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The PTPN22 1858C/T polymorphism is associated with anti-cyclic citrullinated peptide antibody-positive early rheumatoid arthritis in northern Sweden
Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk immunologi.
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2007 (Engelska)Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 9, nr 5, s. 403-Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The PTPN22 1858C/T polymorphism has been associated with several autoimmune diseases including rheumatoid arthritis (RA). We have shown that carriage of the T variant (CT or TT) of PTPN22 in combination with anti-cyclic citrullinated peptide (anti-CCP) antibodies highly increases the odds ratio for developing RA. In the present study we analysed the association between the PTPN22 1858C/T polymorphism and early RA in patients from northern Sweden, related the polymorphism to autoantibodies and the HLA-DR shared epitope, and analysed their association with markers for disease activity and progression. The inception cohort includes individuals who also donated samples before disease onset. A case-control study was performed in patients (n = 505; 342 females and 163 males) with early RA (mean duration of symptoms = 6.3 months) and in population-based matched controls (n = 970) from northern Sweden. Genotyping of the PTPN22 1858C/T polymorphism was performed using a TaqMan instrument. HLA-shared epitope alleles were identified using PCR sequence-specific primers. Anti-CCP2 antibodies were determined using enzyme-linked immunoassays. Disease activity (that is, the number of swollen and tender joints, the global visual analogue scale, and the erythrocyte sedimentation rate) was followed on a regular basis (that is, at baseline and after 6, 12, 18 and 24 months). Both the 1858T allele and the carriage of T were associated with RA (chi2 = 23.84, P = 0.000001, odds ratio = 1.69, 95% confidence interval = 1.36-2.11; and chi2 = 22.68, P = 0.000002, odds ratio = 1.79, 95% confidence interval = 1.40-2.29, respectively). Association of the 1858T variant with RA was confined to seropositive disease. Carriage of 1858T and the presence of anti-CCP antibodies was independently associated with disease onset at an earlier age (P < 0.05 and P < 0.01, respectively), while the combination of both resulted in an even earlier age at onset. Smoking was identified as a risk factor independent of the 1858T variant and anti-CCP antibodies.

Ort, förlag, år, upplaga, sidor
2007. Vol. 9, nr 5, s. 403-
Nationell ämneskategori
Reumatologi och inflammation
Identifikatorer
URN: urn:nbn:se:umu:diva-21627DOI: 10.1186/ar2312PubMedID: 17553139OAI: oai:DiVA.org:umu-21627DiVA, id: diva2:211381
Anmärkning
Correction: After publication of our recent article [1], we noticed an error in Table 6 'Relative risk for developing rheumatoid arthritis in patients, stratified for anti-cyclic citrullinated peptide (anti-CCP) antibodies'. Under the heading of 'Anti-CCP antibody-positive', the first line should read 'HLA-shared epitope-negative', and the second line should read 'HLA-shared epitope-positive'. Similarly, under the heading 'Anti-CCP antibody-negative', the first line should read 'HLA-shared epitope-negative' and the second line should read 'HLA-shared epitope-positive'.Tillgänglig från: 2009-04-14 Skapad: 2009-04-14 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
Ingår i avhandling
1. Pathogenetic factors of importance for the development and progression of rheumatoid arthritis
Öppna denna publikation i ny flik eller fönster >>Pathogenetic factors of importance for the development and progression of rheumatoid arthritis
2012 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation eventually leading to the destruction of cartilage and bone. The aetiopathogenesis is not completely understood, but previous studies have shown that the disease is multifactorial with genetic, environmental and hormonal factors involved. Immune cells, e.g., T- and B-cells, and macrophages, migrate into the joints, with increased expression of numerous soluble factors such as cytokines, chemokines and adhesion molecules functionally active both locally and systemically. Analyses of blood samples from the Medical Biobank in Umeå from individuals before the onset of symptoms of joint disease showed that anti-citrullinated protein/peptide antibodies (ACPA) preceded the development of disease by years and this finding has been confirmed by other studies.                                        

The aim of this thesis was to identify signs of activation of the immune system analysed as up-regulation of pro- and anti-inflammatory cytokines, sero-positivity for autoantibodies, and genetic factors identified as relevant for the development and disease progression of RA. The concentrations of 30 cytokines and chemokines were measured in blood samples from individuals before the onset of symptoms, and when diagnosed with RA, together with population-based matched controls using a multiplex system. The predictive value of different isotypes (IgG, IgA, and IgM) of ACPA and rheumatoid factor (RF) before onset of symptoms and different types of ACPA (e.g., mutated citrullinated vimentin, MCV) were analysed for disease development and progression in patients with early RA and controls from Northern Sweden. These factors were related to the genetic markers, HLA- shared epitope (SE) alleles and the 1858C/T polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene.                           

In paper I, it was shown that in individuals who later developed RA (i.e., pre-patients) the levels of several cytokines and related factors that represent the adaptive immune system (Th1, Th2, and T regulatory cell related factors) were significantly elevated compared with controls, whereas, after the onset of disease the involvement of the immune system was more general and widespread. In paper II, the presence of different isotypes (IgM, IgA and IgG) of ACPA in pre-patients, patients and controls was evaluated showing that both the IgG and IgA isotype predicted the onset of RA by years with the IgG isotype having the highest predictive value. In paper III, the association of the 1858T variant of PTPN22 with RA was confirmed. Furthermore, the association was restricted to autoantibody positive disease and this variant was correlated with an earlier age for disease onset. In paper IV, anti-MCV antibodies were identified as being associated with a more severe disease course of RA, measured by disease activity score, erythrocyte sedimentation rate, and swollen joint count over time compared with anti-CCP2, anti-CCP3, and anti-CCP3.1 antibodies.                                                                                               

In conclusion, individuals who later developed RA had increased concentrations of inflammatory markers reflecting an activation of the immune system years before the clinical symptoms of the disease developed. Also, the presence of ACPA of IgG and IgA isotype prior to disease onset predicted the development of RA. The PTPN22 1858T variant was associated with sero-positive RA and anti-MCV antibodies were associated with a higher inflammatory activity compared with anti-CCP2, -CCP3 and -CCP3.1 antibodies. These findings together present a possibility to better predict the development and progression of RA.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå Universitet, 2012. s. 80
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1490
Nyckelord
rheumatoid arthritis, cytokines, autoantibodies, isotypes, PTPN22, HLA-SE
Nationell ämneskategori
Reumatologi och inflammation
Forskningsämne
medicin, reumatologi
Identifikatorer
urn:nbn:se:umu:diva-54003 (URN)978-91-7459-403-4 (ISBN)
Disputation
2012-05-03, Sal B, 9 tr, byggnad 1D, Norrlands Universitetssjukhus, Umeå, 09:00 (Engelska)
Opponent
Handledare
Forskningsfinansiär
Vetenskapsrådet, K2003-74XD-14705-01, K2007-52X-20307-01-3, K2008-52X-20611-01-3, K2010-52X-20307-04-3
Tillgänglig från: 2012-04-12 Skapad: 2012-04-11 Senast uppdaterad: 2018-06-08Bibliografiskt granskad

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Kokkonen, HeidiInnala, LenaJidell, ErikRantapää Dahlqvist, Solbritt

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