Variation in fasting glucose concentration (FPG) is important for human health. In the normal range FPG is associated with risk of type 2 diabetes and ischaemic heart disease independently of obesity. In pregnancy maternal FPG concentration is an important independent determinant of birth weight in non-diabetic mothers. There is evidence that the regulation of FPG has a strong genetic component.

The main regulator of FPG concentration is the enzyme glucokinase. Our preliminary data shows that common variants in the promoter region of the glucokinase gene are associated with FPG and fetal growth. The minor allele at GCK-30, present in 30% of the UK population raises FPG by0.06 mmol/l (0.04-0.11), p = 0.003; and, when present in the mother, birth weight by 64g (25-102), p = 0.001. We have next shown that variation, further upstream (rs3757840) of the gene, and with no obvious functional role, has a similar, but independent effect on FPG.

In this project we propose to test comprehensively the hypothesis that common genetic variation in GCK alters FPG and birth weight. We will use the latest approaches for capturing the important variation across a gene together with DNA resources from 28,799 mother-child pairs. This approach will establish, if our hypothesis is true, a definitive genetic component to the aetiology of normal variation in FPG and birth weight.