Complement C4 Copy Number Variation is Linked to SSA/Ro and SSB/La Autoantibodies in Systemic Inflammatory Autoimmune Diseases. Issue 8 (27th June 2022)

• Record Type: Journal Article
• Authors: Lundtoft, Christian; Pucholt, Pascal; Martin, Myriam; Bianchi, Matteo; Lundström, Emeli; Eloranta, Maija‐Leena; Sandling, Johanna K.; Sjöwall, Christopher; Jönsen, Andreas; Gunnarsson, Iva; Rantapää‐Dahlqvist, Solbritt; Bengtsson, Anders A.; Leonard, Dag; Baecklund, Eva; Jonsson, Roland; Hammenfors, Daniel; Forsblad‐d'Elia, Helena; Eriksson, Per; Mandl, Thomas; Magnusson Bucher, Sara; Norheim, Katrine B.; Auglænd Johnsen, Svein Joar; Omdal, Roald; Kvarnström, Marika; Wahren‐Herlenius, Marie; Notarnicola, Antonella; Andersson, Helena; Molberg, Øyvind; Diederichsen, Louise Pyndt; Almlöf, Jonas; Syvänen, Ann‐Christine; Kozyrev, Sergey V.; Lindblad‐Toh, Kerstin; Nilsson, Bo; Blom, Anna M.; Lundberg, Ingrid E.; Nordmark, Gunnel; Diaz‐Gallo, Lina Marcela; Svenungsson, Elisabet; Rönnblom, Lars;
• Other Names: Rönnblom Lars investigator.; Nordmark Gunnel investigator.; Lundberg Ingrid E. investigator.; Sandling Johanna K. investigator.; Pucholt Pascal investigator.; Rosenberg Lina Hultin investigator.; Kozyrev Sergey V. investigator.; Eloranta Maija‐Leena investigator.; Alexsson Andrei investigator.; Bianchi Matteo investigator.; Bengtsson Christine investigator.; Jonsson Roland investigator.; Omdal Roald investigator.; Molberg Øyvind investigator.; Syvänen Ann‐Christine investigator.; Jönsen Andreas investigator.; Gunnarsson Iva investigator.; Svenungsson Elisabet investigator.; Rantapää‐Dahlqvist Solbritt investigator.; Bengtsson Anders A. investigator.; Sjöwall Christopher investigator.; Leonard Dag investigator.; Lindblad‐Toh Kerstin investigator.; Almlöf Jonas Carlsson investigator.; Hagberg Niklas investigator.; Meadows Jennifer R. S. investigator.; Nordin Jessika investigator.; Wahren‐Herlenius Marie investigator.; Yavuz Sule investigator.; Tjärnlund Anna investigator.; Notarnicola Antonella investigator.; Hammenfors Daniel investigator.; Theander Elke investigator.; Baecklund Eva investigator.; Thorlacius Guðný Ella investigator.; Chinoy Hector investigator.; Andersson Helena investigator.; Enocsson Helena investigator.; Forsblad‐d'Elia Helena investigator.; Lamb Janine investigator.; Brun Johan G. investigator.; Wetterö Jonas investigator.; Ramírez Sepúlveda Jorge I. investigator.; Imgenberg‐Kreuz Juliana investigator.; Hjorton Karin investigator.; Brokstad Karl A. investigator.; Skarstein Kathrine investigator.; Norheim Katrine Brække investigator.; Vasaitis Lilian investigator.; Diederichsen Louise Pyndt investigator.; Jonsson Malin V. investigator.; Kvarnström Marika investigator.; Dastmalchi Maryam investigator.; Eriksson Per investigator.; Cooper Robert G. investigator.; Bucher Sara Magnusson investigator.; Appel Silke investigator.; Rothwell Simon investigator.; Johnsen Svein Joar investigator.; Mandl Thomas investigator.; Aqrawi Lara Adnan investigator.; Jensen Janicke Liaaen investigator.; Palm Øyvind investigator.; Liden Maria investigator.; Skogh Thomas investigator.; Hanna Balsam investigator.; Hallengren Christina Ståhl investigator.; Hellström Helena investigator.; Häggström Åsa investigator.; Mohammad Aladdin investigator.; Husmark Tomas investigator.; Svärd Anna investigator.; Jalal Awat investigator.; Lindblad‐Toh Kerstin investigator.; Pielberg Gerli Rosengren investigator.; Lobell Anna investigator.; Karlsson Åsa investigator.; Murén Eva investigator.; Andersson Göran investigator.; Ahlgren Kerstin M. investigator.; Rönnblom Lars investigator.; Eloranta Maija‐Leena investigator.; Landegren Nils investigator.; Kämpe Olle investigator.; Söderkvist Peter investigator.;
• Is Part Of: Arthritis & rheumatology. Volume 74:Issue 8(2022)
• Page Start: 1440
• Page End: 1450
• Publication Date: 2022-06-27
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; 616.72
• DOI: 10.1002/art.42122
• Languages: English
• ISSNs: 2326-5191

Abstract

Abstract : Objective: Copy number variation of the C4 complement components, C4A and C4B, has been associated with systemic inflammatory autoimmune diseases. This study was undertaken to investigate whether C4 copy number variation is connected to the autoimmune repertoire in systemic lupus erythematosus (SLE), primary Sjögren's syndrome (SS), or myositis. Methods: Using targeted DNA sequencing, we determined the copy number and genetic variants of C4 in 2, 290 well‐characterized Scandinavian patients with SLE, primary SS, or myositis and 1, 251 healthy controls. Results: A prominent relationship was observed between C4A copy number and the presence of SSA/SSB autoantibodies, which was shared between the 3 diseases. The strongest association was detected in patients with autoantibodies against both SSA and SSB and 0 C4A copies when compared to healthy controls (odds ratio [OR] 18.0 [95% confidence interval (95% CI) 10.2–33.3]), whereas a weaker association was seen in patients without SSA/SSB autoantibodies (OR 3.1 [95% CI 1.7–5.5]). The copy number of C4 correlated positively with C4 plasma levels. Further, a common loss‐of‐function variant in C4A leading to reduced plasma C4 was more prevalent in SLE patients with a low copy number of C4A . Functionally, we showed that absence of C4A reduced the individuals' capacity to deposit C4b on immune complexes. Conclusion: We show that a low C4A copy number is more strongly associated with the autoantibody repertoire than with the clinically defined disease entities. These findings may have implications for understanding the etiopathogenetic mechanisms of systemic inflammatory autoimmune diseases and for patient stratification when taking the genetic profile into account.