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Diabetologia
Published in: Diabetologia 9/2009

Open Access 01-09-2009 | Article

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

Authors: E. Reiling, E. van ’t Riet, M. J. Groenewoud, L. M. C. Welschen, E. C. van Hove, G. Nijpels, J. A. Maassen, J. M. Dekker, L. M. ’t Hart

Published in: Diabetologia | Issue 9/2009

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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 (OR 0.77 [0.65–0.93], p = 0.005 and OR 2.05 [1.50–2.80], p = 4 × 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 HbA1c 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.
Appendix
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Metadata
Title
Combined effects of single-nucleotide polymorphisms in GCK, GCKR, G6PC2 and MTNR1B on fasting plasma glucose and type 2 diabetes risk
Authors
E. Reiling
E. van ’t Riet
M. J. Groenewoud
L. M. C. Welschen
E. C. van Hove
G. Nijpels
J. A. Maassen
J. M. Dekker
L. M. ’t Hart
Publication date
01-09-2009
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 9/2009
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-009-1413-9

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