Dissecting the Etiology of Type 2 Diabetes in the Pima Indian Population

The Pima Indian population of Arizona has one of the highest prevalence of diabetes of any population in the world, and the Pima Indians of the Gila River Indian Community have probably been the most studied group for the causes and consequences of diabetes. They develop what would be considered to be classic type 2 diabetes, characterized by obesity and insulin resistance with progression to diabetes characterized by progressive β-cell dysfunction (1).Given the low degree of admixture and high heritability of type 2 diabetes in the Pima Indians (2), the population should also represent a honeypot for genetic discovery. While in recent years there has been progress in identifying type 2 diabetes risk variants in this population (3,4), the understanding of the genetic contribution to diabetes risk remains far from complete. Like many initiatives in genetics, whole-genome/exome sequencing is now being applied in the hope that rare/low-frequency variants with large effects on diabetes risk will be found.In this issue of Diabetes , Baier et al. (5) report on the results of a targeted sequencing project focusing on the genes encoding the two subunits of the β-cell KATP channel. Variants identified by whole-genome sequencing in ABCC8 and KCNJ11 in 335 Pima Indians are genotyped in 7,710 individuals of full Pima Indian heritage or mixed American Indian heritage (∼4/8th Pima Indian). They identify an R1420H variant present in 3.3% of the population that is associated with …