Title | modifies -induced kidney disease risk. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Zhang J-Y, Wang M, Tian L, Genovese G, Yan P, Wilson JG, Thadhani R, Mottl AK, Appel GB, Bick AG, Sampson MG, Alper SL, Friedman DJ, Pollak MR |
Journal | Proc Natl Acad Sci U S A |
Volume | 115 |
Issue | 13 |
Pagination | 3446-3451 |
Date Published | 2018 Mar 27 |
ISSN | 1091-6490 |
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 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. |
DOI | 10.1073/pnas.1716113115 |
Alternate Journal | Proc. Natl. Acad. Sci. U.S.A. |
PubMed ID | 29531077 |
PubMed Central ID | PMC5879665 |
Grant List | R01 DK054931 / DK / NIDDK NIH HHS / United States R01 MD007898 / MD / NIMHD NIH HHS / United States R56 DK054931 / DK / NIDDK NIH HHS / United States HHSN268201300048C / HL / NHLBI NIH HHS / United States HHSN268201300049C / HL / NHLBI NIH HHS / United States R01 MD007092 / MD / NIMHD NIH HHS / United States HHSN268201300047C / HL / NHLBI NIH HHS / United States HHSN268201300050C / HL / NHLBI NIH HHS / United States HHSN268201300046C / HL / NHLBI NIH HHS / United States U54 GM115428 / GM / NIGMS NIH HHS / United States |
Submitted by kej2006 on June 6, 2018 - 4:13pm