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Association of Complement Genetics with Outcomes in IgA Nephropathy.

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Τίτλος: Association of Complement Genetics with Outcomes in IgA Nephropathy.
Συγγραφείς: Duval A; Inflammation, Complement and Cancer Team, Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université Paris Cité, Paris, France.; Department of Nephrology Dialysis and Transplantation, University Hospital of Strasbourg, Strasbourg, France.; Inserm UMR_1109, Molecular Immuno-Rheumatology, Centre de recherche en biomédecine, Université de Strasbourg, Strasbourg, France., Maillard N; Department of Nephrology Dialysis and Transplantation, University Hospital of Saint Etienne, Saint-Étienne, France.; Groupe sur l'immunité des muqueuses et agents pathogènes, Team 15, CIRI INSERM U1111/UMR5108., Morin M; INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Centrale Nantes, Nantes Université, Nantes, France., El Sissy C; Service d'immunologie biologique, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France., Vieira-Martins P; Service d'immunologie biologique, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France., Durand A; INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Centrale Nantes, Nantes Université, Nantes, France., Roquigny J; Inflammation, Complement and Cancer Team, Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université Paris Cité, Paris, France., Lecerf M; Inflammation, Complement and Cancer Team, Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université Paris Cité, Paris, France., Chauvet S; Inflammation, Complement and Cancer Team, Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université Paris Cité, Paris, France., Olagne J; Department of Nephrology Dialysis and Transplantation, University Hospital of Strasbourg, Strasbourg, France.; Department of Pathology, University Hospital of Strasbourg, Strasbourg, France., Moulin B; Department of Nephrology Dialysis and Transplantation, University Hospital of Strasbourg, Strasbourg, France., Roumenina L; Inflammation, Complement and Cancer Team, Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université Paris Cité, Paris, France., Limou S; INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Centrale Nantes, Nantes Université, Nantes, France., Mariat C; Department of Nephrology Dialysis and Transplantation, University Hospital of Saint Etienne, Saint-Étienne, France.; Groupe sur l'immunité des muqueuses et agents pathogènes, Team 15, CIRI INSERM U1111/UMR5108., Caillard S; Department of Nephrology Dialysis and Transplantation, University Hospital of Strasbourg, Strasbourg, France., Frémeaux-Bacchi V; INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Centrale Nantes, Nantes Université, Nantes, France.
Πηγή: Clinical journal of the American Society of Nephrology : CJASN [Clin J Am Soc Nephrol] 2026 Jul 01; Vol. 21 (7), pp. 1207-1221. Date of Electronic Publication: 2026 May 15.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Wolters Kluwer Health Country of Publication: United States NLM ID: 101271570 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1555-905X (Electronic) Linking ISSN: 15559041 NLM ISO Abbreviation: Clin J Am Soc Nephrol Subsets: MEDLINE
Imprint Name(s): Publication: 2023- : Hagerstown, MD : Wolters Kluwer Health
Original Publication: Washington, D.C. : American Society of Nephrology, c2005-
Ιατρικοί όροι (MeSH): Glomerulonephritis, IGA*/genetics , Glomerulonephritis, IGA*/immunology , Glomerulonephritis, IGA*/complications , Complement Factor H*/genetics , Complement System Proteins*/genetics, Membrane Cofactor Protein/genetics ; Complement Factor B/genetics ; Kidney Failure, Chronic/genetics ; Complement C3/genetics ; Complement Activation/genetics ; Humans ; Adult ; Female ; Male ; Haplotypes ; Middle Aged ; Genetic Predisposition to Disease ; Disease Progression ; Gene Frequency ; Homozygote ; Phenotype
Περίληψη: 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.
(Copyright © 2026 by the American Society of Nephrology.)
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Grant Information: FDM202006011155 FRM (fondation pour la recherche médicale); AO-AIRG-2016 AIRG
Contributed Indexing: Keywords: GN; IgA nephropathy; complement; genetics and development; glomerular diseases; progression of kidney disease
Molecular Sequence: ClinicalTrials.gov NCT05234463
Substance Nomenclature: 80295-65-4 (Complement Factor H)
0 (Membrane Cofactor Protein)
0 (CFH protein, human)
0 (CD46 protein, human)
EC 3.4.21.47 (Complement Factor B)
0 (CFHR5 protein, human)
0 (Complement C3)
9007-36-7 (Complement System Proteins)
Entry Date(s): Date Created: 20260515 Date Completed: 20260710 Latest Revision: 20260922
Update Code: 20260922
PubMed Central ID: PMC13379140
DOI: 10.2215/CJN.0000001062
PMID: 42138996
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1555-905X
DOI:10.2215/CJN.0000001062