title: A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts.
abstract: OBJECTIVE
  In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations.
  
  
  METHODS
  Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS, n = 929) and the Rotterdam Study (n = 182) from the Netherlands, and the CARDS Trial (n = 254) from the UK were genotyped for rs11212617 and tested for an association with both HbA(1c) reduction and treatment success, defined as the ability to reach the treatment target of an HbA(1c) ≤ 7 % (53 mmol/mol). Finally, a meta-analysis including data from literature was performed.
  
  
  RESULTS
  In the DCS cohort, we observed an association between rs11212617 genotype and treatment success on metformin (OR 1.27, 95% CI 1.03, 1.58, p = 0.028); in the smaller Rotterdam Study cohort, a numerically similar but non-significant trend was observed (OR 1.45, 95% CI 0.87, 2.39, p = 0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously published cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95% CI 1.04, 1.49, p = 0.016 and OR 1.25, 95% CI 1.33, 1.38, p = 7.8 × 10(-6), respectively).
  
  
  CONCLUSIONS
  A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetic patients from the Netherlands and the UK. This is the first robustly replicated common susceptibility locus found to be associated with metformin treatment response.
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: van Leeuwen
authors.forename: G
authors.initials: G
authors.lastname: Nijpels
authors.forename: M L
authors.initials: ML
authors.lastname: Becker
authors.forename: H
authors.initials: H
authors.lastname: Deshmukh
authors.forename: K
authors.initials: K
authors.lastname: Zhou
authors.forename: B H C
authors.initials: BH
authors.lastname: Stricker
authors.forename: A G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: A
authors.initials: A
authors.lastname: Hofman
authors.forename: E
authors.initials: E
authors.lastname: van 't Riet
authors.forename: C N A
authors.initials: CN
authors.lastname: Palmer
authors.forename: B
authors.initials: B
authors.lastname: Guigas
authors.forename: P E
authors.initials: PE
authors.lastname: Slagboom
authors.forename: P
authors.initials: P
authors.lastname: Durrington
authors.forename: R A
authors.initials: RA
authors.lastname: Calle
authors.forename: A
authors.initials: A
authors.lastname: Neil
authors.forename: G
authors.initials: G
authors.lastname: Hitman
authors.forename: S J
authors.initials: SJ
authors.lastname: Livingstone
authors.forename: H
authors.initials: H
authors.lastname: Colhoun
authors.forename: R R
authors.initials: RR
authors.lastname: Holman
authors.forename: M I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: J M
authors.initials: JM
authors.lastname: Dekker
authors.forename: L M
authors.initials: LM
authors.lastname: 't Hart
authors.forename: E R
authors.initials: ER
authors.lastname: Pearson
mesh_terms: D000368:Aged; D015331:Cohort Studies; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D055106:Genome-Wide Association Study; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D008875:Middle Aged; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D016896:Treatment Outcome
chemical_list: D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008687:Metformin; C517652:hemoglobin A1c protein, human