Variants in the Cav2.3 (α1E) Subunit of Voltage-Activated Ca2+ Channels Are Associated With Insulin Resistance and Type 2 Diabetes in Pima Indians

Variants in the Ca v 2.3 (α1E) Subunit of Voltage-Activated Ca 2+ Channels Are Associated With Insulin Resistance and Type 2 Diabetes in Pima Indians Yunhua Li Muller , Robert L. Hanson , Collin Zimmerman , Inge Harper , Jeff Sutherland , Sayuko Kobes , the International Type 2 Diabetes 1q Consortium , William C. Knowler , Clifton Bogardus and Leslie J. Baier From the Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona Address correspondence and reprint requests to Leslie Baier, PhD, Diabetes Molecular Genetics Section, NIDDK, NIH, 455 North 5th St., Phoenix, AZ 85004. E-mail: lbaier{at}phx.niddk.nih.gov Abstract OBJECTIVE— Linkage to type 2 diabetes has been reported on chromosome 1q21-25 in Pima Indians. Fine mapping identified single nucleotide polymorphisms (SNPs) near the CACNA1E gene associated with this disease. CACNA1E encodes the voltage-dependent calcium channel Ca v 2.3 Ca 2+ , 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′ untranslated region (UTR). RESULTS— A novel G/A variant in the 3′-UTR was associated with young-onset type 2 diabetes (odds ratio 2.09 per copy of the G-allele [95% CI 1.31–3.33], adjusted P = 0.001) and had an effect on the evidence for linkage at chromosome 1q21-25 ( P = 0.004). Among 372 nondiabetic Pima subjects who had undergone metabolic testing, the risk allele was associated with reduced insulin action including increased fasting, 30, 60, and 120 min 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 nonrisk allele had a 2.3-fold higher expression compared with the risk allele. CONCLUSIONS— A functional variant in CACNA1E contributes to type 2 diabetes susceptibility by affecting insulin action. This variant partially explains the linkage to type 2 diabetes on chromosome 1q21-25 in Pima India