A null variant in the apolipoprotein L3 gene is associated with non-diabetic nephropathy

Karl L. Skorecki, Jessica H. Lee, Carl D. Langefeld, Saharon Rosset, Shay Tzur, Walter G. Wasser, Revital Shemer, Gregory A. Hawkins, Jasmin Divers, Rulan S. Parekh, Man Li, Matthew G. Sampson, Matthias Kretzler, Martin R. Pollak, Shrijal Shah, Daniel Blackler, Brendan Nichols, Michael Wilmot, Seth L. Alper, Barry I. Freedman*David J. Friedman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Background Inheritance of apolipoprotein L1 gene (APOL1) renal-risk variants in a recessive pattern strongly associates with non-diabetic end-stage kidney disease (ESKD). Further evidence supports risk modifiers in APOL1-Associated nephropathy; some studies demonstrate that heterozygotes possess excess risk for ESKD or show earlier age at ESKD, relative to those with zero risk alleles. Nearby loci are also associated with ESKD in non-African Americans. Methods We assessed the role of the APOL3 null allele rs11089781 on risk of non-diabetic ESKD. Four cohorts containing 2781 ESKD cases and 2474 controls were analyzed. Results Stratifying by APOL1 risk genotype (recessive) and adjusting for African ancestry identified a significant additive association between rs11089781 and ESKD in each stratum and in a meta-Analysis [meta-Analysis P=0.0070; odds ratio (OR) = 1.29]; ORs were consistent across APOL1 risk strata. The biological significance of this association is supported by the finding that the APOL3 gene is co-regulated with APOL1, and that APOL3 protein was able to bind to APOL1 protein. Conclusions Taken together, the genetic and biological data support the concept that other APOL proteins besides APOL1 may also influence the risk of non-diabetic ESKD.

Original languageEnglish
Pages (from-to)323-330
Number of pages8
JournalNephrology Dialysis Transplantation
Volume33
Issue number2
DOIs
StatePublished - 1 Feb 2018

Funding

FundersFunder number
NIH/NIMHDR01MD007092
National Institutes of HealthDK070941, RO1 DK084149
National Institutes of Health
National Institute of Diabetes and Digestive and Kidney DiseasesP30DK081943
National Institute of Diabetes and Digestive and Kidney Diseases
Doris Duke Charitable Foundation2011035
Doris Duke Charitable Foundation

    Keywords

    • APOL1
    • APOL3
    • African American
    • FSGS
    • chronic kidney disease

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