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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.