title: Large-scale study of the -232C > G polymorphism of PCK1 in Type 2 diabetes.
abstract: OBJECTIVE
  Phosphoenolpyruvate carboxykinase (PEPCK) is a catalyst of the rate-limiting step in the gluconeogenic pathway and is regulated at the transcriptional level predominantly by insulin, glucocorticoids, glucagon, and cAMP. The -232C > G polymorphism in the gene encoding PEPCK (PCK1) is reported to associate with Type 2 diabetes in Canadian Caucasians and Oji-Cree populations. We have estimated the impact of the PCK1-232C > G polymorphism in a relatively large-scale case-control study of Type 2 diabetes and in association studies of common metabolic phenotypes. Interaction studies of the PCK1-232C > G polymorphism with variants in the genes encoding peroxisome proliferator-activated receptor-gamma co-activator (PGC)-1alpha and hepatic nuclear factor (HNF)-4alpha were also performed.
  
  
  METHODS
  PCK1-232C > G was genotyped in a total of 7467 Danish white subjects using TaqMan allelic discrimination. A case-control study of Type 2 diabetes was performed using 6057 of the participants, and quantitative trait studies of metabolic variables were carried out in a subgroup of 5718 non-diabetic subjects. Additionally, variants in PGC-1alpha (Gly482Ser) and HNF-4alpha (Thr130Ile, Val255Met, and rs1884614) were investigated for epistatic interaction with the PCK1-232C > G polymorphism.
  
  
  RESULTS
  In the case-control study of Type 2 diabetes of 1377 Type 2 diabetic patients and 4680 normoglycaemic and normal glucose-tolerant subjects we found no association of the PCK1-232C > G polymorphism with diabetes. In addition, the variant was not associated with age of clinical onset of Type 2 diabetes. In the study of 5718 non-diabetic subjects, we found no relationships of quantitative metabolic traits with the PCK1-232C > G polymorphism. We failed to demonstrate any convincing epistatic effects of the variants in the genes encoding PGC-1alpha and HNF-4alpha with the PCK1-232C > G polymorphism.
  
  
  CONCLUSIONS
  The PCK1-232C > G polymorphism is not a major contributor to the pathogenesis of Type 2 diabetes in the Danish population.
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark. lwgn@steno.dk
authors.forename: L
authors.initials: L
authors.lastname: Wegner
authors.forename: G
authors.initials: G
authors.lastname: Andersen
authors.forename: A
authors.initials: A
authors.lastname: Albrechtsen
authors.forename: T
authors.initials: T
authors.lastname: Sparsø
authors.forename: C
authors.initials: C
authors.lastname: Glümer
authors.forename: K
authors.initials: K
authors.lastname: Borch-Johnsen
authors.forename: T
authors.initials: T
authors.lastname: Jørgensen
authors.forename: T
authors.initials: T
authors.lastname: Hansen
authors.forename: O
authors.initials: O
authors.lastname: Pedersen
mesh_terms: D016022:Case-Control Studies; D003718:Denmark; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*
chemical_list: D019764:Phosphoenolpyruvate Carboxykinase (ATP)