Comparative effectiveness of RASi- vs. non-RASi-based antihypertensive regimens on adverse kidney and cardiovascular outcomes by APOL genotype

About This Grant

Chronic kidney disease (CKD) is a leading cause of mortality in the United States, affecting ~32 million Americans. Genetic ancestry is increasingly recognized as an important factor in CKD risk. Specifically, 13% of individuals of African ancestry carry two variants in the Apolipoprotein L1 (APOL1) gene, termed “G1” and “G2,” which result in a high-risk genotype when present in homozygosity (G1/G1 or G2/G2) or heterozygosity (G1/G2). It is estimated that 15% of individuals with a high-risk genotype will reach end stage kidney disease (ESKD). APOL1 risk variants may also be associated with cardiovascular disease, but the data supporting this correlation is less certain. Most investigations of people with APOL1 risk variants have analyzed all high-risk genotypes together. However, recent studies show the complexity of the APOL gene structure, including reports of novel sub-genotypes conferred by 1) a protective variant in APOL1, p.N264K, that mitigates risk of APOL1-associated kidney disease and 2) a protein-truncating variant in Apolipoprotein L3 (APOL3), p.Q58*, that increases risk of CKD/ESKD in individuals with one high-risk APOL1 allele. A recent mouse model also showed that treatment with a renin-angiotensin system inhibitor (RASi), a common antihypertensive medication class known to improve kidney and cardiovascular outcomes in certain patients, resulted in markedly reduced proteinuria and in APOL1 G1/G1 transgenic mice compared to APOL1 G2/G2 mice. While research is underway to identify treatment targets for APOL1-nephropathy, little evidence exists regarding how APOL genotypes affect kidney and cardiovascular outcomes, and whether existing treatments may differ by APOL genotype in humans. The hypothesis of this proposal is that there is a differential benefit of RASis based on APOL genotype, which translates to lower risk of adverse kidney and cardiovascular outcomes with RASi-treatment compared to other antihypertensive medications for those with the APOL1 G1/G1 and APOL1 G0/G1 APOL3 p.Q58* genotypes vs. other APOL genotypes. To test this hypothesis, I plan to analyze two well-phenotyped, prospective cohorts with available APOL1 genotyping (the Chronic Renal Insufficiency Cohort [CRIC] and Systolic Blood Pressure Intervention Trial [SPRINT]) and two large, multi-ethnic real-world cohorts with whole exome sequencing to include novel APOL variants (Penn Medicine Biobank [PMBB] and the All of Us Research Program). I will perform mixed effect modeling and inverse probability of treatment weighting with Cox regression to assess risk of CKD progression and cardiovascular events, respectively. In conjunction with a Master’s program in genetics and epidemiology, the proposed application for the NRSA award will provide intensive preparation for a career focused on the improvement of precision medicine in kidney disease.