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.
- 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
- 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.
- 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.
- 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
- INCLUSION CRITERIA:
The cohorts utilized in this study, FIND and CHOICE, are open to adults of both genders
and any ethnicity. However, we will select and utilize only those samples from African -
American participants. We will also utilize African (Yorban) and European controls for
genotyping from the NIGMS HGCR.
Children and all ethnicities other than African - American, African, and European will be
excluded from this study.