Association of Complement Genetics with Outcomes in IgA Nephropathy

KEY POINTS: 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. BACKGROUND: 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. METHODS: 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