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.

The association of common genetic variants in the APOA5, LPL and GCK genes with longitudinal changes in metabolic and cardiovascular traits

“…The BHS is a very comprehensively phenotyped resource, with the selected cohort having been followed up on average four times over 21 years with multiple metabolic measures, and thus was well-suited to addressing the aim of this study. Our cross-sectional association analyses confirmed previous findings of associations between the GCK rs1799884 variant and raised fasting glucose levels [9,22], the APOA5 rs662799 and rs3135506 variants and raised triacylglycerol levels [16,17,34], and the LPL rs328 variant and reduced triacylglycerol levels and raised HDL-C levels [20,21].…”

“…There have been many crosssectional studies of such genotype-phenotype associations in individuals of different ages [6][7][8][9][10]; however, these studies do not test the possible longitudinal effects of variants in the same individuals. Like the associated risks of many diseases, measures of quantitative traits of clinical relevance often alter with age.…”

“…The variants selected were the apolipoprotein A-V (APOA5) single nucleotide polymorphisms (SNPs) rs662799 and rs3135506; the lipoprotein lipase (LPL) SNP rs328; and the glucokinase (GCK) SNP rs1799884, which have been shown in multiple cross-sectional studies to be associated with triacylglycerol (APOA5 and LPL) [16][17][18][19][20][21], HDL-C (LPL) [20,21] and fasting glucose (GCK) [9,22] levels, traits important in the risk of diabetes and cardiovascular disease.…”

Newly identified loci highlight beta cell dysfunction as a key cause of type 2 diabetes: Where are the insulin resistance genes?

“…Even more intriguing is the association of the protective allele at the same locus with prostate cancer [27], a coincidence that remains unexplained. Of the other MODY genes, large-scale association studies and meta-analyses have shown an association of the G-30A SNP in the GCK promoter with fasting glucose [25,26,28]. On the other hand, the previously reported association of the missense A45T SNP in NEUROD1 with type 2 diabetes has not been substantiated in a comprehensive meta-analysis [29].…”

Variants at DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci are associated with reduced glucose-stimulated beta cell function in middle-aged Danish people

“…Type 2 diabetes is a risk factor for development of cardiovascular disease, but increased fasting glucose at non-diabetic levels also increases risk of cardiovascular events [9]. Several loci have been shown to influence this variable [10][11][12][13][14][15][16][17]. Recently, the international Meta-Analysis of Glucose and Insulin-related Trait Consortium (MAGIC) collaboration engaged in a large meta-analysis of data from 21 GWAS and identified novel loci influencing fasting glucose homeostasis.…”