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Genetic Regulation of Birth Weight and Fasting Glucose by a Common Polymorphism in the Islet Cell Promoter of the Glucokinase Gene

¹ Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K
² Department of Endocrinology, Peninsula Medical School, Plymouth, U.K
³ Department of Social Medicine, University of Bristol, Bristol, U.K
⁴ Avon Longitudinal Study of Parents and Children (ALSPAC) Study Team, University of Bristol, Bristol, U.K
⁵ Department of Medical Sciences, Uppsala University, Uppsala, Sweden
⁶ London School of Hygiene and Tropical Medicine, London, U.K

Rare mutations in the glucokinase (GCK) gene cause fasting hyperglycemia and considerably influence birth weight when present in a mother or her offspring. The role of common variation of GCK is uncertain. A polymorphism at position –30 of the GCK ß-cell-specific promoter, present in 30% of the population, has been variably associated with type 2 diabetes and diabetes-related quantitative traits. Using 1,763 U.K. Caucasian normoglycemic adult subjects, we demonstrated that the A allele at GCK(–30) is associated with a 0.06-mmol/l increase in fasting plasma glucose (FPG) (P = 0.003). The A allele was also associated with an increase in FPG in 755 women who were 28 weeks pregnant (0.075 mmol/l, P = 0.003). We then went on to analyze the effect of GCK(–30) on birth weight using 2,689 mother/child pairs. The presence of the A allele in the mother was associated with a 64-g (25–102 g) increase in offspring birth weight (P = 0.001). We did not detect a fetal genotype effect. The increase in offspring birth weight in the 30% of mothers carrying an A allele at GCK(–30) is likely to reflect an elevated FPG during pregnancy. This study establishes that common genetic variation, in addition to rare mutations and environmental factors, can affect both FPG and birth weight.

Abbreviations: ALSPAC, Avon Longitudinal Study of Parents and Children; BCG, Barry Caerphilly Growth; EFS, Exeter Family Study; FPG, fasting plasma glucose; GCK, glucokinase; NGT, normal glucose tolerant; PEB, Plymouth EarlyBird

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