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 in | Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 13; pp. 3446 - 3451 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
27.03.2018
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Abstract | 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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AbstractList | Two common variants in the
APOL1
gene explain most of the high rate of kidney disease in people of recent African ancestry. However, not all
APOL1
high-risk individuals develop kidney disease. Here we identified the
UBD
locus as a genetic modifier of
APOL1
kidney disease using admixture mapping. Focal segmental glomerulosclerosis patients have significantly increased African ancestry at the
UBD
locus, which associates with lower
UBD
gene expression. Using a cell-based system, we show that UBD and APOL1 interact functionally and that higher levels of
UBD
expression mitigate
APOL1
-mediated cell death. These findings are important for understanding the genetic and functional modifiers of the human
APOL1
-associated phenotype and the biological pathways relevant to
APOL1
-associated cell damage.
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. Significance Two common variants in the APOL1 gene explain most of the high rate of kidney disease in people of recent African ancestry. However, not all APOL1 high-risk individuals develop kidney disease. Here we identified the UBD locus as a genetic modifier of APOL1 kidney disease using admixture mapping. Focal segmental glomerulosclerosis patients have significantly increased African ancestry at the UBD locus, which associates with lower UBD gene expression. Using a cell-based system, we show that UBD and APOL1 interact functionally and that higher levels of UBD expression mitigate APOL1 -mediated cell death. These findings are important for understanding the genetic and functional modifiers of the human APOL1 -associated phenotype and the biological pathways relevant to APOL1 -associated cell damage. 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. 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. 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 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 genotype do not develop overt kidney disease, prompting interest in identifying those factors that interact with We performed an admixture mapping study to identify genetic modifiers of -associated kidney disease. Individuals with two risk alleles and focal segmental glomerulosclerosis (FSGS) have significantly increased African ancestry at the (also known as FAT10) locus. UBD is a ubiquitin-like protein modifier that targets proteins for proteasomal degradation. African ancestry at the locus correlates with lower levels of expression. In cell-based experiments, the disease-associated alleles (known as G1 and G2) lead to increased abundance of mRNA but to decreased levels of protein. gene expression inversely correlates with G1 and G2 -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 and , which interact in a functionally important manner. UBD appears to mitigate -mediated toxicity by targeting it for destruction. Thus, genetically encoded differences in and expression appear to modify the -associated kidney phenotype. |
Author | Mottl, Amy K. Wilson, James G. Alper, Seth L. Appel, Gerald B. Tian, Lei Yan, Paul Genovese, Giulio Bick, Alexander G. Pollak, Martin R. Thadhani, Ravi Wang, Minxian Sampson, Matthew G. Friedman, David J. Zhang, Jia-Yue |
Author_xml | – sequence: 1 givenname: Jia-Yue surname: Zhang fullname: Zhang, Jia-Yue organization: Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215 – sequence: 2 givenname: Minxian surname: Wang fullname: Wang, Minxian organization: Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215 – sequence: 3 givenname: Lei surname: Tian fullname: Tian, Lei organization: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305 – sequence: 4 givenname: Giulio surname: Genovese fullname: Genovese, Giulio organization: Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142 – sequence: 5 givenname: Paul surname: Yan fullname: Yan, Paul organization: Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215 – sequence: 6 givenname: James G. surname: Wilson fullname: Wilson, James G. organization: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216 – sequence: 7 givenname: Ravi surname: Thadhani fullname: Thadhani, Ravi organization: Department of Medicine, Massachusetts General Hospital, Boston, MA 02114 – sequence: 8 givenname: Amy K. surname: Mottl fullname: Mottl, Amy K. organization: University of North Carolina Kidney Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599 – sequence: 9 givenname: Gerald B. surname: Appel fullname: Appel, Gerald B. organization: Center for Glomerular Diseases, Columbia University Medical Center, New York, NY 10032 – sequence: 10 givenname: Alexander G. surname: Bick fullname: Bick, Alexander G. organization: Department of Medicine, Massachusetts General Hospital, Boston, MA 02114 – sequence: 11 givenname: Matthew G. surname: Sampson fullname: Sampson, Matthew G. organization: Department of Pediatrics, University of Michigan School of Medicine, Ann Arbor, MI 48109 – sequence: 12 givenname: Seth L. surname: Alper fullname: Alper, Seth L. organization: Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215 – sequence: 13 givenname: David J. surname: Friedman fullname: Friedman, David J. organization: Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215 – sequence: 14 givenname: Martin R. surname: Pollak fullname: Pollak, Martin R. organization: Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215 |
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Copyright | Volumes 1–89 and 106–114, copyright as a collective work only; author(s) retains copyright to individual articles Copyright National Academy of Sciences Mar 27, 2018 2018 |
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Keywords | FSGS FAT10 kidney APOL1 UBD |
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Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 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. |
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Snippet | People of recent African ancestry develop kidney disease at much higher rates than most other groups. Two specific coding variants in the Apolipoprotein-L1... Significance Two common variants in the APOL1 gene explain most of the high rate of kidney disease in people of recent African ancestry. However, not all APOL1... Two common variants in the APOL1 gene explain most of the high rate of kidney disease in people of recent African ancestry. However, not all APOL1 high-risk... |
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SubjectTerms | 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 |
Title | UBD modifies APOL1-induced kidney disease risk |
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