AIMS/HYPOTHESIS Phosphoenolpyruvate carboxykinase (PCK) is the key enzyme involved in the regulation of gluconeogenesis. The aim of this study was to identify genetic polymorphisms in potential candidate genes for type 2 diabetes by sequencing all exons in the PCK genes (PCK1 and PCK2), and examining the association with type 2 diabetes and diabetic phenotypes in a Korean population (775 type 2 diabetic patients and 316 normal control subjects).

MATERIALS AND METHODS Twenty-two polymorphisms in PCK1 and PCK2 were identified in a Korean population (n=24) by direct DNA sequencing. The TaqMan genotyping method was applied for genotyping the remainder of the study population. Associations of PCK polymorphisms with the risk of type 2 diabetes and diabetic phenotypes were analysed using logistic and multiple regressions, adjusting for age, sex and BMI.

RESULTS Although no significant associations between the genetic polymorphisms in PCK genes and the risk of type 2 diabetes were detected, in further haplotype analysis, one of the common haplotypes, PCK1 ht3, revealed susceptibility to type 2 diabetes (p=0.006). One 3' untranslated region (UTR) single nucleotide polymorphism (SNP) also showed an association with HDL levels among non-diabetic control subjects: individuals homozygous for the major allele (T/T) had the lowest HDL level (1.11+/-0.32 mmol/l), heterozygotes (T/C) had an intermediate level (1.27+/-0.37 mmol/l), and those homozygous for the minor allele (C/C) had the highest level (1.39+/-0.28 mmol/l) (p=0.000003). This 3' UTR SNP was also associated with triglyceride levels, with a lower triglyceride level observed among individuals who were homozygous for the minor allele (C/C) than among those who were not.

CONCLUSIONS/INTERPRETATION The strong genetic association of HDL and triglyceride levels with variation/haplotype information identified in this study would be useful for further genetic epidemiological studies of this important gene.