UBD modifies APOL1-induced kidney disease risk

People of recent African ancestry develop kidney disease at much higher rates than most other groups. Two specific coding variants in the Apolipoprotein-L1 gene APOL1 termed G1 and G2 are the causal drivers of much of this difference in risk, following a recessive pattern of inheritance. However, mo...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 115; no. 13; pp. 3446 - 3451
Main Authors Zhang, Jia-Yue, Wang, Minxian, Tian, Lei, Genovese, Giulio, Yan, Paul, Wilson, James G., Thadhani, Ravi, Mottl, Amy K., Appel, Gerald B., Bick, Alexander G., Sampson, Matthew G., Alper, Seth L., Friedman, David J., Pollak, Martin R.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 27.03.2018
Subjects
Admixtures
Alleles
Apolipoproteins
Apoptosis
Biological Sciences
Gene expression
Gene mapping
Genes
Genetic code
Genotype & phenotype
Genotypes
Health risks
Heredity
Inflammation
Kidney diseases
Kidneys
L1 gene
Loci
Phenotypes
Proteasomes
Proteins
Risk
Toxicity
Ubiquitin
FSGS
FAT10
kidney
APOL1
UBD
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Summary:People of recent African ancestry develop kidney disease at much higher rates than most other groups. Two specific coding variants in the Apolipoprotein-L1 gene APOL1 termed G1 and G2 are the causal drivers of much of this difference in risk, following a recessive pattern of inheritance. However, most individuals with a high-risk APOL1 genotype do not develop overt kidney disease, prompting interest in identifying those factors that interact with APOL1. We performed an admixture mapping study to identify genetic modifiers of APOL1-associated kidney disease. Individuals with two APOL1 risk alleles and focal segmental glomerulosclerosis (FSGS) have significantly increased African ancestry at the UBD (also known as FAT10) locus. UBD is a ubiquitin-like protein modifier that targets proteins for proteasomal degradation. African ancestry at the UBD locus correlates with lower levels of UBD expression. In cell-based experiments, the disease-associated APOL1 alleles (known as G1 and G2) lead to increased abundance of UBD mRNA but to decreased levels of UBD protein. UBD gene expression inversely correlates with G1 and G2 APOL1-mediated cell toxicity, as well as with levels of G1 and G2 APOL1 protein in cells. These studies support a model whereby inflammatory stimuli up-regulate both UBD and APOL1, which interact in a functionally important manner. UBD appears to mitigate APOL1-mediated toxicity by targeting it for destruction. Thus, genetically encoded differences in UBD and UBD expression appear to modify the APOL1-associated kidney phenotype.
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4Present address: Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048.
1J.-Y.Z. and M.W. contributed equally to this work.
3Present address: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142.
Author contributions: J.-Y.Z., M.W., M.G.S., S.L.A., D.J.F., and M.R.P. designed research; J.-Y.Z., M.W., P.Y., and J.G.W. performed research; J.G.W., R.T., A.K.M., and G.B.A. contributed new reagents/analytic tools; J.-Y.Z., M.W., L.T., G.G., A.G.B., S.L.A., D.J.F., and M.R.P. analyzed data; and J.-Y.Z., M.W., D.J.F., and M.R.P. wrote the paper.
Contributed by Martin R. Pollak, January 28, 2018 (sent for review September 22, 2017; reviewed by Ali Gharavi and Susan E. Quaggin)
Reviewers: A.G., Columbia University; and S.E.Q., Feinberg School of Medicine, Northwestern University.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1716113115