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 and Simone Sanna-Cherchi ()
Additional contact information
Yask Gupta: Columbia University Irving Medical Center
David J. Friedman: Beth Israel Deaconess Medical Center
Michelle T. McNulty: Boston Children’s Hospital
Atlas Khan: Columbia University Irving Medical Center
Brandon Lane: Duke University School of Medicine
Chen Wang: Columbia University Irving Medical Center
Juntao Ke: Columbia University Irving Medical Center
Gina Jin: Columbia University Irving Medical Center
Benjamin Wooden: Columbia University Irving Medical Center
Andrea L. Knob: Beth Israel Deaconess Medical Center
Tze Y. Lim: Columbia University Irving Medical Center
Gerald B. Appel: Columbia University Irving Medical Center
Kinsie Huggins: Duke University School of Medicine
Lili Liu: Columbia University Irving Medical Center
Adele Mitrotti: University of Bari Aldo Moro
Megan C. Stangl: Duke University School of Medicine
Andrew Bomback: Columbia University Irving Medical Center
Rik Westland: University of Amsterdam
Monica Bodria: IRCCS Istituto Giannina Gaslini
Maddalena Marasa: Columbia University Irving Medical Center
Ning Shang: Columbia University Irving Medical Center
David J. Cohen: Columbia University Irving Medical Center
Russell J. Crew: Columbia University Irving Medical Center
William Morello: Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico
Pietro Canetta: Columbia University Irving Medical Center
Jai Radhakrishnan: Columbia University Irving Medical Center
Jeremiah Martino: Columbia University Irving Medical Center
Qingxue Liu: Columbia University Irving Medical Center
Wendy K. Chung: Columbia University Irving Medical Center
Angelica Espinoza: Northwestern University
Yuan Luo: Northwestern University
Wei-Qi Wei: Vanderbilt University Medical Center
Qiping Feng: Vanderbilt University Medical Center
Chunhua Weng: Columbia University Irving Medical Center
Yilu Fang: Columbia University Irving Medical Center
Iftikhar J. Kullo: Mayo Clinic
Mohammadreza Naderian: Mayo Clinic
Nita Limdi: University of Alabama at Birmingham
Marguerite R. Irvin: University of Alabama at Birmingham
Hemant Tiwari: University of Alabama at Birmingham
Sumit Mohan: Columbia University Irving Medical Center
Maya Rao: Columbia University Irving Medical Center
Geoffrey K. Dube: Columbia University Irving Medical Center
Ninad S. Chaudhary: University of Alabama at Birmingham
Orlando M. Gutiérrez: University of Alabama at Birmingham
Suzanne E. Judd: University of Alabama at Birmingham
Mary Cushman: University of Vermont
Leslie A. Lange: University of Colorado Anschutz Medical Campus
Ethan M. Lange: University of Colorado Anschutz Medical Campus
Daniel L. Bivona: Columbia University Irving Medical Center
Miguel Verbitsky: Columbia University Irving Medical Center
Cheryl A. Winkler: National Institutes of Health and Basic Research Program, Frederick National Laboratory
Jeffrey B. Kopp: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH
Dominick Santoriello: Columbia University Irving Medical Center
Ibrahim Batal: Columbia University Irving Medical Center
Sérgio Veloso Brant Pinheiro: Unidade de Nefrologia Pediátrica
Eduardo Araújo Oliveira: Unidade de Nefrologia Pediátrica
Ana Cristina Simoes e Silva: Unidade de Nefrologia Pediátrica
Isabella Pisani: University of Parma
Enrico Fiaccadori: University of Parma
Fangming Lin: Columbia University
Loreto Gesualdo: University of Bari Aldo Moro
Antonio Amoroso: University of Turin
Gian Marco Ghiggeri: IRCCS Istituto Giannina Gaslini
Vivette D. D’Agati: Columbia University Irving Medical Center
Riccardo Magistroni: University of Modena and Reggio Emilia
Eimear E. Kenny: Icahn School of Medicine at Mount Sinai
Ruth J. F. Loos: Icahn School of Medicine at Mount Sinai
Giovanni Montini: Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico
Friedhelm Hildebrandt: Harvard Medical School
Dirk S. Paul: BioPharmaceuticals R&D, AstraZeneca
Slavé Petrovski: BioPharmaceuticals R&D, AstraZeneca
David B. Goldstein: Columbia University Irving Medical Center
Matthias Kretzler: University of Michigan
Rasheed Gbadegesin: Duke University School of Medicine
Ali G. Gharavi: Columbia University Irving Medical Center
Krzysztof Kiryluk: Columbia University Irving Medical Center
Matthew G. Sampson: Harvard Medical School
Martin R. Pollak: Beth Israel Deaconess Medical Center
Simone Sanna-Cherchi: Columbia University Irving Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-8

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43020-9

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