{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T08:32:36Z","timestamp":1788942756455,"version":"build-2803163510"},"reference-count":86,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","funder":[{"name":"FRM","award":["FDM202006011155"],"award-info":[{"award-number":["FDM202006011155"]}]},{"name":"AIRG","award":["AO-AIRG-2016"],"award-info":[{"award-number":["AO-AIRG-2016"]}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["CJASN"],"published-print":{"date-parts":[[2026,7]]},"abstract":"\n Key Points<\/jats:title>\n \n \n \n Activation of the alternative and lectin complement pathways contributes to disease severity and progression in IgA nephropathy.<\/jats:p>\n <\/jats:list-item>\n \n \n In this French cohort with severe IgA nephropathy, complement factor H\n CFH-H2<\/jats:italic>\n was underrepresented, and rare complement factor H missense variants were more frequent, affecting regulatory domains.\n <\/jats:p>\n <\/jats:list-item>\n \n \n Homozygosity for the membrane cofactor protein\n CD46 ggaac<\/jats:italic>\n haplotype was associated with progression to ESKD, warranting confirmation in larger cohorts.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n \n Complement activation plays a role in IgA nephropathy. Indeed, genome-wide association studies have identified a susceptibility locus for IgA nephropathy complement factor H (\n CHF<\/jats:italic>\n ) and its related proteins genes. However, the relationship between complement genetics and IgA nephropathy severity is not established.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We sequenced 260 adults with a primary IgA nephropathy by\n next-generation sequencing<\/jats:italic>\n of the\n CFH<\/jats:italic>\n , complement factor I, complement factor B, membrane cofactor protein (encoded by\n CD46<\/jats:italic>\n ),\n C3<\/jats:italic>\n , and\n CFH<\/jats:italic>\n related protein 5 genes. The frequencies of rare variants (minor allele frequency <0.1%) and\n CFH<\/jats:italic>\n , membrane cofactor protein, and complement factor B haplotypes were compared with the European population from the 1000 Genomes Project. Functional\n in vitro<\/jats:italic>\n studies were performed on recombinant full-length\n CFH<\/jats:italic>\n variants.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Our genetic analysis revealed a higher prevalence of rare\n CFH<\/jats:italic>\n nonsynonymous variants in patients with IgA nephropathy compared with controls (5% versus 2%,\n P<\/jats:italic>\n = 0.03).\n In vitro<\/jats:italic>\n studies showed impaired complement regulatory activity for five variants. The\n CFH-H2<\/jats:italic>\n haplotype was associated with lower IgA nephropathy susceptibility (odds ratio, 0.52 [0.34 to 0.79],\n P<\/jats:italic>\n = 0.03, dominant model). Moreover, multivariable analysis revealed that the homozygous\n CD46 ggaaac<\/jats:italic>\n haplotype was associated with ESKD 15 years after diagnosis (hazard ratio, 2.83; 95% confidence interval, 1.20 to 6.68;\n P<\/jats:italic>\n = 0.02).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>","DOI":"10.2215\/cjn.0000001062","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T16:02:51Z","timestamp":1778860971000},"page":"1207-1221","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":2,"title":["Association of Complement Genetics with Outcomes in IgA Nephropathy"],"prefix":"10.2215","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6432-881X","authenticated-orcid":false,"given":"Anna","family":"Duval","sequence":"first","affiliation":[{"name":"Inflammation, Complement and Cancer Team, Centre de Recherche des Cordeliers, Sorbonne Universit\u00e9, INSERM, Universit\u00e9 Paris Cit\u00e9, Paris, France"},{"name":"Department of Nephrology Dialysis and Transplantation, University Hospital of Strasbourg, Strasbourg, France"},{"name":"Inserm UMR_1109, Molecular Immuno-Rheumatology, Centre de recherche en biom\u00e9decine, Universit\u00e9 de Strasbourg, Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3073-7252","authenticated-orcid":false,"given":"Nicolas","family":"Maillard","sequence":"additional","affiliation":[{"name":"Department of Nephrology Dialysis and Transplantation, University Hospital of Saint Etienne, Saint-\u00c9tienne, France"},{"name":"Groupe sur l'immunit\u00e9 des muqueuses et agents pathog\u00e8nes, Team 15, CIRI INSERM U1111\/UMR5108"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7181-4067","authenticated-orcid":false,"given":"Martin","family":"Morin","sequence":"additional","affiliation":[{"name":"INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Centrale Nantes, Nantes Universit\u00e9, Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7755-6689","authenticated-orcid":false,"given":"Carine","family":"El Sissy","sequence":"additional","affiliation":[{"name":"Service d'immunologie biologique, H\u00f4pital Europ\u00e9en Georges Pompidou, Assistance Publique-H\u00f4pitaux de Paris, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Vieira-Martins","sequence":"additional","affiliation":[{"name":"Service d'immunologie biologique, H\u00f4pital Europ\u00e9en Georges Pompidou, Assistance Publique-H\u00f4pitaux de Paris, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4291-2281","authenticated-orcid":false,"given":"Axelle","family":"Durand","sequence":"additional","affiliation":[{"name":"INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Centrale Nantes, Nantes Universit\u00e9, Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0575-6714","authenticated-orcid":false,"given":"Julia","family":"Roquigny","sequence":"additional","affiliation":[{"name":"Inflammation, Complement and Cancer Team, Centre de Recherche des Cordeliers, Sorbonne Universit\u00e9, INSERM, Universit\u00e9 Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1477-2162","authenticated-orcid":false,"given":"Maxime","family":"Lecerf","sequence":"additional","affiliation":[{"name":"Inflammation, Complement and Cancer Team, Centre de Recherche des Cordeliers, Sorbonne Universit\u00e9, INSERM, Universit\u00e9 Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6693-3634","authenticated-orcid":false,"given":"Sophie","family":"Chauvet","sequence":"additional","affiliation":[{"name":"Inflammation, Complement and Cancer Team, Centre de Recherche des Cordeliers, Sorbonne Universit\u00e9, INSERM, Universit\u00e9 Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6792-5399","authenticated-orcid":false,"given":"J\u00e9r\u00f4me","family":"Olagne","sequence":"additional","affiliation":[{"name":"Department of Nephrology Dialysis and Transplantation, University Hospital of Strasbourg, Strasbourg, France"},{"name":"Department of Pathology, University Hospital of Strasbourg, Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6772-7165","authenticated-orcid":false,"given":"Bruno","family":"Moulin","sequence":"additional","affiliation":[{"name":"Department of Nephrology Dialysis and Transplantation, University Hospital of Strasbourg, Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9940-0324","authenticated-orcid":false,"given":"Lubka","family":"Roumenina","sequence":"additional","affiliation":[{"name":"Inflammation, Complement and Cancer Team, Centre de Recherche des Cordeliers, Sorbonne Universit\u00e9, INSERM, Universit\u00e9 Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7702-8234","authenticated-orcid":false,"given":"Sophie","family":"Limou","sequence":"additional","affiliation":[{"name":"INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Centrale Nantes, Nantes Universit\u00e9, Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Mariat","sequence":"additional","affiliation":[{"name":"Department of Nephrology Dialysis and Transplantation, University Hospital of Saint Etienne, Saint-\u00c9tienne, France"},{"name":"Groupe sur l'immunit\u00e9 des muqueuses et agents pathog\u00e8nes, Team 15, CIRI INSERM U1111\/UMR5108"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0525-4291","authenticated-orcid":false,"given":"Sophie","family":"Caillard","sequence":"additional","affiliation":[{"name":"Department of Nephrology Dialysis and Transplantation, University Hospital of Strasbourg, Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4865-8528","authenticated-orcid":false,"given":"V\u00e9ronique","family":"Fr\u00e9meaux-Bacchi","sequence":"additional","affiliation":[{"name":"INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Centrale Nantes, Nantes Universit\u00e9, Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"issue":"6","key":"B1-20260723","doi-asserted-by":"crossref","first-page":"727","DOI":"10.2215\/CJN.0000000000000135","article-title":"Long-term outcomes in IgA nephropathy","volume":"18","author":"Pitcher","year":"2023","journal-title":"Clin J Am Soc Nephrol."},{"issue":"10","key":"B2-20260723","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.1093\/ndt\/gfad082","article-title":"The incidence and prevalence of IgA nephropathy in 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