Molecular characterization of the human PEA15 gene on 1q21-q22 and association with type 2 diabetes mellitus in Pima Indians

The PEA15 gene encoding a protein kinase C substrate is widely expressed, a nd its overexpression may contribute to impairment of glucose uptake. PEA15 is located within a region on human 1q linked with type 2 diabetes in both Pima Indians and Caucasians. To assess the potential contribution of genet ic alterations within this locus to disease susceptibility in the Pimas, we have investigated its genomic sequences. The PEA15 locus is composed of fo ur exons spanning approximately 10.2 kb of genomic DNA, flanked upstream by an potentially expressed Alu element, downstream by the H326 gene, and is located within 250 kb of KCNJ9. We also sequenced over 2 kb of the promoter region and identified various motifs analogous to known transcription fact or binding sites. By analysis of 22 Pimas, including 13 diabetic subjects, we detected four single nucleotide polymorphisms (SNPs) in the non-coding r egions of PEA15, including three frequent variants that were in allelic dis equilibrium, and one variant found only in a single Pima. The three SNPs we re not associated with type 2 diabetes mellitus in 50 affected and 50 contr ol Pimas (p = 0.12-0.17), and we conclude that mutations in this gene proba bly do not contribute significantly to disease susceptibility in this Nativ e American tribe, However, knowledge of the genomic structure of PEA15 prov ides the basis for similar systematic examinations of this candidate locus in relation to type 2 diabetes and other metabolic disorders in other popul ations. Published by Elsevier Science B.V.