and glipizide in SUGAR-MGH. Diabetologia. Published 26 May 2023. doi:10.
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