Precision Diagnosis in APOL1 Kidney Disease With the p.N264K M1 Protective Variant
Issued Date
2026-03-02
Resource Type
eISSN
25743805
Scopus ID
2-s2.0-105033211226
Pubmed ID
41811315
Journal Title
JAMA Network Open
Volume
9
Issue
3
Rights Holder(s)
SCOPUS
Bibliographic Citation
JAMA Network Open Vol.9 No.3 (2026) , e261452
Suggested Citation
Martinelli E., Ke J., Khan A., Wongboonsin J., Vanderwall D.R., Lim T.Y., Santoriello D., Gupta Y., McNulty M.T., Koyama S., Puntambekar S., Bomback A.S., Canetta P., Kretzler M., Montini G., Morello W., Maggiore U., Fiaccadori E., Gesualdo L., Ghiggeri G.M., Oliveira E.A., Simoes E Silva A.C., Bendapudi P.K., Motelow J., Garcia C.K., Paul D.S., Petrovski S., Goldstein D.B., Friedman D.J., Radhakrishnan J., Lin F., Mohan S., Appel G.B., Saleem M.A., Natarajan P., Hildebrandt F., Westland R., D'Agati V.D., Gbadegesin R., Gharavi A.G., Pollak M.R., Kiryluk K., Sampson M.G., Sanna-Cherchi S. Precision Diagnosis in APOL1 Kidney Disease With the p.N264K M1 Protective Variant. JAMA Network Open Vol.9 No.3 (2026) , e261452. doi:10.1001/jamanetworkopen.2026.1452 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/115930
Title
Precision Diagnosis in APOL1 Kidney Disease With the p.N264K M1 Protective Variant
Author(s)
Martinelli E.
Ke J.
Khan A.
Wongboonsin J.
Vanderwall D.R.
Lim T.Y.
Santoriello D.
Gupta Y.
McNulty M.T.
Koyama S.
Puntambekar S.
Bomback A.S.
Canetta P.
Kretzler M.
Montini G.
Morello W.
Maggiore U.
Fiaccadori E.
Gesualdo L.
Ghiggeri G.M.
Oliveira E.A.
Simoes E Silva A.C.
Bendapudi P.K.
Motelow J.
Garcia C.K.
Paul D.S.
Petrovski S.
Goldstein D.B.
Friedman D.J.
Radhakrishnan J.
Lin F.
Mohan S.
Appel G.B.
Saleem M.A.
Natarajan P.
Hildebrandt F.
Westland R.
D'Agati V.D.
Gbadegesin R.
Gharavi A.G.
Pollak M.R.
Kiryluk K.
Sampson M.G.
Sanna-Cherchi S.
Ke J.
Khan A.
Wongboonsin J.
Vanderwall D.R.
Lim T.Y.
Santoriello D.
Gupta Y.
McNulty M.T.
Koyama S.
Puntambekar S.
Bomback A.S.
Canetta P.
Kretzler M.
Montini G.
Morello W.
Maggiore U.
Fiaccadori E.
Gesualdo L.
Ghiggeri G.M.
Oliveira E.A.
Simoes E Silva A.C.
Bendapudi P.K.
Motelow J.
Garcia C.K.
Paul D.S.
Petrovski S.
Goldstein D.B.
Friedman D.J.
Radhakrishnan J.
Lin F.
Mohan S.
Appel G.B.
Saleem M.A.
Natarajan P.
Hildebrandt F.
Westland R.
D'Agati V.D.
Gbadegesin R.
Gharavi A.G.
Pollak M.R.
Kiryluk K.
Sampson M.G.
Sanna-Cherchi S.
Author's Affiliation
Harvard Medical School
Massachusetts Institute of Technology
Columbia University
Massachusetts General Hospital
Universiteit van Amsterdam
Brigham and Women's Hospital
University of Bristol
University of Michigan Medical School
Beth Israel Deaconess Medical Center
Boston Children's Hospital
Universidade Federal de Minas Gerais
Università degli studi di Bari Aldo Moro
Columbia University Irving Medical Center
Duke University School of Medicine
Università di Parma
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Universität zu Lübeck
AstraZeneca
Siriraj Hospital
Università degli Studi di Torino, Scuola di Medicina
Istituto Giannina Gaslini
Bumrungrad International Hospital
Actio Biosciences
Massachusetts Institute of Technology
Columbia University
Massachusetts General Hospital
Universiteit van Amsterdam
Brigham and Women's Hospital
University of Bristol
University of Michigan Medical School
Beth Israel Deaconess Medical Center
Boston Children's Hospital
Universidade Federal de Minas Gerais
Università degli studi di Bari Aldo Moro
Columbia University Irving Medical Center
Duke University School of Medicine
Università di Parma
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Universität zu Lübeck
AstraZeneca
Siriraj Hospital
Università degli Studi di Torino, Scuola di Medicina
Istituto Giannina Gaslini
Bumrungrad International Hospital
Actio Biosciences
Corresponding Author(s)
Other Contributor(s)
Abstract
Importance: The APOL1 M1 (p.N264K) variant protects against G2-associated APOL1 focal segmental glomerulosclerosis (FSGS) and chronic kidney disease (CKD). However, the utility of knowing an individual's M1 status in guiding kidney disease diagnosis and other clinical scenarios remains underexplored. Objective: To test 2 hypotheses: (1) in patients with APOL1 high-risk (HR) genotype kidney disease with at least 1 G2 allele, M1 can distinguish APOL1 CKD from non-APOL1 CKD; (2) in people with APOL1 low-risk (LR) genotypes, M1 is independently associated with protection against FSGS and CKD. Design, Setting, and Participants: Retrospective case-control study using data from 2 tertiary care hospitals (Columbia University Irving Medical Center and Mass General Brigham Biobank) and population-based data (the UK Biobank [UKB], Electronic Medical Records and Genomics [eMERGE-III], and All of Us [AoU]). Participants were individuals with a diagnosis of FSGS or steroid-resistant nephrotic syndrome (SRNS), individuals with CKD, and controls. Exposures: Exposures included the M1 variant (p.N264K) obtained from exome or genome sequencing data, sex, and genetic ancestry. Main outcome and measure: The main outcome was the presence or absence of kidney disease, defined as FSGS or non-FSGS CKD, compared with non-kidney disease controls. Association between the M1 variant and disease status was assessed using odds ratios (ORs). Results: A total of 107 696 individuals (54 994 [51.1%] female; 8779 [8.2%] with African ancestry, 78 475 [72.9%] with European ancestry, and 16 129 [15.0%] with multiethnic ancestry), including 3460 with FSGS or SRNS, 24 382 with non-FSGS CKD kidney disease, and 79 854 controls were enrolled in the discovery cohort. In the APOL1-HR group (1413 participants), M1 was significantly inversely associated with FSGS or SRNS cases compared with controls without kidney disease (OR, 0.20; 95% CI, 0.04-0.63; P = 3.69 × 10-3). Among individuals with CKD with APOL1-HR genotypes, M1 was 4 times more frequent in those whose CKD was not due to FSGS or SRNS. Importantly, electronic health record and biopsy review identified an alternative, non-APOL1 cause for CKD in nearly all APOL1-HR-M1 cases. There was no association between individuals with APOL1-LR genotypes with M1 and protection against CKD or FSGS. Conclusions and relevance: In this case-control study of 107 696 individuals, presence of an APOL1-HR genotype M1 was significantly associated with protection against kidney disease, suggesting that it may have a role as a genetic modifier. Patients with CKD with an APOL1-HR genotype and M1 should be evaluated for an alternative and potentially treatable cause of their CKD.