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

AuthorsBroen, Jasper C.; Bossini-Castillo, L.; Bon, Lenny van; Vonk, Madelon C.; Knaapen, Hanneke; Beretta, L.; Rueda, B.; Hesselstrand, R.; Herrick, A.; Worthington, J.; Hunzelmann, Nicolas; Denton, C.; Fonseca, C.; Riemekasten, G.; Kiener, H. P; Scorza, R.; Simeón, Carmen P.; Ortego-Centeno, N.; González-Gay, M. A.; Airó, Paolo; Coenen, M. J.; Martín, J.; Radstake, T. R.
Issue Date2012
PublisherJohn Wiley & Sons
CitationArthritis and Rheumatism 64: 264- 271 (2012)
AbstractObjective 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 α 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. © 2012 by the American College of Rheumatology.
Identifiersdoi: 10.1002/art.33325
issn: 0004-3591
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