Strong protective effect of theAPOL1p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease

• DOI: 10.1101/2023.08.02.23293554
• Publication Date: 2023-08-05T06:00:36Z
• Authors: Yask Gupta; David J. Friedman; Michelle McNulty; Atlas Khan; Brandon Lane; Chen Wang; Juntao Ke; Gina Jin; Benjamin Wooden; Andrea L. Knob; Tze Y. Lim; Gerald B. Appel; Kinsie Huggins; Lili Liu; Adele Mitrotti; Megan C. Stangl; Andrew Bomback; Rik Westland; Monica Bodria; Maddalena Marasa; Ning Shang; David J. Cohen; Russell J. Crew; William Morello; Pietro Canetta; Jai Radhakrishnan; Jeremiah Martino; Qingxue Liu; Wendy K. Chung; Angelica Espinoza; Yuan Luo; Wei-Qi Wei; Qiping Feng; Chunhua Weng; Yilu Fang; Iftikhar J. Kullo; Mohammadreza Nade...; Nita Limdi; Marguerite R. Irvin; Hemant Tiwari; Sumit Mohan; Maya Rao; Geoffrey Dube; Ninad S. Chaudhary; Orlando M. Gutiérrez; Suzanne E. Judd; Mary Cushman; Leslie A. Lange; Ethan M. Lange; Daniel L. Bivona; Miguel Verbitsky; Cheryl A. Winkler; Jeffrey B. Kopp; Dominick Santoriello; Ibrahim Batal; Sérgio Veloso Bra...; Eduardo Araújo Ol...; Ana Cristina Simo...; Isabella Pisani; Enrico Fiaccadori; Fangming Lin; Loreto Gesualdo; Antonio Amoroso; Gian Marco Ghiggeri; Vivette D. D’Agati; Riccardo Magistroni; Eimear E. Kenny; Ruth J.F. Loos; Giovanni Montini; Friedhelm Hildebr...; Dirk S. Paul; Slavé Petrovski; David B. Goldstein; Matthias Kretzler; Rasheed Gbadegesin; Ali G. Gharavi; Krzysztof Kiryluk; Matthew G. Sampson; Martin R. Pollak; Simone Sanna-Cherchi
• Keywords: focal segmental glomerulosclerosis; Genotype; Glomerulosclerosis, Focal Segmental; Science; Q; Apolipoprotein L1; Article; 3. Good health; Apolipoproteins; genotypes; Risk Factors; Humans; Genetic Predisposition to Disease; Apolipoprotein L1; Apolipoproteins; Genetic Predisposition to Disease; Genotype; Glomerulosclerosis, Focal Segmental; Humans; Risk Factors; chronic kidney disease

ABSTRACTBlack 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 theAPOL1gene 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 theAPOL1p.N264K missense variant, when co-inherited with the G2APOL1risk 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 theAPOL1high-risk alleles. These findings have important implications for our understanding of the mechanisms ofAPOL1-associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.