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 | $460,284 | Project Dates | 01/01/1995 - 00/00/0000 |
Fiscal Year | 2015 | 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. Previously, we used admixture mapping to localize a region on chromosome 22 associated with focal segmental glomerulosclerosis (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 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. 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. 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 relative with ESRD. 2) About 20% of patients with primary FSGS or HIV-associated nephropathy carry 1 or 0 copies of APOL1 G1 or G2, suggesting that additional factors in APOL1 might contribute to disease. In an exhaustive study of more than 2000 people world wide, including over a 1000 case and controls for FSGS and HIV-associated nephropathy (HIVAN), we showed that no other common variants lysed trypanosomes and no additional common or rare variants were associated with FSGS or HIVAN using association and burden tests. The immediate relevance of this study is that there is no clinical utility in sequencing APOL1 in patients with FSGS or HIVAN who do not carrying G1 or G2 renal risk variants. This data was published in Kidney International. 3) In a international study with researchers in South Africa we have shown that APOL1 variants are strongly associated with HIVAN, a rapidly progressive kidney disease (OR 89).This manuscript was published in the Journal of the American Society of Nephrology. We are now investigating the role of APOL1 in pediatric HIV disease in collaboration with investigators in South Africa. 4) We have shown that in black children, but not Asian children, with sporadic steroid resistant nephrotic syndrome (SRNS) in Durban, South Africa, more than 20% are homozygous for a single mutation in the podocin gene (NPHS2). This study indicates that for the 30% of children with nephrotic syndrome carrying two copies of the NPHS2 variant, a precision diagnosis of steroid resistant focal segmental glomerulosclerosis can be made, abrogating the need for a renal biopsy or ineffective and potentially harmful steroid therapy. |