부산대학교 도서관

Aims/hypothesis Glucose-stimulated insulin secretion is dependent on the electrical activity of beta cells hence, genes encoding beta cell ion channels are potential candidate genes for type 2 diabetes. The gene encoding the voltage-dependent Ca.sup.2+ channel Ca.sub.V2.3 (CACNA1E), telomeric to a region that has shown suggestive linkage to type 2 diabetes (1q21-q25), has been ascribed a role for second-phase insulin secretion. Methods Based upon the genotyping of 52 haplotype tagging single nucleotide polymorphisms (SNPs) in a type 2 diabetes case--control sample (n=1,467), we selected five SNPs that were nominally associated with type 2 diabetes and genotyped them in the following groups (1) a new case--control sample of 6,570 individuals from Sweden (2) 2,293 individuals from the Botnia prospective cohort and (3) 935 individuals with insulin secretion data from an IVGTT. Results The rs679931 TT genotype was associated with (1) an increased risk of type 2 diabetes in the Botnia case--control sample [odds ratio (OR) 1.4, 95% CI 1.0--2.0, p=0.06] and in the replication sample (OR 1.2, 95% CI 1.0--1.5, p=0.01 one-tailed), with a combined OR of 1.3 (95% CI 1.1--1.5, p=0.004 two-tailed) (2) reduced insulin secretion [insulinogenic index at 30 min p=0.02, disposition index (D .sub.I) p=0.03] in control participants during an OGTT (3) reduced second-phase insulin secretion at 30 min (p=0.04) and 60 min (p=0.02) during an IVGTT and (4) reduced D .sub.I over time in the Botnia prospective cohort (p=0.05). Conclusions/interpretation We conclude that genetic variation in the CACNA1E gene contributes to an increased risk of the development of type 2 diabetes by reducing insulin secretion.