학술논문
Complement C4 copy number variation is linked to SSA/Ro and SSB/La autoantibodies in systemic inflammatory autoimmune diseases
Document Type
Author
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; Leonard, Dag; Baecklund, Eva; Jonsson, Roland; Hammenfors, Daniel; Forsblad-d'Elia, Helena; Mandl, Thomas; Bucher, Sara Magnusson; Norheim, Katrine B; Johnsen, Svein Joar Auglaend; Omdal, Roald; Kvarnström, Marika; Wahren-Herlenius, Marie; Notarnicola, Antonella; Molberg, Øyvind; Diederichsen, Louise Pyndt; Almlöf, Jonas; Syvänen, Ann-Christine; Kozyrev, Sergey V; Lindblad-Toh, Kerstin
Source
Arthritis & Rheumatology. 74(8):1440-1450
Subject
Language
English
ISSN
2326-5205
Abstract
OBJECTIVE: Copy number variation of the C4 complement components, C4A and C4B, has been associated with systemic inflammatory autoimmune diseases. We asked if C4 copy number variation is connected to the autoimmune repertoire in systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS) or myositis.METHODS: Using targeted DNA sequencing, we determined the copy number and genetic variants of C4 in 2,290 well-characterised Scandinavian patients with SLE, pSS 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 three diseases. The strongest association was detected for patients with autoantibodies against both SSA and SSB and 0 C4A copies when compared to healthy controls (OR = 18.0; CI95% : 10.2-33.3), whereas a weaker association was seen for patients without SSA/SSB autoantibodies (OR = 3.1; CI95% : 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 more strongly is associated with the autoantibody repertoire than with the clinically defined disease entities. These results may have implication for understanding the aetiopathogenetic mechanisms of systemic inflammatory autoimmune diseases, and for patient stratification when taking the genetic profile into account. This article is protected by copyright. All rights reserved.