End Stage Renal Disease (ESRD) Clinical Trial
Official title:
Mapping of End Stage Renal Disease Genetic Susceptibility in African Americans by Admixture Linkage Disequilibrium
This study will identify which regions on the genes, and genes themselves, may account for an
increased risk of end stage renal disease (ESRD), that is, near-total loss of kidney
function, for people of African American descent. Researchers will use a technique called
admixture linkage disequilibrium (MALD) to study genomes, genetic material, in about 2,500
participants from two existing studies and participants who will serve as controls. ESRD
disproportionately affects African Americans, who constitute 29% of all ESRD patients in the
Medicare ESRD program. The disease can result from a variety of diseases, with diabetes as
the leading underlying cause (44% of cases) and hypertension as the second leading cause
(26%). The proportion of ESRD cases caused by diabetes has increased dramatically.
Patients age 18 and older who are African American, who have ESRD, and who are participants
of the FIND and CHOICE studies may be eligible for this study. FIND, or Family Investigation
of Diabetes and Nephropathy, involves a multicenter study to identify susceptibility genes,
that is, those with a risk, for diabetic and other forms of kidney disease. CHOICE, or
Choices for Healthy Outcomes in Caring for ESRD patients is an ongoing study that identifies
risk factors for cardiovascular outcomes in ESRD patients. The principle of mapping by MALD
involves genetic variations that exist across populations. When mixing occurs between
populations having different (heterogeneous) genes, the admixed offspring inherits
chromosomes of distinct ancestry. However, over generations of mating, and recombination over
several generations, originally large blocks of DNA from African ancestry have become part of
smaller segments throughout the chromosome. The study will focus on risk alleles, that is,
alternative forms of genes that carry a disease risk. Risk alleles are closely related to
nearby ancestral gene markers found in a person.
Patients will undergo a collection of blood and urine for genetic testing. Researchers are
conducting separate analyses in this study. Case-control analysis of ESRD will consist of
1,150 participants from FIND and 250 from CHOICE. There will also be 750 control participants
from FIND. For the case-control analysis of diabetic ESRD, there will be about 750
participants from FIND, 125 from CHOICE, and 750 controls from FIND. Finally, there is the
quantitative trait analysis, which looks at the phenotype-meaning visible characteristics
produced by the interaction of a person's genetic makeup with the environment. That analysis
will involve 350 patients with diabetic nephropathy but not ESRD and 750 controls from FIND.
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.
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