A rare polymorphism in the gene for Toll-like receptor 2 is associated with systemic sclerosis phenotype and increases the production of inflammatory mediators.

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Publication year
2012Author(s)
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Arthritis and Rheumatism, 64, 1, (2012), pp. 264-71ISSN
Annotation
01 januari 2012
Publication type
Article / Letter to editor

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Organization
Rheumatology
Human Genetics
Journal title
Arthritis and Rheumatism
Volume
vol. 64
Issue
iss. 1
Page start
p. 264
Page end
p. 71
Subject
IGMD 3: Genomic disorders and inherited multi-system disorders NCEBP 1: Molecular epidemiology; NCEBP 2: Evaluation of complex medical interventions N4i 4: Auto-immunity, transplantation and immunotherapy; NCMLS 1: Infection and autoimmunity N4i 4: Auto-immunity, transplantation and immunotherapyAbstract
OBJECTIVE: To investigate whether polymorphisms in Toll-like receptor (TLR) genes, previously reported to be associated with immune-mediated diseases, are involved in systemic sclerosis (SSc). METHODS: We genotyped 14 polymorphisms in the genes for TLRs 2, 4, 7, 8, and 9 in a discovery cohort comprising 452 SSc patients and 537 controls and a replication cohort consisting of 1,170 SSc patients and 925 controls. In addition, we analyzed 15-year followup data on 964 patients to assess the potential association of TLR variants with the development of disease complications. We analyzed the functional impact of the associated polymorphism on monocyte-derived dendritic cells. RESULTS: In the discovery cohort, we observed that a rare functional polymorphism in TLR2 (Pro631His) was associated with antitopoisomerase (antitopo) positivity (odds ratio 2.24 [95% confidence interval 1.24-4.04], P=0.003). This observation was validated in the replication cohort (odds ratio 2.73 [95% confidence interval 1.85-4.04], P=0.0001). In addition, in the replication cohort the TLR2 variant was associated with the diffuse subtype of the disease (P=0.02) and with the development of pulmonary arterial hypertension (PAH) (Cox proportional hazards ratio 5.61 [95% confidence interval 1.53-20.58], P=0.003 by log rank test). Functional analysis revealed that monocyte-derived dendritic cells carrying the Pro63His variant produced increased levels of inflammatory mediators (tumor necrosis factor alpha and interleukin-6) upon TLR-2-mediated stimulation (both P<0.0001). CONCLUSION: Among patients with SSc, the rare TLR2 Pro631His variant is robustly associated with antitopoisomerase positivity, the diffuse form of the disease, and the development of PAH. In addition, this variant influences TLR-2-mediated cell responses. Further research is needed to elucidate the precise role of TLR-2 in the pathogenesis of SSc.
This item appears in the following Collection(s)
- Academic publications [205106]
- Electronic publications [103309]
- Faculty of Medical Sciences [81055]
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