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- Diaz-Gallo, LM, et al.
(författare)
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Systematic approach demonstrates enrichment of multiple interactions between non-HLA risk variants and HLA-DRB1 risk alleles in rheumatoid arthritis
- 2018
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 77:10, s. 1454-1462
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Tidskriftsartikel (refereegranskat)abstract
- In anti-citrullinated protein antibody positive rheumatoid arthritis (ACPA-positive RA), a particular subset of HLA-DRB1 alleles, called shared epitope (SE) alleles, is a highly influential genetic risk factor. Here, we investigated whether non-HLA single nucleotide polymorphisms (SNP), conferring low disease risk on their own, interact with SE alleles more frequently than expected by chance and if such genetic interactions influence the HLA-DRB1 SE effect concerning risk to ACPA-positive RA.MethodsWe computed the attributable proportion (AP) due to additive interaction at genome-wide level for two independent ACPA-positive RA cohorts: the Swedish epidemiological investigation of rheumatoid arthritis (EIRA) and the North American rheumatoid arthritis consortium (NARAC). Then, we tested for differences in the AP p value distributions observed for two groups of SNPs, non-associated and associated with disease. We also evaluated whether the SNPs in interaction with HLA-DRB1 were cis-eQTLs in the SE alleles context in peripheral blood mononuclear cells from patients with ACPA-positive RA (SE-eQTLs).ResultsWe found a strong enrichment of significant interactions (AP p<0.05) between the HLA-DRB1 SE alleles and the group of SNPs associated with ACPA-positive RA in both cohorts (Kolmogorov-Smirnov test D=0.35 for EIRA and D=0.25 for NARAC, p<2.2e-16 for both). Interestingly, 564 out of 1492 SNPs in consistent interaction for both cohorts were significant SE-eQTLs. Finally, we observed that the effect size of HLA-DRB1 SE alleles for disease decreases from 5.2 to 2.5 after removal of the risk alleles of the two top interacting SNPs (rs2476601 and rs10739581).ConclusionOur data demonstrate that there are massive genetic interactions between the HLA-DRB1 SE alleles and non-HLA genetic variants in ACPA-positive RA.
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- Gronwall, C, et al.
(författare)
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THE RELATIONSHIP BETWEEN DIFFERENT IGG AND IGA ANTI-MODIFIED PROTEIN AUTOANTIBODIES IN RHEUMATOID ARTHRITIS
- 2021
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 206-207
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Seropositive rheumatoid arthritis (RA) is characterized by the presence of rheumatoid factor (RF) and anti-citrullinated protein autoantibodies (ACPA) with different fine-specificities. Yet, other serum anti-modified protein autoantibodies (AMPA), e.g. anti-carbamylated (Carb), anti-acetylated (KAc), and anti-malondialdehyde acetaldehyde (MAA) modified protein antibodies, have been described. By using RA patient single-cell derived monoclonal antibodies we have previously shown that individual ACPA clones recognize small distinct citrulline-containing epitopes giving them extensive multireactivity when these epitopes are found in many peptides and proteins. Moreover, certain CCP2+ multireactive ACPA clones bind also to cabamylated and acetylated autoantigens [1].Objectives:To provide a comprehensive evaluation of serum IgG and IgA autoreactivity to different post-translational modifications in RA.Methods:We analyzed 30 different IgG and IgA AMPA reactivities to modified antigens by ELISA and autoantigen arrays, in N=1985 newly diagnosed RA patients and population controls. The study utilized both previously established (i.e IgG and IgA CCP2; IgG ACPA fine-specificities; IgG anti-Carb fibrinogen and Carb FCS; IgG and IgA Cit/Carb/KAc/Orn(Ac)-vimentin), and novel assays (e.g. IgG anti-MAA and IgG anti-acetylated histones). Association with patient characteristics such as smoking and disease activity were explored. The newly developed assays were also evaluated in SLE disease controls and CCP2+ RA-risk individuals without arthritis.Results:Carb and KAc reactivities by different assays were primarily seen in patients also positive for citrulline-reactivity. Modified vimentin (mod-Vim) peptides were used for direct comparison of different AMPA reactivities, revealing that IgA AMPA recognizing mod-Vim was mainly detected in subsets of patients with high IgG anti-Cit-Vim levels and a history of smoking. IgG acetylation reactivity was mainly detected in a subset of patients with Cit and Carb reactivity. Anti-acetylated histone 2B reactivity was RA-specific and associated with high anti-CCP2 IgG levels, multiple ACPA fine-specificities, and smoking. This reactivity was also found to be present in CCP2+ RA-risk individuals without arthritis. Our data further demonstrate that IgG autoreactivity to MAA was increased in RA compared to controls with highest levels in CCP2+ RA, but was not RA-specific, and showed low correlation with other AMPA. Anti-MAA was instead associated with disease activity and was not significantly increased in CCP2+ individuals at risk of RA. Notably, RA patients could be subdivided into four different subsets based on their AMPA IgG and IgA reactivity profiles.Conclusion:We conclude that autoantibodies exhibiting different patterns of ACPA fine-specificities as well as Carb and KAc reactivity are present in RA and may be derived from multireactive B-cell clones. Anti-Carb and anti-KAc could be considered reactivities within the “Cit-umbrella” similar to ACPA fine-specificities, while MAA is distinctly different.References:[1]Sahlström P, Hansson M, Steen J, Amara K, Titcombe PJ, Forsström B, Stålesen R, Israelsson L, Piccoli L, Lundberg K, Klareskog L, Mueller DL, Catrina AI, Skriner K, Malmström V, Grönwall C. Different Hierarchies of Anti-Modified Protein Autoantibody Reactivities in Rheumatoid Arthritis. Arthritis Rheumatol. 2020 Oct;72(10):1643-1657. PMID: 32501655Caroline Grönwall: None declared, Lisa Liljefors: None declared, Holger Bang Employee of: Employee at ORGENTEC Diagnostika GmbH, Aase Hensvold: None declared, Monika Hansson: None declared, Linda Mathsson-Alm Employee of: Employee at Thermo Fisher Scientific, Lena Israelsson: None declared, Anna Svärd: None declared, Cyril CLAVEL: None declared, Elisabet Svenungsson: None declared, Iva Gunnarsson: None declared, Guy Serre: None declared, Saedis Saevarsdottir: None declared, Alf Kastbom: None declared, Lars Alfredsson: None declared, Vivianne Malmström: None declared, Johan Rönnelid: None declared, Anca Catrina: None declared, Karin Lundberg: None declared, Lars Klareskog: None declared
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- Hagman, J, et al.
(författare)
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THE EFFECT OF UV-B RADIATION EXPOSURE ON THE RISK OF DEVELOPING RHEUMATOID ARTHRITIS
- 2021
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 145-145
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- UV-B radiation has known immunomodulatory properties, but to what extent UV-B radiation exposure might affect the occurrence of rheumatoid arthritis (RA) has been relatively little studied, and with partially contradictory results.Objectives:To investigate the association between sun- and travel habits, as proxy markers for UV-B radiation exposure, and risk of incident RA, overall and by RA subtype.Methods:We performed a matched case-control study of 1151 incident cases with new-onset RA and 2374 population controls from the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study, recruited between 2006 and 2017. The association between sunbathing frequency, solarium use, and frequency of travels to sunnier countries than Sweden (exposures) and risk of RA (outcome) were assessed as odds ratios (OR) with 95 % confidence intervals (CI) through logistic regression, and adjusted for age, sex, residential region, year of study entry, body mass index, education, income, smoking and alcohol consumption. We further assessed effect modification by self-reported skin type, income and education, and by rheumatoid factor (RF) serostatus.Results:Overall, the frequency of sunbathing, and solarium use, were similar among RA cases and controls: ‘never doing sunbathing’ amongst RA cases vs. controls: 22% vs. 21 %, ‘sunbathing daily when possible’: 10% vs. 12%, and solarium use 13% vs. 12%. The proportion of ‘not travelled abroad to a sunnier country than Sweden during the past 5 years’ was higher for RA cases than controls: 27% vs. 23%, and ‘travelling abroad more than once a year’ was less common among RA cases: 15% vs. 20%.Sunbathing frequency was not linked to risk of RA (OR 0.91, 95% CI 0.69-1.20), nor was solarium use (OR 1.07, 95% CI 0.85-1.35). Stratification by skin type revealed no major effect modification, nor did stratification by RF status. In contrast, frequency of travel to sunnier countries than Sweden was inversely associated with RA risk comparing the most to least frequent travelers (OR 0.68, 95% CI 0.54-0.87). When stratified by educational level, this association was confined to individuals with medium (OR 0.69, 95% CI 0.48-0.98) or high (OR 0.60, 95% CI 0.50-0.91) and absent among subjects with low education (OR 1.10, 95% CI 0.56-1.99). No such interaction was observed between travel habits and income.Table 1.RA cases and controls with adjusted odds ratios and confidence intervals for overall risk of RA and by RA serostatus.NOR* for RA (95% CI)Exposure variableRA casesControlsRF+RF-All RARF+RF-SunbathingaNever24949516185refrefrefAt least once a month3988442651241.05 (0.85-1.29)1.07 (0.84-1.36)0.98 (0.72-1.34)At least once a week3767512391301.11 (0.90-1.38)1.07 (0.83-1.37)1.21 (0.88-1.66)Daily12027875430.91 (0.69-1.20)0.86 (0.62-1.20)0.96 (0.64-1.46)TravelbNever314537208103refrefRefSeldom294568193970.98 (0.79-1.21)0.98 (0.77-1.25)0.98 (0.71-1.35)Once a year3598052271210.82 (0.67-1.01)0.80 (0.63-1.02)0.83 (0.61-1.13)More than once a year176463112610.68 (0.54-0.87)0.68 (0.51-0.91)0.70 (0.48-1.01)SolariumcNever9912083634336refrefRefOnce per year or more153290107461.07 (0.85-1.35)1.08 (0.83-1.40)1.11 (0.77-1.59)OR = adjusted odds ratio, CI = confidence interval, N = number of participants, RA = rheumatoid arthritis, ref = reference, RF= rheumatoid factor. a Frequency of sunbathing if the weather invites to it? b Frequency of travels to a country sunnier than Sweden in the last 5 years? c Frequency of solarium use in the last 5 years? *Adjusting for age, sex, region, index year, BMI, smoking, alcohol consumption, education level and income. <4 % of data was missing for all variables.Conclusion:Proxy markers for UV-B exposure (sunbathing frequency and solarium use within the past five years) do not seem to be strong risk factors for RA. Frequency of travels abroad was inversely associated to RA risk. The nature behind this association remains unclear.Disclosure of Interests:Johanna Hagman: None declared, Bénédicte Delcoigne: None declared, Lars Klareskog: None declared, Lars Alfredsson: None declared, Johan Askling Grant/research support from: JA acts or has acted as PI for agreements between Karolinska Institutet and the following entities, mainly in the context of the ARTIS national safety monitoring programme of immunomodulators in rheumatology: Abbvie, BMS, Eli Lilly, Merck, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB Pharma
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