APOL1 Kidney Disease Risk Variants: An Evolving Landscape

Patrick D. Dummer, Sophie Limou, Avi Z. Rosenberg, Jurgen Heymann, George Nelson, Cheryl A. Winkler, Jeffrey B. Kopp

Research output: Contribution to journalReview articlepeer-review

Abstract

Apolipoprotein L1 (. APOL1) genetic variants account for much of the excess risk of chronic and end-stage kidney disease, which results in a significant global health disparity for persons of African ancestry. We estimate the lifetime risk of kidney disease in APOL1 dual-risk allele individuals to be at least 15%. Experimental evidence suggests a direct role of APOL1 in pore formation, cellular injury, and programmed cell death in renal injury. The APOL1 BH3 motif, often associated with cell death, is unlikely to play a role in APOL1-induced cytotoxicity because it is not conserved within the APOL family and is dispensable for cell death in vitro. We discuss two models for APOL1 trypanolytic activity: one involving lysosome permeabilization and another involving colloid-osmotic swelling of the cell body, as well as their relevance to human pathophysiology. Experimental evidence from human cell culture models suggests that both mechanisms may be operative. A systems biology approach whereby APOL1-associated perturbations in gene and protein expression in affected individuals are correlated with molecular pathways may be productive to elucidate APOL1 function in vivo.

Original languageEnglish (US)
Pages (from-to)222-236
Number of pages15
JournalSeminars in Nephrology
Volume35
Issue number3
DOIs
StatePublished - May 1 2015

Keywords

  • APOL1
  • Chronic kidney disease
  • Focal segmental glomerulosclerosis
  • Health disparities
  • Innate immunity

ASJC Scopus subject areas

  • Nephrology

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