| 1. |
- Gorlova, Olga, et al.
(författare)
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Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy
- 2011
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 7:7
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (IcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32x10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 x 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39x10(-7), OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79x10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57x10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84x10(-21), OR = 0.55) and ATA (P = 1.14x10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and autoantibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.
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| 2. |
- Radstake, Timothy R. D. J., et al.
(författare)
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Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:5, s. 71-426
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Tidskriftsartikel (refereegranskat)abstract
- Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry including a total of 2,296 individuals with SSc and 5,171 controls. Analysis of 279,621 autosomal SNPs followed by replication testing in an independent case-control set of European ancestry (2,753 individuals with SSc (cases) and 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22-23, rs2056626, P = 2.09 x 10(-7) in the discovery samples, P = 3.39 x 10(-9) in the combined analysis). Additionally, we confirm and firmly establish the role of the MHC (P = 2.31 x 10(-18)), IRF5 (P = 1.86 x 10(-13)) and STAT4 (P = 3.37 x 10(-9)) gene regions as SSc genetic risk factors.
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| 3. |
- Wenink, Mark H., et al.
(författare)
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The inhibitory Fc gamma IIb receptor dampens TLR4-mediated immune responses and is selectively up-regulated on dendritic cells from rheumatoid arthritis patients with quiescent disease
- 2009
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 183:7, s. 4509-4520
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) is a common autoimmune disease leading to profound disability and premature death. Although a role for FcgammaRs and TLRs is accepted, their precise involvement remains to be elucidated. FcgammaRIIb is an inhibitory FcR important in the maintenance of tolerance. We hypothesized that the inhibitory FcgammaRIIb inhibits TLR responses on monocyte-derived dendritic cells (DC) and serves as a counterregulatory mechanism to dampen inflammation, and we surmised that this mechanism might be defective in RA. The expression of the inhibitory FcgammaRIIb was found to be significantly higher on DCs from RA patients having low RA disease activity in the absence of treatment with antirheumatic drugs. The expression of activating FcgammaRs was similarly distributed among all RA patients and healthy controls. Intriguingly, only DCs with a high expression of FcgammaRIIb were able to inhibit TLR4-mediated secretion of proinflammatory cytokines when stimulated with immune complexes. In addition, when these DCs were coincubated with the combination of a TLR4 agonist and immune complexes, a markedly inhibited T cell proliferation was apparent, regulatory T cell development was promoted, and T cells were primed to produce high levels of IL-13 compared with stimulation of the DCs with the TLR4 agonist alone. Blocking FcgammaRIIb with specific Abs fully abrogated these effects demonstrating the full dependence on the inhibitory FcgammaRIIb in the induction of these phenomena. This TLR4-FcgammaRIIb interaction was shown to dependent on the PI3K and Akt pathway.
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| 4. |
- Coenen, Marieke J H, et al.
(författare)
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Genetic Variants in Toll-Like Receptors Are Not Associated with Rheumatoid Arthritis Susceptibility or Anti-Tumour Necrosis Factor Treatment Outcome
- 2010
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Several studies point to a role of Toll-like receptors (TLRs) in the development of rheumatoid arthritis (RA). We investigated if genetic variants in TLR genes are associated with RA and response to tumour necrosis factor blocking (anti-TNF) medication. Methodology and Principal Findings: 22 single nucleotide polymorphisms (SNPs) in seven TLR genes were genotyped in a Dutch cohort consisting of 378 RA patients and 294 controls. Significantly associated variants were investigated in replication cohorts from The Netherlands, United Kingdom and Sweden (2877 RA patients and 2025 controls). 182 of the Dutch patients were treated with anti-TNF medication. Using these patients and a replication cohort (269 Swedish patients) we analysed if genetic variants in TLR genes were associated with anti-TNF outcome. In the discovery phase of the study we found a significant association of SNPs rs2072493 in TLR5 and rs3853839 in TLR7 with RA disease susceptibility. Meta-analysis of discovery and replication cohorts did not confirm these findings. SNP rs2072493 in TLR5 was associated with anti-TNF outcome in the Dutch but not in the Swedish population. Conclusion: We conclude that genetic variants in TLRs do not play a major role in susceptibility for developing RA nor in anti-TNF treatment outcome in a Caucasian population.
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| 5. |
- Okada, Yukinori, et al.
(författare)
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Genetics of rheumatoid arthritis contributes to biology and drug discovery
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 506:7488, s. 376-381
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)(1). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating similar to 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2-4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation(5), cis-acting expression quantitative trait loci(6) and pathway analyses(7-9)-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
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| 6. |
- Orozco, Gisela, et al.
(författare)
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Association of STAT4 with rheumatoid arthritis : a replication study in three European populations
- 2008
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 58:7, s. 1974-1980
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: This study was undertaken to investigate the previously reported association of the STAT4 polymorphism rs7574865 with rheumatoid arthritis (RA) in 3 different European populations from Spain, Sweden, and The Netherlands, comprising a total of 2,072 patients and 2,474 controls. METHODS: Three different cohorts were included in the study: 923 RA patients and 1,296 healthy controls from Spain, 273 RA patients and 285 healthy controls from Sweden, and 876 RA patients and 893 healthy controls from The Netherlands. DNA from patients and controls was obtained from peripheral blood. Samples were genotyped for the STAT4 single-nucleotide polymorphism rs7574865 using a TaqMan 5'-allele discrimination assay. The chi-square test was performed to compare allele and genotype distributions. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: We observed a significantly increased frequency of the minor T allele in RA patients compared with healthy controls in the Spanish population (24.8% versus 20.8%; P = 0.001, OR 1.26 [95% CI 1.09-1.45]). This association was confirmed in both the Swedish population (P = 0.03, OR 1.35 [95% CI 1.03-1.77]) and the Dutch population (P = 0.03, OR 1.45 [95% CI 1.21-1.73]). The overall P value for all 3 populations was 9.79 x 10(-6) (OR 1.25 [95% CI 1.13-1.37]). No association between rs7574865 and the presence of rheumatoid factor or anti-cyclic citrullinated peptide autoantibodies was observed. A meta-analysis of all published STAT4 associations revealed an OR of 1.25 (95% CI 1.19-1.33) (P = 1 x 10(-5)). CONCLUSION: Our findings indicate an association between the STAT4 polymorphism rs7574865 and RA in 3 different populations, from Spain, Sweden, and The Netherlands, thereby confirming previous data.
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| 7. |
- Crowson, Cynthia S., et al.
(författare)
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Impact of risk factors associated with cardiovascular outcomes in patients with rheumatoid arthritis
- 2018
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 77:1, s. 48-54
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Patients with rheumatoid arthritis (RA) have an excess risk of cardiovascular disease (CVD). We aimed to assess the impact of CVD risk factors, including potential sex differences, and RA-specific variables on CVD outcome in a large, international cohort of patients with RA. Methods: In 13 rheumatology centres, data on CVD risk factors and RA characteristics were collected at baseline. CVD outcomes (myocardial infarction, angina, revascularisation, stroke, peripheral vascular disease and CVD death) were collected using standardised definitions. Results: 5638 patients with RA and no prior CVD were included (mean age: 55.3 (SD: 14.0) years, 76% women). During mean follow-up of 5.8 (SD: 4.4) years, 148 men and 241 women developed a CVD event (10-year cumulative incidence 20.9% and 11.1%, respectively). Men had a higher burden of CVD risk factors, including increased blood pressure, higher total cholesterol and smoking prevalence than women (all p<0.001). Among the traditional CVD risk factors, smoking and hypertension had the highest population attributable risk (PAR) overall and among both sexes, followed by total cholesterol. The PAR for Disease Activity Score and for seropositivity were comparable in magnitude to the PAR for lipids. A total of 70% of CVD events were attributable to all CVD risk factors and RA characteristics combined (separately 49% CVD risk factors and 30% RA characteristics). Conclusions: In a large, international cohort of patients with RA, 30% of CVD events were attributable to RA characteristics. This finding indicates that RA characteristics play an important role in efforts to reduce CVD risk among patients with RA.
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| 8. |
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| 9. |
- Broen, Jasper C A, et al.
(författare)
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The Functional Polymorphism 844 A>G in Fc{alpha}RI (CD89) Does Not Contribute to Systemic Sclerosis or Rheumatoid Arthritis Susceptibility.
- 2011
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Ingår i: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 38:3, s. 446-449
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate the role of the Fc(α)RI 844 A>G functional polymorphism in the genetic predisposition to rheumatoid arthritis (RA) and systemic sclerosis (SSc) susceptibility. METHODS: The study population was composed of 1401 patients with SSc, 642 patients with RA, and 1317 healthy controls. The Fc(α)RI (CD89) single-nucleotide polymorphism rs16986050 was genotyped by pyrosequencing. RESULTS: We observed no significant deviation of the genotype and allele frequencies in RA and SSc compared to controls. A metaanalysis and a recessive and dominant model yielded similar negative results. CONCLUSION: Our data show that the Fc(α)RI 844 A>G polymorphism is not associated with SSc or RA susceptibility.
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