Genetic modifiers of Sickle Cell Kidney Disease

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Project Summary/Abstract This proposal presents a five-year research career development plan focused on prospectively studying the role of genetic polymorphisms in the development and progression of chronic kidney disease in sickle cell disease (SCD). The candidate, an assistant professor of pediatrics and attending nephrologist at the University of Tennessee Health Science Center at Memphis, has devised a research development plan that will provide mentorship, training and research experience to expedite her development into an independent clinician scientist in the field of genetic epidemiology. To achieve the candidate’s long-term goal of becoming an expert in genomic contributions to the development and progression of chronic kidney disease in individuals with sickle cell disease, the candidate and her mentorship team have devised the following development plan: 1) intensive, personal mentorship from an experienced team; 2) focused training on techniques in epidemiology and genomic analysis methods; and 3) an innovative research plan using a large and extensively phenotyped patient cohort with genomic data to study kidney disease manifestations. The candidate’s research development plan outlines a focused route to obtain the knowledge, skills and experience necessary to make a lasting impact in the field sickle cell disease-associated kidney disease. Compared with whites, African Americans have an increased risk for chronic kidney disease, resulting in irreversible end stage kidney disease and increased mortality. This racial disparity in kidney disease raised the possibility of genetic contributors and drove studies showing an association between the apolipoprotein L1 gene (APOL1) and development of CKD. Although APOL1 is a significant risk factor for the development of kidney disease in SCD, it does not fully account for the increased risk. This proposal will further address the role of APOL1 as well as other known genetic variants associated with CKD in SCD. The candidate will test two related hypotheses: a) -a3.7, HMOX1, BCL11A and APOL1 alleles act independently to modify the onset and progression of kidney disease in SCD and will have improved predictive power when considered together in a genetic risk profile (GRP) and analyzed longitudinally; and b) known genetic modifiers of CKD discovered in the general African American population also influence the development of kidney disease in SCD. This proposal will generate a multi-gene genetic risk profile to identify patients at increased risk for development and progression of kidney disease and will set the stage for future clinical studies investigating novel disease- modifying therapies.