A combined risk allele score calculated from variants in four genes associated with fasting plasma glucose levels significantly predicts risk for Type 2 diabetes, show results from the Dutch New Hoorn Study.

“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 fasting plasma glucose,” say L ‘t Hart (Leiden University, The Netherlands) and colleagues.

In this study, the team tested 2361 non-diabetic individuals and 2628 individuals with Type 2 diabetes from the Dutch New Hoorn Study for the single nucleotide polymorphisms (SNPs) rs1799884 (GCK), rs1260326 (GCKR), rs560887 (G6PC2), and rs10830963 (MTNR1B).

They found that the GCK, G6PC2, and MTNR1B variants, but not the GCKR SNP, were significantly associated with fasting plasma glucose levels.

When these three SNPs were combined to form a risk allele score, fasting plasma glucose levels went up by 0.05 mmol/l per additional risk allele and glycated hemoglobin went up by around 0.03% per risk allele.

The most common risk allele score was four and therefore was used as a reference group. Individuals with less than three risk alleles had a 23% reduction in the risk for Type 2 diabetes, whereas those with more than five had a 2.05-fold increased risk for the condition.

Of note, age at diagnosis was significantly associated with the number of risk alleles present.

“To our knowledge, this is the first report showing that the analyzed loci have a combined effect on Type 2 diabetes susceptibility, although the contribution of each individual variant to the risk of Type 2 diabetes is very low or undetectable,” say ‘t Hart and team.

They conclude in the journal Diabetologia: “If replicated, our results imply that these loci not only influence fasting plasma glucose levels, probably through an altered set point for glucose at which an insulin response is elicited, but also jointly increase the risk of Type 2 diabetes and the age at diagnosis.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

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