Genetic regulation of birth weight and fasting glucose by a common polymorphism in the islet cell promoter of the glucokinase gene.
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 beta-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.
Weedon
Michael N
MN
Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter EX2 5AX, U.K.
Frayling
Timothy M
TM
Shields
Beverley
B
Knight
Beatrice
B
Turner
Tina
T
Metcalf
Bradley S
BS
Voss
Linda
L
Wilkin
Terence J
TJ
McCarthy
Anne
A
Ben-Shlomo
Yoav
Y
Davey Smith
George
G
Ring
Sue
S
Jones
Richard
R
Golding
Jean
J
Byberg
Liisa
L
Mann
Vera
V
Axelsson
Tomas
T
Syvänen
Ann-Christine
AC
Leon
David
D
Hattersley
Andrew T
AT
D000328:Adult; D000483:Alleles; D001724:Birth Weight / Q000235:genetics*; D001786:Blood Glucose / Q000235:genetics / Q000378:metabolism*; D004739:England; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D005941:Glucokinase / Q000235:genetics*; D018149:Glucose Intolerance / Q000235:genetics*; D006801:Humans; D007515:Islets of Langerhans / Q000201:enzymology*; D008297:Male; D009035:Mothers; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D013548:Sweden
D001786:Blood Glucose; D005941:Glucokinase