Combined effects of single-nucleotide polymorphisms in GCK, GCKR, G6PC2 and MTNR1B on fasting plasma glucose and type 2 diabetes risk.
OBJECTIVE
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.
Reiling
E
E
Department of Molecular Cell Biology, Leiden University Medical Centre, PO Box 9600, 2300RC, Leiden, the Netherlands.
van 't Riet
E
E
Groenewoud
M J
MJ
Welschen
L M C
LM
van Hove
E C
EC
Nijpels
G
G
Maassen
J A
JA
Dekker
J M
JM
't Hart
L M
LM
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D001786:Blood Glucose / Q000032:analysis*; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000235:genetics; D005215:Fasting; D005260:Female; D020022:Genetic Predisposition to Disease; D005941:Glucokinase / Q000235:genetics*; D018149:Glucose Intolerance / Q000235:genetics; D005952:Glucose-6-Phosphatase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D044123:Receptor, Melatonin, MT2 / Q000235:genetics*; D012016:Reference Values; D012307:Risk Factors
D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; C485100:GCKR protein, human; D044123:Receptor, Melatonin, MT2; D005941:Glucokinase; D005952:Glucose-6-Phosphatase; C492194:G6PC2 protein, human