Association of a polymorphism in the gene encoding phosphoenolpyruvate carboxykinase 1 with high-density lipoprotein and triglyceride levels

Abstract

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 nondiabetic 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.

Lack of Association Between PCK1 Polymorphisms and Obesity, Physical Activity, and Fitness in European Youth Heart Study (EYHS)

“…Despite strong evidence from animal studies (11,12,13), we could not find any evidence for the association of PCK1 variants with obesity‐related phenotypes in children and adolescents. Previous studies have shown association between genetic variation in PCK1 and the risk of type 2 diabetes and related traits (4,17,18,19,20), of which we genotyped four (rs6070157, rs2179706, rs1042531, and rs707555) but found no evidence for association in the EYHS. As this is the first study examining the association of genetic variants in PCK1 gene with obesity in young individuals, more studies are needed to explore the association of PCK1 gene variants with obesity‐related phenotypes in other populations.…”

“…Regions near the PCK1 locus on human chromosome 20 have been implicated in obesity (16). In addition, several studies in humans have shown associations of specific polymorphsims in the PCK1 gene with type 2 diabetes and related metabolic traits (4,17,18,19,20). However, the present study investigates the association of single‐nucleotide polymorphisms (SNPs) in the PCK1 gene with obesity, PA, and fitness and examines the interaction between the PCK1 SNPs, and PA and fitness on obesity risk in the European Youth Heart Study (EYHS), a large population‐based study of children and adolescents from Denmark and Estonia.…”

The promoter polymorphism -232C/G of the PCK1 gene is associated with type 2 diabetes in a UK-resident South Asian population

“…As with many genetic association studies investigating polygenic diseases, attempts to replicate the association between PCK1 and T2D have produced mixed results. A haplotype of PCK1 variants was shown to confer risk of developing the disease in a Korean population (OR not given, p = 6 × 10 -3 ) [ 5 ], and a screen of 134 candidate susceptibility SNPs showed that the -232C/G SNP was a risk factor for T2D in a Finnish cohort (OR = 1.27, 95% CI 1.02 - 1.57, p = 0.031) [ 6 ]. A recent study reported that multiple PCK1 variants are associated with T2D in a Chinese population [ 7 ].…”

Large‐scale study of the −232C > G polymorphism of PCK1 in Type 2 diabetes

“…Thus, for a promoter polymorphism, −232C > G, the minor G allele was reported to associate with Type 2 diabetes in 375 Canadian Caucasians as well as in 562 subjects in the Canadian Oji‐Cree population, and the polymorphism was shown to be functional in studies of mouse preadipocytes [9]. No association between Type 2 diabetes and the −232C > G polymorphism was observed in Japanese or Korean study populations [10,11]; however, in the Japanese cohort, age of clinical onset of Type 2 diabetes was significantly lower among carriers of the G allele [10].…”