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

• Published in: medRxiv : the preprint server for health sciences
• Main Authors: Gupta, Yask, Friedman, David J, McNulty, Michelle, 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, 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, Brant Pinheiro, Sérgio Veloso, Araújo Oliveira, Eduardo, E Silva, Ana Cristina Simoes, 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
• Format: Journal Article
• Language: English
• Published: United States 04.08.2023

Black Americans have a significantly higher risk of developing chronic kidney disease (CKD), especially focal segmental glomerulosclerosis (FSGS), than European Americans. Two coding variants (G1 and G2) in the gene play a major role in this disparity. While 13% of Black 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 p.N264K missense variant, when co-inherited with the G2 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 high-risk alleles. These findings have important implications for our understanding of the mechanisms of -associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.