Novel American Indian exomic variants and diabetic nephropathy
In response to the Diabetic Complications Consortium request for Pilot and Feasibility projects in the high impact areas of diabetes complications, this study proposes to generate preliminary data on novel genetic risk factors associated with chronic kidney disease (CKD), through interrogation of human samples and genetic resources in American Indians, a population with a high burden of diabetes and CKD complications. CKD is a progressive and devastating condition that leads to premature cardiovascular disease and death, and a common complication of type 2 diabetes (T2D). Genome wide association studies (GWAS) have identified loci for kidney traits and T2D, but findings for T2D-related CKD complications have been less successful. American Indian-specific variants may contribute to diabetic complications, and could impact other populations, which share Native American ancestry through admixture, such as Hispanics. We recently identified several novel single nucleotide variants (SNVs) through exome sequence of 94 unrelated individuals from the Strong Heart Family Study, a family study of American Indians recruited from three geographically-distinct regions of the U.S., without disease ascertainment. These novel variants have not been interrogated in GWAS. To provide pilot evidence for association of novel SNVs with T2D related CKD, we propose to genotype SNVs in T2D and kidney loci in CKD cases and controls and to test their association using statistical methods for common and rare variants. This project will support a larger application seeking whole genome sequencing to catalog novel SNVs and to study the association of novel variants with diabetic CKD in a large sample of American Indians and in Hispanics. This project fills an important gap in research of diabetic CKD by studying a diverse ancestry population of American Indians who has high risk of diabetes and its complications.

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