Association of Complement Genetics with Outcomes in IgA Nephropathy

Activation of the alternative and lectin complement pathways contributes to disease severity and progression in IgA nephropathy. In this French cohort with severe IgA nephropathy, complement factor H CFH-H2 was underrepresented, and rare complement factor H missense variants were more frequent, affecting regulatory domains. Homozygosity for the membrane cofactor protein CD46 ggaac haplotype was associated with progression to ESKD, warranting confirmation in larger cohorts.

Complement activation plays a role in IgA nephropathy. Indeed, genome-wide association studies have identified a susceptibility locus for IgA nephropathy complement factor H ( CHF ) and its related proteins genes. However, the relationship between complement genetics and IgA nephropathy severity is not established.

We sequenced 260 adults with a primary IgA nephropathy by next-generation sequencing of the CFH , complement factor I, complement factor B, membrane cofactor protein (encoded by CD46 ), C3 , and CFH related protein 5 genes. The frequencies of rare variants (minor allele frequency <0.1%) and CFH , membrane cofactor protein, and complement factor B haplotypes were compared with the European population from the 1000 Genomes Project. Functional in vitro studies were performed on recombinant full-length CFH variants.

Our genetic analysis revealed a higher prevalence of rare CFH nonsynonymous variants in patients with IgA nephropathy compared with controls (5% versus 2%, P = 0.03). In vitro studies showed impaired complement regulatory activity for five variants. The CFH-H2 haplotype was associated with lower IgA nephropathy susceptibility (odds ratio, 0.52 [0.34 to 0.79], P = 0.03, dominant model). Moreover, multivariable analysis revealed that the homozygous CD46 ggaaac haplotype was associated with ESKD 15 years after diagnosis (hazard ratio, 2.83; 95% confidence interval, 1.20 to 6.68; P = 0.02).

Our study shed light on the dual role of complement genetics in IgA nephropathy. Our exploratory findings strengthen the evidence for a role of complement genetics in IgA nephropathy but will need confirmation in larger and independent studies.