The APOL1 gene encodes Apoliprotein L1, an innate immune response protein that confers protection against Trypanosomal diseases and likely other infectious diseases. 1 Thomson R. Genovese G. Canon C. et al. Evolution of the primate trypanolytic factor APOL1. Proc Natl Acad Sci U S A. 2014; 111: E2130-2139 Crossref PubMed Scopus (160) Google Scholar ,2 Limou S. Dummer P.D. Nelson G.W. et al. APOL1 toxin, innate immunity, and kidney injury. Kidney Int. 2015; 88: 28-34 Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar The G1 and G2 variants of APOL1, which are enriched in persons of West African ancestry, provide enhanced protection against Trypanosome infection, but persons with APOL1 high risk (HR) genotypes (two risk alleles) have markedly increased risk of progressive CKD. 2 Limou S. Dummer P.D. Nelson G.W. et al. APOL1 toxin, innate immunity, and kidney injury. Kidney Int. 2015; 88: 28-34 Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Because most individuals with HR genotypes do not develop kidney disease, it is likely that a “second hit” may be necessary to unmask the HR genotype-associated risk. APOL1 HR genotype is most strongly associated with severe kidney disease occurring in the setting of high interferon levels due to infection (HIV or COVID-19), 3 Kopp J.B. Nelson G.W. Sampath K. et al. APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol. 2011; 22: 2129-2137 Crossref PubMed Scopus (602) Google Scholar ,4 Kudose S. Batal I. Santoriello D. et al. Kidney Biopsy Findings in Patients with COVID-19. J Am Soc Nephrol. 2020; 31: 1959-1968 Crossref PubMed Scopus (245) Google Scholar lupus nephritis, 5 Freedman B.I. Langefeld C.D. Andringa K.K. et al. End-stage renal disease in African Americans with lupus nephritis is associated with APOL1. Arthritis Rheumatol. 2014; 66: 390-396 Crossref PubMed Scopus (203) Google Scholar interferon treatment, 6 Nichols B. Jog P. Lee J.H. et al. Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1. Kidney Int. 2015; 87: 332-342 Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar and kidney transplantation. 7 Santoriello D. Husain S.A. De Serres S.A. et al. Donor APOL1 high-risk genotypes are associated with increased risk and inferior prognosis of de novo collapsing glomerulopathy in renal allografts. Kidney Int. 2018; 94: 1189-1198 Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar As APOL1 expression is strongly induced by interferons, 6 Nichols B. Jog P. Lee J.H. et al. Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1. Kidney Int. 2015; 87: 332-342 Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar upregulation of toxic G1 and G2 variants in the setting of high interferon is hypothesized to be an important contributor to kidney injury. Thus, improved understanding of the factors that regulate APOL1 expression may provide new strategies to prevent or treat kidney disease in individuals with HR genotypes.
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