Large-scale study of the -232C > G polymorphism of PCK1 in Type 2 diabetes.
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.
Wegner
L
L
Steno Diabetes Center, Gentofte, Denmark. lwgn@steno.dk
Andersen
G
G
Albrechtsen
A
A
Sparsø
T
T
Glümer
C
C
Borch-Johnsen
K
K
Jørgensen
T
T
Hansen
T
T
Pedersen
O
O
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*
D019764:Phosphoenolpyruvate Carboxykinase (ATP)