Trial Information

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.