A common haplotype of the glucokinase gene alters fasting glucose and birth weight: association in six studies and population-genetics analyses.
Fasting glucose is associated with future risk of type 2 diabetes and ischemic heart disease and is tightly regulated despite considerable variation in quantity, type, and timing of food intake. In pregnancy, maternal fasting glucose concentration is an important determinant of offspring birth weight. The key determinant of fasting glucose is the enzyme glucokinase (GCK). Rare mutations of GCK cause fasting hyperglycemia and alter birth weight. The extent to which common variation of GCK explains normal variation of fasting glucose and birth weight is not known. We aimed to comprehensively define the role of variation of GCK in determination of fasting glucose and birth weight, using a tagging SNP (tSNP) approach and studying 19,806 subjects from six population-based studies. Using 22 tSNPs, we showed that the variant rs1799884 is associated with fasting glucose at all ages in the normal population and exceeded genomewide levels of significance (P=10-9). rs3757840 was also highly significantly associated with fasting glucose (P=8x10-7), but haplotype analysis revealed that this is explained by linkage disequilibrium (r2=0.2) with rs1799884. A maternal A allele at rs1799884 was associated with a 32-g (95% confidence interval 11-53 g) increase in offspring birth weight (P=.002). Genetic variation influencing birth weight may have conferred a selective advantage in human populations. We performed extensive population-genetics analyses to look for evidence of recent positive natural selection on patterns of GCK variation. However, we found no strong signature of positive selection. In conclusion, a comprehensive analysis of common variation of the glucokinase gene shows that this is the first gene to be reproducibly associated with fasting glucose and fetal growth.
Weedon
Michael N
MN
Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, EX1 2LU, UK.
Clark
Vanessa J
VJ
Qian
Yudong
Y
Ben-Shlomo
Yoav
Y
Timpson
Nicholas
N
Ebrahim
Shah
S
Lawlor
Debbie A
DA
Pembrey
Marcus E
ME
Ring
Susan
S
Wilkin
Terry J
TJ
Voss
Linda D
LD
Jeffery
Alison N
AN
Metcalf
Brad
B
Ferrucci
Luigi
L
Corsi
Anna Maria
AM
Murray
Anna
A
Melzer
David
D
Knight
Bridget
B
Shields
Bev
B
Smith
George Davey
GD
Hattersley
Andrew T
AT
Di Rienzo
Anna
A
Frayling
Tim M
TM
D000328:Adult; D000368:Aged; D001724:Birth Weight / Q000235:genetics*; D001786:Blood Glucose / Q000032:analysis*; D002648:Child; D015340:Epidemiologic Research Design; D005215:Fasting; D005260:Female; D005828:Genetics, Population; D005941:Glucokinase / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide
D001786:Blood Glucose; D005941:Glucokinase