Variants in the Ca_v2.3 (α1E) Subunit of Voltage-Activated Ca²⁺ Channels are Associated with Insulin Resistance and Type 2 Diabetes in Pima Indians

Abstract

Objective: Linkage to type 2 diabetes mellitus (T2DM) has been reported on chromosome 1q21-25 in Pima Indians. Fine mapping identified SNPs near the CACNA1E gene associated with this disease. CACNA1E encodes the voltage-dependent calcium channel Ca_v2.3 Ca²⁺, and mice lacking this channel exhibit impaired glucose tolerance and insulin secretion. Therefore, CACNA1E was investigated as a positional candidate gene.

Research Design and Methods: CACNA1E was sequenced and 28 SNPs were genotyped in the same group of Pima subjects who had been analyzed in the linkage study. Allele specific expression was used to functionally evaluate a variant in the 3′UTR.

Results: A novel G/A variant in the 3′UTR was associated with young-onset T2DM (odds ratio=2.09 per copy of the G allele; 95% CI=1.31-3.33, adjusted p=0.001) and had an effect upon the evidence for linkage at chromosome 1q21-25 (p=0.004). Among 372 non-diabetic Pima subjects who had undergone metabolic testing, the risk allele was associated with reduced insulin action that included increased fasting, 30, 60 and 120 minute plasma glucose concentrations and increased fasting plasma insulin during an oral glucose tolerance test (all p<0.01) as well as a decreased rate of insulin-stimulated glucose disposal at both physiologically and maximally stimulated insulin concentrations (both p<0.002). Functional analysis of this variant showed that the non-risk allele had a 2.3 fold higher expression as compared to the risk allele.

Conclusion: A functional variant in CACNA1E contributes to T2DM susceptibility by affecting insulin action. This variant partially explains the linkage to T2DM on chromosome 1q21-25 in Pima Indians.