Common variants in the ATP-sensitive K+ channel genes KCNJ11 (Kir6.2) and ABCC8 (SUR1) in relation to glucose intolerance:: population-based studies and meta-analyses

Aims To evaluate the relation between common variants in the ATP-sensitive K+ channel genes and glucose intolerance. Methods We conducted a meta-analysis of reported association studies in Caucasian populations for common variants in the ABCC8 (exons 16 and 18) and the KCNJ11 (E23K) gene and examined sources of heterogeneity in the results. The meta-analysis was based on 7768-10216 subjects (depending on the gene variant), and included two new population-based studies in the Netherlands with 725 cases and 742 controls. Results For the KCNJ11 variant, the summary odds ratio (OR) for glucose intolerance was 1.12 (1.01-1.23, P = 0.03) for the EK genotype and 1.44 (1.17-1.78, P = 0.0007) for the KK genotype, as compared with the EE genotype. For the ABCC8 exon 16 variant, the OR was 1.06 (0.94-1.19, P = 0.34) for ct and 0.93 (0.71-1.20, P = 0.56) for tt, as compared with the cc genotype. For ABCC8 exon 18, the OR was 1.20 (0.97-1.49, P = 0.10) for CT/TT, as compared with the CC genotype. Studies of the ABCC8 variants that were published first or had smaller sample sizes (for the exon 18 variant) showed stronger associations, which may indicate publication bias. For the ABCC8 exon 18 and the KCNJ11 variant, associations were stronger for studies of clinical diabetes than newly detected glucose intolerance. The population attributable risk for clinical Type 2 diabetes was 6.2% for the KCNJ11 KK genotype and 10.1% for the KCNJ11 EK and KK genotype combined. Conclusions The common KCNJ11 E23K gene variant, but not the ABCC8 exon 16 or exon 18 variant, was consistently associated with Type 2 diabetes.