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

Yask Gupta; David J. Friedman; Michelle T. McNulty; Atlas Khan; Brandon M. Lane; Chen Wang; Juntao Ke; Gina Ying Jin; Benjamin Wooden; Andrea L. Uscinski Knob; Tze Yin Lim; Gerald B. Appel; Kinsie Huggins; Lili Liu; Adele Mitrotti; Megan Chryst-Stangl; Andrew S. Bomback; Rik Westland; Monica Bodria; Maddalena Marasà; Ning Shang; David J. Cohen; Russell John Crew; William Morello; Pietro A. Canetta; Jai Radhakrishnan; Jeremiah Martino; Qingxue Liu; Wendy K. Chung; Angelica Espinoza

doi:10.1038/s41467-023-43020-9

Genetic & Genomic MedicineNature CommunicationsNov 30, 2023

Peer-reviewed journal article

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

Yask Gupta iD, David J. Friedman iD, Michelle T. McNulty iD, Atlas Khan iD, Brandon M. Lane iD, Chen Wang iD, Juntao Ke iD, Gina Ying Jin iD, Benjamin Wooden iD, Andrea L. Uscinski Knob iD, Tze Yin Lim iD, Gerald B. Appel, Kinsie Huggins, Lili Liu iD, Adele Mitrotti iD, Megan Chryst-Stangl, Andrew S. Bomback iD, Rik Westland iD, Monica Bodria iD, Maddalena Marasà iD, Ning Shang iD, David J. Cohen iD, Russell John Crew iD, William Morello iD, Pietro A. Canetta iD, , Simone Sanna‐Cherchi iD

Abstract

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 APOL1 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 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.

PDF DOI