| 1. |
- Norheim, Katrine Braekke, et al.
(författare)
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Genetic variants at the RTP4/MASP1 locus are associated with fatigue in Scandinavian patients with primary Sjogren's syndrome
- 2021
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Ingår i: RMD Open. - : BMJ Publishing Group Ltd. - 2056-5933. ; 7:3
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Fatigue is common and severe in primary Sjogren's syndrome (pSS). The aim of this study was to identify genetic determinants of fatigue in pSS through a genome-wide association study. Methods Patients with pSS from Norway, Sweden, UK and USA with fatigue and genotype data available were included. After genotype imputation and quality control, 682 patients and 4 966 157 genetic markers were available. Association analysis in each cohort using linear regression with fatigue as a continuous variable and meta-analyses between the cohorts were performed. Results Meta-analysis of the Norwegian and Swedish cohorts identified five polymorphisms within the same linkage disequilibrium block at the receptor transporter protein 4 (RTP4)/MASP1 locus associated with fatigue with genome-wide significance (GWS) (p<5x10(-8)). Patients homozygous for the major allele scored 25 mm higher on the fatigue Visual Analogue Scale than patients homozygous for the minor allele. There were no variants associated with fatigue with GWS in meta-analyses of the US/UK cohorts, or all four cohorts. RTP4 expression in pSS B cells was upregulated and positively correlated with the type I interferon score. Expression quantitative trait loci effects in whole blood for fatigue-associated variants at RTP4/MASP1 and levels of RTP4 and MASP1 expression were identified. Conclusion Genetic variations at RTP4/MASP1 are associated with fatigue in Scandinavian pSS patients. RTP4 encodes a Golgi chaperone that influences opioid pain receptor function and MASP1 is involved in complement activation. These results add evidence for genetic influence over fatigue in pSS.
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| 2. |
- Kottyan, Leah C., et al.
(författare)
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The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share.
- 2015
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 24:2, s. 582-596
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Tidskriftsartikel (refereegranskat)abstract
- Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögrens syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.
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| 3. |
- 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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| 4. |
- Liu, Ke, et al.
(författare)
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X Chromosome Dose and Sex Bias in Autoimmune Diseases
- 2016
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Ingår i: Arthritis & Rheumatology. - : WILEY-BLACKWELL. - 2326-5191 .- 2326-5205. ; 68:5, s. 1290-1300
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Tidskriftsartikel (refereegranskat)abstract
- Objective. More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47, XXX; occurring in similar to 1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjogrens syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls. Methods. All subjects in this study were female. We identified subjects with 47, XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47, XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction. Results. We found 47, XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67-86.79], P = 0.003 and odds ratio 10.29 [95% confidence interval 1.18-123.47], P = 0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47, XXX. There was an excess of 47, XXX among SLE and SS patients. Conclusion. The estimated prevalence of SLE and SS in women with 47, XXX was similar to 2.5 and similar to 2.9 times higher, respectively, than that in women with 46, XX and similar to 25 and similar to 41 times higher, respectively, than that in men with 46, XY. No statistically significant increase of 47, XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.
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| 5. |
- Brito-Zerón, Pilar, et al.
(författare)
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Early diagnosis of primary Sjögren's syndrome: EULAR-SS task force clinical recommendations.
- 2016
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Ingår i: Expert Review of Clinical Immunology. - 1744-8409. ; 12:2, s. 137-156
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Forskningsöversikt (refereegranskat)abstract
- Sjögren's syndrome (SjS) is a systemic autoimmune disease that mainly affects the exocrine glands, leading to generalized mucosal dryness. However, primary SjS may initially present with non-sicca (systemic) manifestations. When these features appear before the onset of an overt sicca syndrome, we may talk of an underlying 'occult' SjS. The European League Against Rheumatism (EULAR) has promoted and supported an international collaborative study group (EULAR-SS Task Force) aimed at developing consensual recommendations to provide a homogeneous approach to the patient with primary SjS presenting with systemic involvement. This review summarizes the key factors that should be taken into account in the diagnostic approach in a patient with suspected SjS according to the main clinical patterns of presentation, and is especially focused on organ-specific systemic disease presentations, including a consensus set of recommendations in order to reach an early diagnosis. Close collaboration with the different specialties involved through a comprehensive multidisciplinary approach is essential in SjS patients presenting with systemic involvements.
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| 6. |
- Brito-Zerón, Pilar, et al.
(författare)
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Efficacy and safety of topical and systemic medications : A systematic literature review informing the EULAR recommendations for the management of Sjögren's syndrome
- 2019
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Ingår i: RMD Open. - : BMJ. - 2056-5933. ; 5:2
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Forskningsöversikt (refereegranskat)abstract
- Objective To evaluate current evidence on the efficacy and safety of topical and systemic medications in patients with primary Sjögren syndrome (SjS) to inform European League Against Rheumatism treatment recommendations. Methods The MEDLINE, EMBASE and Cochrane databases were searched for case-control/prospective cohort studies, randomised controlled trials (RCTs) and systematic reviews. Results Current evidence in primary SjS patients fulfilling the 2002 criteria is based on the data from 9 RCTs, 18 prospective cohort studies and 5 case-control studies. Two Cochrane systematic literature reviews (SLRs) have reported that topical treatments for dry mouth and dry eye are safe and effective. Ocular cyclosporine A was safe and effective in two RCTs including 1039 patients with dry eye syndrome. Two Cochrane SLRs on serum tear drops and plugs showed inconsistency in possible benefits, both for symptoms and objective measures. Five RCTs reported significant improvements in oral dryness and salivary flow rates for pilocarpine and cevimeline. An RCT showed no significant placebo-differences for hydroxychloroquine 400 mg/day for the primary outcome (visual analogue scale (VAS) composite of dryness, fatigue and pain). We identified seven RCTs carried out in primary SjS patients. RCTs using infliximab, anakinra and baminercept found no placebo-differences for the primary outcomes. The two largest RCTs randomised 255 patients to receive rituximab or placebo and reported no significant results in the primary outcome (VAS composite), while prospective studies suggested efficacy in systemic disease. Conclusion The current evidence supporting the use of the main topical therapeutic options of primary SjS is solid, while limited data from RCTs are available to guide systemic therapies.
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| 7. |
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| 8. |
- Harris, Valerie M., et al.
(författare)
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Klinefelters syndrome (47,XXY) is in excess among men with Sjogrens syndrome
- 2016
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Ingår i: Clinical Immunology. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 1521-6616 .- 1521-7035. ; 168, s. 25-29
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Tidskriftsartikel (refereegranskat)abstract
- Primary Sjogrens syndrome (pSS) has a strong female bias. We evaluated an X chromosome dose effect by analyzing 47,XXY (Klinefelters syndrome, 1 in 500 live male births) among subjects with pSS. 47,XXY was determined by examination of fluorescence intensity of single nucleotide polymorphisms from the X and Y chromosomes. Among 136 pSS men there were 4 with 47,XXY. This was significantly different from healthy controls (1 of 1254 had 47)0(Y, p = 0.0012 by Fishers exact test) as well men with rheumatoid arthritis (0 of 363 with 47,XXY), but not different compared to men with systemic lupus erythematosus (SLE) (4 of 136 versus 8 of 306, Fishers exact test p = NS). These results are consistent with the hypothesis that the number of X chromosomes is critical for the female bias of pSS, a property that may be shared with SLE but not RA. Published by Elsevier Inc.
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| 9. |
- Jousse-Joulin, Sandrine, et al.
(författare)
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Is salivary gland ultrasonography a useful tool in Sjögren's syndrome? A systematic review
- 2016
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Ingår i: Rheumatology. - : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 55:5, s. 789-800
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Ultrasonography (US) is a sensitive tool in the diagnosis of major salivary gland abnormalities in primary Sjögren's syndrome (pSS). The aim of this systematic review was to assess the metric properties of this technique. Methods. PUBMED and EMBASE databases were searched. All publications between January 1988 and January 2013 were considered. Data were extracted from the articles meeting the inclusion criteria according to US definition of salivary gland scoring system and metric properties studied. The type and number of glands tested, study design and metric properties according to OMERACT filter (truth, discrimination, feasibility) were assessed. Results. Of 167 publications identified initially with PUBMED and EMBASE, 31 met the inclusion criteria. The number of pSS patients varied among the studies from 16 to 140. The diagnosis of pSS was in line in most of the cases with the American-European Consensus Group (AECG) classification criteria for Sjögren's syndrome. The US examination was performed in suspected pSS only in studies in which the sensitivity ranged from 45.8 to 91.6% and specificity from 73 to 98.1%. There was heterogeneity in regard to the definition of US in B-mode and few studies used US in colour Doppler. Few studies reported reliability of US and sensitivity to change in pSS. Conclusion. US is a valuable tool for detecting salivary gland abnormalities in pSS. Its reliability has been poorly investigated and there is considerable variation in the definition of US abnormalities. Further studies are required to validate and standardize the US definition of salivary gland in pSS.
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| 10. |
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