title: Common variation in oxidative phosphorylation genes is not a major cause of insulin resistance or type 2 diabetes.
abstract: OBJECTIVE
  There is substantial evidence that mitochondrial dysfunction is linked to insulin resistance and is present in several tissues relevant to the pathogenesis of type 2 diabetes. Here, we examined whether common variation in genes involved in oxidative phosphorylation (OxPhos) contributes to type 2 diabetes susceptibility or influences diabetes-related metabolic traits.
  
  
  METHODS
  OxPhos gene variants (n = 10) that had been nominally associated (p < 0.01) with type 2 diabetes in a recent genome-wide meta-analysis (n = 10,108) were selected for follow-up in 3,599 type 2 diabetic and 4,956 glucose-tolerant Danish individuals. A meta-analysis of these variants was performed in 11,729 type 2 diabetic patients and 43,943 non-diabetic individuals. The impact on OGTT-derived metabolic traits was evaluated in 5,869 treatment-naive individuals from the Danish Inter99 study.
  
  
  RESULTS
  The minor alleles of COX10 rs9915302 (p = 0.02) and COX5B rs1466100 (p = 0.005) showed nominal association with type 2 diabetes in our Danish cohort. However, in the meta-analysis, none of the investigated variants showed a robust association with type 2 diabetes after correction for multiple testing. Among the alleles potentially associated with type 2 diabetes, none negatively influenced surrogate markers of insulin sensitivity in non-diabetic participants, while the minor alleles of UQCRC1 rs2228561 and COX10 rs10521253 showed a weak (p < 0.01 to p < 0.05) negative influence on indices of glucose-stimulated insulin secretion.
  
  
  CONCLUSIONS
  We cannot rule out the possibility that common variants in or near OxPhos genes may influence beta cell function in non-diabetic individuals. However, our quantitative trait studies and a sufficiently large meta-analysis indicate that common variation in proximity to the examined OxPhos genes is not a major cause of insulin resistance or type 2 diabetes.
authors.affiliation: Diabetes Research Centre, Department of Endocrinology, Odense University Hospital, Kløvervænget 6, 4th Floor, 5000 Odense, Denmark.
authors.forename: L S
authors.initials: LS
authors.lastname: Snogdal
authors.forename: M
authors.initials: M
authors.lastname: Wod
authors.forename: N
authors.initials: N
authors.lastname: Grarup
authors.forename: M
authors.initials: M
authors.lastname: Vestmar
authors.forename: T
authors.initials: T
authors.lastname: Sparsø
authors.forename: T
authors.initials: T
authors.lastname: Jørgensen
authors.forename: T
authors.initials: T
authors.lastname: Lauritzen
authors.forename: H
authors.initials: H
authors.lastname: Beck-Nielsen
authors.forename: J E
authors.initials: JE
authors.lastname: Henriksen
authors.forename: O
authors.initials: O
authors.lastname: Pedersen
authors.forename: T
authors.initials: T
authors.lastname: Hansen
authors.forename: K
authors.initials: K
authors.lastname: Højlund
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D003718:Denmark; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000235:genetics / Q000378:metabolism*; D003576:Electron Transport Complex IV / Q000235:genetics*; D014644:Genetic Variation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D008957:Models, Genetic; D010085:Oxidative Phosphorylation; D010100:Oxygen / Q000737:chemistry*; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci
chemical_list: D003576:Electron Transport Complex IV; D005947:Glucose; D010100:Oxygen
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