APOL1 polymorphisms and kidney disease: loss-of-function or gain-of-function?

Am J Physiol Renal Physiol. 2019 Jan 1;316(1):F1-F8. doi: 10.1152/ajprenal.00426.2018. Epub 2018 Oct 17.


The mechanism that explains the association of APOL1 variants with nondiabetic kidney diseases in African Americans remains unclear. Kidney disease risk is inherited as a recessive trait, and many studies investigating the intracellular function of APOL1 have indicated the APOL1 variants G1 and G2 are associated with cytotoxicity. Whether cytotoxicity results from the absence of a protective effect conferred by the G0 allele or is induced by a deleterious effect of variant allele expression has not be conclusively established. A central issue hampering basic biology studies is the lack of model systems that authentically replicate APOL1 expression patterns. APOL1 is present in humans and a few other primates and appears to have important functions in the kidney, as the kidney is the primary target for disease associated with the genetic variance. There have been no studies to date assessing the function of untagged APOL1 protein under native expression in human or primate kidney cells, and no studies have examined the heterozygous state, a disease-free condition in humans. A second major issue is the chronic kidney disease (CKD)-associated APOL1 variants are conditional mutations, where the disease-inducing function is only evident under the appropriate environmental stimulus. In addition, it is possible there may be more than one mechanism of pathogenesis that is dependent on the nature of the stressor or other genetic variabilities. Studies addressing the function of APOL1 and how the CKD-associated APOL1 variants cause kidney disease are challenging and remain to be fully investigated under conditions that faithfully model known human genetics and physiology.

Keywords: chronic kidney disease; genetics; podocytes.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • African Americans / genetics
  • Animals
  • Apolipoprotein L1 / genetics*
  • Apolipoprotein L1 / metabolism
  • Gain of Function Mutation*
  • Gene-Environment Interaction
  • Genetic Predisposition to Disease
  • Heredity
  • Humans
  • Loss of Function Mutation*
  • Phenotype
  • Podocytes / metabolism
  • Podocytes / pathology
  • Polymorphism, Genetic*
  • Renal Insufficiency, Chronic / ethnology
  • Renal Insufficiency, Chronic / genetics*
  • Renal Insufficiency, Chronic / pathology
  • Risk Factors


  • APOL1 protein, human
  • Apolipoprotein L1