Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease
Articolo
Data di Pubblicazione:
2023
Abstract:
: African Americans have a significantly higher risk of developing chronic kidney disease, especially focal segmental glomerulosclerosis -, than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of African Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1-associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.
Tipologia CRIS:
03A-Articolo su Rivista
Elenco autori:
Gupta, Yask; Friedman, David J; McNulty, Michelle T; Khan, Atlas; Lane, Brandon; Wang, Chen; Ke, Juntao; Jin, Gina; Wooden, Benjamin; Knob, Andrea L; Lim, Tze Y; Appel, Gerald B; Huggins, Kinsie; Liu, Lili; Mitrotti, Adele; Stangl, Megan C; Bomback, Andrew; Westland, Rik; Bodria, Monica; Marasa, Maddalena; Shang, Ning; Cohen, David J; Crew, Russell J; Morello, William; Canetta, Pietro; Radhakrishnan, Jai; Martino, Jeremiah; Liu, Qingxue; Chung, Wendy K; Espinoza, Angelica; Luo, Yuan; Wei, Wei-Qi; Feng, Qiping; Weng, Chunhua; Fang, Yilu; Kullo, Iftikhar J; Naderian, Mohammadreza; Limdi, Nita; Irvin, Marguerite R; Tiwari, Hemant; Mohan, Sumit; Rao, Maya; Dube, Geoffrey K; Chaudhary, Ninad S; Gutiérrez, Orlando M; Judd, Suzanne E; Cushman, Mary; Lange, Leslie A; Lange, Ethan M; Bivona, Daniel L; Verbitsky, Miguel; Winkler, Cheryl A; Kopp, Jeffrey B; Santoriello, Dominick; Batal, Ibrahim; Pinheiro, Sérgio Veloso Brant; Oliveira, Eduardo Araújo; Simoes E Silva, Ana Cristina; Pisani, Isabella; Fiaccadori, Enrico; Lin, Fangming; Gesualdo, Loreto; Amoroso, Antonio; Ghiggeri, Gian Marco; D'Agati, Vivette D; Magistroni, Riccardo; Kenny, Eimear E; Loos, Ruth J F; Montini, Giovanni; Hildebrandt, Friedhelm; Paul, Dirk S; Petrovski, Slavé; Goldstein, David B; Kretzler, Matthias; Gbadegesin, Rasheed; Gharavi, Ali G; Kiryluk, Krzysztof; Sampson, Matthew G; Pollak, Martin R; Sanna-Cherchi, Simone
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