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.
Original language | English |
---|---|
Article number | 7836 |
Journal | Nature communications |
Volume | 14 |
Issue number | 1 |
DOIs | |
Publication status | Published - Dec 2023 |
Access to Document
Other files and links
Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver
}
In: Nature communications, Vol. 14, No. 1, 7836, 12.2023.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease.
AU - Westland, R.
N1 - Funding Information: We thank the patients and their family members for participating in this study. This research was supported by the Department of Defense (W81XWH-16-1-0451, W81XWH-22-1-0966) and by the National Center for Advancing Translational Sciences, National Institutes of Health (Grant Number UL1TR001873), to S.S.-C., by the National Institute of Health Grant RC2-DK122397, to S.S.-C, M.R.P., F.H. and M.G.S, by the National Institute of Health Grant R01-DK007092 to M.R.P. and D.J.F., and by the National Institute of Health Grant RC2-DK116690 to K.K. and M.K. M.G.S is also supported by R01-DK119380 and the Pura Vida Kidney Foundation. J.B.K. is supported by the Intramural Research Program, NIDDK, NIH. A.G.G. is supported by NIDDK 1U01-DK100876 and DOD W81XWH2110550. K.K. is additionally supported by R01-DK105124, R01-DK136765, R01-LM013061, 2U01-HG008680, U01-AI152960, and 5UL1-TR001873. R.G. is supported by 1R01-DK134347-01, NIH/NICHD 1R21-HD104176-01. F.H. is supported by R01-DK076683. The eMERGE Network was initiated and funded by NHGRI through the following grants: Phase IV: U01HG011172 (Cincinnati Children’s Hospital Medical Center); U01HG011175 (Children’s Hospital of Philadelphia); U01HG008680 (Columbia University); U01HG011176 (Icahn School of Medicine at Mount Sinai); U01HG008685 (Mass General Brigham); U01HG006379 (Mayo Clinic); U01HG011169 (Northwestern University); U01HG011167 (University of Alabama at Birmingham); U01HG008657 (University of Washington); U01HG011181 (Vanderbilt University Medical Center); U01HG011166 (Vanderbilt University Medical Center serving as the Coordinating Center); Phase III: U01HG8657 (Group Health Cooperative/University of Washington); U01HG8685 (Brigham and Women’s Hospital); U01HG8672 (Vanderbilt University Medical Center); U01HG8666 (Cincinnati Children’s Hospital Medical Center); U01HG6379 (Mayo Clinic); U01HG8679 (Geisinger Clinic); U01HG8680 (Columbia University Health Sciences); U01HG8684 (Children’s Hospital of Philadelphia); U01HG8673 (Northwestern University); U01HG8701 (Vanderbilt University Medical Center serving as the Coordinating Center); U01HG8676 (Partners Healthcare/Broad Institute); and U01HG8664 (Baylor College of Medicine); Phase I–II: U01HG006828 (Cincinnati Children’s Hospital Medical Center/Boston Children’s Hospital); U01HG006830 (Children’s Hospital of Philadelphia); U01HG006389 (Essentia Institute of Rural Health, Marshfield Clinic Research Foundation and Pennsylvania State University); U01-HG006382 (Geisinger Clinic); U01-HG006375 (Group Health Cooperative/University of Washington); U01-HG006379 (Mayo Clinic); U01-HG006380 (Icahn School of Medicine at Mount Sinai); U01HG006388 (Northwestern University); U01-HG006378 (Vanderbilt University Medical Center); U01-HG006385 (Vanderbilt University Medical Center serving as the Coordinating Center); U01HG004438 (CIDR) and U01HG004424 (the Broad Institute) were serving as phase I Genotyping Centers. The CureGN Study is supported by the National Institute of Health grants 2U01-DK100876. The Nephrotic Syndrome Study Network (NEPTUNE) is part of the Rare Diseases Clinical Research Network (RDCRN), which is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Division of Rare Diseases Research Innovation (DRDRI). NEPTUNE is funded under grant number U54DK083912 as a collaboration between NCATS and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Additional funding and/or programmatic support is provided by the University of Michigan, NephCure Kidney International, Alport Syndrome Foundation, and the Halpin Foundation. RDCRN consortia are supported by the RDCRN Data Management and Coordinating Center (DMCC), funded by NCATS and the National Institute of Neurological Disorders and Stroke (NINDS) under U2CTR002818. The REGARDS study is supported by cooperative agreement U01 NS041588 co-funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA), National Institutes of Health, Department of Health and Human Service. Representatives of the NINDS were involved in the review of the manuscript but were not directly involved in the collection, management, analysis or interpretation of the data. The authors thank the other investigators, the staff, and the participants of the REGARDS study for their valuable contributions. A full list of participating REGARDS investigators and institutions can be found at: https://www.uab.edu/soph/regardsstudy/ . N.A.L. is supported by the NIH Grant U01-HG011167. Y.G. is supported by the NEPTUNE Fellowship UMINCH-SUBK00018902. A.M. received support from the American Society of Nephrology KidneyCure Ben J. Lipps Research Fellowship. A.M., L.G, W.M., and G.M. are members of the European Reference Network for Rare Kidney Diseases (ERKNet). A.K. is supported by the NIDDK grant 5K25-DK128563-03. The generation of the whole-genome sequencing data in the CureGN Study was supported by AstraZeneca. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. L.L. is supported by the NIDDK grant 1K01DK137031-01. Funding Information: 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. Funding Information: We thank the patients and their family members for participating in this study. This research was supported by the Department of Defense (W81XWH-16-1-0451, W81XWH-22-1-0966) and by the National Center for Advancing Translational Sciences, National Institutes of Health (Grant Number UL1TR001873), to S.S.-C., by the National Institute of Health Grant RC2-DK122397, to S.S.-C, M.R.P., F.H. and M.G.S, by the National Institute of Health Grant R01-DK007092 to M.R.P. and D.J.F., and by the National Institute of Health Grant RC2-DK116690 to K.K. and M.K. M.G.S is also supported by R01-DK119380 and the Pura Vida Kidney Foundation. J.B.K. is supported by the Intramural Research Program, NIDDK, NIH. A.G.G. is supported by NIDDK 1U01-DK100876 and DOD W81XWH2110550. K.K. is additionally supported by R01-DK105124, R01-DK136765, R01-LM013061, 2U01-HG008680, U01-AI152960, and 5UL1-TR001873. R.G. is supported by 1R01-DK134347-01, NIH/NICHD 1R21-HD104176-01. F.H. is supported by R01-DK076683. The eMERGE Network was initiated and funded by NHGRI through the following grants: Phase IV: U01HG011172 (Cincinnati Children’s Hospital Medical Center); U01HG011175 (Children’s Hospital of Philadelphia); U01HG008680 (Columbia University); U01HG011176 (Icahn School of Medicine at Mount Sinai); U01HG008685 (Mass General Brigham); U01HG006379 (Mayo Clinic); U01HG011169 (Northwestern University); U01HG011167 (University of Alabama at Birmingham); U01HG008657 (University of Washington); U01HG011181 (Vanderbilt University Medical Center); U01HG011166 (Vanderbilt University Medical Center serving as the Coordinating Center); Phase III: U01HG8657 (Group Health Cooperative/University of Washington); U01HG8685 (Brigham and Women’s Hospital); U01HG8672 (Vanderbilt University Medical Center); U01HG8666 (Cincinnati Children’s Hospital Medical Center); U01HG6379 (Mayo Clinic); U01HG8679 (Geisinger Clinic); U01HG8680 (Columbia University Health Sciences); U01HG8684 (Children’s Hospital of Philadelphia); U01HG8673 (Northwestern University); U01HG8701 (Vanderbilt University Medical Center serving as the Coordinating Center); U01HG8676 (Partners Healthcare/Broad Institute); and U01HG8664 (Baylor College of Medicine); Phase I–II: U01HG006828 (Cincinnati Children’s Hospital Medical Center/Boston Children’s Hospital); U01HG006830 (Children’s Hospital of Philadelphia); U01HG006389 (Essentia Institute of Rural Health, Marshfield Clinic Research Foundation and Pennsylvania State University); U01-HG006382 (Geisinger Clinic); U01-HG006375 (Group Health Cooperative/University of Washington); U01-HG006379 (Mayo Clinic); U01-HG006380 (Icahn School of Medicine at Mount Sinai); U01HG006388 (Northwestern University); U01-HG006378 (Vanderbilt University Medical Center); U01-HG006385 (Vanderbilt University Medical Center serving as the Coordinating Center); U01HG004438 (CIDR) and U01HG004424 (the Broad Institute) were serving as phase I Genotyping Centers. The CureGN Study is supported by the National Institute of Health grants 2U01-DK100876. The Nephrotic Syndrome Study Network (NEPTUNE) is part of the Rare Diseases Clinical Research Network (RDCRN), which is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Division of Rare Diseases Research Innovation (DRDRI). NEPTUNE is funded under grant number U54DK083912 as a collaboration between NCATS and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Additional funding and/or programmatic support is provided by the University of Michigan, NephCure Kidney International, Alport Syndrome Foundation, and the Halpin Foundation. RDCRN consortia are supported by the RDCRN Data Management and Coordinating Center (DMCC), funded by NCATS and the National Institute of Neurological Disorders and Stroke (NINDS) under U2CTR002818. The REGARDS study is supported by cooperative agreement U01 NS041588 co-funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA), National Institutes of Health, Department of Health and Human Service. Representatives of the NINDS were involved in the review of the manuscript but were not directly involved in the collection, management, analysis or interpretation of the data. The authors thank the other investigators, the staff, and the participants of the REGARDS study for their valuable contributions. A full list of participating REGARDS investigators and institutions can be found at: https://www.uab.edu/soph/regardsstudy/. N.A.L. is supported by the NIH Grant U01-HG011167. Y.G. is supported by the NEPTUNE Fellowship UMINCH-SUBK00018902. A.M. received support from the American Society of Nephrology KidneyCure Ben J. Lipps Research Fellowship. A.M., L.G, W.M., and G.M. are members of the European Reference Network for Rare Kidney Diseases (ERKNet). A.K. is supported by the NIDDK grant 5K25-DK128563-03. The generation of the whole-genome sequencing data in the CureGN Study was supported by AstraZeneca. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. L.L. is supported by the NIDDK grant 1K01DK137031-01. Publisher Copyright: © 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85178413239&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-023-43020-9
DO - https://doi.org/10.1038/s41467-023-43020-9
M3 - Article
C2 - 38036523
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 7836
ER -