Combined effects of single-nucleotide polymorphisms in GCK, GCKR, G6PC2 and MTNR1B on fasting plasma glucose and type 2 diabetes risk

Abstract

Aims/hypothesis Variation in fasting plasma glucose (FPG) within the normal range is a known risk factor for the development of type 2 diabetes. Several reports have shown that genetic variation in the genes for glucokinase (GCK), glucokinase regulatory protein (GCKR), islet-specific glucose 6 phosphatase catalytic subunit-related protein (G6PC2) and melatonin receptor type 1B (MTNR1B) is associated with FPG. In this study we examined whether these loci also contribute to type 2 diabetes susceptibility. Methods A random selection from the Dutch New Hoorn Study was used for replication of the association with FGP (2,361 non-diabetic participants). For the genetic association study we extended the study sample with 2,628 participants with type 2 diabetes. Risk allele counting was used to calculate a four-gene risk allele score for each individual. Results Variants of the GCK, G6PC2 and MTNR1B genes but not GCKR were associated with FPG (all, p≤0.001; GCKR, p=0.23). Combining these four genes in a risk allele score resulted in an increase of 0.05 mmol/l (0.04-0.07) per additional risk allele (p=2×10 −13). Furthermore, participants with less than three or more than five risk alleles showed significantly different type 2 diabetes susceptibility compared with the most common group with four risk alleles respectively). The age at diagnosis was also significantly associated with the number of risk alleles (p=0.009). Conclusions A combined risk allele score for singlenucleotide polymorphisms in four known FPG loci is significantly associated with FPG and HbA 1c in a Dutch population-based sample of non-diabetic participants. Carriers of low or high numbers of risk alleles show significantly different risks for type 2 diabetes compared with the reference group.

Associations of <i>apolipoprotein A5 (APOA5), glucokinase (GCK)</i> and <i>glucokinase regulatory protein (GCKR)</i> polymorphisms and lifestyle factors with the risk of dyslipidemia and dysglycemia in Japanese — a cross-sectional data from the J-MICC Study

“…The associations of GCK and GCKR polymorphisms with glucose metabolism disorders have been also well described [27,28], and our study results were in line with these previous findings, underscoring the importance of these associations. We also observed a possible risk reduction of dyslipidemia in those with GCKR rs780094 G/G genotype or GCKR rs1260326 C/C genaction between GCKR rs780094 A/A genotype and low carbohydrate intake (OR for interaction = 1.73; 95% CI 1.06-2.84, P = 0.030) on the risk of dyslipidemia (Table 6).…”

Common variants at the GCK, GCKR, G6PC2–ABCB11 and MTNR1B loci are associated with fasting glucose in two Asian populations

“…It has been debated whether the genetic determinants regulating FPG levels in physiological states differ from those increasing type 2 diabetes risk. Some studies report that carriers of glucose-increasing alleles at three loci (MTNR1B, GCK and GCKR) show a higher risk of type 2 diabetes [8,17,18], although there is no significant association between G6PC2-ABCB11 variants and type 2 diabetes in populations of European descent [14,17,35]. In this context, our data not only supported the concordant association of G6PC2-ABCB11 variants for FPG and type 2 diabetes in two Asian populations, but also indicated that genetic determinants regulating FPG levels could, at least in part, differ from those increasing type 2 diabetes risk (ESM Fig.…”

Liver Glucokinase and Lipid Metabolism

“…However, it has been demonstrated that human islets express GKRP at very low levels ). This issue should be revisited because of the recent publication of several genome-wide association studies that associate GK, GCKR, G6PC2, MTNR1B with type 2 diabetes risk linked to -cell function (Reiling, 2009& Bonetti, 2011. Whether, -cell GK function is affected directly by a hypothetic pancreatic GKRP, or indirectly by liver GKRP impaired activity, still needs clarification.…”

“…Finally glucose-6-phosphatase deficiency causes severe hyperlipidemia and hepatic steatosis (Bandsma, 2002(Bandsma, , 2008, therefore giving rise that this enzyme may also participate or influence the GK/GKRP system in the regulation of hepatic glucose fate. To support this hypothesis, Reiling and colleagues described combined effects of single-nucleotide polymorphisms in GK, GKRP and glucose-6-phosphatase on fasting plasma glucose and type 2 diabetes (Reiling, 2009). Therefore, it is a field that needs further exploration.…”