Clinical journal of the American Society of Nephrology : CJASN · 2026
Association of Complement Genetics with Outcomes in IgA Nephropathy.
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Duval Anna, Maillard Nicolas, Morin Martin, El Sissy Carine, Vieira-Martins Paula, Durand Axelle, Roquigny Julia, Lecerf Maxime, Chauvet Sophie, Olagne Jérôme, Moulin Bruno, Roumenina Lubka, Limou Sophie, Mariat Christophe, Caillard Sophie, Frémeaux-Bacchi Véronique
Аннотация
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 <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.
RESULTS: 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).
CONCLUSIONS: 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.
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 <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.
RESULTS: 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).
CONCLUSIONS: 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.