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

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. 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. Variants of the GCK, G6PC2 and MTNR1B genes but not GCKR were associated with FPG (all, p a parts per thousand currency signaEuro parts per thousand 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 x 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 (OR 0.77 [0.65-0.93], p = 0.005 and OR 2.05 [1.50-2.80], p = 4 x 10(-6) respectively). The age at diagnosis was also significantly associated with the number of risk alleles (p = 0.009). A combined risk allele score for single-nucleotide 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.