? End stage renal disease (ESRD) is a major clinical and public health problem, especially in African Americans. This proposal is an ancillary study to the NIH-NIDDK funded Family Investigation of Diabetes and Nephropathy (FIND) and the Choices for Healthy Outcomes in Caring for ESRD patients (CHOICE) studies, ongoing multicenter studies to identify susceptibility genes for nephropathy (FIND), and risk factors for cardiovascular outcomes in ESRD patients (CHOICE). ? The overall objective of this proposal is to identify novel loci, and ultimately genes, that may partially account for excess risk of ESRD in African Americans compared to whites. To achieve this goal, we will employ Mapping by Admixture Linkage Disequilibrium (MALD) analysis, a specialized form of linkage disequilibrium mapping, to perform a genome-wide association study in approximately 2,500 African-American participants who have already been recruited and characterized with respect to renal phenotypes and had DNA collected and isolated. We hypothesize that some renal disease susceptibility alleles are present at higher frequency in African Americans than in whites and that specific regions of the genome in African Americans contain marker alleles that are in ALD with ESRD susceptibility alleles. This hypothesis will be tested by comprehensively evaluating MALD markers in approximately 1,400 African-American cases with ESRD and 750 African-American controls without renal disease. We will: 1) genotype ~3,000 African-American MALD markers (1.2 cM average spacing) in DNA from approximately 2,500 African-American participants (almost 7 million genotypes) using an advanced, high-throughput genotyping system; 2) perform a genome-wide association analysis utilizing a ~1 cM dense genetic map and identify chromosomal loci that are in ALD with ESRD in a case-control design, ESRD attributable to diabetes in a case-control design, and quantitative renal phenotypes amongst 1,100 individuals without ESRD, 3) use closely-spaced SNP markers to fine map putative chromosomal region in ALD with ESRD. ? The proposed genetic analyses are innovative and complementary to the more traditional linkage techniques and not part of the core protocols of the parent studies. This study will provide key insights into the genetic control of susceptibility of ESRD ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK070657-02
Application #
7103520
Study Section
Special Emphasis Panel (ZDK1-GRB-6 (J3))
Program Officer
Rasooly, Rebekah S
Project Start
2005-08-01
Project End
2008-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
2
Fiscal Year
2006
Total Cost
$742,919
Indirect Cost
Name
Johns Hopkins University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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
Hawkins, Gregory A; Friedman, David J; Lu, Lingyi et al. (2015) Re-Sequencing of the APOL1-APOL4 and MYH9 Gene Regions in African Americans Does Not Identify Additional Risks for CKD Progression. Am J Nephrol 42:99-106
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
Scialla, Julia J; Kao, W H Linda; Crainiceanu, Ciprian et al. (2014) Biomarkers of vascular calcification and mortality in patients with ESRD. Clin J Am Soc Nephrol 9:745-55
Ng, Maggie C Y; Shriner, Daniel; Chen, Brian H et al. (2014) Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes. PLoS Genet 10:e1004517
Sandholm, Niina; McKnight, Amy Jayne; Salem, Rany M et al. (2013) Chromosome 2q31.1 associates with ESRD in women with type 1 diabetes. J Am Soc Nephrol 24:1537-43
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
Scialla, Julia J; Plantinga, Laura C; Kao, W H Linda et al. (2011) Soluble P-selectin levels are associated with cardiovascular mortality and sudden cardiac death in male dialysis patients. Am J Nephrol 33:224-30
Igo Jr, Robert P; Iyengar, Sudha K; Nicholas, Susanne B et al. (2011) Genomewide linkage scan for diabetic renal failure and albuminuria: the FIND study. Am J Nephrol 33:381-9
Estrella, Michelle M; Sperati, Chistopher J; Kao, Wen H L et al. (2010) Genetic epidemiology of chronic kidney disease. Curr Opin Nephrol Hypertens 19:283-91

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