title: Two common genetic variants near nuclear-encoded OXPHOS genes are associated with insulin secretion in vivo.
abstract: BACKGROUND
  Mitochondrial ATP production is important in the regulation of glucose-stimulated insulin secretion. Genetic factors may modulate the capacity of the β-cells to secrete insulin and thereby contribute to the risk of type 2 diabetes.
  
  
  OBJECTIVE
  The aim of this study was to identify genetic loci in or adjacent to nuclear-encoded genes of the oxidative phosphorylation (OXPHOS) pathway that are associated with insulin secretion in vivo.
  
  
  METHODS
  To find polymorphisms associated with glucose-stimulated insulin secretion, data from a genome-wide association study (GWAS) of 1467 non-diabetic individuals, including the Diabetes Genetic Initiative (DGI), was examined. A total of 413 single nucleotide polymorphisms with a minor allele frequency ≥0.05 located in or adjacent to 76 OXPHOS genes were included in the DGI GWAS. A more extensive population-based study of 4323 non-diabetics, the PPP-Botnia, was used as a replication cohort. Insulinogenic index during an oral glucose tolerance test was used as a surrogate marker of glucose-stimulated insulin secretion. Multivariate linear regression analyses were used to test genotype-phenotype associations.
  
  
  RESULTS
  Two common variants were identified in the DGI, where the major C-allele of rs606164, adjacent to NADH dehydrogenase (ubiquinone) 1 subunit C2 (NDUFC2), and the minor G-allele of rs1323070, adjacent to cytochrome c oxidase subunit VIIa polypeptide 2 (COX7A2), showed nominal associations with decreased glucose-stimulated insulin secretion (P=0.0009, respective P=0.003). These associations were replicated in PPP-Botnia (P=0.002 and P=0.05).
  
  
  CONCLUSIONS
  Our study shows that genetic variation near genes involved in OXPHOS may influence glucose-stimulated insulin secretion in vivo.
authors.affiliation: Department of Clinical Sciences, Lund University, Scania University Hospital, Malmö, Sweden.
authors.forename: Anders H
authors.initials: AH
authors.lastname: Olsson
authors.forename: Tina
authors.initials: T
authors.lastname: Rönn
authors.forename: Claes
authors.initials: C
authors.lastname: Ladenvall
authors.forename: Hemang
authors.initials: H
authors.lastname: Parikh
authors.forename: Bo
authors.initials: B
authors.lastname: Isomaa
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ling
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002467:Cell Nucleus / Q000235:genetics* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D007328:Insulin / Q000235:genetics* / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D010085:Oxidative Phosphorylation; D011110:Polymorphism, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D007328:Insulin