title: A common haplotype of the glucokinase gene alters fasting glucose and birth weight: association in six studies and population-genetics analyses.
abstract: 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.
authors.affiliation: Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, EX1 2LU, UK.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
authors.forename: Vanessa J
authors.initials: VJ
authors.lastname: Clark
authors.forename: Yudong
authors.initials: Y
authors.lastname: Qian
authors.forename: Yoav
authors.initials: Y
authors.lastname: Ben-Shlomo
authors.forename: Nicholas
authors.initials: N
authors.lastname: Timpson
authors.forename: Shah
authors.initials: S
authors.lastname: Ebrahim
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Lawlor
authors.forename: Marcus E
authors.initials: ME
authors.lastname: Pembrey
authors.forename: Susan
authors.initials: S
authors.lastname: Ring
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Wilkin
authors.forename: Linda D
authors.initials: LD
authors.lastname: Voss
authors.forename: Alison N
authors.initials: AN
authors.lastname: Jeffery
authors.forename: Brad
authors.initials: B
authors.lastname: Metcalf
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Corsi
authors.forename: Anna
authors.initials: A
authors.lastname: Murray
authors.forename: David
authors.initials: D
authors.lastname: Melzer
authors.forename: Bridget
authors.initials: B
authors.lastname: Knight
authors.forename: Bev
authors.initials: B
authors.lastname: Shields
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: Anna
authors.initials: A
authors.lastname: Di Rienzo
authors.forename: Tim M
authors.initials: TM
authors.lastname: Frayling
mesh_terms: 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
chemical_list: D001786:Blood Glucose; D005941:Glucokinase