Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease
Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease
ABSTRACT Black Americans have a significantly higher risk of developing chronic kidney disease (CKD), especially focal segmental glomerulosclerosis (FSGS), than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of Black 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.
e Silva Ana Cristina Simoes、Lin Fangming、Mohan Sumit、Bivona Daniel L.、Brant Pinheiro S¨|rgio Veloso、Wooden Benjamin、Kenny Eimear E.、Judd Suzanne E.、Lange Leslie A.、Ara¨2jo Oliveira Eduardo、Ghiggeri Gian Marco、D?ˉAgati Vivette D.、Montini Giovanni、Fiaccadori Enrico、Paul Dirk S.、Ke Juntao、Jin Gina、Bomback Andrew、Cohen David J.、Crew Russell J.、Canetta Pietro、Liu Qingxue、Chung Wendy K.、Espinoza Angelica、Weng Chunhua、Fang Yilu、Irvin Marguerite R.、Rao Maya、Dube Geoffrey、Kullo Iftikhar J.、Guti¨|rrez Orlando M.、Shang Ning、Huggins Kinsie、Gbadegesin Rasheed、Gharavi Ali G.、Pollak Martin R.、Lange Ethan M.、Wei Wei-Qi、Sampson Matthew G.、Hildebrandt Friedhelm、Winkler Cheryl A.、Bodria Monica、Knob Andrea L.、Feng Qiping、Appel Gerald B.、Pisani Isabella、Limdi Nita、Magistroni Riccardo、Verbitsky Miguel、Goldstein David B.、Stangl Megan C.、Radhakrishnan Jai、Morello William、Wang Chen、Marasa Maddalena、Amoroso Antonio、Kretzler Matthias、Petrovski Slav¨|、Friedman David J.、Santoriello Dominick、Chaudhary Ninad S.、Naderian Mohammadreza、Kiryluk Krzysztof、Gupta Yask、McNulty Michelle、Tiwari Hemant、Martino Jeremiah、Batal Ibrahim、Sanna-Cherchi Simone、Luo Yuan、Lane Brandon、Liu Lili、Loos Ruth J.F.、Khan Atlas、Gesualdo Loreto、Westland Rik、Mitrotti Adele、Lim Tze Y.、Kopp Jeffrey B.、Cushman Mary
Universidade Federal de Minas Gerais (UFMG), Faculdade de Medicina, Laborat¨?rio Interdisciplinar de Investiga??o M¨|dica, Departamento de Pediatria, Unidade de Nefrologia Pedi¨￠tricaDivision of Pediatric Nephrology, Department of Pediatrics, Columbia UniversityDepartment of Medicine, Columbia University Irving Medical Center||Department of Epidemiology, Mailman School of Public Health, Columbia UniversityDepartment of Medicine, Columbia University Irving Medical CenterUniversidade Federal de Minas Gerais (UFMG), Faculdade de Medicina, Laborat¨?rio Interdisciplinar de Investiga??o M¨|dica, Departamento de Pediatria, Unidade de Nefrologia Pedi¨￠tricaDepartment of Medicine, Columbia University Irving Medical CenterInstitute for Genomic Health, Icahn School of Medicine at Mount Sinai||Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiDepartment of Biostatistics, School of Public Health, University of Alabama at BirminghamDivision of Biomedical Informatics and Personalized Medicine, Department of Medicine University of Colorado Anschutz Medical CampusUniversidade Federal de Minas Gerais (UFMG), Faculdade de Medicina, Laborat¨?rio Interdisciplinar de Investiga??o M¨|dica, Departamento de Pediatria, Unidade de Nefrologia Pedi¨￠tricaDivision of Nephrology and Renal Transplantation, IRCCS Istituto Giannina Gaslini||Laboratory on Molecular Nephrology, IRCCS Istituto Giannina GasliniDepartment of Pathology and Cell Biology, Columbia University Irving Medical CenterPediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca?ˉ Granda-Ospedale Maggiore Policlinico||Department of Clinical Sciences and Community Health, Giuliana and Bernardo Caprotti Chair of Pediatrics, University of MilanoNephrology Unit, Parma University Hospital, and Department of Medicine and Surgery, University of ParmaCentre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&DDepartment of Medicine, Columbia University Irving Medical CenterDepartment of Medicine, Columbia University Irving Medical CenterDepartment of Medicine, Columbia University Irving Medical CenterDepartment of Medicine, Columbia University Irving Medical CenterDepartment of Medicine, Columbia University Irving Medical CenterDepartment of Medicine, Columbia University Irving Medical CenterDepartment of Medicine, Columbia University Irving Medical CenterDepartments of Pediatrics and Medicine, Columbia University Irving Medical CenterCenter for Genetic Medicine, Feinberg School of Medicine, Northwestern UniversityDepartment of Biomedical Informatics, Columbia University Irving Medical CenterDepartment of Biomedical Informatics, Columbia University Irving Medical CenterDepartment of Epidemiology, School of Public Health, University of Alabama at BirminghamDepartment of Medicine, Columbia University Irving Medical CenterDepartment of Medicine, Columbia University Irving Medical CenterAtherosclerosis and Lipid Genomics LaboratoryDepartment of Epidemiology, School of Public Health, University of Alabama at Birmingham||Division of Nephrology, Department of Medicine, Heersink School of Medicine, University of Alabama at BirminghamDepartment of Medicine, Columbia University Irving Medical CenterDivision of Nephrology, Department of Pediatrics, Duke University School of MedicineDivision of Nephrology, Department of Pediatrics, Duke University School of MedicineDepartment of Medicine, Columbia University Irving Medical CenterNephrology Division, Department of Medicine, Beth Israel Deaconess Medical CenterDivision of Biomedical Informatics and Personalized Medicine, Department of Medicine University of Colorado Anschutz Medical CampusDivision of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical CenterHarvard Medical School||Division of Pediatric Nephrology, Boston Children?ˉs Hospital||Kidney Disease Initiative and Medical and Population Genetics Program, Broad InstituteHarvard Medical School||Division of Pediatric Nephrology, Boston Children?ˉs HospitalCancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health and Basic Research Program, Frederick National LaboratoryDivision of Nephrology and Renal Transplantation, IRCCS Istituto Giannina Gaslini||Laboratory on Molecular Nephrology, IRCCS Istituto Giannina GasliniNephrology Division, Department of Medicine, Beth Israel Deaconess Medical Center||Harvard Medical SchoolDivision of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical CenterDepartment of Medicine, Columbia University Irving Medical CenterNephrology Unit, Parma University Hospital, and Department of Medicine and Surgery, University of ParmaDepartment of Neurology, Heersink School of Medicine, University of Alabama at BirminghamSurgical, Medical and Dental Department of Morphological Sciences, Section of Nephrology, University of Modena and Reggio EmiliaDepartment of Medicine, Columbia University Irving Medical CenterInstitute for Genomic Medicine, Columbia University Irving Medical CenterDivision of Nephrology, Department of Pediatrics, Duke University School of MedicineDepartment of Medicine, Columbia University Irving Medical CenterPediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca?ˉ Granda-Ospedale Maggiore PoliclinicoDepartment of Medicine, Columbia University Irving Medical CenterDepartment of Medicine, Columbia University Irving Medical CenterImmunogenetics and Transplant Biology Service, University Hospital ?°Citt¨¤ della Salute e della Scienza di Torino?±, Department of Medical Sciences, University of TurinDepartment of Internal Medicine, Division of Nephrology, University of MichiganCentre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&DNephrology Division, Department of Medicine, Beth Israel Deaconess Medical Center||Harvard Medical SchoolDepartment of Pathology and Cell Biology, Columbia University Irving Medical CenterDepartment of Epidemiology, School of Public Health, University of Alabama at BirminghamAtherosclerosis and Lipid Genomics LaboratoryDepartment of Medicine, Columbia University Irving Medical CenterDepartment of Medicine, Columbia University Irving Medical CenterDivision of Pediatric Nephrology, Boston Children?ˉs Hospital||Kidney Disease Initiative and Medical and Population Genetics Program, Broad InstituteDepartment of Biostatistics, School of Public Health, University of Alabama at BirminghamDepartment of Medicine, Columbia University Irving Medical CenterDepartment of Pathology and Cell Biology, Columbia University Irving Medical CenterDepartment of Medicine, Columbia University Irving Medical CenterCenter for Genetic Medicine, Feinberg School of Medicine, Northwestern UniversityDivision of Nephrology, Department of Pediatrics, Duke University School of MedicineDepartment of Medicine, Columbia University Irving Medical CenterThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai||Novo Nordisk Foundation Center for Basic Metabolic Research, University of CopenhagenDepartment of Medicine, Columbia University Irving Medical CenterDepartment of Precision and Regenerative Medicine and Ionian Area (DiMePre-J) Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo MoroDepartment of Pediatric Nephrology, Emma Children?ˉs Hospital, University of AmsterdamDepartment of Precision and Regenerative Medicine and Ionian Area (DiMePre-J) Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo MoroDepartment of Medicine, Columbia University Irving Medical CenterKidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIHDepartment of Medicine and Pathology and Laboratory Medicine, University of Vermont
基础医学内科学医学研究方法
e Silva Ana Cristina Simoes,Lin Fangming,Mohan Sumit,Bivona Daniel L.,Brant Pinheiro S¨|rgio Veloso,Wooden Benjamin,Kenny Eimear E.,Judd Suzanne E.,Lange Leslie A.,Ara¨2jo Oliveira Eduardo,Ghiggeri Gian Marco,D?ˉAgati Vivette D.,Montini Giovanni,Fiaccadori Enrico,Paul Dirk S.,Ke Juntao,Jin Gina,Bomback Andrew,Cohen David J.,Crew Russell J.,Canetta Pietro,Liu Qingxue,Chung Wendy K.,Espinoza Angelica,Weng Chunhua,Fang Yilu,Irvin Marguerite R.,Rao Maya,Dube Geoffrey,Kullo Iftikhar J.,Guti¨|rrez Orlando M.,Shang Ning,Huggins Kinsie,Gbadegesin Rasheed,Gharavi Ali G.,Pollak Martin R.,Lange Ethan M.,Wei Wei-Qi,Sampson Matthew G.,Hildebrandt Friedhelm,Winkler Cheryl A.,Bodria Monica,Knob Andrea L.,Feng Qiping,Appel Gerald B.,Pisani Isabella,Limdi Nita,Magistroni Riccardo,Verbitsky Miguel,Goldstein David B.,Stangl Megan C.,Radhakrishnan Jai,Morello William,Wang Chen,Marasa Maddalena,Amoroso Antonio,Kretzler Matthias,Petrovski Slav¨|,Friedman David J.,Santoriello Dominick,Chaudhary Ninad S.,Naderian Mohammadreza,Kiryluk Krzysztof,Gupta Yask,McNulty Michelle,Tiwari Hemant,Martino Jeremiah,Batal Ibrahim,Sanna-Cherchi Simone,Luo Yuan,Lane Brandon,Liu Lili,Loos Ruth J.F.,Khan Atlas,Gesualdo Loreto,Westland Rik,Mitrotti Adele,Lim Tze Y.,Kopp Jeffrey B.,Cushman Mary.Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease[EB/OL].(2025-03-28)[2025-06-13].https://www.medrxiv.org/content/10.1101/2023.08.02.23293554.点此复制
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