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UBD Modifies APOL1-Induced Kidney Disease Risk

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UBD Modifies APOL1-Induced Kidney Disease Risk UBD modifies APOL1-induced kidney disease risk Jia-Yue Zhanga,b,1, Minxian Wanga,b,1,2,3, Lei Tianc, Giulio Genovesed, Paul Yana,b, James G. Wilsone, Ravi Thadhanif,4, Amy K. Mottlg, Gerald B. Appelh, Alexander G. Bickf,i, Matthew G. Sampsonj, Seth L. Alpera,b,i, David J. Friedmana,b, and Martin R. Pollaka,b,i,2 aDivision of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215; bDepartment of Medicine, Harvard Medical School, Boston, MA 02115; cStanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305; dStanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142; eDepartment of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216; fDepartment of Medicine, Massachusetts General Hospital, Boston, MA 02114; gUniversity of North Carolina Kidney Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599; hCenter for Glomerular Diseases, Columbia University Medical Center, New York, NY 10032; iBroad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142; and jDepartment of Pediatrics, University of Michigan School of Medicine, Ann Arbor, MI 48109 Contributed by Martin R. Pollak, January 28, 2018 (sent for review September 22, 2017; reviewed by Ali Gharavi and Susan E. Quaggin) People of recent African ancestry develop kidney disease at much do some people with the high-risk genotype develop kidney disease higher rates than most other groups. Two specific coding variants but not others? Why do some develop early-onset FSGS and others in the Apolipoprotein-L1 gene APOL1 termed G1 and G2 are the late-onset progressive CKD and ESRD? Both genetic and nongenetic causal drivers of much of this difference in risk, following a re- factors likely can modify the clinical phenotype associated with a high- cessive pattern of inheritance. However, most individuals with a risk APOL1 genotype, leading to various forms of overt kidney disease high-risk APOL1 genotype do not develop overt kidney disease, (and/or protecting against overt kidney disease) in some but not others. prompting interest in identifying those factors that interact with Here we show that variation at the UBD locus (also called APOL1. We performed an admixture mapping study to identify ge- FAT10) is a genetic modifier of the risk of FSGS in individuals netic modifiers of APOL1-associated kidney disease. Individuals with with a high-risk APOL1 genotype. UBD encodes a ubiquitin-like two APOL1 risk alleles and focal segmental glomerulosclerosis (FSGS) protein modifier that targets proteins to the 26S proteasome for have significantly increased African ancestry at the UBD (also known degradation (6, 7). Like APOL1, UBD is up-regulated in response as FAT10) locus. UBD is a ubiquitin-like protein modifier that targets to proinflammatory stimuli including IFN-γ (8). In a mouse model of proteins for proteasomal degradation. African ancestry at the UBD HIV-associated nephropathy, UBD is among the most up-regulated locus correlates with lower levels of UBD expression. In cell-based genes in the kidney (9). Previous studies have shown that intrarenal experiments, the disease-associated APOL1 alleles (known as G1 and UBD G2) lead to increased abundance of mRNA but to decreased Significance levels of UBD protein. UBD gene expression inversely correlates with G1 and G2 APOL1-mediated cell toxicity, as well as with levels of G1 Two common variants in the APOL1 gene explain most of the and G2 APOL1 protein in cells. These studies support a model whereby high rate of kidney disease in people of recent African ancestry. inflammatory stimuli up-regulate both UBD and APOL1, which interact However, not all APOL1 high-risk individuals develop kidney in a functionally important manner. UBD appears to mitigate APOL1- disease. Here we identified the UBD locus as a genetic modifier of mediated toxicity by targeting it for destruction. Thus, genetically APOL1 kidney disease using admixture mapping. Focal segmental encoded differences in UBD and UBD expression appear to modify glomerulosclerosis patients have significantly increased African the APOL1-associated kidney phenotype. ancestry at the UBD locus, which associates with lower UBD gene expression. Using a cell-based system, we show that UBD and APOL1 | UBD | FAT10 | kidney | FSGS APOL1 interact functionally and that higher levels of UBD ex- pression mitigate APOL1-mediated cell death. These findings are idney disease is much more common in people of recent important for understanding the genetic and functional modifiers KAfrican ancestry than in other groups. Two coding variants of the human APOL1-associated phenotype and the biological in the APOL1 gene are the drivers of much of this difference in pathways relevant to APOL1-associated cell damage. disease risk (1, 2). The more common of these alleles, G1, encodes two amino acid substitutions near the C terminus of the protein that Author contributions: J.-Y.Z., M.W., M.G.S., S.L.A., D.J.F., and M.R.P. designed research; almost always occur together. The second risk allele, G2, is a two- 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. con- tributed new reagents/analytic tools; J.-Y.Z., M.W., L.T., G.G., A.G.B., S.L.A., D.J.F., and amino acid deletion adjacent to the location of the G1 allele. Two M.R.P. analyzed data; and J.-Y.Z., M.W., D.J.F., and M.R.P. wrote the paper. risk alleles are required for these large increases in risk, consistent Reviewers: A.G., Columbia University; and S.E.Q., Feinberg School of Medicine, Northwestern with a recessive mode of inheritance. University. APOL1 It is remarkable that variants as common as G1 and G2 Conflict of interest statement: M.R.P. and S.E.Q. are coauthors on a 2014 review article. have such a large effect on the risk of multiple forms of kidney M.G.S. and G.B.A. are coauthors on several papers published in the past 4 years with A.G. disease. The increased risk in individuals compound heterozygous D.J.F. and M.R.P. have filed patents related to ApoL1-associated kidney disease and own or homozygous for APOL1 risk alleles is approximately fourfold to equity in ApoLo1 Bio, LLC. sevenfold for hypertension-associated end-stage renal disease (H- Published under the PNAS license. ESRD), 17-fold for FSGS, and 29- to 89-fold for HIV-associated Data deposition: Data used in this study have been deposited on figshare (https://doi.org/ APOL1 10.6084/m9.figshare.5917771). nephropathy (3, 4). The mechanism(s) of -associated kid- 1 ney disease risk remain unclear. However, investigators have J.-Y.Z. and M.W. contributed equally to this work. 2 consistently shown, in cell culture and in vivo systems, that the To whom correspondence may be addressed. Email: [email protected] or APOL1 [email protected]. high-risk variants are toxic to cells (reviewed in ref. 5). 3 APOL1 Present address: Program in Medical and Population Genetics, Broad Institute of Harvard Despite the high risk of kidney disease associated with , and Massachusetts Institute of Technology, Cambridge, MA 02142. APOL1 most people with a high-risk genotype neither have nor 4Present address: Department of Biomedical Sciences, Cedars Sinai Medical Center, Los develop kidney disease. Our rough estimates put the lifetime risk of Angeles, CA 90048. nondiabetic ESRD and/or chronic kidney disease (CKD)-related This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. mortality in people with a high-risk genotype at about 20%, in 1073/pnas.1716113115/-/DCSupplemental. contrast to 2% to those without. This raises obvious questions: Why Published online March 12, 2018. 3446–3451 | PNAS | March 27, 2018 | vol. 115 | no. 13 www.pnas.org/cgi/doi/10.1073/pnas.1716113115 Downloaded by guest on September 25, 2021 expression of UBD is increased in individuals with glomerular dis- chosen on the basis of APOL1 genotype, whereas self-identified AA ease and a high-risk APOL1 genotype (10). race was a prerequisite for entry into the other study groups. By use of admixture mapping, we demonstrate that individuals We then estimated the locus-specific African ancestry for each with a high-risk APOL1 genotype and FSGS have significantly in- group after normalizing global ancestry person by person, fol- creased African ancestry at the UBD locus compared with their lowing the method in Patterson et al. (16) to control the global whole genome background and compared with control groups at this ancestry difference between study groups. Using two complementary locus. African ancestry at the UBD locus is associated with lower local ancestry inference algorithms and two sources of reference data levels of UBD RNA expression. Using cell-based experiments, we (12, 13), we sought loci with ancestral bias greater than 3 SDs from demonstrate that UBD interacts with APOL1 to modify APOL1 risk variant-mediated cell death. Specifically, we show that induction of expression of the toxic variant forms of APOL1 in a cell system leads to increased expression of UBD mRNA. Increased expression of UBD leads to a decrease in the amount of the G1 and G2 APOL1 protein (but not the nondisease-associated G0 form). Results Detecting Ancestral Biases for FSGS in Individuals with High-Risk APOL1 Genotypes. We genotyped DNA from 253 African Amer- ican (AA) individuals with either FSGS or nondiabetic ESRD to identify potential loci that interact with and modify the APOL1- associated phenotype(s). We used admixture mapping to dis- cover genetic modifier(s) for the APOL1 high-risk genotype individuals (G1G1, G2G2, or G1G2) with FSGS, then compared the candidate loci with APOL1 high-risk individuals with ESRD and high-risk people without known kidney disease, conditioned on each person’s genome-wide admixture background.
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