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

Yask Gupta^{1

2}, David J Friedman^{3

4}, Michelle T McNulty^{5

6}, Atlas Khan¹, Brandon Lane⁷, Chen Wang¹, Juntao Ke¹, Gina Jin¹, Benjamin Wooden¹, Andrea L Knob^{3

4}, Tze Y Lim^{1

8}, Gerald B Appel¹, Kinsie Huggins⁷, Lili Liu¹, Adele Mitrotti⁹, Megan C Stangl⁷, Andrew Bomback¹, Rik Westland¹⁰, Monica Bodria^{11

12}, Maddalena Marasa¹, Ning Shang¹, David J Cohen¹, Russell J Crew¹, William Morello¹³, Pietro Canetta¹, Jai Radhakrishnan¹, Jeremiah Martino¹, Qingxue Liu¹, Wendy K Chung¹⁴, Angelica Espinoza¹⁵, Yuan Luo¹⁵, Wei-Qi Wei¹⁶, Qiping Feng¹⁶, Chunhua Weng¹⁷, Yilu Fang¹⁷, Iftikhar J Kullo¹⁸, Mohammadreza Naderian¹⁸, Nita Limdi¹⁹, Marguerite R Irvin²⁰, Hemant Tiwari²¹, Sumit Mohan^{1

22}, Maya Rao¹, Geoffrey K Dube¹, Ninad S Chaudhary²⁰, Orlando M Gutiérrez^{20

23}, Suzanne E Judd²¹, Mary Cushman²⁴, Leslie A Lange²⁵, Ethan M Lange²⁵, Daniel L Bivona¹, Miguel Verbitsky¹, Cheryl A Winkler²⁶, Jeffrey B Kopp²⁷, Dominick Santoriello²⁸, Ibrahim Batal²⁸, Sérgio Veloso Brant Pinheiro²⁹, Eduardo Araújo Oliveira²⁹, Ana Cristina Simoes E Silva²⁹, Isabella Pisani³⁰, Enrico Fiaccadori³⁰, Fangming Lin³¹, Loreto Gesualdo⁹, Antonio Amoroso³², Gian Marco Ghiggeri^{11

12}, Vivette D D'Agati²⁸, Riccardo Magistroni³³, Eimear E Kenny^{34

35

36

37}, Ruth J F Loos^{38

39}, Giovanni Montini^{13

40}, Friedhelm Hildebrandt^{4

5}, Dirk S Paul⁴¹, Slavé Petrovski⁴¹, David B Goldstein⁴², Matthias Kretzler⁴³, Rasheed Gbadegesin⁷, Ali G Gharavi¹, Krzysztof Kiryluk¹, Matthew G Sampson^{4

5

6}, Martin R Pollak^{3

4}, Simone Sanna-Cherchi⁴⁴

Affiliations

¹ Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
² Institute for Inflammation Medicine, University of Lubeck, Lübeck, Germany.
³ Nephrology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁴ Harvard Medical School, Boston, MA, USA.
⁵ Division of Pediatric Nephrology, Boston Children's Hospital, Boston, MA, USA.
⁶ Kidney Disease Initiative and Medical and Population Genetics Program, Broad Institute, Boston, MA, USA.
⁷ Division of Nephrology, Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.
⁸ Unit of Genomic Variability and Complex Diseases, Department of Medical Sciences, University of Turin, Turin, Italy.
⁹ Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J) Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy.
¹⁰ Department of Pediatric Nephrology, Emma Children's Hospital, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.
¹¹ Division of Nephrology and Renal Transplantation, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
¹² Laboratory on Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
¹³ Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milano, Italy.
¹⁴ Departments of Pediatrics and Medicine, Columbia University Irving Medical Center, New York, NY, USA.
¹⁵ Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
¹⁶ Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁷ Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY, USA.
¹⁸ Atherosclerosis and Lipid Genomics Laboratory, Mayo Clinic, Rochester, MN, USA.
¹⁹ Department of Neurology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
²⁰ Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
²¹ Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
²² Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
²³ Division of Nephrology, Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
²⁴ Department of Medicine and Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA.
²⁵ Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
²⁶ Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health and Basic Research Program, Frederick National Laboratory, Frederick, MD, USA.
²⁷ Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD, USA.
²⁸ Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
²⁹ Universidade Federal de Minas Gerais (UFMG), Faculdade de Medicina, Laboratório Interdisciplinar de Investigação Médica, Departamento de Pediatria, Unidade de Nefrologia Pediátrica, Belo Horizonte, MG, Brazil.
³⁰ Nephrology Unit, Parma University Hospital, and Department of Medicine and Surgery, University of Parma, Parma, Italy.
³¹ Division of Pediatric Nephrology, Department of Pediatrics, Columbia University, New York, NY, USA.
³² Immunogenetics and Transplant Biology Service, University Hospital "Città della Salute e della Scienza di Torino", Department of Medical Sciences, University of Turin, Turin, Italy.
³³ Surgical, Medical and Dental Department of Morphological Sciences, Section of Nephrology, University of Modena and Reggio Emilia, Modena, Italy.
³⁴ Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁵ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁶ Center for Translational Genomics, Icahn School of Medicine, New York, NY, 10027, USA.
³⁷ Division of Genomic Medicine, Department of Medicine, Icahn School of Medicine, New York, NY, 10027, USA.
³⁸ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁹ Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
⁴⁰ Department of Clinical Sciences and Community Health, Giuliana and Bernardo Caprotti Chair of Pediatrics, University of Milano, Milano, Italy.
⁴¹ Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
⁴² Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA.
⁴³ Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI, USA.
⁴⁴ Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA. ss2517@cumc.columbia.edu.

PMID: 38036523
PMCID: PMC10689833
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 et al. Nat Commun. 2023.

. 2023 Nov 30;14(1):7836.

doi: 10.1038/s41467-023-43020-9.

Authors

Affiliations

¹ Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
² Institute for Inflammation Medicine, University of Lubeck, Lübeck, Germany.
³ Nephrology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁴ Harvard Medical School, Boston, MA, USA.
⁵ Division of Pediatric Nephrology, Boston Children's Hospital, Boston, MA, USA.
⁶ Kidney Disease Initiative and Medical and Population Genetics Program, Broad Institute, Boston, MA, USA.
⁷ Division of Nephrology, Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.
⁸ Unit of Genomic Variability and Complex Diseases, Department of Medical Sciences, University of Turin, Turin, Italy.
⁹ Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J) Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy.
¹⁰ Department of Pediatric Nephrology, Emma Children's Hospital, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.
¹¹ Division of Nephrology and Renal Transplantation, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
¹² Laboratory on Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
¹³ Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milano, Italy.
¹⁴ Departments of Pediatrics and Medicine, Columbia University Irving Medical Center, New York, NY, USA.
¹⁵ Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
¹⁶ Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁷ Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY, USA.
¹⁸ Atherosclerosis and Lipid Genomics Laboratory, Mayo Clinic, Rochester, MN, USA.
¹⁹ Department of Neurology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
²⁰ Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
²¹ Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
²² Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
²³ Division of Nephrology, Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
²⁴ Department of Medicine and Pathology and Laboratory Medicine, University of Vermont, Burlington, VT, USA.
²⁵ Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
²⁶ Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health and Basic Research Program, Frederick National Laboratory, Frederick, MD, USA.
²⁷ Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, MD, USA.
²⁸ Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
²⁹ Universidade Federal de Minas Gerais (UFMG), Faculdade de Medicina, Laboratório Interdisciplinar de Investigação Médica, Departamento de Pediatria, Unidade de Nefrologia Pediátrica, Belo Horizonte, MG, Brazil.
³⁰ Nephrology Unit, Parma University Hospital, and Department of Medicine and Surgery, University of Parma, Parma, Italy.
³¹ Division of Pediatric Nephrology, Department of Pediatrics, Columbia University, New York, NY, USA.
³² Immunogenetics and Transplant Biology Service, University Hospital "Città della Salute e della Scienza di Torino", Department of Medical Sciences, University of Turin, Turin, Italy.
³³ Surgical, Medical and Dental Department of Morphological Sciences, Section of Nephrology, University of Modena and Reggio Emilia, Modena, Italy.
³⁴ Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁵ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁶ Center for Translational Genomics, Icahn School of Medicine, New York, NY, 10027, USA.
³⁷ Division of Genomic Medicine, Department of Medicine, Icahn School of Medicine, New York, NY, 10027, USA.
³⁸ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁹ Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
⁴⁰ Department of Clinical Sciences and Community Health, Giuliana and Bernardo Caprotti Chair of Pediatrics, University of Milano, Milano, Italy.
⁴¹ Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
⁴² Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA.
⁴³ Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI, USA.
⁴⁴ Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA. ss2517@cumc.columbia.edu.

PMID: 38036523
PMCID: PMC10689833
DOI: 10.1038/s41467-023-43020-9

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.

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Conflict of interest statement

M.R.P. and D.J.F. report research support from Vertex. E.E.K. has received personal fees from Regeneron Pharmaceuticals, 23&Me, Allelica, and Illumina; has received research support from Allelica; and serves on the advisory boards for Encompass Biosciences, Overtone, and Galatea Bio Inc. D.S.P. and S.P. are current employees and stockholders of AstraZeneca. W.K.C. is on the Board of Directors of Prime Medicine and RallyBio. D.B.G. is the Co-founder and CEO of Actio Biosciences. A.G.G. receives a research grant from Natera and has served on advisory boards for Natera through a service agreement with Columbia University. A.G.G. has served on advisory boards for Actio Biosciences, Novartis, Travere, and Alnylam and has stock options for Actio Biosciences. The remaining authors declare no competing interests.

Figures

**Fig. 1. Protective effect of the *APOL1* p.N264K missense variant against G2-associated FSGS.**
A Graphical representation of the study design, cohorts and main results of the study. Stratified association analysis of the combined cohort of 528 *APOL1* high-risk FSGS and 2606 genetically-matched *APOL1* high-risk controls: B stacked bar plot for the p.N264K MAF across APOL1-HR genotypes in cases and controls; the Allele C is the reference allele encoding for the p.N264; the Allele A is the minor allele resulting the p.K264 variant amino acid; C Forest plot for the p.N264K association analysis showing significantly protective odds ratios across APOL1 high risk (G1G1, G2G2 and G1G2) genotypes. The plot describes odd ratio and confidence interval for HR (OR = 0.067), G1G2 (OR = 0.136), G2G2 (OR = 0) and G1G2 + G2G2 (OR = 0.081). The P values were obtained separately for aforementioned individual risk alleles using two sided Cochran-Mantel-Haenszel chi-squared test without multiple correction across the alleles (See Methods). No OR or CI for the G1G1 genotype (263 cases, 991 controls) are shown in forest plot because the p.N264K was absent in both groups (the *APOL1* G1 and p.N264K alleles are mutually exclusive), resulting in undefined OR, infinite CI, and a p-value of 1. FSGS focal segmental glomerulosclerosis, CKD chronic kidney disease, ESKD end-stage kidney disease, AF allele frequency, Ctrls controls, OR odds ratio, CI = 95% confidence interval, MAF minor allele frequency. The cartoon in (A) has been created using BioRender at www.biorender.com.

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Update of

Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease.
Gupta Y, Friedman DJ, McNulty M, 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 G, Chaudhary NS, Gutiérrez OM, Judd SE, Cushman M, Lange LA, Lange EM, Bivona DL, Verbitsky M, Winkler CA, Kopp JB, Santoriello D, Batal I, Brant Pinheiro SV, Araújo Oliveira E, E Silva ACS, 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. Gupta Y, et al. medRxiv [Preprint]. 2023 Aug 4:2023.08.02.23293554. doi: 10.1101/2023.08.02.23293554. medRxiv. 2023. Update in: Nat Commun. 2023 Nov 30;14(1):7836. doi: 10.1038/s41467-023-43020-9. PMID: 37577628 Free PMC article. Updated. Preprint.

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

Affiliations

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

Authors

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Abstract

Conflict of interest statement

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