Protein-truncating variant in APOL3 increases chronic kidney disease risk in epistasis with APOL1 risk alleles

• DOI: 10.1172/jci.insight.181238
• Publication Date: 2024-08-20T16:00:55Z
• Authors: David Y. Zhang; Michael G. Levin; Jeffrey T. Duda; Latrice G. Landry; Walter R. Witschey; Scott M. Damrauer; Marylyn D. Ritchie; Daniel J. Rader
• Keywords: Epistasis

BACKGROUNDTwo coding alleles within the APOL1 gene, G1 and G2, found almost exclusively in individuals genetically similar to West African populations, contribute substantially pathogenesis of chronic kidney disease (CKD). The APOL gene cluster on chromosome 22 contains a total 6 genes that have arisen as result duplication.METHODSUsing genome-first approach Penn Medicine BioBank, we identified 62 protein-altering variants with minor allele frequency >0.1% population participants reference populations performed population-specific phenome-wide association studies.RESULTSWe rs1108978, stop-gain variant APOL3 (p.Q58*), be significantly associated increased CKD risk, even after conditioning G1/G2 carrier status. These findings were replicated Veterans Affairs Million Veteran Program All Us Research Program. p.Q58* was also number quantitative traits linked CKD, including decreased volume. This truncating contributed most risk for patients monoallelic G1/G2, suggesting an epistatic interaction potential protective effect wild-type against APOL1-induced disease.CONCLUSIONThis study demonstrates utility targeting approach, context well-studied gene-disease relationships.FUNDINGNational Heart, Lung, Blood Institute (F30HL172382, R01HL169378, R01HL169458), Doris Duke Foundation (grant 2023-2024), National Biomedical Imaging Bioengineering (P41EB029460), Center Advancing Translational Sciences (UL1-TR-001878).