54
views
0
recommends
+1 Recommend
0 collections
    4
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      A genetic study on C5-TRAF1 and progression of joint damage in rheumatoid arthritis

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Introduction

          The severity of joint damage progression in rheumatoid arthritis (RA) is heritable. Several genetic variants have been identified, but together explain only part of the total genetic effect. Variants in Interleukin-6 (IL-6), Interleukin-10 (IL-10), C5-TRAF1, and Fc-receptor-like-3 (FCRL3) have been described to associate with radiographic progression, but results of different studies were incongruent. We aimed to clarify associations of these variants with radiographic progression by evaluating six independent cohorts.

          Methods

          In total 5,895 sets of radiographs of 2,493 RA-patients included in six different independent datasets from the Netherlands, Sweden, Spain and North-America were studied in relation to rs1800795 (IL-6), rs1800896 (IL-10), rs2900180 ( C5-TRAF1) and rs7528684 (FCRL3). Associations were tested in the total RA-populations and in anti-citrullinated peptide antibodies (ACPA)-positive and ACPA-negative subgroups per cohort, followed by meta-analyses. Furthermore, the associated region C5-TRAF1 was fine-mapped in the ACPA-negative Dutch RA-patients.

          Results

          No associations were found for rs1800795 (IL-6), rs1800896 (IL-10) and rs7528684 (FCRL3) in the total RA-population and after stratification for ACPA. Rs2900180 in C5-TRAF1 was associated with radiographic progression in the ACPA-negative population ( P-value meta-analysis = 5.85 × 10 −7); the minor allele was associated with more radiographic progression. Fine-mapping revealed a region of 66Kb that was associated; the lowest P-value was for rs7021880 in TRAF1. The P-value for rs7021880 in meta-analysis was 6.35 × 10 −8. Previous studies indicate that the region of rs7021880 was associated with RNA expression of TRAF1 and C5.

          Conclusion

          Variants in IL-6, IL-10 and FCRL3 were not associated with radiographic progression. Rs2900180 in C5-TRAF1 and linked variants in a 66Kb region were associated with radiographic progression in ACPA-negative RA.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13075-014-0514-0) contains supplementary material, which is available to authorized users.

          Related collections

          Most cited references34

          • Record: found
          • Abstract: found
          • Article: not found

          TRAF1-C5 as a risk locus for rheumatoid arthritis--a genomewide study.

          Rheumatoid arthritis has a complex mode of inheritance. Although HLA-DRB1 and PTPN22 are well-established susceptibility loci, other genes that confer a modest level of risk have been identified recently. We carried out a genomewide association analysis to identify additional genetic loci associated with an increased risk of rheumatoid arthritis. We genotyped 317,503 single-nucleotide polymorphisms (SNPs) in a combined case-control study of 1522 case subjects with rheumatoid arthritis and 1850 matched control subjects. The patients were seropositive for autoantibodies against cyclic citrullinated peptide (CCP). We obtained samples from two data sets, the North American Rheumatoid Arthritis Consortium (NARAC) and the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA). Results from NARAC and EIRA for 297,086 SNPs that passed quality-control filters were combined with the use of Cochran-Mantel-Haenszel stratified analysis. SNPs showing a significant association with disease (P<1x10(-8)) were genotyped in an independent set of case subjects with anti-CCP-positive rheumatoid arthritis (485 from NARAC and 512 from EIRA) and in control subjects (1282 from NARAC and 495 from EIRA). We observed associations between disease and variants in the major-histocompatibility-complex locus, in PTPN22, and in a SNP (rs3761847) on chromosome 9 for all samples tested, the latter with an odds ratio of 1.32 (95% confidence interval, 1.23 to 1.42; P=4x10(-14)). The SNP is in linkage disequilibrium with two genes relevant to chronic inflammation: TRAF1 (encoding tumor necrosis factor receptor-associated factor 1) and C5 (encoding complement component 5). A common genetic variant at the TRAF1-C5 locus on chromosome 9 is associated with an increased risk of anti-CCP-positive rheumatoid arthritis. Copyright 2007 Massachusetts Medical Society.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes.

            To extend our understanding of the genetic basis of human immune function and dysfunction, we performed an expression quantitative trait locus (eQTL) study of purified CD4(+) T cells and monocytes, representing adaptive and innate immunity, in a multi-ethnic cohort of 461 healthy individuals. Context-specific cis- and trans-eQTLs were identified, and cross-population mapping allowed, in some cases, putative functional assignment of candidate causal regulatory variants for disease-associated loci. We note an over-representation of T cell-specific eQTLs among susceptibility alleles for autoimmune diseases and of monocyte-specific eQTLs among Alzheimer's and Parkinson's disease variants. This polarization implicates specific immune cell types in these diseases and points to the need to identify the cell-autonomous effects of disease susceptibility variants.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study.

              Methotrexate is the most frequent choice of disease-modifying antirheumatic therapy for rheumatoid arthritis. Although results of studies have shown the efficacy of such drugs, including methotrexate, on rheumatoid arthritis morbidity measures, their effect on mortality in patients with the disease remains unknown. Our aim was to prospectively assess the effect on mortality of methotrexate in a cohort of patients with rheumatoid arthritis. Our cohort included 1240 patients with rheumatoid arthritis seen at the Wichita Arthritis Center, an outpatient rheumatology facility. Patients' details were entered into a computerised database at the time of their first clinic visit. We also obtained and recorded demographic, clinical, laboratory, and self-reported data at each follow-up visit (average interval 3.5 months). We estimated the mortality hazard ratio of methotrexate with a marginal structural Cox proportional hazards model. 191 individuals died during follow-up. Patients who began treatment with methotrexate (n=588) had worse prognostic factors for mortality. After adjustment for this confounding by indication, the mortality hazard ratio for methotrexate use compared with no methotrexate use was 0.4 (95% CI 0.2-0.8). Other conventional disease-modifying antirheumatic drugs did not have a significant effect on mortality. The hazard ratio of methotrexate use for cardiovascular death was 0.3 (0.2-0.7), whereas that for non-cardiovascular deaths was 0.6 (0.2-1.2). Our data indicate that methotrexate may provide a substantial survival benefit, largely by reducing cardiovascular mortality. This survival benefit of methotrexate would set a standard against which new disease-modifying antirheumatic drugs could be compared.
                Bookmark

                Author and article information

                Contributors
                H.W.van_Steenbergen@lumc.nl
                lrrodriguez@salud.madrid.org
                ewa.berglin@vll.se
                sashazhernakova@gmail.com
                R.Knevel@lumc.nl
                ivorra_jos@gva.es
                T.W.J.Huizinga@lumc.nl
                benjamin.fernandez@salud.madrid.org
                PGregers@NSHS.edu
                solbritt.rantapaa.dahlqvist@medicin.umu.se
                A.H.M.van_der_Helm@lumc.nl
                Journal
                Arthritis Res Ther
                Arthritis Research & Therapy
                BioMed Central (London )
                1478-6354
                1478-6362
                8 January 2015
                8 January 2015
                2015
                : 17
                : 1
                : 1
                Affiliations
                [ ]Department of Rheumatology, Leiden University Medical Center, P.O. Box 9600, Leiden, 2300 RC the Netherlands
                [ ]Department of Rheumatology and Health Research Institute, San Carlos Clinical Hospital, Madrid, Spain
                [ ]Department of Public Health and Clinical Medicine/Rheumatology, University Hospital, Umeå, Sweden
                [ ]Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands
                [ ]Department of Rheumatology, University Hospital la Fe, Valencia, Spain
                [ ]Feinstein Institute for Medical Research and North Shore-LIJ Health System, Manhasset, NY USA
                Article
                514
                10.1186/s13075-014-0514-0
                4318544
                25566937
                52a897d9-a61a-454c-8e18-dce6a5693ede
                © van Steenbergen et al.; licensee BioMed Central. 2015

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 2 September 2014
                : 23 December 2014
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2015

                Orthopedics
                Orthopedics

                Comments

                Comment on this article