Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease-Reference-Cited by-全球学者库

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

Published:2023-11-30 Issue:1 Volume:14 Page:
ISSN:2041-1723
Container-title:Nature Communications
language:en
Short-container-title:Nat Commun

Author:

Gupta Yask,Friedman David J.,McNulty Michelle T.^ORCID,Khan Atlas^ORCID,Lane Brandon^ORCID,Wang Chen^ORCID,Ke Juntao,Jin Gina,Wooden Benjamin,Knob Andrea L.^ORCID,Lim Tze Y.,Appel Gerald B.,Huggins Kinsie,Liu Lili^ORCID,Mitrotti Adele,Stangl Megan C.,Bomback Andrew,Westland Rik^ORCID,Bodria Monica,Marasa Maddalena^ORCID,Shang Ning^ORCID,Cohen David J.,Crew Russell J.,Morello William^ORCID,Canetta Pietro^ORCID,Radhakrishnan Jai,Martino Jeremiah,Liu Qingxue,Chung Wendy K.^ORCID,Espinoza Angelica,Luo Yuan,Wei Wei-Qi^ORCID,Feng Qiping^ORCID,Weng Chunhua^ORCID,Fang Yilu^ORCID,Kullo Iftikhar J.^ORCID,Naderian Mohammadreza,Limdi Nita,Irvin Marguerite R.,Tiwari Hemant,Mohan Sumit^ORCID,Rao Maya,Dube Geoffrey K.,Chaudhary Ninad S.,Gutiérrez Orlando M.,Judd Suzanne E.,Cushman Mary^ORCID,Lange Leslie A.,Lange Ethan M.,Bivona Daniel L.,Verbitsky Miguel^ORCID,Winkler Cheryl A.^ORCID,Kopp Jeffrey B.^ORCID,Santoriello Dominick,Batal Ibrahim^ORCID,Pinheiro Sérgio Veloso Brant,Oliveira Eduardo Araújo,Simoes e Silva Ana Cristina^ORCID,Pisani Isabella,Fiaccadori Enrico,Lin Fangming^ORCID,Gesualdo Loreto,Amoroso Antonio^ORCID,Ghiggeri Gian Marco^ORCID,D’Agati Vivette D.,Magistroni Riccardo^ORCID,Kenny Eimear E.,Loos Ruth J. F.^ORCID,Montini Giovanni^ORCID,Hildebrandt Friedhelm^ORCID,Paul Dirk S.^ORCID,Petrovski Slavé^ORCID,Goldstein David B.^ORCID,Kretzler Matthias,Gbadegesin Rasheed^ORCID,Gharavi Ali G.^ORCID,Kiryluk Krzysztof^ORCID,Sampson Matthew G.^ORCID,Pollak Martin R.,Sanna-Cherchi Simone^ORCID

Abstract

AbstractAfrican 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.

Funder

U.S. Department of Defense

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

Link

https://www.nature.com/articles/s41467-023-43020-9.pdf

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