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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).

Titel:	Genome-wide association analysis identifies ancestry-specific genetic variation associated with acute response to metformin and glipizide in SUGAR-MGH.
Autor/in / Beteiligte Person:	Li, JH ; Brenner, LN ; Kaur, V ; Figueroa, K ; Schroeder, P ; Huerta-Chagoya, A ; Udler, MS ; Leong, A ; Mercader, JM ; Florez, JC
Link:	Zum Volltext
Zeitschrift:	Diabetologia, Jg. 66 (2023-07-01), Heft 7, S. 1260-1272
Veröffentlichung:	Berlin Springer Verlag, 2023
Medientyp:	academicJournal
ISSN:	1432-0428 (electronic)
DOI:	10.1007/s00125-023-05922-7
Schlagwort:	Humans Glipizide therapeutic use Genome-Wide Association Study Blood Glucose metabolism Glucose Genetic Variation genetics Hypoglycemic Agents therapeutic use Metformin therapeutic use Diabetes Mellitus, Type 2 drug therapy Diabetes Mellitus, Type 2 genetics Diabetes Mellitus, Type 2 metabolism
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(PMID: 10.2337/db08-0896193366792682689) Grant Information: T32 DK007028 United States DK NIDDK NIH HHS; K23 DK114551 United States DK NIDDK NIH HHS; MC_EX_MR/M009203/1 United Kingdom MRC_ Medical Research Council; MC_UU_00033/1 United Kingdom MRC_ Medical Research Council; P30 DK036836 United States DK NIDDK NIH HHS; M01 RR001066 United States RR NCRR NIH HHS; R01 DK088214 United States DK NIDDK NIH HHS; U01 HG011723 United States HG NHGRI NIH HHS; MR/M009203/1 United Kingdom MRC_ Medical Research Council; S10 OD030463 United States OD NIH HHS; UL1 TR000170 United States TR NCATS NIH HHS; K23 DK131345 United States DK NIDDK NIH HHS; R03 DK077675 United States DK NIDDK NIH HHS; R01 HD030880 United States HD NICHD NIH HHS; S10 OD026880 United States OD NIH HHS; MR/R024227/1 United Kingdom MRC_ Medical Research Council; MC_UU_00007/10 United Kingdom MRC_ Medical Research Council; R01 GM117163 United States DK NIDDK NIH HHS; UL1 RR025758 United States RR NCRR NIH HHS; R01 GM117163 United States GM NIGMS NIH HHS; 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RL Hanson; WC Knowler; TI Pollin; AR Shuldiner; K Jablonski; PW Franks; MF Hivert; JH Li; JA Perry; S Srinivasan; JM Mercader; JN Todd ; Keywords: Genetics; Genome-wide association study; Glipizide; Incretin; Metformin; Multi-ancestry; Pathophysiology; Pharmacogenetics; Sulfonylurea; Type 2 diabetes Substance Nomenclature: 9100L32L2N (Metformin) ; X7WDT95N5C (Glipizide) ; 0 (Blood Glucose) ; IY9XDZ35W2 (Glucose) ; 0 (Hypoglycemic Agents) Entry Date(s): Date Created: 20230526 Date Completed: 20230608 Latest Revision: 20240614 Update Code: 20240614 PubMed Central ID: PMC10790310

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