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 / Gupta, Y.; Friedman, D. J.; Mcnulty, M. T.; Khan, A.; Lane, B.; Wang, C.; Ke, J.; Jin, G.; Wooden, B.; Knob, A. L.; Lim, T. Y.; Appel, G. B.; Huggins, K.; Liu, L.; Mitrotti, A.; Stangl, M. C.; Bomback, A.; Westland, R.; Bodria, M.; Marasa, M.; Shang, N.; Cohen, D. J.; Crew, R. J.; Morello, W.; Canetta, P.; Radhakrishnan, J.; Martino, J.; Liu, Q.; Chung, W. K.; Espinoza, A.; Luo, Y.; Wei, W. -Q.; Feng, Q.; Weng, C.; Fang, Y.; Kullo, I. J.; Naderian, M.; Limdi, N.; Irvin, M. R.; Tiwari, H.; Mohan, S.; Rao, M.; Dube, G. K.; Chaudhary, N. S.; Gutierrez, O. M.; Judd, S. E.; Cushman, M.; Lange, L. A.; Lange, E. M.; Bivona, D. L.; Verbitsky, M.; Winkler, C. A.; Kopp, J. B.; Santoriello, D.; Batal, I.; Pinheiro, S. V. B.; Oliveira, E. A.; Simoes e Silva, A. C.; Pisani, I.; Fiaccadori, E.; Lin, F.; Gesualdo, L.; Amoroso, A.; Ghiggeri, G. M.; D'Agati, V. D.; Magistroni, R.; Kenny, E. E.; Loos, R. J. F.; Montini, G.; Hildebrandt, F.; Paul, D. S.; Petrovski, S.; Goldstein, D. B.; Kretzler, M.; Gbadegesin, R.; Gharavi, A. G.; Kiryluk, K.; Sampson, M. G.; Pollak, M. R.; Sanna-Cherchi, S.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 14:1(2023), pp. 7836-7844. [10.1038/s41467-023-43020-9]

Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease

Magistroni R.;
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.
2023
14
1
7836
7844
Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease / Gupta, Y.; Friedman, D. J.; Mcnulty, M. T.; Khan, A.; Lane, B.; Wang, C.; Ke, J.; Jin, G.; Wooden, B.; Knob, A. L.; Lim, T. Y.; Appel, G. B.; Huggins, K.; Liu, L.; Mitrotti, A.; Stangl, M. C.; Bomback, A.; Westland, R.; Bodria, M.; Marasa, M.; Shang, N.; Cohen, D. J.; Crew, R. J.; Morello, W.; Canetta, P.; Radhakrishnan, J.; Martino, J.; Liu, Q.; Chung, W. K.; Espinoza, A.; Luo, Y.; Wei, W. -Q.; Feng, Q.; Weng, C.; Fang, Y.; Kullo, I. J.; Naderian, M.; Limdi, N.; Irvin, M. R.; Tiwari, H.; Mohan, S.; Rao, M.; Dube, G. K.; Chaudhary, N. S.; Gutierrez, O. M.; Judd, S. E.; Cushman, M.; Lange, L. A.; Lange, E. M.; Bivona, D. L.; Verbitsky, M.; Winkler, C. A.; Kopp, J. B.; Santoriello, D.; Batal, I.; Pinheiro, S. V. B.; Oliveira, E. A.; Simoes e Silva, A. C.; Pisani, I.; Fiaccadori, E.; Lin, F.; Gesualdo, L.; Amoroso, A.; Ghiggeri, G. M.; D'Agati, V. D.; Magistroni, R.; Kenny, E. E.; Loos, R. J. F.; Montini, G.; Hildebrandt, F.; Paul, D. S.; Petrovski, S.; Goldstein, D. B.; Kretzler, M.; Gbadegesin, R.; Gharavi, A. G.; Kiryluk, K.; Sampson, M. G.; Pollak, M. R.; Sanna-Cherchi, S.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 14:1(2023), pp. 7836-7844. [10.1038/s41467-023-43020-9]
Gupta, Y.; Friedman, D. J.; Mcnulty, M. T.; Khan, A.; Lane, B.; Wang, C.; Ke, J.; Jin, G.; Wooden, B.; Knob, A. L.; Lim, T. Y.; Appel, G. B.; Huggins, K.; Liu, L.; Mitrotti, A.; Stangl, M. C.; Bomback, A.; Westland, R.; Bodria, M.; Marasa, M.; Shang, N.; Cohen, D. J.; Crew, R. J.; Morello, W.; Canetta, P.; Radhakrishnan, J.; Martino, J.; Liu, Q.; Chung, W. K.; Espinoza, A.; Luo, Y.; Wei, W. -Q.; Feng, Q.; Weng, C.; Fang, Y.; Kullo, I. J.; Naderian, M.; Limdi, N.; Irvin, M. R.; Tiwari, H.; Mohan, S.; Rao, M.; Dube, G. K.; Chaudhary, N. S.; Gutierrez, O. M.; Judd, S. E.; Cushman, M.; Lange, L. A.; Lange, E. M.; Bivona, D. L.; Verbitsky, M.; Winkler, C. A.; Kopp, J. B.; Santoriello, D.; Batal, I.; Pinheiro, S. V. B.; Oliveira, E. A.; Simoes e Silva, A. C.; Pisani, I.; Fiaccadori, E.; Lin, F.; Gesualdo, L.; Amoroso, A.; Ghiggeri, G. M.; D'Agati, V. D.; Magistroni, R.; Kenny, E. E.; Loos, R. J. F.; Montini, G.; Hildebrandt, F.; Paul, D. S.; Petrovski, S.; Goldstein, D. B.; Kretzler, M.; Gbadegesin, R.; Gharavi, A. G.; Kiryluk, K.; Sampson, M. G.; Pollak, M. R.; Sanna-Cherchi, S.
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