Association of Complement Genetics with Outcomes in IgA Nephropathy

Background Complement activation plays a role in IgA nephropathy (IgAN). Indeed, genome-wide association studies have identified a susceptibility locus for IgAN in the CFH-CFHR genes. However, the relationship between complement genetics and IgAN severity is not established. Methods We sequenced 260 adults with a primary IgAN by next-generation sequencing of the CFH , CFI , CFB , MCP , C3 and CFHR5 genes. The frequencies of rare variants (MAF<0.1%) and CFH , MCP and CFB haplotypes were compared with the European population from the 1000 Genomes Project. Functional in vitro studies were performed on recombinant full-length CFH variants. Results Our genetic analysis revealed a higher prevalence of rare CFH non-synonymous variants in patients with IgAN compared to controls (5% versus 2%, p=0.03). In vitro studies showed impaired complement regulatory activity for 5 variants. The CFH-H2 haplotype was associated with lower IgAN susceptibility (OR 0.52 [0.34-0.79], p=0.03, dominant model). Moreover, multivariable analysis revealed that the homozygous MCP ggaac haplotype was associated with end-stage-kidney disease 15 years after diagnosis (HR: 2.83, 95% CI 1.20-6.68, p=0.02). Conclusion . Our study shed light on the dual role of complement genetics in IgAN. Our exploratory findings strengthen the evidence for a role of complement genetics in IgAN but will need confirmation in larger and independent studies.