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 | $469,536 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2017 | 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. We have now extended our research to investigate the independent and interactive effects of sickle cell trait on cardiovascular and kidney diseases. Accomplishments 1) Sickle cell trait (SCT) and the risk of end stage renal disease (ESKD) in African Americans (AA). Compared to whites, African Americans have nearly 4-fold increased risk for ESKD, much of which is attributable to APOL1 renal risk variants. We sought to determine if SCT and hemoglobin C trait had an independent role in ESKD. We evaluated nearly 10,000 African Americans enrolled in the REasons for Geographic and Racial Differences in Stroke (REGARDS) and determined that incident rates for carries of SCT were 2-fold higher than for non-carriers (8.5 versus 4.0/1000 person years), with a hazards ratio (HR) for ESKD of 2.2, which is similar to the risk incurred by carriage of APOL1 renal risk variants. These results have important public health policy implications for genetic counseling of SCT carriers with chronic kidney disease. 2) Using genetic data provided by our laboratory, academic investigators found that a tripartite complex of suPAR (soluble urokinase plasminogen activator receptor), APOL1 risk variants, and integrin is responsible for decline in kidney function. Mechanistically, the APOL1 variant alleles have a higher affinity for suPAR, which augments integrin activation leading to proteinuria in mice. In humans decline in kidney function in patients with APOL1 high risk genotypes is positively correlated with suPAR levels. 3) The role of APOL1 risk variants in cardiovascular disease is conflicted with some studies showing a protective association and others reporting a susceptible or no association. We found that APOL1 high risk genotypes were not associated with hypertension in young adults with preserve kidney function enrolled in the CARDIA study and were not associated with cardiovascular disease (CVD) in persons with chronic kidney disease (CKD). On the other hand, we find a 2-fold increased risk of stroke and trend towards increased risk of myocardial infarction in patients without the well-established CVD risk factors of diabetes or chronic kidney disease. In participants with albuminuria, chronic kidney disease or diabetes, we found no association between APOL1 and CVD events. Previous studies reporting a positive association between APO |