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.
Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease / Y. Gupta, D.J. Friedman, M.T. Mcnulty, A. Khan, B. Lane, C. Wang, J. Ke, G. Jin, B. Wooden, A.L. Knob, T.Y. Lim, G.B. Appel, K. Huggins, L. Liu, A. Mitrotti, M.C. Stangl, A. Bomback, R. Westland, M. Bodria, M. Marasa, N. Shang, D.J. Cohen, R.J. Crew, W. Morello, P. Canetta, J. Radhakrishnan, J. Martino, Q. Liu, W.K. Chung, A. Espinoza, Y. Luo, W.-. Wei, Q. Feng, C. Weng, Y. Fang, I.J. Kullo, M. Naderian, N. Limdi, M.R. Irvin, H. Tiwari, S. Mohan, M. Rao, G.K. Dube, N.S. Chaudhary, O.M. Gutierrez, S.E. Judd, M. Cushman, L.A. Lange, E.M. Lange, D.L. Bivona, M. Verbitsky, C.A. Winkler, J.B. Kopp, D. Santoriello, I. Batal, S.V.B. Pinheiro, E.A. Oliveira, A.C. Simoes e Silva, I. Pisani, E. Fiaccadori, F. Lin, L. Gesualdo, A. Amoroso, G.M. Ghiggeri, V.D. D'Agati, R. Magistroni, E.E. Kenny, R.J.F. Loos, G. Montini, F. Hildebrandt, D.S. Paul, S. Petrovski, D.B. Goldstein, M. Kretzler, R. Gbadegesin, A.G. Gharavi, K. Kiryluk, M.G. Sampson, M.R. Pollak, S. Sanna-Cherchi. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 14:1(2023 Dec), pp. 7836.1-7836.8. [10.1038/s41467-023-43020-9]
Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease
G. Montini;
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.
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