Apolipoprotein L1 (APOL1) risk variant toxicity depends on the haplotype background.

The Apolipoprotein L1 (APOL1) risk variants G1 and G2 are associated with high rates of kidney disease in African Americans in genetic studies. However, our understanding of APOL1 biology has lagged far behind. Here we report that engineering G1 and G2 mutations on unnatural haplotype backgrounds instead of on the specific G1 and G2 haplotype backgrounds that occur in nature profoundly alters APOL1-mediated cytotoxicity in experimental systems. Thus, in addition to helping resolve some important controversies in the APOL1 field, our demonstration of the critical influence of haplotype background may apply more generally to the study of other genetic variants that cause or predispose to human disease.

A null variant in the apolipoprotein L3 gene is associated with non-diabetic nephropathy.

Background: Inheritance of apolipoprotein L1 gene (APOL1) renal-risk variants in a recessive pattern strongly associates with non-diabetic end-stage kidney disease (ESKD). Further evidence supports risk modifiers in APOL1-associated nephropathy; some studies demonstrate that heterozygotes possess excess risk for ESKD or show earlier age at ESKD, relative to those with zero risk alleles. Nearby loci are also associated with ESKD in non-African Americans. Methods: We assessed the role of the APOL3 null allele rs11089781 on risk of non-diabetic ESKD. Four cohorts containing 2781 ESKD cases and 2474 controls were analyzed. Results: Stratifying by APOL1 risk genotype (recessive) and adjusting for African ancestry identified a significant additive association between rs11089781 and ESKD in each stratum and in a meta-analysis [meta-analysis P = 0.0070; odds ratio (OR) = 1.29]; ORs were consistent across APOL1 risk strata. The biological significance of this association is supported by the finding that the APOL3 gene is co-regulated with APOL1, and that APOL3 protein was able to bind to APOL1 protein. Conclusions: Taken together, the genetic and biological data support the concept that other APOL proteins besides APOL1 may also influence the risk of non-diabetic ESKD.

Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1.

Apolipoprotein L1 (APOL1) risk variants greatly elevate the risk of kidney disease in African Americans. Here we report a cohort of patients who developed collapsing focal segmental glomerulosclerosis while receiving therapeutic interferon, all of whom carried the APOL1 high-risk genotype. This finding raised the possibility that interferons and the molecular pattern recognition receptors that stimulate interferon production may contribute to APOL1-associated kidney disease. In cell culture, interferons and Toll-like receptor (TLR) agonists increased APOL1 expression by up to 200-fold, in some cases with the appearance of transcripts not detected under basal conditions. PolyI:C, a double-stranded RNA TLR3 agonist, increased APOL1 expression by upregulating interferons directly or through an interferon-independent, IFN-regulatory factor 3 (IRF3)-dependent pathway. Using pharmacological inhibitors, small hairpin RNA knockdown, and chromatin immunoprecipitation, we found that the interferon-independent TLR3 pathway relied on signaling through TBK1, NF-κB, and Jak kinases, and on binding of IRF1, IRF2, and STAT2 at the APOL1 transcription start site. We also demonstrate that overexpression of the APOL1 risk variants is more injurious to cells than overexpression of the wild-type APOL1 protein. Our study illustrates that antiviral pathways may be important inducers of kidney disease in individuals with the APOL1 high-risk genotype and identifies potential targets for prevention or treatment.