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

Broen, J. C. A.; Bossini-Castillo, L.; van Bon, L.; Vonk, M. C.; Knaapen, H.; Beretta, L.; Rueda, B.; Hesselstrand, Roger; Herrick, A.; Worthington, J.; Hunzelman, N.; Denton, C. P.; Fonseca, C.; Riemekasten, G.; Kiener, H. P.; Scorza, R.; Simeon, C. P.; Ortego-Centeno, N.; Gonzalez-Gay, M. A.; Airo, P.; Coenen, M. J. H.; Martin, J.; Radstake, T. R. D. J.

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

Mark

Broen, J. C. A. ; Bossini-Castillo, L. ; van Bon, L. ; Vonk, M. C. ; Knaapen, H. ; Beretta, L. ; Rueda, B. ; Hesselstrand, Roger ^LU ; Herrick, A. and Worthington, J. , et al. (2012) In Arthritis and Rheumatism 64(1). p.264-271

Abstract: 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... (More); 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. (Less)

Please use this url to cite or link to this publication: https://lup.lub.lu.se/record/2355037

author

Broen, J. C. A. ; Bossini-Castillo, L. ; van Bon, L. ; Vonk, M. C. ; Knaapen, H. ; Beretta, L. ; Rueda, B. ; Hesselstrand, Roger ^LU ; Herrick, A. and Worthington, J. , et al. (More)

Broen, J. C. A. ; Bossini-Castillo, L. ; van Bon, L. ; Vonk, M. C. ; Knaapen, H. ; Beretta, L. ; Rueda, B. ; Hesselstrand, Roger ^LU ; Herrick, A. ; Worthington, J. ; Hunzelman, N. ; Denton, C. P. ; Fonseca, C. ; Riemekasten, G. ; Kiener, H. P. ; Scorza, R. ; Simeon, C. P. ; Ortego-Centeno, N. ; Gonzalez-Gay, M. A. ; Airo, P. ; Coenen, M. J. H. ; Martin, J. and Radstake, T. R. D. J. (Less)

organization

Rheumatology

publishing date

2012

type

Contribution to journal

publication status

published

subject

Rheumatology and Autoimmunity

in

Arthritis and Rheumatism

volume

64

issue

1

pages

264 - 271

publisher

John Wiley & Sons Inc.

external identifiers

wos:000298598100032
scopus:84855281875
pmid:21905008

ISSN

1529-0131

DOI

10.1002/art.33325

language

English

LU publication?

yes

id

8d53e17a-1c1a-40b8-b08f-1da53588d85a (old id 2355037)

date added to LUP

2016-04-01 11:16:42

date last changed

2022-04-20 18:24:21

@article{8d53e17a-1c1a-40b8-b08f-1da53588d85a,
  abstract     = {{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 &lt; 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.}},
  author       = {{Broen, J. C. A. and Bossini-Castillo, L. and van Bon, L. and Vonk, M. C. and Knaapen, H. and Beretta, L. and Rueda, B. and Hesselstrand, Roger and Herrick, A. and Worthington, J. and Hunzelman, N. and Denton, C. P. and Fonseca, C. and Riemekasten, G. and Kiener, H. P. and Scorza, R. and Simeon, C. P. and Ortego-Centeno, N. and Gonzalez-Gay, M. A. and Airo, P. and Coenen, M. J. H. and Martin, J. and Radstake, T. R. D. J.}},
  issn         = {{1529-0131}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{264--271}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Arthritis and Rheumatism}},
  title        = {{A rare polymorphism in the gene for Toll-like receptor 2 is associated with systemic sclerosis phenotype and increases the production of inflammatory mediators}},
  url          = {{http://dx.doi.org/10.1002/art.33325}},
  doi          = {{10.1002/art.33325}},
  volume       = {{64}},
  year         = {{2012}},
}

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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