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 | $588,017 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) |
Kidney Disease (100.0%) Urinary System (100.0%) Kidney Cancer (25.0%) |
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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. 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 increased risk of chronic kidney disease in black Americans. 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 now extended our research to investigate the independent and interactive effects of sickle cell trait on cardiovascular and kidney diseases. 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 are investigating the role of APOL1 in cardiovascular disease in large well-powered community-based studies to separate the mediating effects of underlying co-morbidities (CKD and diabetes) from APOL1 associations. Accomplishments: 1) APOL1 coding variants and risk of heart failure in aging women. Compared to whites, stroke and heart failure is more common among African American women as they age. We found that among post-menopausal women enrolled in the Women's' Health Initiative, APOL1 was not associated with increased risk of cardiovascular diseases; however, APOL1 is associated with heart failure with preserved injection fraction, possibly mediated by underlying chronic kidney disease. 2) Cardiovascular disease, including ischemic stroke and myocardial infarction, is more common among African Americans. We evaluated nearly 10,000 African Americans enrolled in the REasons for Geographic and Racial Differences in Stroke (REGARDS) for APOL1 risk variants and determined that carriers of two APOL1 risk alleles were at a 2.3 -fold higher than for non-carriers for composite cardiovascular events; however, these associations were driven ischemic stroke. Carriers of high risk APOL1 genotypes were over 5-fold more likely to experience small vessel ischemic stroke compared to those with low-risk genotypes who did not have chronic kidney disease or diabetes, indicating that APOL1 is a direct contributor to these outcomes and not a moderator acting through underlying co-morbidities. These results have important public health policy implications for genetic counseling of high risk carriers. 3) Sickle cell trait has long been considered a benign condition however, its role in health and disease as not been analyzed in large-scale studies or by meta-analysis. We contributed our REGARDS APOL1 genotyping results for a meta-analysis of the association of sickle cell trait with ischemic stroke. Fortunately, SCT, which is carried by 7% of African Americans does not appear to be a risk factor for stroke. 4) Because of power issues, it is difficult to assess the role of APOL1 in premature death or sudden death. Age, cause of death, and nephrosclerosis were studied in 162 African Americans and 136 whites experiencing sudden death who were genotyped for APOL1 variants. Among those with dying from cardiovascular death, carriers of one APOL1 risk allele died 7 years earlier, and those with two risk alleles died 12.2 years earlier than African Americans with no risk alleles and 8.7 and 13.9 years younger than whites, who do carry APOL1 risk alleles. Carriage of APOL1 risk variants |