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Investigating ancestry-specific genetic variation in apolipoprotein L genes associated with electron

David Y. Zhang BA, Department of Genetics, Perelman School of Medicine, University of Pennsylvania Michael G. Levin MD, Division of Cardiovascular Medicine, Perelman School of Medicine, University of Pennsylvania Scott M. Damrauer MD, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA Marylyn D. Ritchie PhD, Department of Genetics, Perelman School of Medicine, University of Pennsylvania Daniel J. Rader MD, Department of Genetics, Perelman School of Medicine, University of Pennsylvania


Poster # 58


Health care disparities between people of different ancestries and ethnicities are well-documented in every field of medicine. Of the ~6,401 studies currently compiled in the genome-wide association studies (GWAS) catalog as of June 2023, ~95% of all GWAS participants are of European (EUR) ancestry with less than 1% of participants being of African American (AFR) ancestry. Using the Penn Medicine Biobank (PMBB) and adopting a genome-first approach, we investigated 100 predicted loss-of-function (pLOF) and 737 missense variants in the apolipoprotein L gene family with a specific interest in those more common in non-European populations. We performed phenome-wide association studies (PheWAS) on 62 variants with a MAF > 0.1% in the PMBB AFR population (n = 11,198) against 1,236 binary phenotypes derived from electronic health records data with at least 20 cases. Our results identified a stop-gain variant rs11089781 (p.Gln58*) in the APOL3 gene found to be significantly associated with increased risk for end-stage renal disease (ESRD) (OR = 1.38, P = 3.64e-08). This variant has a gnomAD minor allele frequency of 0.22 in AFR compared to 3.97e-04 in EUR. It is also in linkage equilibrium (r2 < 0.05) with the APOL1 G1 and G2 known risk alleles for renal disease. Replication of this association in up to 121,790 AFR individuals from the Million Veterans Program also yielded a significant association with ESRD (OR = 1.16, P = 1.01e-08). Initial hypotheses suggest that APOL3 may play a protective role against APOL1 and loss-of-function in APOL3 increases susceptibility to APOL1-induced kidney dysfunction.

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