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.
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http://dx.doi.org/10.1038/s41467-023-43020-9 | DOI Listing |
Kidney Int
December 2024
Institute of Systems Genetics, New York University Langone Health, Grossman School of Medicine, New York, NY, USA. Electronic address:
The advent of more affordable genomic analytical pipelines has facilitated the expansion of genetic studies in kidney transplantation. Advances in genetic sequencing have allowed for a greater understanding of the genetic basis of chronic kidney disease, which has helped to guide transplant management and address issues related to living donation in specific disease settings. Recent efforts have shown significant effects of genetic ancestry and donor APOL1 risk genotypes in determining worse allograft outcomes and increased donation risks.
View Article and Find Full Text PDF[This corrects the article DOI: 10.1016/j.ekir.
View Article and Find Full Text PDFKidney Int Rep
December 2024
Division of Molecular Medicine, University of São Paulo School of Medicine, São Paulo, Brazil.
Introduction: The profile of genetic and nongenetic factors associated with progression to kidney failure (KF) in steroid-resistant nephrotic syndrome (SRNS) is largely unknown in admixed populations.
Methods: A total of 101 pediatric patients with primary SRNS were genetically assessed targeting Mendelian causes and status with a 62-NS-gene panel or whole exome sequencing, as well as genetic ancestry. Variant pathogenicity was evaluated using the American College Medical of Genetics and Genomics (ACMG) criteria.
Clin J Am Soc Nephrol
December 2024
University of Kansas School of Medicine, Kansas City, Kansas.
Genes Dis
March 2025
Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
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