title: Heritability of variation in glycaemic response to metformin: a genome-wide complex trait analysis.
abstract: 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 HbA1c 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 HbA1c; proportional reduction in HbA1c; adjusted reduction in HbA1c; and whether or not the target on-treatment HbA1c of less than 7% (53 mmol/mol) was achieved, with adjustment for baseline HbA1c and known clinical covariates. Chromosome-wise heritability estimation was used to obtain further information about the genetic architecture.
  
  
  RESULTS
  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 HbA1c, adjusted for pretreatment HbA1c. 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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Wellcome Trust.
authors.affiliation: Medical Research Institute, University of Dundee, Dundee, UK. Electronic address: k.zhou@dundee.ac.uk.
authors.forename: Kaixin
authors.initials: K
authors.lastname: Zhou
authors.affiliation: Medical Research Institute, University of Dundee, Dundee, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Donnelly
authors.affiliation: University of Queensland, Queensland Brain Institute, Brisbane, QLD, Australia.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Psychiatry, Centre for Genomic Sciences and State Key Laboratory in Brain and Cognitive Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Miaoxin
authors.initials: M
authors.lastname: Li
authors.affiliation: Medical Research Institute, University of Dundee, Dundee, UK.
authors.forename: Harshal
authors.initials: H
authors.lastname: Deshmukh
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
authors.forename: Natalie
authors.initials: N
authors.lastname: Van Zuydam
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Skåne, Malmö, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Ahlqvist
authors.affiliation: Churchill Hospital, and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Chris C
authors.initials: CC
authors.lastname: Spencer
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Skåne, Malmö, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.affiliation: Medical Research Institute, University of Dundee, Dundee, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Morris
authors.affiliation: Medical Research Institute, University of Dundee, Dundee, UK.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Colhoun
authors.affiliation: Department of Psychiatry, Centre for Genomic Sciences and State Key Laboratory in Brain and Cognitive Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Pak C
authors.initials: PC
authors.lastname: Sham
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK; Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK; Churchill Hospital, and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Medical Research Institute, University of Dundee, Dundee, UK.
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
authors.affiliation: Medical Research Institute, University of Dundee, Dundee, UK. Electronic address: e.z.pearson@dundee.ac.uk.
authors.forename: Ewan R
authors.initials: ER
authors.lastname: Pearson
mesh_terms: D001786:Blood Glucose; D015992:Body Mass Index; D003627:Data Interpretation, Statistical; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D012606:Scotland / Q000453:epidemiology
chemical_list: D001786:Blood Glucose; D005819:Genetic Markers; D007004:Hypoglycemic Agents; D008687:Metformin
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