A common haplotype of the glucokinase gene alters fasting glucose and birth weight: association in six studies and population-genetics analyses - PubMed (original) (raw)

. 2006 Dec;79(6):991-1001.

doi: 10.1086/509517. Epub 2006 Oct 6.

Vanessa J Clark, Yudong Qian, Yoav Ben-Shlomo, Nicholas Timpson, Shah Ebrahim, Debbie A Lawlor, Marcus E Pembrey, Susan Ring, Terry J Wilkin, Linda D Voss, Alison N Jeffery, Brad Metcalf, Luigi Ferrucci, Anna Maria Corsi, Anna Murray, David Melzer, Bridget Knight, Bev Shields, George Davey Smith, Andrew T Hattersley, Anna Di Rienzo, Tim M Frayling

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A common haplotype of the glucokinase gene alters fasting glucose and birth weight: association in six studies and population-genetics analyses

Michael N Weedon et al. Am J Hum Genet. 2006 Dec.

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.

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Figures

Figure 1.

Figure 1.

LD structure of glucokinase. _r_2 values between the 84 SNPs across a 116-kb region are presented. Arrows indicate tSNPs used in association study.

Figure 2.

Figure 2.

Comparison of LD structure determined in this study with that determined from HapMap 2 data. The LD structures are based on the _r_2 values between the 17 SNPs that are present in both data sets.

Figure 3.

Figure 3.

Comparison of LD structure determined for 16 Italians from the Natural Selection study with that determined from U.K. samples used for the tSNP-association study. The LD structure is based on the _r_2 and values between 20 SNPs that are present in both data sets.

Figure 4.

Figure 4.

A, Meta-analysis of the fasting glucose association results of rs1799884 AA and AG versus GG for all studies. Studies are ordered by ascending age of the cohort. Heterogeneity

_P_=.94

; combined

_P_=1×10-9

. B, Meta-analysis of the fasting glucose association results of rs3757840. The effect size per allele is presented. Heterogeneity

_P_=.56

; combined

_P_=8×10-7

.

Figure 5.

Figure 5.

Meta-analysis of the pairwise differences between haplotypes of rs1799884 and rs3757840 across fasting glucose. A, GA versus GC. B, AA versus GA. C, AA versus GC. Heterogeneity

_P_=.40

, .41, and .65, respectively.

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References

Web Resources

    1. dbSNP, http://www.ncbi.nlm.nih.gov/SNP/
    1. Haplotter, http://hg-wen.uchicago.edu/selection/haplotter.htm
    1. HKA, http://genapps.uchicago.edu/hka/index.html
    1. Kbioscience, http://www.kbioscience.co.uk/
    1. MAXDIP, http://genapps.uchicago.edu/maxdip/index.html

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