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Semin Nephrol. 2015 May;35(3):222-36. doi: 10.1016/j.semnephrol.2015.04.008.

APOL1 Kidney Disease Risk Variants: An Evolving Landscape.

Author information

1
Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
2
Molecular Epidemiology Genetics Section, Center for Cancer Research, National Cancer Institute, Frederick MD.
3
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.
4
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.

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.

KEYWORDS:

APOL1; Health disparities; chronic kidney disease; focal segmental glomerulosclerosis; innate immunity

PMID:
26215860
PMCID:
PMC4562465
DOI:
10.1016/j.semnephrol.2015.04.008
[Indexed for MEDLINE]
Free PMC Article

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