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Evaluation of three different polymorphisms of PTPN22 in rheumatoid arthritis
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Objectives To compare the associations of three SNPs (rs3811021, rs2476601 (1858C/T) and rs2488457 (-1123G/C)) of the PTPN22 gene: in patients with RA and to analyse functional properties of the 1858T allele.

Methods A total of 769 consecutively included patients with early RA and 1054 population-based matched controls were genotyped for the rs3811021, rs2476601, and rs2488457 polymorphisms using a TaqMan instrument.  T-lymphocytes from RA patients, SLE patients and controls, heterozygous for the +1858T allele were compared with cells homozygous for +1858C. The T-cells were cultivated in the presence or absence of either PMA/Ionomycine or antibodies to CD3ε and CD28. Cell activation was quantified by measuring levels of interleukin-2 produced using an ELISA.

Results The -1123C and 1858T alleles were associated with RA (OR=1.35(1.14-1.60), p=0.0004 and OR=1.65(1.35-2.01), p=3x10-6, respectively). These associations, together with a haplotype containing both risk alleles, retained statistical significance after conducting a permutation test. The SNPs -1123G/C and 1858C/T were in strong linkage disequilibrium (LD), however, the 1858T allele was mainly associated with HLA-SE, IgM-RF or ACPA positive RA whereas the -1123C allele was associated regardless of any stratification of the patient group. Patients having both -1123C and 1858T had significantly higher frequency of HLA-SE (OR=2.03(1.29-3.19)) and ACPA (OR=2.21(1.38-3.53)) compared with patients having -1123C but not 1858T. In the functional study, the 1858T allele was not shown to increase the negative regulation of T-lymphocyte activation compared with 1858C in either patients or controls.

Conclusions The true association with RA was seen with the 1858T allele. The -1123C allele was only associated with RA through being in LD with the 1858T allele. The 1858T allele was associated with HLA-SE positive and ACPA positive RA whereas the -1123C allele was associated regardless of stratification.  The proposed function of the 1858T allele could not be shown using this experimental protocol.

Keyword [en]
Rheumatoid arthritis, PTPN22, SNP, 1858T, -1123C. haplotype, functional study, T-lymphocyte
National Category
Rheumatology and Autoimmunity
Research subject
Medicine
Identifiers
URN: urn:nbn:se:umu:diva-30387OAI: oai:DiVA.org:umu-30387DiVA: diva2:282537
Available from: 2009-12-21 Created: 2009-12-21 Last updated: 2011-01-18Bibliographically approved
In thesis
1. Systemic lupus erythematosus and rheumatoid arthritis: analyses of candidate genes involved in immune functions, for susceptibility and severity
Open this publication in new window or tab >>Systemic lupus erythematosus and rheumatoid arthritis: analyses of candidate genes involved in immune functions, for susceptibility and severity
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease with systemic manifestations characterized by auto-antibodies directed against different parts of the cell nucleus including DNA, histones and ribosomes. The systemic inflammation can cause damage to multiple organs, e.g., kidneys, skin, heart, lungs and the nervous system. Rheumatoid arthritis (RA) is another autoimmune rheumatic disease characterized by auto-antibodies, mainly directed against the Fc-part of immunoglobulin G (rheumatoid factor (RF)) but also against citrullinated peptides/proteins (ACPAs). The inflammation in RA primarily involves the joints resulting in inflamed synovial tissue and destruction of cartilage. The aetiology of both SLE and RA is unclear but there is a genetic contribution predominantly of genes involved in inflammation. The diseases are believed to be multifactorial, or complex, meaning that multiple genes interact with environmental, infectious and hormonal factors, thus increasing the risk of developing disease.

The aim of this study was to investigate different candidate genes involved in functions of the immune system and their relationship with SLE and RA susceptibility and severity.

The patients and controls were from the four northernmost counties of Sweden, which is a fairly homogenous population well suited for genetic studies. Two single nucleotide polymorphisms (SNPs) in the oestrogen receptor α (ESR1) gene were analysed in SLE. No association was found between the SNPs and SLE per se however the minor alleles (PvuII C and XbaI G) were associated with skin manifestations and later disease onset, thus representing a milder form of the disease. A SNP in the programmed cell-death 1 (PDCD1) gene, which codes for PD-1, an inhibitory molecule involved in T-cell activation, was studied. No association was seen between the risk allele (PD-1.3A) and SLE susceptibility but a strong association was found with renal disease. A risk allele of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene that codes for a protein called Lyp which acts as a negative regulator of T-cell receptor (TCR) signalling was significantly associated with SLE in three different case-control sets across Sweden. Both PDCD1 and PTPN22 were independently associated with renal disease. The PTPN22 gene has been associated with numerous autoimmune diseases and was evaluated in another auto-antibody producing disease, RA. From the Medical Biobank of northern Sweden samples donated before the development of symptoms of RA were identified. In these individuals, who subsequently developed RA, the 1858T risk allele in combination with ACPAs gave a high relative risk (>132) for developing RA. The association between PTPN22 and RA was confirmed in a larger material of patients with early RA. The 1858T allele, of the three SNPs investigated, was shown to be the true risk allele associated with auto-antibody positive RA. A functional role of PTPN22 in TCR-mediated activation of T cells from patients with SLE and RA was not demonstrated.

In conclusion, minor alleles of two SNPs in the ESR1 gene were associated with a milder form of SLE. The risk allele in the PDCD1 gene was associated with renal disorder in SLE. The risk allele 1858T of the PTPN22 gene was associated with SLE, particularly with renal disease. The 1858T allele in combination with auto-antibodies was a risk factor for developing RA. In early diagnosed RA, the 1858T allele was highly associated with RA and in particular with auto-antibody positive RA.

Place, publisher, year, edition, pages
Umeå: Umeå university, 2010. 76 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1310
Keyword
SLE, RA, oestrogen, renal disorder, ESR1, PDCD1, PTPN22, association, severity
National Category
Rheumatology and Autoimmunity
Research subject
Medicine
Identifiers
urn:nbn:se:umu:diva-30388 (URN)978-91-7264-896-8 (ISBN)
Public defence
2010-01-22, Sal B, 9 trappor, Byggnad 1D, Norrlands Universitetssjukhus, Umeå, Sal B, 9 trappor, Byggnad 1D, Norrlands Universitetssjukhus, Umeå, 09:00 (Swedish)
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Available from: 2010-01-05 Created: 2009-12-21 Last updated: 2010-01-05Bibliographically approved

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