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- Lundtoft, Christian, et al.
(författare)
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Complement C4 copy number variation is linked to SSA/Ro and SSB/La autoantibodies in systemic inflammatory autoimmune diseases.
- 2022
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Ingår i: Arthritis & rheumatology (Hoboken, N.J.). - : Wiley. - 2326-5205 .- 2326-5191. ; 74:8, s. 1440-1450
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Tidskriftsartikel (refereegranskat)abstract
- 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.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.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.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.
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- Mofors, Johannes, et al.
(författare)
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Cigarette smoking patterns preceding primary Sjögren's syndrome
- 2020
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Ingår i: RMD Open. - : BMJ Publishing Group Ltd. - 2056-5933. ; 6:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cigarette smoking is a well-established risk factor for several autoimmune diseases, but its role in primary Sjogren's syndrome (pSS) remains unclear. Here, we investigated the association between cigarette smoking and subsequent development of pSS.Methods: Information on smoking habits was collected from lifestyle habit questionnaires of patients with pSS (n=815) and a matched control group (n=4425) for a case-control study. Differences in smoking exposure were analysed by conditional logistic regression. Potential interactions between smoking and risk-associated human leucocyte antigens (HLA) were assessed by multivariate regression.Results: The fraction of patients with pSS having ever smoked prior to diagnosis was lower than in controls (OR 0.67, 95% CI 0.55 to 0.81). Current smoking at diagnosis was also less prevalent in cases (OR 0.37, 95% CI 0.26 to 0.53). However, period prevalence of smoking during early adulthood was not statistically different from controls (OR 0.89, 95% CI 0.66 to 1.22) but markedly decreased over time. This was partly due to patients being more prone to stop smoking, starting already 30 years prior to diagnosis (OR 2.01, 95% CI 1.22 to 3.30). Smoking patterns were also stratified by autoantibody status, yielding similar estimates. No interaction effects between HLA-DRB1 haplotypes and smoking were observed.Conclusion: The observed smoking patterns indicate that individuals who develop pSS smoke equally much as the general population during early life but are then more prone to stop. The data can be interpreted as smoking conferring protective effects, or reflecting early symptoms of pSS that affect smoking habits, emphasising the slow, progressive development of the disease.
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- Nordmark, Gunnel, et al.
(författare)
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Association of Genes in the NF-κB Pathway with Antibody-Positive Primary Sjögren's Syndrome
- 2013
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Ingår i: Scandinavian Journal of Immunology. - : Wiley-Blackwell. - 0300-9475 .- 1365-3083. ; 78:5, s. 447-454
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Tidskriftsartikel (refereegranskat)abstract
- Primary Sjogrens syndrome (SS) is a systemic autoimmune inflammatory disease characterized by focal lymphocytic infiltrates in the lachrymal and salivary glands and autoantibodies against the SSA/Ro and SSB/La antigens. Experimental studies have shown an activation of NF-B in primary SS. NF-B activation results in inflammation and autoimmunity and is regulated by inhibitory and activating proteins. Genetic studies have shown an association between multiple autoimmune diseases and TNFAIP3 (A20) and TNIP1 (ABIN1), both repressors of NF-B and of IKBKE (IKK epsilon), which is an NF-B activator. The aim of this study was to analyse single nucleotide polymorphisms (SNPs) in the IKBKE, NFKB1, TNIP1 and TNFAIP3 genes for association with primary SS. A total of 12 SNPs were genotyped in 1105 patients from Scandinavia (Sweden and Norway, n=684) and the UK (n=421) and 4460 controls (Scandinavia, n=1662, UK, n=2798). When patients were stratified for the presence of anti-SSA and/or anti-SSB antibodies (n=868), case-control meta-analysis found an association between antibody-positive primary SS and two SNPs in TNIP1 (P=3.4x10(-5), OR=1.33, 95%CI: 1.16-1.52 for rs3792783 and P=1.3x10(-3), OR=1.21, 95%CI: 1.08-1.36 for rs7708392). A TNIP1 risk haplotype was associated with antibody-positive primary SS (P=5.7x10(-3), OR=1.47, 95%CI: 1.12-1.92). There were no significant associations with IKBKE, NFKB1 or TNFAIP3 in the meta-analysis of the Scandinavian and UK cohorts. We conclude that polymorphisms in TNIP1 are associated with antibody-positive primary SS.
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