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Meta-Analysis
. 2023 Nov 1;34(11):1889-1899.
doi: 10.1681/ASN.0000000000000219. Epub 2023 Oct 6.

Genetic Inhibition of APOL1 Pore-Forming Function Prevents APOL1-Mediated Kidney Disease

Adriana M Hung  1   2 , Victoria A Assimon  3 , Hua-Chang Chen  1   4 , Zhihong Yu  1   4 , Caitlyn Vlasschaert  5 , Jefferson L Triozzi  2 , Helen Chan  3 , Lee Wheless  6 , Otis Wilson  1   2 , Shailja C Shah  7 , Taralynn Mack  1   8 , Trevor Thompson  2 , Michael E Matheny  1   4   9 , Saranya Chandrasekar  3 , Sahar V Mozaffari  3 , Cecilia P Chung  10 , Philip Tsao  11   12 , Katalin Susztak  13 , Edward D Siew  1   2 , Karol Estrada  3 , J Michael Gaziano  14   15 , Robert R Graham  3 , Ran Tao  1   4 , Maarten Hoek  3 , Cassianne Robinson-Cohen  2 , Eric M Green  3 , Alexander G Bick  8   14 ; Million Veteran Program
Collaborators, Affiliations
Meta-Analysis

Genetic Inhibition of APOL1 Pore-Forming Function Prevents APOL1-Mediated Kidney Disease

Adriana M Hung et al. J Am Soc Nephrol. .

Abstract

Significance statement: African Americans are at increased risk of CKD in part due to high-risk (HR) variants in the apolipoprotein L1 ( APOL1 ) gene, termed G1/G2. A different APOL1 variant, p.N264K , reduced the risk of CKD and ESKD among carriers of APOL1 HR variants to levels comparable with individuals with APOL1 low-risk variants in an analysis of 121,492 participants of African ancestry from the Million Veteran Program (MVP). Functional genetic studies in cell models showed that APOL1 p.N264K blocked APOL1 pore-forming function and ion channel conduction and reduced toxicity of APOL1 HR mutations. Pharmacologic inhibitors that mimic this mutation blocking APOL1 -mediated pore formation may be able to prevent and/or treat APOL1 -associated kidney disease.

Background: African Americans are at increased risk for nondiabetic CKD in part due to HR variants in the APOL1 gene.

Methods: We tested whether a different APOL1 variant, p.N264K , modified the association between APOL1 HR genotypes (two copies of G1/G2) and CKD in a cross-sectional analysis of 121,492 participants of African ancestry from the MVP. We replicated our findings in the Vanderbilt University Biobank ( n =14,386) and National Institutes of Health All of Us ( n =14,704). Primary outcome was CKD and secondary outcome was ESKD among nondiabetic patients. Primary analysis compared APOL1 HR genotypes with and without p.N264K . Secondary analyses included APOL1 low-risk genotypes and tested for interaction. In MVP, we performed sequential logistic regression models adjusting for demographics, comorbidities, medications, and ten principal components of ancestry. Functional genomic studies expressed APOL1 HR variants with and without APOL1 p.N264K in cell models.

Results: In the MVP cohort, 15,604 (12.8%) had two APOL1 HR variants, of which 582 (0.5%) also had APOL1 p.N264K . In MVP, 18,831 (15%) had CKD, 4177 (3%) had ESKD, and 34% had diabetes. MVP APOL1 HR, without p.N264K , was associated with increased odds of CKD (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.60 to 1.85) and ESKD (OR, 3.94; 95% CI, 3.52 to 4.41). In MVP, APOL1 p.N264K mitigated the renal risk of APOL1 HR, in CKD (OR, 0.43; 95% CI, 0.28 to 0.65) and ESKD (OR, 0.19; CI 0.07 to 0.51). In the replication cohorts meta-analysis, APOL1 p.N264K mitigated the renal risk of APOL1 HR in CKD (OR, 0.40; 95% CI, 0.18 to 0.92) and ESKD (OR, 0.19; 95% CI, 0.05 to 0.79). In the mechanistic studies, APOL1 p.N264K blocked APOL1 pore-forming function and ion channel conduction and reduced toxicity of APOL1 HR variants.

Conclusions: APOL1 p.N264K is associated with reduced risk of CKD and ESKD among carriers of APOL1 HR to levels comparable with individuals with APOL1 low-risk genotypes.

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Conflict of interest statement

V.A. Assimon reports Employer: Cartography Biosciences, Maze Therapeutics, and Soteria Biotherapeutics; Consultancy: Capstan Therapeutics and Soteria Biotherapeutics; Ownership Interest: Cartography Biosciences, Cleave Therapeutics, Denali Therapeutics, Maze Therapeutics, and Soteria Biotherapeutics; Research Funding: Cartography Biosciences, Maze Therapeutics, and Soteria Biotherapeutics; and Patents or Royalties: Maze Therapeutics, Soteria Biotherapeutics, and University of California San Francisco. A.G. Bick reports Ownership Interest: TenSixteen Bio. H. Chan reports Employer: Maze Therapeutics; and Ownership Interest: Cytokinetics, Gilead, Illumina, Nektar, and Vertex.S. Chandrasekar reports Employer: Apple Inc., Arcus Biosciences, and Maze Therapeutics; and Ownership Interest: Apple Inc., Arcus Biosciences, and Maze Therapeutics. C.P. Chung reports Advisory or Leadership Role: Journals: Arthritis Care & Research, Clinical Pharmacology & Therapeutics, and Clinical Rheumatology. K. Estrada reports Employer: Maze TX; and Ownership Interest: BioMarin, Maze TX, and Regeneron. R.R. Graham reports Employer: Maze Therapeutics; Ownership Interest: Maze Therapeutics; and Patents or Royalties: Maze Therapeutics. E.M. Green reports Employer: Maze Therapeutics; Ownership Interest: Maze Therapeutics; Patents or Royalties: Maze Therapeutics; and Advisory or Leadership Role: Maze Therapeutics. M. Hoek reports Employer: Maze Therapeutics; Ownership Interest: Maze Therapeutics and Merck & Co.; Research Funding: Maze Therapeutics and Merck & Co.; and Patents or Royalties: Maze Therapeutics and Merck & Co. A.M. Hung reports Consultancy: NHLBI consultant for Gene and life interaction grant; Research Funding: Vertex Grant to VUMC and VHA CSR&D Merit “Genetics of Kidney Disease and Hypertension, Risk Prediction and Drug Response”; and Advisory or Leadership Role: Ad-hoc Scientific Review Committee CSR&D, Ad-Scientific Review Committee KNOD, Ad-hoc SRC NHLBI, Co-Chair Million Veteran Program Publications and Presentation committee, Co-Chair Pharmacogenomics for COVID-19 Million Veteran Program, Section Editor, Clinical Nephrology; Standing member SRC HSR&D bioinformatics, and Veterans Affairs. M.E. Matheny reports Consultancy: Food and Drug Administration (FDA) and NIH-VA-DoD Pain Management Grant Consortium (PMC3); and Advisory or Leadership Role: SMRB Study Section, Steering Committee—Indianapolis VA HSR&D COIN Center, Steering Committee—VA HSR&D VIREC, Steering Committee—Salt Lake City VA HSR&D COIN Center, VA HSR&D, Informatics & Methods Section, and VA ORD Million Veterans Program Executive Steering Committee. S.V. Mozaffari reports Employer: Maze Therapeutics; and Ownership Interest: Maze Therapeutics; 23andMe. C. Robinson-Cohen reports Advisory or Leadership Role: BMC Nephrology Editorial Board Member, CJASN Editorial Board Member, and Clinical Nephrology, Genetics Section Editor. S.C. Shah reports Consultancy: Medscape, Phathom Pharmaceuticals, and RedHill Biopharma; and Research Funding: American Gastroenterological Association, National Institute of Health, US Department of Veterans Affairs. E.D. Siew reports Ownership Interest: Amazon stock and Apple stock; Patents or Royalties: Author for UptoDate (royalties); Advisory or Leadership Role: Editorial board of CJASN. Personal fees; and Other Interests or Relationships: Consultancy Agreement with Novartis (no fees received during past 24 months). K. Susztak reports Consultancy: Astra Zeneca, GSK, Novo Nordisk, and Pfizer; Ownership Interest: Jnana; Research Funding: Astra Zeneca, Bayer, Boehringer Ingelheim, Calico, Gilead, GSK, Jnana, Kyowa Kirin Genentech, Maze, Novartis, Novo Nordisk, ONO Pharma, Regeneron, and Variant Bio; Honoraria: AstraZeneca, Bayer, Jnana, Maze, and Pfizer; and Advisory or Leadership Role: Editorial board; Cell Metabolism, EBioMedicine, JASN, Jnana, Journal of Clinical Investigation, Kidney International, Med, and Pfizer. T. Thompson reports the following: Ownership Interest: Tenacious Products, LLC. L. Wheless reports Research Funding: Dermatology Foundation and VA ClinicalSciences R&D; and Advisory or Leadership Role: Board of Directors, International Immunosuppression and Transplant Skin Cancer Collaborative. R. Tao reports Employer: Vanderbilt University Medical Center, and Genentech. All remaining authors have nothing to disclose.

Because Katalin Susztak is an editor of the Journal of the American Society of Nephrology, she was not involved in the peer review process for this manuscript. A guest editor oversaw the peer review and decision-making process for this manuscript.

Figures

None
Graphical abstract
Figure 1
Figure 1
Association of APOL1 HR (homozygous for G1 or G2 or compound heterozygous for G1/G2) with and without p.N264K allele with CKD and ESKD among MVP participants, BioVU and the All of Us. APOL1, apolipoprotein L1; BioVU, Vanderbilt University Biobank; CI, confidence interval; FE, Fixed effect; HR, high risk; MVP, Million Veteran Program; OR, odds ratio.
Figure 2
Figure 2
The presence of an allele p.N264K in patients with APOL1 HR group (homozygous for G1 or G2 or compound heterozygous for G1/G2) mitigates the risk of CKD and ESKD among MVP participants to values similar to those of participants in the APOL1 low-risk group. All OR are relative to the reference and reported as OR (95% CI). Reference group: APOL1 low-risk genotype, and N264K− APOL1 HR refers to two copies of the APOL1 HR variants G1 or G2 or G1 and G2. APOL1 LR, 0 or 1 total copy of the G1 or G2 HR variant. N264K+, carrying 1 or 2 copies of APOL1 N264K. N264K−, carrying 0 copies of APOL1 N264K. Logistic regression was used to evaluate the association of APOL1 HR and p.N264K allele genotype and CKD (A) and ESKD (B). ORs were adjusted for age, sex, ten principal components of ancestry, BMI, hypertension, and renin–angiotensin–aldosterone system blockade. Minimally adjusted models are presented in Supplemental Table 2. BMI, body mass index.
Figure 3
Figure 3
Effects of APOL1 p.N264K on protein function. (A) APOL1 disease variants, G1 and G2, are toxic when overexpressed in human immortalized podocytes. APOL1 G0 overexpression does not affect podocyte cell viability. Error bars represent SEM. (B) The cytotoxicity of APOL1 G1 and G2 risk variants is attenuated by the N264K mutation. Error bars represent SEM. (C) G2 APOL1-mediated calcium transit is blocked by the N264K mutation in HEK cells. The expression of APOL1 G2 or APOL1 G2 with p.N264K was induced with doxycycline, and fluorescence was measured in the presence of increasing concentrations of calcium. The fluorescence level in (C) is a measure of intracellular calcium. Error bars represent SD. HEK, human embryonic kidney.
See this image and copyright information in PMC

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