<i>UBD</i> modifies <i>APOL1</i>-induced kidney disease risk.

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 <i>APOL1</i> 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 <i>APOL1</i> genotype do not develop overt kidney disease, prompting interest in identifying those factors that interact with <i>APOL1</i> We performed an admixture mapping study to identify genetic modifiers of <i>APOL1</i>-associated kidney disease. Individuals with two <i>APOL1</i> risk alleles and focal segmental glomerulosclerosis (FSGS) have significantly increased African ancestry at the <i>UBD</i> (also known as FAT10) locus. UBD is a ubiquitin-like protein modifier that targets proteins for proteasomal degradation. African ancestry at the <i>UBD</i> locus correlates with lower levels of <i>UBD</i> expression. In cell-based experiments, the disease-associated <i>APOL1</i> alleles (known as G1 and G2) lead to increased abundance of <i>UBD</i> mRNA but to decreased levels of <i>UBD</i> protein. <i>UBD</i> gene expression inversely correlates with G1 and G2 <i>APOL1</i>-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 <i>UBD</i> and <i>APOL1</i>, which interact in a functionally important manner. UBD appears to mitigate <i>APOL1</i>-mediated toxicity by targeting it for destruction. Thus, genetically encoded differences in <i>UBD</i> and <i>UBD</i> expression appear to modify the <i>APOL1</i>-associated kidney phenotype.