期刊
LANCET DIABETES & ENDOCRINOLOGY
卷 2, 期 6, 页码 481-487出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/S2213-8587(14)70050-6
关键词
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资金
- Wellcome Trust UK type 2 diabetes case-control collection (GoDARTS) [099177/Z/12/12]
- Chief Scientist Office
- Wellcome Trust Centre for Human Genetics in Oxford
- Wellcome Trust Case Control Consortium 2 [084726/Z/08/Z]
- Innovative Medicines Initiative Joint Undertaking [115006]
- European Union
- European Federation of Pharmaceutical Industries and Associations companies' kind contributions
- Hong Kong Research Grants Council General Research Fund project [777511, 776513]
- European Commission
- National Institute for Health Research Senior Investigator award
- Wellcome Trust [098381, 092272/Z/10/Z]
- Medical Research Council [G0601261, MR/K007017/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10099] Funding Source: researchfish
- MRC [G0601261, MR/K007017/1] Funding Source: UKRI
- Wellcome Trust [092272/Z/10/Z] Funding Source: Wellcome Trust
Background Metformin is a first-line oral agent used in the treatment of type 2 diabetes, but glycaemic response to this drug is highly variable. Understanding the genetic contribution to metformin response might increase the possibility of personalising metformin treatment. We aimed to establish the heritability of glycaemic response to metformin using the genome-wide complex trait analysis (GCTA) method. Methods In this GCTA study, we obtained data about HbA(1c) concentrations before and during metformin treatment from patients in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) study, which includes a cohort of patients with type 2 diabetes and is linked to comprehensive clinical databases and genome-wide association study data. We applied the GCTA method to estimate heritability for four definitions of glycaemic response to metformin: absolute reduction in HbA(1c); proportional reduction in HbA(1c); adjusted reduction in HbA(1c); and whether or not the target on-treatment HbA(1c) of less than 7% (53 mmol/mol) was achieved, with adjustment for baseline HbA(1c) and known clinical covariates. Chromosome-wise heritability estimation was used to obtain further information about the genetic architecture. Findings 5386 individuals were included in the final dataset, of whom 2085 had enough clinical data to define glycaemic response to metformin. The heritability of glycaemic response to metformin varied by response phenotype, with a heritability of 34% (95% CI 1-68; p=0.022) for the absolute reduction in HbA(1c), adjusted for pretreatment HbA(1c). Chromosome-wise heritability estimates suggest that the genetic contribution is probably from individual variants scattered across the genome, which each have a small to moderate effect, rather than from a few loci that each have a large effect. Interpretation Glycaemic response to metformin is heritable, thus glycaemic response to metformin is, in part, intrinsic to individual biological variation. Further genetic analysis might enable us to make better predictions for stratified medicine and to unravel new mechanisms of metformin action.
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