Mapping of End Stage Renal Disease Genetic Susceptibility in African Americans by Admixture Linkage Disequilibrium

Background:

• End stage renal disease (ESRD) is the near-total loss of kidney function which can result from a variety of diseases. ESRD disproportionately affects African Americans; this group comprises 29% of all ESRD patients treated in the Medicare ESRD program, a proportion that markedly exceeds their representation in the general population.
• The Family Investigation of Diabetes and Nephropathy (FIND) study is an ongoing study to identify susceptibility genes for diabetic and other forms of nephropathy, and the Choices for Healthy Outcomes in Caring for ESRD patients (CHOICE) study is an ongoing prospective study to identify risk factors for cardiovascular outcomes in ESRD patients. Participants of these studies have already been recruited and characterized with respect to renal phenotypes; furthermore, DNAs from these individuals have already been collected and isolated. In this study, we intend to genotype markers suitable for MALD analysis in African Americans. The central hypothesis of the present study is 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 admixture linkage disequilibrium with ESRD susceptibility alleles.

Objectives:

• The overall objective of this study is to identify novel loci, genes, and gene products, that may partially account for excess risk of end stage renal disease (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 from the FIND and CHOICE studies.

Eligibility:

• Specific Inclusion/Exclusion criteria: African American
• Gender and minority inclusion. The FIND and CHOICE studies are open to both men and women of any ethnicity; however, due to the underlying principle of MALD analysis, this study will only include African-American participants of these cohorts.

Design:

• Genotype 1536 African-American MALD markers (2 cM average spacing) utilizing DNA from approximately 2,500 African-American participants in FIND and CHOICE.

• Perform a genome-wide association analysis utilizing a 2 cM dense genetic map and identify chromosomal loci that are in admixture linkage disequilibrium with:

  • ESRD in a case-control design
  • ESRD attributable to diabetes in a case-control design
  • Quantitative renal phenotypes
• Fine map putative chromosomal region in admixture linkage disequilibrium with ESRD with densely-spaced single nucleotide polymorphisms.
• A characterization of the MYH9 gene, its mRNA and the proteins encoded is planned for cases and controls. Gene sequencing of the region implicated will be undertaken. Characterization of mRNA products for quantities and alternative splicing will be evaluated. Experimental characterization of the MYH9 proteins for isoforms, post-translational modifications, interactions, and immunohistochemical staining will be performed.