Abstract
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. 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. 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. The PCK1-232C > G polymorphism is not a major contributor to the pathogenesis of Type 2 diabetes in the Danish population.
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