Nature Communications (Nov 2023)
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
Affiliations
- Yask Gupta
- Department of Medicine, Columbia University Irving Medical Center
- David J. Friedman
- Nephrology Division, Department of Medicine, Beth Israel Deaconess Medical Center
- Michelle T. McNulty
- Division of Pediatric Nephrology, Boston Children’s Hospital
- Atlas Khan
- Department of Medicine, Columbia University Irving Medical Center
- Brandon Lane
- Division of Nephrology, Department of Pediatrics, Duke University School of Medicine
- Chen Wang
- Department of Medicine, Columbia University Irving Medical Center
- Juntao Ke
- Department of Medicine, Columbia University Irving Medical Center
- Gina Jin
- Department of Medicine, Columbia University Irving Medical Center
- Benjamin Wooden
- Department of Medicine, Columbia University Irving Medical Center
- Andrea L. Knob
- Nephrology Division, Department of Medicine, Beth Israel Deaconess Medical Center
- Tze Y. Lim
- Department of Medicine, Columbia University Irving Medical Center
- Gerald B. Appel
- Department of Medicine, Columbia University Irving Medical Center
- Kinsie Huggins
- Division of Nephrology, Department of Pediatrics, Duke University School of Medicine
- Lili Liu
- Department of Medicine, Columbia University Irving Medical Center
- Adele Mitrotti
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J) Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro
- Megan C. Stangl
- Division of Nephrology, Department of Pediatrics, Duke University School of Medicine
- Andrew Bomback
- Department of Medicine, Columbia University Irving Medical Center
- Rik Westland
- Department of Pediatric Nephrology, Emma Children’s Hospital, University of Amsterdam
- Monica Bodria
- Division of Nephrology and Renal Transplantation, IRCCS Istituto Giannina Gaslini
- Maddalena Marasa
- Department of Medicine, Columbia University Irving Medical Center
- Ning Shang
- Department of Medicine, Columbia University Irving Medical Center
- David J. Cohen
- Department of Medicine, Columbia University Irving Medical Center
- Russell J. Crew
- Department of Medicine, Columbia University Irving Medical Center
- William Morello
- Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico
- Pietro Canetta
- Department of Medicine, Columbia University Irving Medical Center
- Jai Radhakrishnan
- Department of Medicine, Columbia University Irving Medical Center
- Jeremiah Martino
- Department of Medicine, Columbia University Irving Medical Center
- Qingxue Liu
- Department of Medicine, Columbia University Irving Medical Center
- Wendy K. Chung
- Departments of Pediatrics and Medicine, Columbia University Irving Medical Center
- Angelica Espinoza
- Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University
- Yuan Luo
- Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University
- Wei-Qi Wei
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center
- Qiping Feng
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center
- Chunhua Weng
- Department of Biomedical Informatics, Columbia University Irving Medical Center
- Yilu Fang
- Department of Biomedical Informatics, Columbia University Irving Medical Center
- Iftikhar J. Kullo
- Atherosclerosis and Lipid Genomics Laboratory, Mayo Clinic
- Mohammadreza Naderian
- Atherosclerosis and Lipid Genomics Laboratory, Mayo Clinic
- Nita Limdi
- Department of Neurology, Heersink School of Medicine, University of Alabama at Birmingham
- Marguerite R. Irvin
- Department of Epidemiology, School of Public Health, University of Alabama at Birmingham
- Hemant Tiwari
- Department of Biostatistics, School of Public Health, University of Alabama at Birmingham
- Sumit Mohan
- Department of Medicine, Columbia University Irving Medical Center
- Maya Rao
- Department of Medicine, Columbia University Irving Medical Center
- Geoffrey K. Dube
- Department of Medicine, Columbia University Irving Medical Center
- Ninad S. Chaudhary
- Department of Epidemiology, School of Public Health, University of Alabama at Birmingham
- Orlando M. Gutiérrez
- Department of Epidemiology, School of Public Health, University of Alabama at Birmingham
- Suzanne E. Judd
- Department of Biostatistics, School of Public Health, University of Alabama at Birmingham
- Mary Cushman
- Department of Medicine and Pathology and Laboratory Medicine, University of Vermont
- Leslie A. Lange
- Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus
- Ethan M. Lange
- Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus
- Daniel L. Bivona
- Department of Medicine, Columbia University Irving Medical Center
- Miguel Verbitsky
- Department of Medicine, Columbia University Irving Medical Center
- Cheryl A. Winkler
- Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health and Basic Research Program, Frederick National Laboratory
- Jeffrey B. Kopp
- Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH
- Dominick Santoriello
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center
- Ibrahim Batal
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center
- Sérgio Veloso Brant Pinheiro
- Universidade Federal de Minas Gerais (UFMG), Faculdade de Medicina, Laboratório Interdisciplinar de Investigação Médica, Departamento de Pediatria, Unidade de Nefrologia Pediátrica
- Eduardo Araújo Oliveira
- Universidade Federal de Minas Gerais (UFMG), Faculdade de Medicina, Laboratório Interdisciplinar de Investigação Médica, Departamento de Pediatria, Unidade de Nefrologia Pediátrica
- Ana Cristina Simoes e Silva
- Universidade Federal de Minas Gerais (UFMG), Faculdade de Medicina, Laboratório Interdisciplinar de Investigação Médica, Departamento de Pediatria, Unidade de Nefrologia Pediátrica
- Isabella Pisani
- Nephrology Unit, Parma University Hospital, and Department of Medicine and Surgery, University of Parma
- Enrico Fiaccadori
- Nephrology Unit, Parma University Hospital, and Department of Medicine and Surgery, University of Parma
- Fangming Lin
- Division of Pediatric Nephrology, Department of Pediatrics, Columbia University
- Loreto Gesualdo
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J) Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro
- Antonio Amoroso
- Immunogenetics and Transplant Biology Service, University Hospital “Città della Salute e della Scienza di Torino”, Department of Medical Sciences, University of Turin
- Gian Marco Ghiggeri
- Division of Nephrology and Renal Transplantation, IRCCS Istituto Giannina Gaslini
- Vivette D. D’Agati
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center
- Riccardo Magistroni
- Surgical, Medical and Dental Department of Morphological Sciences, Section of Nephrology, University of Modena and Reggio Emilia
- Eimear E. Kenny
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai
- Ruth J. F. Loos
- The Charles Bronfman Institute for Personalized Medicine, 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
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca
- Slavé Petrovski
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca
- David B. Goldstein
- Institute for Genomic Medicine, Columbia University Irving Medical Center
- Matthias Kretzler
- Department of Internal Medicine, Division of Nephrology, University of Michigan
- Rasheed Gbadegesin
- Division of Nephrology, Department of Pediatrics, Duke University School of Medicine
- Ali G. Gharavi
- Department of Medicine, Columbia University Irving Medical Center
- Krzysztof Kiryluk
- Department of Medicine, Columbia University Irving Medical Center
- Matthew G. Sampson
- Harvard Medical School
- Martin R. Pollak
- Nephrology Division, Department of Medicine, Beth Israel Deaconess Medical Center
- Simone Sanna-Cherchi
- Department of Medicine, Columbia University Irving Medical Center
- DOI
- https://doi.org/10.1038/s41467-023-43020-9
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 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.
