학술논문
Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease
Document Type
Original Paper
Author
Gupta, Yask; Friedman, David J.; McNulty, Michelle T.; Khan, Atlas; Lane, Brandon; Wang, Chen; Ke, Juntao; Jin, Gina; Wooden, Benjamin; Knob, Andrea L.; Lim, Tze Y.; Appel, Gerald B.; Huggins, Kinsie; Liu, Lili; Mitrotti, Adele; Stangl, Megan C.; Bomback, Andrew; Westland, Rik; Bodria, Monica; Marasa, Maddalena; Shang, Ning; Cohen, David J.; Crew, Russell J.; Morello, William; Canetta, Pietro; Radhakrishnan, Jai; Martino, Jeremiah; Liu, Qingxue; Chung, Wendy K.; Espinoza, Angelica; Luo, Yuan; Wei, Wei-Qi; Feng, Qiping; Weng, Chunhua; Fang, Yilu; Kullo, Iftikhar J.; Naderian, Mohammadreza; Limdi, Nita; Irvin, Marguerite R.; Tiwari, Hemant; Mohan, Sumit; Rao, Maya; Dube, Geoffrey K.; Chaudhary, Ninad S.; Gutiérrez, Orlando M.; Judd, Suzanne E.; Cushman, Mary; Lange, Leslie A.; Lange, Ethan M.; Bivona, Daniel L.; Verbitsky, Miguel; Winkler, Cheryl A.; Kopp, Jeffrey B.; Santoriello, Dominick; Batal, Ibrahim; Pinheiro, Sérgio Veloso Brant; Oliveira, Eduardo Araújo; Simoes e Silva, Ana Cristina; Pisani, Isabella; Fiaccadori, Enrico; Lin, Fangming; Gesualdo, Loreto; Amoroso, Antonio; Ghiggeri, Gian Marco; D’Agati, Vivette D.; Magistroni, Riccardo; Kenny, Eimear E.; Loos, Ruth J. F.; Montini, Giovanni; Hildebrandt, Friedhelm; Paul, Dirk S.; Petrovski, Slavé; Goldstein, David B.; Kretzler, Matthias; Gbadegesin, Rasheed; Gharavi, Ali G.; Kiryluk, Krzysztof; Sampson, Matthew G.; Pollak, Martin R.; Sanna-Cherchi, Simone
Source
Nature Communications. 14(1)
Subject
Language
English
ISSN
2041-1723
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.
African Americans have an elevated risk of developing chronic kidney disease, yet only a fraction of those with high-risk genotypes develop the disease. Here, the authors show that a missense variant in APOL1 has a strong protective effect when co-inherited with the high-risk G2 allele of APOL1, with important implications for clinical practice and translational research.
African Americans have an elevated risk of developing chronic kidney disease, yet only a fraction of those with high-risk genotypes develop the disease. Here, the authors show that a missense variant in APOL1 has a strong protective effect when co-inherited with the high-risk G2 allele of APOL1, with important implications for clinical practice and translational research.