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 Indians.

A prior linkage scan in Pima Indians identified a putative locus for type two diabetes (T2D) and body mass index (BMI) on chromosome 11q23-25. Association mapping across this region identified single nucleotide polymorphisms (SNPs) in the trehalase gene (TREH) that were associated with T2D. To assess the putative connection between trehalase activity and T2D, we performed a linkage study for trehalase activity in 570 Pima Indians who had measures of trehalase activity. Strong evidence of linkage of plasma trehalase activity (LOD = 7.0) was observed in the TREH locus. Four tag SNPs in TREH were genotyped in these subjects and plasma trehalase activity was highly associated with three SNPs: rs2276064, rs117619140 and rs558907 (p = 2.2 × 10−11–1.4 × 10−23), and the fourth SNP, rs10790256, was associated conditionally on these three (p = 2.9 × 10−7). Together, the four tag SNPs explained 51 % of the variance in plasma trehalase activity and 79 % of the variance attributed to the linked locus. These four tag SNPs were further genotyped in 828 subjects used for association mapping of T2D, and rs558907 was associated with T2D (odds ratio (OR) 1.94, p = 0.002). To assess replication of the T2D association, all four tag SNPs were additionally genotyped in two non-overlapping samples of Native Americans. Rs558907 was reproducibly associated with T2D in 2,942 full-heritage Pima Indians (OR 1.27 p = 0.03) and 3,897 “mixed” heritage Native Americans (OR 1.21, p = 0.03), and the strongest evidence for association came from combining all samples (OR 1.27 p = 1.6 × 10−4, n = 7,667). However, among 320 longitudinally studied subjects, measures of trehalase activity from a non-diabetic exam did not predict those who would eventually develop diabetes versus those who would remain non-diabetic (hazard ratio 0.94 per SD of trehalase activity, p = 0.29). We conclude that variants in TREH control trehalase activity, and although one of these variants is also reproducibly associated with T2D, it is likely that the effect of the SNP on risk of T2D occurs by a mechanism different than affecting trehalase activity. Alternatively, TREH variants may be tagging a nearby T2D locus.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-013-1278-3) contains supplementary material, which is available to authorized users.

PTF1 complex is critical for pancreatic development and maintenance of adult exocrine pancreas. As a part of our ongoing studies to identify genetic variation that contributes to type 2 diabetes (T2D) in American Indians, we analyzed variation in genes that form this complex, namely PTF1A, RBPJ, and its paralogue RBPJL. A c.839C>T (p.(Thr280Met)) variant (rs200998587:C>T, risk allele frequency = 0.03) in RBPJL, identified only in Amerindian-derived populations, associated with T2D (OR = 1.60[1.21–2.13] per Met allele, P = 0.001) and age of diabetes onset (HR = 1.40[1.14–1.72], P = 0.001). Knockdown of Rbpjl in mouse pancreatic acinar cells resulted in a significant decrease in the mRNA expression of genes encoding exocrine enzymes including Ctrb. CTRB1/2 is an established T2D locus where the protective allele associates with increased GLP-1-stimulated insulin secretion and higher expression of CTRB1/2. In vitro studies show that cells expressing the Met280 allele had lower RBPJL protein levels than cells expressing the Thr280 allele, despite having comparable levels of RNA, suggesting that the Met280 RBPJL is less stable. Additionally, luciferase assays in HEK293 cells which examined two different RBPJL responsive promoters, including the promoter for CTRB1, also identified reduced transactivation by the Met280 RBPJL. Similarly, overexpression of both Met280 and Thr280 RBPJL in mouse pancreatic acinar cells identified a significant impairment in the expression of Cel when transactivated by the Met280 RBPJL. In summary, we identified a functional, Amerindian-derived population-specific c.839C>T (p.(Thr280Met)) variant in the pancreas specific RBPJL that may modify T2D risk by regulating exocrine enzyme expression.