| 1. |
- van Wesemael, Tineke J., et al.
(author)
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Smoking is associated with the concurrent presence of multiple autoantibodies in rheumatoid arthritis rather than with anti-citrullinated protein antibodies per se : A multicenter cohort study
- 2016
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In: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 18:1
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Journal article (peer-reviewed)abstract
- Background: The contribution of smoking to rheumatoid arthritis (RA) is hypothesized to be mediated through formation of anti-citrullinated protein antibodies (ACPA). In RA, however, autoantibodies such as ACPA, rheumatoid factor (RF), and anti-carbamylated protein antibodies (anti-CarP) often occur together, and it is thus unclear whether smoking is specifically associated with some autoantibodies rather than others. We therefore investigated whether smoking is only associated with ACPA or with the presence of multiple RA-related autoantibodies. Methods: A population-based Japanese cohort (n = 9575) was used to investigate the association of smoking with RF and anti-cyclic citrullinated peptide antibodies (anti-CCP2) in individuals without RA. Furthermore, RA patients fulfilling the 1987 criteria from three early arthritis cohorts from the Netherlands (n = 678), the United Kingdom (n = 761), and Sweden (n = 795) were used. Data on smoking, RF, anti-CCP2, and anti-CarP were available. A total score of autoantibodies was calculated, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by logistic regression. Results: In the population-based non-RA cohort, no association was found between smoking and one autoantibody (RF or anti-CCP2), but smoking was associated with double-autoantibody positivity (OR 2.95, 95% CI 1.32-6.58). In RA patients, there was no association between smoking and the presence of one autoantibody (OR 0.99, 95% CI 0.78-1.26), but smoking was associated with double-autoantibody positivity (OR 1.32, 95% CI 1.04-1.68) and triple-autoantibody positivity (OR 2.05, 95% CI 1.53-2.73). Conclusions: Smoking is associated with the concurrent presence of multiple RA-associated autoantibodies rather than just ACPA. This indicates that smoking is a risk factor for breaking tolerance to multiple autoantigens in RA.
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| 2. |
- Verheul, Marije K., et al.
(author)
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Triple positivity for anti–citrullinated protein autoantibodies, rheumatoid factor, and anti–carbamylated protein antibodies conferring high specificity for rheumatoid arthritis : implications for very early identification of at‐risk individuals
- 2018
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In: Arthritis & Rheumatology. - Hoboken : John Wiley & Sons. - 2326-5191 .- 2326-5205. ; 70:11, s. 1721-1731
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Journal article (peer-reviewed)abstract
- OBJECTIVE: In rheumatoid arthritis(RA), the autoantibodies anti-citrullinated protein antibodies(ACPA) and rheumatoid factor(RF) are commonly used to aid RA diagnosis. Although these autoantibodies are mainly found in RA, their specificity is not optimal. It is therefore difficult to identify RA patients, especially in very early disease, based on the presence of ACPA and RF alone. Also, anti-carbamylated protein(anti-CarP) antibodies have diagnostic and prognostic value as the presence of anti-CarP antibodies associates with joint damage in RA patients and with future RA development in arthralgia patients. Therefore, we aimed to investigate the value of combined antibody testing in relation to prediction and diagnosis of (early) RA.METHODS: A literature search resulted in twelve studies, consisting of RA patients, pre-RA individuals, disease controls, healthy first-degree relatives of RA patients or healthy controls, in which data on RF, ACPA and anti-CarP antibody-status was available. Random effects meta-analyses were carried out for several antibody combinations.RESULTS: The individual antibodies are highly prevalent in RA(34%-80%) compared to the control groups, but are also present in non-RA controls(0%-23%). To classify most people correctly as RA or non-RA, the combination of ACPA and/or RF often performs well(specificity:65-100, sensitivity:59-88). However, triple positivity for ACPA, RF and anti-CarP antibodies results in a higher specificity(98-100) (accompanied by a lower sensitivity(11-39)).CONCLUSIONS: As the rheumatology field is moving towards very early identification of RA and possible screening for individuals at maximum risk in populations with a low pre-test probability, triple positivity provides interesting information on individuals at risk to develop RA.
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| 3. |
- de Rooy, Diederik P C, et al.
(author)
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Genetic Factors for the Severity of ACPA-negative Rheumatoid Arthritis in 2 Cohorts of Early Disease: A Genome-wide Study.
- 2015
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In: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 42:8, s. 1383-1391
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Journal article (peer-reviewed)abstract
- Rheumatoid arthritis (RA) that is negative for anticitrullinated protein antibodies (ACPA) is a subentity of RA, characterized by less severe disease. At the individual level, however, considerable differences in the severity of joint destruction occur. We performed a study on genetic factors underlying the differences in joint destruction in ACPA-negative patients.
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| 4. |
- Kissel, Theresa, et al.
(author)
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IgG Anti–Citrullinated Protein Antibody Variable Domain Glycosylation Increases Before the Onset of Rheumatoid Arthritis and Stabilizes Thereafter : A Cross-Sectional Study Encompassing ~1,500 Samples
- 2022
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In: Arthritis & Rheumatology. - : John Wiley & Sons. - 2326-5191 .- 2326-5205. ; 74:7, s. 1147-1158
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Journal article (peer-reviewed)abstract
- Objective: The autoimmune response in rheumatoid arthritis (RA) is marked by the presence of anti–citrullinated protein antibodies (ACPAs). A notable feature of IgG ACPA is the abundant expression of N-linked glycans in the variable domain. However, the presence of ACPA variable domain glycosylation (VDG) across disease stages, and its response to therapy, are poorly described. To understand its dynamics, we investigated the abundance of IgG ACPA VDG in 1,498 samples from individuals in different clinical stages.Methods: Using liquid chromatography, we analyzed IgG ACPA VDG profiles in 7 different cohorts from Japan, Canada, The Netherlands, and Sweden. We assessed 106 healthy individuals, 228 individuals with presymptomatic RA, 277 individuals with arthralgia, 307 patients with new-onset/early RA, and 117 RA patients after prespecified treatment regimens. Additionally, we measured VDG in 234 samples from patients with RA who did or did not achieve long-term drug-free remission (DFR) during up to 16 years follow-up.Results: IgG ACPA VDG significantly increased (P < 0.0001) toward disease onset and was associated with ACPA levels and epitope spreading prior to diagnosis. A slight increase in VDG was observed in patients with established RA, with a moderate influence of treatment (P = 0.007). In patients in whom DFR was later achieved, IgG ACPA VDG was already reduced at the time of RA onset.Conclusion: The abundance of IgG ACPA VDG increases toward RA onset and correlates with maturation of the ACPA response. While IgG ACPA VDG levels are fairly stable in established disease, a lower degree of VDG at RA onset correlates with DFR. Although the underlying biologic mechanisms remain elusive, our data support the concept that VDG relates to an expansion of the ACPA response in the pre-disease phase and contributes to disease development.
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| 5. |
- Burgers, Leonie E., et al.
(author)
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Validation of the EULAR definition of arthralgia suspicious for progression to rheumatoid arthritis
- 2017
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In: Rheumatology. - : OXFORD UNIV PRESS. - 1462-0324 .- 1462-0332. ; 56:12, s. 2123-2128
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Journal article (peer-reviewed)abstract
- Objectives. Recently a EULAR-taskforce defined arthralgia suspicious for progression to RA, in order to allow inclusion of homogeneous sets of arthralgia patients in clinical studies. This longitudinal study aimed (i) to validate this definition in arthralgia patients in whom rheumatologists felt that imminent RA was more likely than other arthralgias [clinically suspect arthralgia (CSA)], that is, the target population fulfilling the entry criterion, and (ii) to explore the performance in arthralgia patients who were referred to secondary care prior to rheumatological evaluation, hence ignoring the entry criterion. Methods. The definition was assessed in 241 Dutch patients identified with CSA by rheumatologists and 113 patients referred to the Umea university hospital with recent-onset arthralgia in small joints. The external reference was arthritis development < 2 years' follow-up. Results. CSA patients with a positive definition (>= 3/7 parameters present) had an increased risk for developing arthritis compared with definition-negative CSA patients (hazard ratio = 2.1, 95% CI: 0.9, 4.7). The sensitivity was 84% and the positive predictive value 30%. In arthralgia patients in whom the definition was applied before rheumatological evaluation, a positive definition was neither sensitive (10%) nor predictive (positive predictive value 3%). Conclusion. The EULAR definition of arthralgia suspicious for progression to RA is sensitive when used to support the rheumatologist's opinion on imminent RA. This validation study shows that the definition, when used as designed, further homogenizes patients that rheumatologists consider at risk for RA. To arrive at a high specificity, the clinical definition needs to be combined with biomarkers.
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| 6. |
- Mangnus, Lukas, et al.
(author)
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Studies on ageing and the severity of radiographic joint damage in rheumatoid arthritis
- 2015
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In: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 17
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Journal article (peer-reviewed)abstract
- INTRODUCTION: The western population is ageing. It is unknown whether age at diagnosis affects the severity of Rheumatoid Arthritis (RA), we therefore performed the present study.METHOD: 1,875 RA-patients (7,219 radiographs) included in five European and North-American cohorts (Leiden-EAC, Wichita, Umeå, Groningen and Lund) were studied on associations between age at diagnosis and joint damage severity. In 698 Leiden RA-patients with 7-years follow-up it was explored if symptom duration, anti-citrullinated-peptide-antibodies (ACPA), swollen joint count (SJC) and C-reactive-protein (CRP) mediated the association of age with joint damage. Fifty-six other RA-patients of the EAC-cohort underwent baseline MRIs of wrist, MCP and MTP-joints; MRI-inflammation (RAMRIS-synovitis plus bone marrow edema) was also evaluated in mediation analyses. Linear regression and multivariate normal regression models were used.RESULTS: Analysis on the five cohorts and the Leiden-EAC separately revealed 1.026-fold and 1.034-fold increase of radiographic joint damage per year increase in age (β=1.026, 1.034, both p<0.001); this effect was present at baseline and persisted over time. Age correlated stronger with baseline erosion-scores compared to joint space narrowing (JSN)-scores (r=0.38 versus 0.29). Symptom duration, ACPA, SJC and CRP did not mediate the association of age with joint damage severity. Age was significantly associated with the MRI-inflammation-score after adjusting for CRP and SJC (β=1.018, p=0.027). The association of age with joint damage (β=1.032, p=0.004) decreased after also including the MRI-inflammation-score (β=1.025, p=0.021), suggesting partial mediation.CONCLUSION: RA-patients presenting at higher age have more severe joint damage; this might be partially explained by more severe MRI-detected inflammation at higher age.
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| 7. |
- van Delft, Myrthe A. M., et al.
(author)
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The anti-carbamylated protein antibody response is of overall low avidity despite extensive isotype switching
- 2018
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In: Rheumatology. - : Oxford University Press. - 1462-0324 .- 1462-0332. ; 57:9, s. 1583-1591
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Journal article (peer-reviewed)abstract
- Objective: To better understand the contribution of autoantibodies in RA and the biology of their responses, we evaluated the avidity of the anti-carbamylated protein (anti-CarP) antibody response.Methods: The avidity of anti-CarP antibody, ACPA and anti-tetanus toxoid IgG were determined using elution assays. Anti-CarP IgG avidity was measured in sera of 107 RA patients, 15 paired SF and serum samples and 8 serially sampled sera before and after disease onset.Results: The avidity of anti-CarP IgG is low compared with the avidity of anti-tetanus toxoid IgG present in the same sera. Likewise, although less pronounced, anti-CarP also displayed a lower avidity as compared with the avidity of ACPA IgG. No difference in anti-CarP IgG avidity is observed between ACPA positive or ACPA negative patients. Anti-CarP IgG avidity is higher in anti-CarP IgM-negative compared with IgM-positive individuals. Furthermore, the anti-CarP avidity in serum is higher than in SF. Using samples of individuals that over time developed RA we observed no anti-CarP avidity maturation in the years before disease onset. In contrast to ACPA avidity, the anti-CarP avidity is not associated with severity of joint destruction.Conclusion: The anti-CarP response is of overall low avidity, even lower than the ACPA IgG avidity, and does not show apparent avidity maturation before or around disease onset. Overall, isotype switch and avidity maturation seem to be uncoupled as isotype switch occurs without avidity maturation, pointing towards a commonality in the regulation of both autoantibody responses as opposed to the pathways governing recall responses.
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| 8. |
- van Steenbergen, Hanna W, et al.
(author)
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EULAR definition of arthralgia suspicious for progression to rheumatoid arthritis
- 2017
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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 76:3, s. 491-496
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Journal article (peer-reviewed)abstract
- BACKGROUND: During the transition to rheumatoid arthritis (RA) many patients pass through a phase characterised by the presence of symptoms without clinically apparent synovitis. These symptoms are not well-characterised. This taskforce aimed to define the clinical characteristics of patients with arthralgia who are considered at risk for RA by experts based on their clinical experience.METHODS: The taskforce consisted of 18 rheumatologists, 1 methodologist, 2 patients, 3 health professionals and 1 research fellow. The process had three phases. In phase I, a list of parameters considered characteristic for clinically suspect arthralgia (CSA) was derived; the most important parameters were selected by a three-phased Delphi approach. In phase II, the experts evaluated 50 existing patients on paper, classified them as CSA/no-CSA and indicated their level of confidence. A provisional set of parameters was derived. This was studied for validation in phase III, where all rheumatologists collected patients with and without CSA from their outpatient clinics.RESULTS: The comprehensive list consisted of 55 parameters, of which 16 were considered most important. A multivariable model based on the data from phase II identified seven relevant parameters: symptom duration <1 year, symptoms of metacarpophalangeal (MCP) joints, morning stiffness duration ≥60 min, most severe symptoms in early morning, first-degree relative with RA, difficulty with making a fist and positive squeeze test of MCP joints. In phase III, the combination of these parameters was accurate in identifying patients with arthralgia who were considered at risk of developing RA (area under the receiver operating characteristic curve 0.92, 95% CI 0.87 to 0.96). Test characteristics for different cut-off points were determined.CONCLUSIONS: A set of clinical characteristics for patients with arthralgia who are at risk of progression to RA was established.
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| 9. |
- Boeters, Debbie M., et al.
(author)
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The prevalence of ACPA is lower in rheumatoid arthritis patients with an older age of onset but the composition of the ACPA response appears identical
- 2017
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In: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 19:1, s. 1-10
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Journal article (peer-reviewed)abstract
- Background: Rheumatoid arthritis (RA) consists of two syndromes, one autoantibody-positive and one autoantibody-negative. Existing data on the relation between age of onset and prevalence of autoantibodies were conflicting. Therefore this multicohort study assessed the age of onset in relation to the presence of autoantibodies. The association with characteristics of the anti-citrullinated protein antibodies (ACPA) response was also explored. Methods: The 1987 criteria-positive RA patients included in the Leiden EAC, BARFOT, ESPOIR, Umeå and Lund cohorts (n = 3321) were studied at presentation for age of onset and the presence of ACPA, rheumatoid factor (RF) and anti-carbamylated protein (anti-CarP) antibodies. Logistic regression analyses were performed; effect sizes were summarized in inverse-weighted meta-analyses. Within ACPA-positive RA, ACPA level was studied in all cohorts; ACPA isotypes, ACPA fine specificity and ACPA avidity index and clinical characteristics were studied in the Leiden EAC. Results: From the age of 50 onward, the proportion of ACPA-negative RA patients increased with age in the five cohorts. Similar observations were made for RF and anti-CarP. The composition of the ACPA response did not change with increasing age of onset with respect to titer, isotype distribution, fine specificity and avidity index. With increasing age of onset, RA patients smoked less often, had higher acute phase reactants and more often had a sub(acute) symptom onset. Conclusions: Data of five cohorts revealed that with older age of onset ACPA-negative RA is more frequent than ACPA-positive RA, while characteristics of ACPA-positive RA as judged by the composition of the ACPA response appeared not age dependent. Further biologic studies are needed to characterize the pathogenesis of ACPA-negative polyarthritis at older age and to promote personalized treatment decisions in ACPA-negative patients in daily practice.
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| 10. |
- Franke, Lude, et al.
(author)
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Association analysis of copy numbers of FC-gamma receptor genes for rheumatoid arthritis and other immune-mediated phenotypes
- 2016
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In: European Journal of Human Genetics. - : Nature Publishing Group. - 1018-4813 .- 1476-5438. ; 24:2, s. 263-270
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Journal article (peer-reviewed)abstract
- Segmental duplications (SDs) comprise about 5% of the human genome and are enriched for immune genes. SD loci often show copy numbers variations (CNV), which are difficult to tag with genotyping methods. CNV in the Fc gamma receptor region (FCGR) has been suggested to be associated with rheumatic diseases. The objective of this study was to delineate association of FCGR-CNV with rheumatoid arthritis (RA), coeliac disease and Inflammatory bowel disease incidence. We developed a method to accurately quantify CNV in SD loci based on the intensity values from the Immunochip platform and applied it to the FCGR locus. We determined the method's validity using three independent assays: segregation analysis in families, arrayCGH, and whole genome sequencing. Our data showed the presence of two separate CNVs in the FCGR locus. The first region encodes FCGR2A, FCGR3A and part of FCGR2C gene, the second encodes another part of FCGR2C, FCGR3B and FCGR2B. Analysis of CNV status in 4578 individuals with RA and 5457 controls indicated association of duplications in the FCGR3B gene in antibody-negative RA (P = 0.002, OR = 1.43). Deletion in FCGR3B was associated with increased risk of antibody-positive RA, consistently with previous reports (P = 0.023, OR = 1.23). A clear genotype-phenotype relationship was observed: CNV polymorphisms of the FCGR3A gene correlated to CD16A expression (encoded by FCGR3A) on CD8 T-cells. In conclusion, our method allows determining the CNV status of the FCGR locus, we identified association of CNV in FCGR3B to RA and showed a functional relationship between CNV in the FCGR3A gene and CD16A expression.
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| 11. |
- Knevel, Rachel, et al.
(author)
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A genetic variant in osteoprotegerin is associated with progression of joint destruction in rheumatoid arthritis
- 2014
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In: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 16:3
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Journal article (peer-reviewed)abstract
- Introduction: Progression of joint destruction in rheumatoid arthritis (RA) is partly heritably; 45 to 58% of the variance in joint destruction is estimated to be explained by genetic factors. The binding of RANKL (Receptor Activator for Nuclear Factor kappa B Ligand) to RANK results in the activation of TRAF6 (tumor necrosis factor (TNF) receptor associated factor-6), and osteoclast formation ultimately leading to enhanced bone resorption. This bone resorption is inhibited by osteoprotegerin (OPG) which prevents RANKL-RANK interactions. The OPG/RANK/RANKL/TRAF6 pathway plays an important role in bone remodeling. Therefore, we investigated whether genetic variants in OPG, RANK, RANKL and TRAF6 are associated with the rate of joint destruction in RA. Methods: 1,418 patients with 4,885 X-rays of hands and feet derived from four independent data-sets were studied. In each data-set the relative increase of the progression rate per year in the presence of a genotype was assessed. First, explorative analyses were performed on 600 RA-patients from Leiden. 109 SNPs, tagging OPG, RANK, RANKL and TRAF6, were tested. Single nucleotide polymorphisms (SNPs) significantly associated in phase-1 were genotyped in data-sets from Groningen (Netherlands), Sheffield (United Kingdom) and Lund (Switzerland). Data were summarized in an inverse weighted variance meta-analysis. Bonferonni correction for multiple testing was applied. Results: We found that 33 SNPs were significantly associated with the rate of joint destruction in phase-1. In phase-2, six SNPs in OPG and four SNPs in RANK were associated with progression of joint destruction with P-value <0.05. In the meta-analyses of all four data-sets, RA-patients with the minor allele of OPG-rs1485305 expressed higher rates of joint destruction compared to patients without these risk variants (P = 2.35x10(-4)). This variant was also significant after Bonferroni correction. Conclusions: These results indicate that a genetic variant in OPG is associated with a more severe rate of joint destruction in RA.
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| 12. |
- Källberg, Henrik, et al.
(author)
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Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis
- 2007
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 80:5, s. 867-875
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Journal article (peer-reviewed)abstract
- Gene-gene and gene-environment interactions are key features in the development of rheumatoid arthritis (RA) and other complex diseases. The aim of this study was to use and compare three different definitions of interaction between the two major genetic risk factors of RA—the HLA-DRB1 shared epitope (SE) alleles and the PTPN22 R620W allele—in three large case-control studies: the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study, the North American RA Consortium (NARAC) study, and the Dutch Leiden Early Arthritis Clinic study (in total, 1,977 cases and 2,405 controls). The EIRA study was also used to analyze interactions between smoking and the two genes. “Interaction” was defined either as a departure from additivity, as interaction in a multiplicative model, or in terms of linkage disequilibrium—for example, deviation from independence of penetrance of two unlinked loci. Consistent interaction, defined as departure from additivity, between HLA-DRB1 SE alleles and the A allele of PTPN22 R620W was seen in all three studies regarding anti-CCP–positive RA. Testing for multiplicative interactions demonstrated an interaction between the two genes only when the three studies were pooled. The linkage disequilibrium approach indicated a gene-gene interaction in EIRA and NARAC, as well as in the pooled analysis. No interaction was seen between smoking and PTPN22 R620W. A new pattern of interactions is described between the two major known genetic risk factors and the major environmental risk factor concerning the risk of developing anti-CCP–positive RA. The data extend the basis for a pathogenetic hypothesis for RA involving genetic and environmental factors. The study also raises and illustrates principal questions concerning ways to define interactions in complex diseases.
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| 13. |
- Maehlen, Marthe T., et al.
(author)
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Associations between APOE Genotypes and Disease Susceptibility, Joint Damage and Lipid Levels in Patients with Rheumatoid Arthritis
- 2013
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:4
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Journal article (peer-reviewed)abstract
- Objective: Apolipoprotein E (APOE) genotypes are associated with cardiovascular disease (CVD) and lipid levels. In rheumatoid arthritis (RA), an association has been found with disease activity. We examined the associations between APOE genotypes and disease susceptibility and markers of disease severity in RA, including radiographic joint damage, inflammatory markers, lipid levels and cardiovascular markers. Method: A Norwegian cohort of 945 RA patients and 988 controls were genotyped for two APOE polymorphisms. We examined longitudinal associations between APOE genotypes and C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) as well as hand radiographs (van der Heijde Sharp Score(SHS)) in 207 patients with 10 year longitudinal data. Lipid levels, cardiovascular markers and history of CVD were compared across genotypes in a cross sectional study of 136 patients. Longitudinal radiological data of cohorts from Lund and Leiden were available for replication. (N = 935, with 4799 radiographs). Results: In the Norwegian cohort, associations between APOE genotypes and total cholesterol (TC) and low-density lipoproteins (LDL) were observed (epsilon 2
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| 14. |
- de Rooy, Diederik P. C., et al.
(author)
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Genetic studies on components of the Wnt signalling pathway and the severity of joint destruction in rheumatoid arthritis
- 2013
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In: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 72:5, s. 769-775
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Journal article (peer-reviewed)abstract
- Background Progression of joint destruction in rheumatoid arthritis (RA) is partly heritable; knowledge of genetic factors may increase our understanding of the mechanisms underlying joint destruction. The activity of the Wnt/beta-catenin pathway influences osteoblast differentiation. Dickkopf-1 (Dkk-1) and sclerostin (Sost) are negative regulators and lipoprotein receptor-related protein-5 (LRP-5) and Kremen-1 are transmembrane receptors involved in this pathway. Objective To study variants in the genes encoding these proteins in relation to progression of joint destruction. Methods 1418 patients with RA of four cohorts with 4885 sets of hands and feet x-rays were studied. Explorative analyses were performed on 600 patients with RA from Leiden on single nucleotide polymorphisms (SNPs) tagging Dkk-1, Sost, Kremen-1 and LRP-5. SNPs significantly associating with joint damage progression were subsequently genotyped in cohorts from Groningen (NL), Sheffield (UK) and Lund (Sweden). Data were summarised in meta-analyses. Serum levels of functional Dkk-1 and sclerostin were measured and studied in relation to genotypes. Results In the first cohort, six Dkk-1, three Sost, one Kremen-1 and 10 LRP-5 SNPs were significantly associated with radiological progression of joint destruction. Three Dkk-1 SNPs were associated significantly with progression of joint damage in the meta-analysis, also after correction for multiple testing (rs1896368, rs1896367 and rs1528873). Two Sost SNPs tended to significance (rs4792909 and rs6503475, p=0.07 after false discovery rate correction). Gene-gene interactions between SNPs on Dkk-1 and Sost were seen. Serum levels of Dkk-1 were significantly correlated with the genotypes in rs1896368 (p=0.02). Conclusions Patients with RA carrying risk alleles of genetic variants in Dkk-1 have higher serum levels of functional Dkk-1 and more progressive joint destruction over time.
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| 15. |
- López-Isac, Elena, et al.
(author)
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Brief Report : IRF4 Newly Identified as a Common Susceptibility Locus for Systemic Sclerosis and Rheumatoid Arthritis in a Cross-Disease Meta-Analysis of Genome-Wide Association Studies
- 2016
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In: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 68:9, s. 2338-2344
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Journal article (peer-reviewed)abstract
- Objective: Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that have similar clinical and immunologic characteristics. To date, several shared SSc–RA genetic loci have been identified independently. The aim of the current study was to systematically search for new common SSc–RA loci through an interdisease meta–genome-wide association (meta-GWAS) strategy. Methods: The study was designed as a meta-analysis combining GWAS data sets of patients with SSc and patients with RA, using a strategy that allowed identification of loci with both same-direction and opposite-direction allelic effects. The top single-nucleotide polymorphisms were followed up in independent SSc and RA case–control cohorts. This allowed an increase in the sample size to a total of 8,830 patients with SSc, 16,870 patients with RA, and 43,393 healthy controls. Results: This cross-disease meta-analysis of the GWAS data sets identified several loci with nominal association signals (P < 5 × 10−6) that also showed evidence of association in the disease-specific GWAS scans. These loci included several genomic regions not previously reported as shared loci, as well as several risk factors that were previously found to be associated with both diseases. Follow-up analyses of the putatively new SSc–RA loci identified IRF4 as a shared risk factor for these 2 diseases (Pcombined = 3.29 × 10−12). Analysis of the biologic relevance of the known SSc–RA shared loci identified the type I interferon and interleukin-12 signaling pathways as the main common etiologic factors. Conclusion: This study identified a novel shared locus, IRF4, for the risk of SSc and RA, and highlighted the usefulness of a cross-disease GWAS meta-analysis strategy in the identification of common risk loci.
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| 16. |
- van Steenbergen, Hanna W., et al.
(author)
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A genetic study on C5-TRAF1 and progression of joint damage in rheumatoid arthritis
- 2015
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In: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 17
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Journal article (peer-reviewed)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 x 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 x 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.
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| 17. |
- de Rooy, Diederik P C, et al.
(author)
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Loss of metacarpal bone density predicts RA development in recent-onset arthritis
- 2012
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In: Rheumatology. - : Oxford University Press (OUP): Policy B. - 1462-0324 .- 1462-0332. ; 51:6, s. 1037-1041
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Journal article (peer-reviewed)abstract
- Objective. Serum samples taken before the onset of RA suggest that one of the first features of RA is BMD loss. We determined the ability of radiographic BMD loss to predict RA development and arthritis persistency in patients with early undifferentiated arthritis (UA). less thanbrgreater than less thanbrgreater thanMethods. Five hundred and seventeen patients with early UA, included in the Leiden Early Arthritis Clinic, were assessed. Of these, 101 had hand radiographs made at first visit as well as after 6 months. BMD loss was measured using digital X-ray radiogrammetry (DXR) online. The outcome measures fulfilled the 1987 ACR criteria for RA after 1 year and arthritis persistency during a mean follow-up of 7 years. Additionally, it was assessed whether BMD measurements improved predictions compared with a validated prediction rule. less thanbrgreater than less thanbrgreater thanResults. A total of 53.8% of UA patients developed RA and 67.5% had persistent disease after 7 years follow-up. Highly elevated BMD loss (epsilon 2.5 mg/cm(2)/month) was present in 16.3% of patients and associated with RA development [odds ratio (OR) 6.1, 95% CI 1.2, 29.2, positive predictive value (PPV) 85%, negative predictive value (NPV) 52%, sensitivity 26%, specificity 95%]. BMD loss may have an independent effect of anti-CCP when tested in a logistic regression analysis (OR 4.1, 95% CI 0.8, 21.2), although the CI is large. All UA patients that were unclassified with the prediction rule and had highly elevated BMD loss progressed to RA. BMD loss was not significantly associated with arthritis persistency (HR = 0.56, 95% CI 0.14, 2.29). less thanbrgreater than less thanbrgreater thanConclusion. Present data suggest that BMD loss predicts RA development. These findings need to be verified in larger studies.
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