In the current project, genetic determinants of diabetic nephropathy and related traits are being sought using techniques of genetic linkage and association analysis. Lymphoblast cell lines have been established from informative pedigrees. DNA is available from other families in nuclear pellets extracted from blood specimens obtained in the epidemiologic studies. An autosomal genome-wide linkage study conducted in Pima Indians identified suggestive evidence for linkage to diabetic nephropathy on chromosome 3q and chromosome 7q. Efforts to identify potential causative variants in both of these regions are currently underway using both a systematic analysis of linkage disequilibrium and analyses of candidate genes. Through collaboration with multicenter Family Investigation of Nephropathy (FIND) consortium, the genetics of diabetic nephropathy and of diabetic retinopathy are also being studied. FIND was initiated as a genome-wide linkage study and is currently using a genome-wide association strategy to identify regions of interest. Fine-mapping of regions of linkage identified in the Pima study and in FIND is currently underway. In addition, a genome-wide association study for diabetic nephropathy using 1,000,000 single nucleotide polymorphisms has been conducted part of the FIND consortium. Initial analyses showed several regions that potentially harbor nephropathy-susceptibility loci, although none reached genome-wide significance. Additional follow-up analyses are currently underway. An analysis of nondiabetic African-Americans conducted within FIND suggested more variants in APOL1 (in addition to the well-validated amino acid substitutions discovered recently) that may contribute to susceptibility to kidney disease. Variants in ERBB4, which are associated with diabetic nephropathy in type 1 diabetes, are also associated with transcript levels in kidney tissue from Pimas with type 2 diabetes. Current efforts are focused on analysis of genome-wide association in the full collection of samples from the FIND consortium. With collaborators, dense linkage disequilibrium maps are being generated in the candidate regions on chromosomes 3q and 7q. Replication studies of PVT1 and other candidate genes are also being pursued. Additional American Indian families informative for linkage and association studies of diabetic nephropathy continue to be recruited. In conjunction with collaborators, additional families informative for study of genetics of diabetic nephropathy have been recruited in Micronesia and in Phoenix. Genotyping of additional individuals is planned for replication.

Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2013
Total Cost
$376,950
Indirect Cost
City
State
Country
Zip Code
Brown, Lisa A; Sofer, Tamar; Stilp, Adrienne M et al. (2017) Admixture Mapping Identifies an Amerindian Ancestry Locus Associated with Albuminuria in Hispanics in the United States. J Am Soc Nephrol 28:2211-2220
Williams, Robert C; Elston, Robert C; Kumar, Pankaj et al. (2016) Selecting SNPs informative for African, American Indian and European Ancestry: application to the Family Investigation of Nephropathy and Diabetes (FIND). BMC Genomics 17:325
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Muller, Yunhua L; Piaggi, Paolo; Hanson, Robert L et al. (2015) A cis-eQTL in PFKFB2 is associated with diabetic nephropathy, adiposity and insulin secretion in American Indians. Hum Mol Genet 24:2985-96
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Thameem, Farook; Igo Jr, Robert P; Freedman, Barry I et al. (2013) A genome-wide search for linkage of estimated glomerular filtration rate (eGFR) in the Family Investigation of Nephropathy and Diabetes (FIND). PLoS One 8:e81888
Sandholm, Niina; Salem, Rany M; McKnight, Amy Jayne et al. (2012) New susceptibility loci associated with kidney disease in type 1 diabetes. PLoS Genet 8:e1002921
Bostrom, Meredith A; Kao, W H Linda; Li, Man et al. (2012) Genetic association and gene-gene interaction analyses in African American dialysis patients with nondiabetic nephropathy. Am J Kidney Dis 59:210-21
Chakkera, Harini A; Hanson, Robert L; Kobes, Sayuko et al. (2011) Association of variants in the carnosine peptidase 1 gene (CNDP1) with diabetic nephropathy in American Indians. Mol Genet Metab 103:185-90

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