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- Saevarsdottir, S., et al.
(författare)
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Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset
- 2022
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 81:8
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.
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| 4. |
- Turesson, C, et al.
(författare)
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Increased endothelial expression of HLA-DQ and interleukin 1alpha in extra-articular rheumatoid arthritis. Results from immunohistochemical studies of skeletal muscle
- 2001
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Ingår i: Rheumatology. - : Oxford University Press (OUP). - 1462-0332. ; 40:12, s. 1346-1354
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate markers of endothelial activation in muscle biopsies from rheumatoid arthritis (RA) patients with and without extra-articular manifestations (ExRA). PATIENTS AND METHODS: Nine consecutive ExRA patients were compared with nine RA controls without ExRA, matched for age, sex and duration of RA. Muscle biopsies were obtained from the lateral vastus or anterior tibial muscle. Macrophage and lymphocyte CD markers, HLA molecules, cytokines and adhesion molecules were investigated using immunohistochemistry, and stainings were evaluated using computer image analysis and conventional microscopy. Serum concentrations of soluble adhesion molecules, tumour necrosis factor alpha (TNF-alpha) and rheumatoid factor (RF) were determined using immunoassays. RESULTS: The number of HLA-DQ-positive capillaries (P=0.039) and the expression of interleukin 1alpha (IL-1alpha) in endothelial cells (mean pairwise difference 0.26%; 95% confidence interval 0-0.52) were increased in ExRA patients compared with non-ExRA controls. There were no signs of inflammatory cell infiltrates or fibre degeneration. Serum levels of TNF-alpha, the soluble form of intercellular adhesion molecule 1, the soluble form of vascular cell adhesion molecule 1 and IgM RF were increased in the ExRA group. CONCLUSION: The increased expression of HLA-DQ and IL-1alpha may indicate systemic endothelial activation in extra-articular RA, which could be of importance for cardiovascular comorbidity and mortality in such patients.
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| 5. |
- Duran-Lozano, Laura, et al.
(författare)
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Germline variants at SOHLH2 influence multiple myeloma risk
- 2021
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Ingår i: Blood Cancer Journal. - : Springer Science and Business Media LLC. - 2044-5385. ; 11:4
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Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is caused by the uncontrolled, clonal expansion of plasma cells. While there is epidemiological evidence for inherited susceptibility, the molecular basis remains incompletely understood. We report a genome-wide association study totalling 5,320 cases and 422,289 controls from four Nordic populations, and find a novel MM risk variant at SOHLH2 at 13q13.3 (risk allele frequency = 3.5%; odds ratio = 1.38; P = 2.2 × 10-14). This gene encodes a transcription factor involved in gametogenesis that is normally only weakly expressed in plasma cells. The association is represented by 14 variants in linkage disequilibrium. Among these, rs75712673 maps to a genomic region with open chromatin in plasma cells, and upregulates SOHLH2 in this cell type. Moreover, rs75712673 influences transcriptional activity in luciferase assays, and shows a chromatin looping interaction with the SOHLH2 promoter. Our work provides novel insight into MM susceptibility.
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| 6. |
- Geborek, Pierre, et al.
(författare)
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Tumour necrosis factor blockers do not increase overall tumour risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas
- 2005
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 64:5, s. 699-703
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To determine whether TNF blockers increase tumour risk in patients with RA. Material and methods: The South Swedish Arthritis Treatment Group register (SSATG) comprises over 90% of anti-TNF treated patients with RA in the area. 757 patients treated with etanercept or infliximab included between 1 February 1999 and 31 December 2002 were identified. 800 patients with conventional antirheumatic treatment in a community based cohort served as a comparison cohort. Tumours and deaths were identified in the cancer registry and population census registers. Patients were followed up from initiation of anti-TNF treatment or 1 July 1997 for the comparison group, until death or 31 December 2002. Results: In the anti-TNF group, 16 tumours ( 5 lymphomas) were identified in 1603 person-years at risk, and in the comparison group 69 tumours ( 2 lymphomas) in 3948 person-years. Standardised incidence ratios (SIRs) for total tumour relative risk for the anti-TNF group and the comparison group were 1.1 (95% confidence interval (CI) 0.6 to 1.8) and 1.4 ( 95% CI 1.1 to 1.8), respectively. The lymphoma relative risk (RR) was 11.5 ( 95% CI 3.7 to 26.9) and 1.3 ( 95% CI 0.2 to 4.5), respectively The total tumour RR excluding lymphoma was 0.79 ( 95% CI 0.4 to 1.42) and 1.39 ( 95% CI 1.08 to 1.76), respectively. Proportional hazard analysis for lymphomas yielded RR 4.9 ( 95% CI 0.9 to 26.2) in anti-TNF treated versus untreated patients. Conclusion: Community based patients with RA treated conventionally had an increased overall tumour risk compared with the background population. A possible additional increased risk for lymphoma associated with TNF blockers was based on few cases and needs confirmation.
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| 9. |
- Olsson, Peter, et al.
(författare)
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Associations of cigarette smoking with disease phenotype and type I interferon expression in primary Sjogren's syndrome
- 2019
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Ingår i: Rheumatology International. - : Springer Science and Business Media LLC. - 0172-8172 .- 1437-160X. ; 39:9, s. 1575-1584
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Tidskriftsartikel (refereegranskat)abstract
- Several studies have shown a negative association between smoking and primary Sjogren's syndrome (pSS), and smoking may interfere with the immune response. The purpose of this study was to investigate if smoking affects disease activity and disease phenotype in pSS. In this cross-sectional study, consecutive pSS patients filled out the EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) form and a structured questionnaire regarding smoking habits. EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) scores were calculated and blood samples were analysed for type I interferon signature using RT-PCR. Of 90 patients (93% women, median age 66.5 years), 72% were type I IFN signature positive and 6, 42 and 53% were current, former and never smokers, respectively. No significant differences by smoking status were found regarding ESSDAI total score, activity in the ESSDAI domains or type I IFN signature. Patients with a higher cumulative cigarette consumption (>= median) had higher scores in ESSPRI total [5.0 (3.0-6.3) vs 8.0 (6.0-8.3); p < 0.01] and ESSPRI sicca and pain domains. Comparing type I IFN signature negative and positive patients, the latter had significantly lower activity in ESSDAI articular domain (7/25 vs 3/64; p < 0.01) and lower scores in ESSPRI total [7.7 (5.2-8.2) vs 6.0 (4.0-7.7); p = 0.04]. Smoking was not associated with disease phenotype although patients with a higher cumulative cigarette consumption had worse symptoms in some disease domains. Current smokers were few making it difficult to draw any firm conclusions about associations to current smoking.
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| 10. |
- Pearlstein, E, et al.
(författare)
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Expression of protein HC on the plasma membrane of different human cell types
- 1977
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Ingår i: Journal of immunology. - 0022-1767. ; 119:3, s. 9-824
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Tidskriftsartikel (refereegranskat)abstract
- The surface expression of a recently described plasma glycoprotein called human complex-forming glycoprotein, hetergeneous in charge (protein HC) on a number of different human cell types was investigated. By means of direct and indirect immunofluorescence, protein HC was shown to be associated with the surface of virtually all cells of the investigated normal cell types including erythrocytes, peripheral blood B and T lymphocytes, and the human fibroblast lines HE 81, HE 31, and WI 38. When transformed and malignant cell populations were studied, it was found that some populations (e.g., the T cell line Molt-4) carried protein HC on the surfaces of very few cells, whereas other cell populations (e.g., chronic lymphocytic leukemia lymphocytes) carried the protein on most cells. Malignant cell populations with intermediary percentages of protein HC-positive cells were also found. Protein HC on the cell surface of normal peripheral blood lymphocytes could be redistributed by incubation of the cells with anti-protein HC-antiserum at 37 degrees C, and this reaction could be inhibited by sodium azide.
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