ZIA BC 010022 (ZIA) | |||
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Title | Genetics of Complex Diseases and Health Disparities | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Winkler, Cheryl | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $476,229 | Project Dates | 10/01/1995 - 00/00/0000 |
Fiscal Year | 2014 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) |
Kidney Cancer (25.0%) Kidney Disease (100.0%) Urinary System (100.0%) |
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Research Type | |||
Endogenous Factors in the Origin and Cause of Cancer Technology Development and/or Marker Discovery |
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Abstract | |||
Project Summary: Chronic kidney disease (CKD), affecting over 26 million Americans, frequently leads to kidney failure. More than 100,000 individuals develop end stage kidney disease (ESKD) annually and nearly 500,000 receive kidney transplants or are ongoing dialysis patients at an annual cost of $30 billion dollars. The three leading causes of ESKD are type 2 diabetes, hypertension, and glomerulosclerosis. African Americans are 3-4 times more likely to develop end ESKD compared to their white counterparts. Focal segmental glomerulosclerosis (FSGS) is the leading cause of primary nephrotic syndrome in adults and the leading cause of ESKD in children. FSGS comprises a syndrome that includes idiopathic forms as well as forms associated with reduced nephron numbers, hypertension, and HIV-1 infection. Previously, we used admixture mapping to localize a region on chromosome 22 associated with FSGS and HIV-associated nephropathy (HIVAN). Subsequently, we and others showed that APOL1 coding variants within this region comprising 2 missense variants in absolute linkage disequilibrium (G1 allele) and an in frame 6 base pair deletion (G2 allele) were responsible for the association, with OR of 7, 19, and 27 for hypertensive ESKD, focal segmental glomerulosclerosis (FSGS), and HIV-associated nephropathy (HIVAN), respectively. ApoL1 provides protection against infection with Trypanosoma brucei brucei; the APOL1 G1 and G2 risk alleles in heterozygotes restore protection against ApoL1 resistant T. b. rhodesiense, a cause of sleeping sickness. APOL1 G1 and G2 alleles have been under recent positive selection resulting in haplotype homozygosity across the region comprising MYH9/APOL1. The APOL1 risk alleles emerged recently in sub-Saharan Africa, but are found in other regions of the world as a result of the African Diaspora. The combined frequencies of G1 and G2 alleles are approximately 35% in African Americans. These alleles explain nearly all the excess risk of kidney disease in African Americans, thus providing a genetic basis for a major global health disparity. We have continued our studies of APOL1 to determine if the risk variants are associated with other non-renal or renal phenotypes that show racial disparities, such as papillary renal cancer and cardiovascular disease, in collaborative studies with intramural and extramural investigators. An important question, as yet unresolved, is the affect of high-risk genotypes on living kidney donors or their kidney recipients. Although studies suggest that the genotype of the kidney recipient does not impact graft survival, it is not known if high risk genotypes in the donor increases risk of future kidney disease/failure in the living donor or graft survival in the recipient. We hypothesize that: 1) living donors with high risk APOL1 genotypes are at greater risk for developing kidney failure in his or her remaining kidney and 2) it is the genotype of the donor and not the genotype of the recipient that is associated with transplant kidney failure. We also are addressing the question of the impact of these variants in sub-Saharan Africa on people with HIV infection. Accomplishments 1) We have entered into collaborations with researchers at the University of Chicago and Wayne State University to investigate the role of APOL1 variants on development of hypertension, chronic kidney disease, and kidney survival in the living donor. To date 47 AA and 71 (n=119) former living donors now in need of renal replacement therapy have been enrolled and genotyped for APOL1. We found that more than half of former donors with kidney failure carried two APOL1 risk alleles (57%) compared to 13% in the general population. This result is confounded by the fact that the majority of living donors were first-degree relatives of the recipients and therefore more likely to carry APOL1 risk variants. It was reported by others that amongst African Americans with ESRD and 2 risk alleles, 23% had a first degree rela" |