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.
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 α and interleukin-6) upon TLR-2-mediated stimulation (both P<0.0001).
  
  
  CONCLUSIONS
  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.
authors: Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors: J C A
authors: JC
authors: Broen
authors: L
authors: L
authors: Bossini-Castillo
authors: L
authors: L
authors: van Bon
authors: M C
authors: MC
authors: Vonk
authors: H
authors: H
authors: Knaapen
authors: L
authors: L
authors: Beretta
authors: B
authors: B
authors: Rueda
authors: R
authors: R
authors: Hesselstrand
authors: A
authors: A
authors: Herrick
authors: J
authors: J
authors: Worthington
authors: N
authors: N
authors: Hunzelman
authors: C P
authors: CP
authors: Denton
authors: C
authors: C
authors: Fonseca
authors: G
authors: G
authors: Riemekasten
authors: H P
authors: HP
authors: Kiener
authors: R
authors: R
authors: Scorza
authors: C P
authors: CP
authors: Simeón
authors: N
authors: N
authors: Ortego-Centeno
authors: M A
authors: MA
authors: Gonzalez-Gay
authors: P
authors: P
authors: Airò
authors: M J H
authors: MJ
authors: Coenen
authors: J
authors: J
authors: Martín
authors: T R D J
authors: TR
authors: Radstake
mesh_terms: D015331:Cohort Studies; D015897:Comorbidity; D003713:Dendritic Cells / Q000378:metabolism; D005060:Europe / Q000453:epidemiology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006976:Hypertension, Pulmonary / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D009000:Monocytes / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011651:Pulmonary Artery / Q000503:physiopathology; D012595:Scleroderma, Systemic / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha