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

被引：73

作者：

Broen, J. C. A.

Bossini-Castillo, L. ^{[2
]}

van Bon, L.

Vonk, M. C.

Knaapen, H.

Beretta, L. ^{[3
,4
]}

Rueda, B. ^{[2
]}

Hesselstrand, R. ^{[5
]}

Herrick, A. ^{[6
,7
]}

Worthington, J. ^{[6
,7
]}

Hunzelman, N. ^{[8
]}

Denton, C. P. ^{[9
]}

Fonseca, C. ^{[9
]}

Riemekasten, G. ^{[10
,11
]}

Kiener, H. P. ^{[12
]}

Scorza, R. ^{[3
,4
]}

Simeon, C. P. ^{[13
]}

Ortego-Centeno, N. ^{[14
]}

Gonzalez-Gay, M. A. ^{[15
]}

Airo, P. ^{[16
]}

Coenen, M. J. H.

Martin, J. ^{[2
]}

Radstake, T. R. D. J. ^{[1
]}

机构：

[1] Radboud Univ Nijmegen, Dept Rheumatol, Med Ctr, NL-6500 HB Nijmegen, Netherlands

[2] CSIC, Inst Parasitol & Biomed, Granada, Spain

[3] Univ Milan, Milan, Italy

[4] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Milan, Italy

[5] Lund Univ, Lund, Sweden

[6] Univ Manchester, Manchester, Lancs, England

[7] Salford Royal NHS Fdn Trust, Salford, Lancs, England

[8] Univ Cologne, D-50931 Cologne, Germany

[9] Royal Free & Univ Coll Med Sch, London WC1E 6BT, England

[10] German Rheumatism Res Ctr, Berlin, Germany

[11] Charite, Berlin, Germany

[12] Med Univ Vienna, Vienna, Austria

[13] Hosp Valle de Hebron, Barcelona, Spain

[14] Hosp Univ Cent Asturias, Oviedo, Spain

[15] Hosp Univ Marques de Valdecilla, IFIMAV, Santandor, Spain

[16] Spedali Civil Brescia, I-25125 Brescia, Italy

来源：

ARTHRITIS AND RHEUMATISM | 2012年 / 64卷 / 01期

关键词：

DISEASE; SUSCEPTIBILITY; SCLERODERMA; ANTIBODIES; TLR7; TOLL-LIKE-RECEPTOR-4; EXPRESSION; MUTATIONS; ARTHRITIS; ASTHMA;

D O I：

10.1002/art.33325

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

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.

引用

页码：264 / 271

页数：8

共 34 条

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