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M C Cénit,
C P Simeón,
V Fonollosa,
G Espinosa,
E Beltrán,
L Sáez-Comet,
E Vicente-Rabaneda,
F J García-Hernández,
L Martínez-Estupiñán,
M Rodríguez-Carballeira, [......],
F J Narváez, A Pros,
M Gallego,
R Ríos-Fernández,
M T Camps,
A Fernández-Nebro,
M V Egurbide,
P Carreira,
M A González-Gay,
J Martín
[show abstract]
[hide abstract]
ABSTRACT: Systemic sclerosis (SSc) is a complex autoimmune disease which genetic component has not been yet completely understood. IL6 encodes a cytokine with a crucial role in the development of autoimmunity and fibrosis and its actions mainly are controlled by IL-6 receptor (IL-6R). We aimed to investigate whether the functional genetic variants rs8192284 and rs2228044 previously associated with several autoimmune diseases, located within the IL-6 receptor (IL-6R) subunits IL6R and IL6ST genes, respectively, are involved in the susceptibility to SSc and/or its major clinical subphenotypes. A Spanish cohort including 1013 SSc patients and 1375 controls was genotyped using the TaqMan® allelic discrimination technology. SSc patients were subdivided according to the major clinical forms, autoantibody status and presence of fibrotic lung affection. Our data showed no influence of the selected variants in global SSc susceptibility (rs8192284: P=0.67, odds ratios (OR)=0.98; rs2228044: P=0.99, OR=1.00). Similarly, the clinical/autoantibody subphenotype analyses did not yielded significant results. Our data suggest that the analyzed polymorphisms may not play a significant role in the SSc susceptibility.
Tissue Antigens 06/2012; 80(3):254-8. · 2.59 Impact Factor
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L M Diaz-Gallo,
P Gourh,
J Broen,
C Simeon,
V Fonollosa,
N Ortego-Centeno,
S Agarwal,
M C Vonk,
M Coenen,
G Riemekasten, [......],
G Espinosa,
I Castellvi,
T Witte,
F de Keyser,
M Vanthuyne,
M D Mayes,
T R D J Radstake,
F C Arnett,
J Martin,
B Rueda
[show abstract]
[hide abstract]
ABSTRACT: Two functional single nucleotide polymorphisms (SNP) in the PTPN22 gene (rs24746601 and rs33996649) have been associated with autoimmunity. The aim of this study was to investigate the role of the R263Q SNP for the first time and to re-evaluate the role of the R620W SNP in the genetic predisposition to systemic sclerosis (SSc) susceptibility and clinical phenotypes.
3422 SSc patients (2020 with limited cutaneous SSc and 1208 with diffuse cutaneous SSc) and 3638 healthy controls of Caucasian ancestry from an initial case--control set of Spain and seven additional independent replication cohorts were included in our study. Both rs33996649 and rs2476601 PTPN22 polymorphisms were genotyped by TaqMan allelic discrimination assay. A meta-analysis was performed to test the overall effect of these PTPN22 polymorphisms in SSc.
The meta-analysis revealed evidence of association of the rs2476601 T allele with SSc susceptibility (p(FDRcorrected)=0.03 pooled, OR 1.15, 95% CI 1.03 to 1.28). In addition, the rs2476601 T allele was significantly associated with anticentromere-positive status (p(FDRcorrected)=0.02 pooled, OR 1.22, 95% CI 1.05 to 1.42). Although the rs33996649 A allele was significantly associated with SSc in the Spanish population (p(FDRcorrected)=0.04, OR 0.58, 95% CI 0.36 to 0.92), this association was not confirmed in the meta-analysis (p=0.36 pooled, OR 0.89, 95% CI 0.72 to 1.1).
The study suggests that the PTPN22 R620W polymorphism influences SSc genetic susceptibility but the novel R263Q genetic variant does not. These data strengthen evidence that the R620W mutation is a common risk factor in autoimmune diseases.
Annals of the rheumatic diseases 03/2011; 70(3):454-62. · 8.11 Impact Factor
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L Bossini-Castillo,
JCA Broen,
C Simeon,
L Beretta,
M Vonk,
N Ortego-Centeno,
G Espinosa,
P Carreira,
M Camps,
N Navarrete, [......],
P Airó,
R Scorza,
van Laar J,
N Hunzelmann,
A Kreuter,
A Herrick,
J Worthington,
TRDJ Radstake,
J Martín,
B Rueda
Journal of Translational Medicine. 01/2010;
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B Rueda,
J Broen,
C Simeon,
R Hesselstrand,
B Diaz,
H Suárez,
N Ortego-Centeno,
G Riemekasten,
V Fonollosa,
M C Vonk, [......],
M A Gonzalez-Gay,
M J H Coenen,
P Airo,
L Beretta,
R Scorza,
J van Laar,
M F Gonzalez-Escribano,
J L Nelson,
T R D J Radstake,
J Martin
[show abstract]
[hide abstract]
ABSTRACT: The aim of this study was to investigate the possible role of STAT4 gene in the genetic predisposition to systemic sclerosis (SSc) susceptibility or clinical phenotype. A total of 1317 SSc patients [896 with limited cutaneous SSc (lcSSc) and 421 with diffuse cutaneous SSc (dcSSc)] and 3113 healthy controls, from an initial case-control set of Spanish Caucasian ancestry and five independent cohorts of European ancestry (The Netherlands, Germany, Sweden, Italy and USA), were included in the study. The rs7574865 polymorphism was selected as STAT4 genetic marker. We observed that the rs7574865 T allele was significantly associated with susceptibility to lcSSc in the Spanish population [P = 1.9 x 10(-5) odds ratio (OR) 1.61 95% confidence intervals (CI) 1.29-1.99], but not with dcSSc (P = 0.41 OR 0.84 95% CI 0.59-1.21). Additionally, a dosage effect was observed showing individuals with rs7574865 TT genotype higher risk for lcSSc (OR 3.34, P = 1.02 x 10(-7) 95% CI 2.11-5.31). The association of the rs7574865 T allele with lcSSc was confirmed in all the replication cohorts with different effect sizes (OR ranging between 1.15 and 1.86), as well as the lack of association of STAT4 with dcSSc. A meta-analysis to test the overall effect of the rs7574865 polymorphism showed a strong risk effect of the T allele for lcSSc susceptibility (pooled OR 1.54 95% CI 1.36-1.74; P < 0.0001). Our data show a strong and reproducible association of the STAT4 gene with the genetic predisposition to lcSSc suggesting that this gene seems to be one of the genetic markers influencing SSc phenotype.
Human Molecular Genetics 04/2009; 18(11):2071-7. · 7.64 Impact Factor
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B Rueda,
C Simeon,
R Hesselstrand,
A Herrick,
J Worthington,
N Ortego-Centeno,
G Riemekasten,
V Fonollosa,
M C Vonk,
F H J van den Hoogen, [......],
R García-Portales, A Pros,
M T Camps,
M A Gonzalez-Gay,
M F Gonzalez-Escribano,
M J Coenen,
N Lambert,
J L Nelson,
T R D J Radstake,
J Martin
[show abstract]
[hide abstract]
ABSTRACT: To conduct a replication study to investigate whether the -945 CTGF genetic variant is associated with systemic sclerosis (SSc) susceptibility or specific SSc phenotype.
The study population comprised 1180 patients with SSc and 1784 healthy controls from seven independent case-control sets of European ancestry (Spanish, French, Dutch, German, British, Swedish and North American). The -945 CTGF genetic variant was genotyped using a Taqman 5' allelic discrimination assay.
An independent association study showed in all the case-control cohorts no association of the CTGF -945 polymorphism with SSc susceptibility. These findings were confirmed by a meta-analysis giving a pooled OR = 1.12 (95% CI 0.99 to 1.25), p = 0.06. Investigation of the possible contribution of the -945 CTGF genetic variant to SSc phenotype showed that stratification according to SSc subtypes (limited or diffuse), selective autoantibodies (anti-topoisomerase I or anticentromere) or pulmonary involvement reached no statistically significant skewing.
The results do not confirm previous findings and suggest that the CTGF -945 promoter polymorphism does not play a major role in SSc susceptibility or clinical phenotype.
Annals of the rheumatic diseases 01/2009; 68(10):1618-20. · 8.11 Impact Factor
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B Rueda,
J Broen,
O Torres,
C Simeon,
N Ortego-Centeno,
M M V A P Schrijvenaars,
M C Vonk,
V Fonollosa,
F H J van den Hoogen,
M J H Coenen,
J Sanchez-Román,
M A Aguirre-Zamorano,
R García-Portales, A Pros,
M T Camps,
M A Gonzalez-Gay,
J Martin,
T R D J Radstake
[show abstract]
[hide abstract]
ABSTRACT: Multiple studies indicate the role of the interleukin (IL)-17/IL-23 axis in autoimmune diseases, including systemic sclerosis (SSc). The aim of the current study was to investigate the possible implication of the IL23R gene in SSc susceptibility and/or clinical phenotype.
An initial case-control study in 143 Dutch patients with SSc and geographically matched healthy individuals (n = 246) was carried out and followed by a replication study in a cohort of 365 Spanish patients with SSc and 515 healthy individuals. Seven single nucleotide polymorphisms (SNPs) spanning the IL23R gene were selected and genotyped using a Taqman assay.
Using a Dutch cohort of patients with SSc and controls we observed an association between two (rs11209032, rs1495965) of the seven tested SNPs and disease susceptibility (allelic p values: p = 0.02 and p = 0.01 respectively). However, a replication study in an independent Spanish cohort did not confirm these findings and reveal no association of any of the IL23R-tested SNP with disease susceptibility or clinical phenotype. Similarly, a meta-analysis considering both populations did not reveal any significant association. In addition, no association was observed between IL23R genetic variants and SSc clinical phenotypes.
Our results suggest that the IL23R gene is not associated with SSc susceptibility or clinical phenotype.
Annals of the rheumatic diseases 09/2008; 68(2):253-6. · 8.11 Impact Factor
