title: APOL1 Kidney Disease Risk Variants: An Evolving Landscape.
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.
authors.affiliation: Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Dummer
authors.affiliation: Molecular Epidemiology Genetics Section, Center for Cancer Research, National Cancer Institute, Frederick MD.
authors.forename: Sophie
authors.initials: S
authors.lastname: Limou
authors.affiliation: Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; Department of Pathology Johns Hopkins University, Baltimore, MD.
authors.forename: Avi Z
authors.initials: AZ
authors.lastname: Rosenberg
authors.affiliation: Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Heymann
authors.affiliation: Molecular Epidemiology Genetics Section, Center for Cancer Research, National Cancer Institute, Frederick MD.
authors.forename: George
authors.initials: G
authors.lastname: Nelson
authors.affiliation: Molecular Epidemiology Genetics Section, Center for Cancer Research, National Cancer Institute, Frederick MD.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Winkler
authors.affiliation: Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD. Electronic address: jeffreyk@intra.niddk.nih.gov.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kopp
mesh_terms: D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics* / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D008075:Lipoproteins, HDL
keywords: APOL1; Health disparities; chronic kidney disease; focal segmental glomerulosclerosis; innate immunity