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. Mapping studies, using both genetic linkage and association methods, are being used to identify genomic regions containing variants that confer susceptibilitly to diabetic kidney disease and related traits. 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. Replication studies in additional samples identified a variant between CNKSR3 and SCAF8 that was associated with nephropathy at genome-wide statistical significance, and across multiple ethnic groups. 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. Current efforts are focused on analysis of genome-wide association in the full collection of samples from the FIND consortium; further genome-wide association studies are being conducted in the Pima study. With collaborators, dense linkage disequilibrium maps are being generated in candidate regions for linkage with nephropathy and total cholesterol in Pimas. Recent analyses have identified variants in PFKFB2 as associated with diabetic nephropathy. 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. Genotyping of additional individuals is planned for replication.

Project Start
Project End
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Budget End
Support Year
9
Fiscal Year
2015
Total Cost
Indirect Cost
Name
U.S. National Inst Diabetes/Digst/Kidney
Department
Type
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Qiu, Chengxiang; Hanson, Robert L; Fufaa, Gudeta et al. (2018) Cytosine methylation predicts renal function decline in American Indians. Kidney Int 93:1417-1431
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
Hsueh, Wen-Chi; Nair, Anup K; Kobes, Sayuko et al. (2017) Identity-by-Descent Mapping Identifies Major Locus for Serum Triglycerides in Amerindians Largely Explained by an APOC3 Founder Mutation. Circ Cardiovasc Genet 10:
Hanson, Robert L; Leti, Fatjon; Tsinajinnie, Darwin et al. (2016) The Arg59Trp variant in ANGPTL8 (betatrophin) is associated with total and HDL-cholesterol in American Indians and Mexican Americans and differentially affects cleavage of ANGPTL3. Mol Genet Metab 118:128-37
Nair, Anup K; Piaggi, Paolo; McLean, Nellie A et al. (2016) Assessment of established HDL-C loci for association with HDL-C levels and type 2 diabetes in Pima Indians. Diabetologia 59:481-91
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
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
Iyengar, Sudha K; Sedor, John R; Freedman, Barry I et al. (2015) Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND). PLoS Genet 11:e1005352
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

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