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

Yask Gupta; David J. Friedman; Michelle T. McNulty; Atlas Khan; Brandon Lane; Chen Wang; Juntao Ke; Gina Jin; Benjamin Wooden; Andrea L. Knob; Tze Y. Lim; Gerald B. Appel; Kinsie Huggins; Lili Liu; Adele Mitrotti; Megan C. Stangl; Andrew Bomback; Rik Westland; Monica Bodria; Maddalena Marasa; Ning Shang; David J. Cohen; Russell J. Crew; William Morello; Pietro Canetta; Jai Radhakrishnan; Jeremiah Martino; Qingxue Liu; Wendy K. Chung; Angelica Espinoza; Yuan Luo; Wei Qi Wei; Qiping Feng; Chunhua Weng; Yilu Fang; Iftikhar J. Kullo; Mohammadreza Naderian; Nita Limdi; Marguerite R. Irvin; Hemant Tiwari; Sumit Mohan; Maya Rao; Geoffrey K. Dube; Ninad S. Chaudhary; Orlando M. Gutiérrez; Suzanne E. Judd; Mary Cushman; Leslie A. Lange; Ethan M. Lange; Daniel L. Bivona; Miguel Verbitsky; Cheryl A. Winkler; Jeffrey B. Kopp; Dominick Santoriello; Ibrahim Batal; Sérgio Veloso Brant Pinheiro; Eduardo Araújo Oliveira; Ana Cristina Simoes e Silva; Isabella Pisani; Enrico Fiaccadori; Fangming Lin; Loreto Gesualdo; Antonio Amoroso; Gian Marco Ghiggeri; Vivette D. D’Agati; Riccardo Magistroni; Eimear E. Kenny; Ruth J.F. Loos; Giovanni Montini; Friedhelm Hildebrandt; Dirk S. Paul; Slavé Petrovski; David B. Goldstein; Matthias Kretzler; Rasheed Gbadegesin; Ali G. Gharavi; Krzysztof Kiryluk; Matthew G. Sampson; Martin R. Pollak; Simone Sanna-Cherchi

doi:10.1038/s41467-023-43020-9

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

Yask Gupta, David J. Friedman, Michelle T. McNulty, Atlas Khan, Brandon Lane, Chen Wang, Juntao Ke, Gina Jin, Benjamin Wooden, Andrea L. Knob, Tze Y. Lim, Gerald B. Appel, Kinsie Huggins, Lili Liu, Adele Mitrotti, Megan C. Stangl, Andrew Bomback, Rik Westland, Monica Bodria, Maddalena MarasaNing Shang, David J. Cohen, Russell J. Crew, William Morello, Pietro Canetta, Jai Radhakrishnan, Jeremiah Martino, Qingxue Liu, Wendy K. Chung, Angelica Espinoza, Yuan Luo, Wei Qi Wei, Qiping Feng, Chunhua Weng, Yilu Fang, Iftikhar J. Kullo, Mohammadreza Naderian, Nita Limdi, Marguerite R. Irvin, Hemant Tiwari, Sumit Mohan, Maya Rao, Geoffrey K. Dube, Ninad S. Chaudhary, Orlando M. Gutiérrez, Suzanne E. Judd, Mary Cushman, Leslie A. Lange, Ethan M. Lange, Daniel L. Bivona, Miguel Verbitsky, Cheryl A. Winkler, Jeffrey B. Kopp, Dominick Santoriello, Ibrahim Batal, Sérgio Veloso Brant Pinheiro, Eduardo Araújo Oliveira, Ana Cristina Simoes e Silva, Isabella Pisani, Enrico Fiaccadori, Fangming Lin, Loreto Gesualdo, Antonio Amoroso, Gian Marco Ghiggeri, Vivette D. D’Agati, Riccardo Magistroni, Eimear E. Kenny, Ruth J.F. Loos, Giovanni Montini, Friedhelm Hildebrandt, Dirk S. Paul, Slavé Petrovski, David B. Goldstein, Matthias Kretzler, Rasheed Gbadegesin, Ali G. Gharavi, Krzysztof Kiryluk, Matthew G. Sampson, Martin R. Pollak, Simone Sanna-Cherchi

Cardiovascular Medicine

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	7836
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-43020-9
State	Published - Dec 2023

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-023-43020-9

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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., ... Sanna-Cherchi, S. (2023). Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease. Nature communications, 14(1), Article 7836. https://doi.org/10.1038/s41467-023-43020-9

Gupta, Y, Friedman, DJ, McNulty, MT, Khan, A, Lane, B, Wang, C, Ke, J, Jin, G, Wooden, B, Knob, AL, Lim, TY, Appel, GB, Huggins, K, Liu, L, Mitrotti, A, Stangl, MC, Bomback, A, Westland, R, Bodria, M, Marasa, M, Shang, N, Cohen, DJ, Crew, RJ, Morello, W, Canetta, P, Radhakrishnan, J, Martino, J, Liu, Q, Chung, WK, Espinoza, A, Luo, Y, Wei, WQ, Feng, Q, Weng, C, Fang, Y, Kullo, IJ, Naderian, M, Limdi, N, Irvin, MR, Tiwari, H, Mohan, S, Rao, M, Dube, GK, Chaudhary, NS, Gutiérrez, OM, Judd, SE, Cushman, M, Lange, LA, Lange, EM, Bivona, DL, Verbitsky, M, Winkler, CA, Kopp, JB, Santoriello, D, Batal, I, Pinheiro, SVB, Oliveira, EA, Simoes e Silva, AC, Pisani, I, Fiaccadori, E, Lin, F, Gesualdo, L, Amoroso, A, Ghiggeri, GM, D’Agati, VD, Magistroni, R, Kenny, EE, Loos, RJF, Montini, G, Hildebrandt, F, Paul, DS, Petrovski, S, Goldstein, DB, Kretzler, M, Gbadegesin, R, Gharavi, AG, Kiryluk, K, Sampson, MG, Pollak, MR & Sanna-Cherchi, S 2023, 'Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease', Nature communications, vol. 14, no. 1, 7836. https://doi.org/10.1038/s41467-023-43020-9

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

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.",

author = "Yask Gupta and Friedman, {David J.} and McNulty, {Michelle T.} and Atlas Khan and Brandon Lane and Chen Wang and Juntao Ke and Gina Jin and Benjamin Wooden and Knob, {Andrea L.} and Lim, {Tze Y.} and Appel, {Gerald B.} and Kinsie Huggins and Lili Liu and Adele Mitrotti and Stangl, {Megan C.} and Andrew Bomback and Rik Westland and Monica Bodria and Maddalena Marasa and Ning Shang and Cohen, {David J.} and Crew, {Russell J.} and William Morello and Pietro Canetta and Jai Radhakrishnan and Jeremiah Martino and Qingxue Liu and Chung, {Wendy K.} and Angelica Espinoza and Yuan Luo and Wei, {Wei Qi} and Qiping Feng and Chunhua Weng and Yilu Fang and Kullo, {Iftikhar J.} and Mohammadreza Naderian and Nita Limdi and Irvin, {Marguerite R.} and Hemant Tiwari and Sumit Mohan and Maya Rao and Dube, {Geoffrey K.} and Chaudhary, {Ninad S.} and Guti{\'e}rrez, {Orlando M.} and Judd, {Suzanne E.} and Mary Cushman and Lange, {Leslie A.} and Lange, {Ethan M.} and Bivona, {Daniel L.} and Miguel Verbitsky and Winkler, {Cheryl A.} and Kopp, {Jeffrey B.} and Dominick Santoriello and Ibrahim Batal and Pinheiro, {S{\'e}rgio Veloso Brant} and Oliveira, {Eduardo Ara{\'u}jo} and {Simoes e Silva}, {Ana Cristina} and Isabella Pisani and Enrico Fiaccadori and Fangming Lin and Loreto Gesualdo and Antonio Amoroso and Ghiggeri, {Gian Marco} and D{\textquoteright}Agati, {Vivette D.} and Riccardo Magistroni and Kenny, {Eimear E.} and Loos, {Ruth J.F.} and Giovanni Montini and Friedhelm Hildebrandt and Paul, {Dirk S.} and Slav{\'e} Petrovski and Goldstein, {David B.} and Matthias Kretzler and Rasheed Gbadegesin and Gharavi, {Ali G.} and Krzysztof Kiryluk and Sampson, {Matthew G.} and Pollak, {Martin R.} and Simone Sanna-Cherchi",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-43020-9",

language = "English (US)",

volume = "14",

journal = "Nature communications",

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AU - Gupta, Yask

AU - Friedman, David J.

AU - McNulty, Michelle T.

AU - Khan, Atlas

AU - Lane, Brandon

AU - Wang, Chen

AU - Ke, Juntao

AU - Jin, Gina

AU - Wooden, Benjamin

AU - Knob, Andrea L.

AU - Lim, Tze Y.

AU - Appel, Gerald B.

AU - Huggins, Kinsie

AU - Liu, Lili

AU - Mitrotti, Adele

AU - Stangl, Megan C.

AU - Bomback, Andrew

AU - Westland, Rik

AU - Bodria, Monica

AU - Marasa, Maddalena

AU - Shang, Ning

AU - Cohen, David J.

AU - Crew, Russell J.

AU - Morello, William

AU - Canetta, Pietro

AU - Radhakrishnan, Jai

AU - Martino, Jeremiah

AU - Liu, Qingxue

AU - Chung, Wendy K.

AU - Espinoza, Angelica

AU - Luo, Yuan

AU - Wei, Wei Qi

AU - Feng, Qiping

AU - Weng, Chunhua

AU - Fang, Yilu

AU - Kullo, Iftikhar J.

AU - Naderian, Mohammadreza

AU - Limdi, Nita

AU - Irvin, Marguerite R.

AU - Tiwari, Hemant

AU - Mohan, Sumit

AU - Rao, Maya

AU - Dube, Geoffrey K.

AU - Chaudhary, Ninad S.

AU - Gutiérrez, Orlando M.

AU - Judd, Suzanne E.

AU - Cushman, Mary

AU - Lange, Leslie A.

AU - Lange, Ethan M.

AU - Bivona, Daniel L.

AU - Verbitsky, Miguel

AU - Winkler, Cheryl A.

AU - Kopp, Jeffrey B.

AU - Santoriello, Dominick

AU - Batal, Ibrahim

AU - Pinheiro, Sérgio Veloso Brant

AU - Oliveira, Eduardo Araújo

AU - Simoes e Silva, Ana Cristina

AU - Pisani, Isabella

AU - Fiaccadori, Enrico

AU - Lin, Fangming

AU - Gesualdo, Loreto

AU - Amoroso, Antonio

AU - Ghiggeri, Gian Marco

AU - D’Agati, Vivette D.

AU - Magistroni, Riccardo

AU - Kenny, Eimear E.

AU - Loos, Ruth J.F.

AU - Montini, Giovanni

AU - Hildebrandt, Friedhelm

AU - Paul, Dirk S.

AU - Petrovski, Slavé

AU - Goldstein, David B.

AU - Kretzler, Matthias

AU - Gbadegesin, Rasheed

AU - Gharavi, Ali G.

AU - Kiryluk, Krzysztof

AU - Sampson, Matthew G.

AU - Pollak, Martin R.

AU - Sanna-Cherchi, Simone

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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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SN - 2041-1723

VL - 14

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 7836

ER -

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

Abstract

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