Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels

Abstract

Identifying the genetic variants that regulate fasting glucose concentrations may further our understanding of the pathogenesis of diabetes. We therefore investigated the association of fasting glucose levels with SNPs in 2 genome-wide scans including a total of 5,088 nondiabetic individuals from Finland and Sardinia. We found a significant association between the SNP rs563694 and fasting glucose concentrations (P = 3.5 x 10(-7)). This association was further investigated in an additional 18,436 nondiabetic individuals of mixed European descent from 7 different studies. The combined P value for association in these follow-up samples was 6.9 x 10(-26), and combining results from all studies resulted in an overall P value for association of 6.4 x 10(-33). Across these studies, fasting glucose concentrations increased 0.01-0.16 mM with each copy of the major allele, accounting for approximately 1% of the total variation in fasting glucose. The rs563694 SNP is located between the genes glucose-6-phosphatase catalytic subunit 2 (G6PC2) and ATP-binding cassette, subfamily B (MDR/TAP), member 11 (ABCB11). Our results in combination with data reported in the literature suggest that G6PC2, a glucose-6-phosphatase almost exclusively expressed in pancreatic islet cells, may underlie variation in fasting glucose, though it is possible that ABCB11, which is expressed primarily in liver, may also contribute to such variation.

Figure 1. Fasting glucose association in the FUSION and SardiNIA GWA metaanalysis.

Top panel shows evidence for association with fasting glucose under an additive genetic model for the combined FUSION stage 1 and SardiNIA metaanalysis. The –log(P value) for the test of association is plotted against genomic position (NCBI build 35) for all genotyped (red circles, SardiNIA; blue circles, FUSION) and imputed (gray circles) SNPs in the SardiNIA data. SNPs typed in both samples are indicated by red circles with blue centers. SNPs rs560887 and rs853789 were later typed in the SardiNIA samples, and the actual genotypes resulted in even stronger association than shown here. Bottom panel shows the LD pattern (r²) around G6PC2 and ABCB11 for the CEPH (Utah residents with ancestry from northern and western Europe) sample from the HapMap. The scale at the bottom shows the magnitude of LD in 15 colors, ranging from blue for low LD to red for high LD.

Figure 2. Effect size and 95% CI for rs563694 are shown for the 8 studies.

The overall metaanalysis across these studies yielded an effect size of 0.065 mM (95% CI: 0.053, 0.077 mM).