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@article{Li:2023:10.1007/s00125-023-05922-7,
author = {Li, JH and Brenner, LN and Kaur, V and Figueroa, K and Schroeder, P and Huerta-Chagoya, A and MAGIC, Investigators and Diabetes, Prevention Program DPP Research Group and Udler, MS and Leong, A and Mercader, JM and Florez, JC},
doi = {10.1007/s00125-023-05922-7},
journal = {Diabetologia},
pages = {1260--1272},
title = {Genome-wide association analysis identifies ancestry-specific genetic variation associated with acute response to metformin and glipizide in SUGAR-MGH.},
url = {http://dx.doi.org/10.1007/s00125-023-05922-7},
volume = {66},
year = {2023}
}

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TY  - JOUR
AB  - 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 [MAFAfr]=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 (MAFAfr=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 increa
AU  - Li,JH
AU  - Brenner,LN
AU  - Kaur,V
AU  - Figueroa,K
AU  - Schroeder,P
AU  - Huerta-Chagoya,A
AU  - MAGIC,Investigators
AU  - Diabetes,Prevention Program DPP Research Group
AU  - Udler,MS
AU  - Leong,A
AU  - Mercader,JM
AU  - Florez,JC
DO  - 10.1007/s00125-023-05922-7
EP  - 1272
PY  - 2023///
SP  - 1260
TI  - Genome-wide association analysis identifies ancestry-specific genetic variation associated with acute response to metformin and glipizide in SUGAR-MGH.
T2  - Diabetologia
UR  - http://dx.doi.org/10.1007/s00125-023-05922-7
UR  - https://www.ncbi.nlm.nih.gov/pubmed/37233759
VL  - 66
ER  -

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