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

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

E Reiling et al. Diabetologia. 2009 Sep.

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 <or= 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).

Conclusions: 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.

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Figures

Fig. 1

Fig. 1

Combined effect of GCK, GCKR, G6PC2 and MTNR1B on FPG and HbA1c in non-diabetic participants from the New Hoorn Study. a Fasting plasma glucose. Numbers within the bars are numbers of participants per allele group. The per allele effect was 0.05 (0.04–0.07) mmol/l, p = 2 × 10−13). Error bars represent 95% CI. b HbA1c. Numbers within the bars represent the number of participants per allele group. The per allele effect was 0.03% (0.02–0.04%), p = 5 × 10−10 Error bars represent 95% CI

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