Carmen P Simeon

Hospital Valle Del Nalon, Rianxo, Galicia, Spain

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Publications (95)500.85 Total impact

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    ABSTRACT: TYK2 is a common genetic risk factor for several autoimmune diseases. This gene encodes a protein kinase involved in interleukin 12 (IL-12) pathway, which is a well-known player in the pathogenesis of systemic sclerosis (SSc). Therefore, we aimed to assess the possible role of this locus in SSc. This study comprised a total of 7103 patients with SSc and 12 220 healthy controls of European ancestry from Spain, USA, Germany, the Netherlands, Italy and the UK. Four TYK2 single-nucleotide polymorphisms (V362F (rs2304256), P1104A (rs34536443), I684S (rs12720356) and A928V (rs35018800)) were selected for follow-up based on the results of an Immunochip screening phase of the locus. Association and dependence analyses were performed by the means of logistic regression and conditional logistic regression. Meta-analyses were performed using the inverse variance method. Genome-wide significance level was reached for TYK2 V362F common variant in our pooled analysis (p=3.08×10(-13), OR=0.83), while the association of P1104A, A928V and I684S rare and low-frequency missense variants remained significant with nominal signals (p=2.28×10(-3), OR=0.80; p=1.27×10(-3), OR=0.59; p=2.63×10(-5), OR=0.83, respectively). Interestingly, dependence and allelic combination analyses showed that the strong association observed for V362F with SSc, corresponded to a synthetic association dependent on the effect of the three previously mentioned TYK2 missense variants. We report for the first time the association of TYK2 with SSc and reinforce the relevance of the IL-12 pathway in SSc pathophysiology. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Full-text · Article · Sep 2015 · Annals of the rheumatic diseases
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    ABSTRACT: Objectives: The current knowledge of the influence of systemic sclerosis (SSc) risk loci in the clinical sub-phenotypes is still limited. The main limitation lies in the low frequency of some sub-phenotypes which could be solved by replication studies in independent cohorts and meta-analysis between studies. In this regard, CCR6 gene variants have been recently associated with anti-topoisomerase I positive (ATA+) production in SSc patients in a candidate gene study. This gene has been proposed to have a critical role in IL-17-driven autoimmunity in human diseases. Methods: In order to confirm the association between CCR6 and ATA+ SSc patients, we performed an independent replication study in populations of European ancestry. We studied two CCR6 genetic variants (rs968334 and rs3093024) in a total of 901 ATA+ SSc cases, 3,258 ATA- SSc cases and 7,865 healthy controls and compared allelic frequencies for those SNPs in ATA+ SSc with healthy controls and also with ATA- SSc patients. Results: The comparison performed between ATA+ SSc patients and healthy controls showed significant association with SNP rs968334 (p=4.88 x 10-2, OR=1.11). When we compared ATA+ SSc cases with ATA- SSc, both SNPs, rs3093024 and rs968334, showed significant associations (p=2.89 x 10-2, OR=1.13; p=1.69 x 10-2, OR=1.15). Finally, in order to increase even more sample size and statistical power, we meta-analysed our study with the previous reported and found a significant association between SNP rs3093024 and ATA+ SSc patients (p=1.00 x 10-4, OR=1.16) comparing with healthy controls. Conclusions: Our work confirms the association of CCR6 gene and ATA+ SSc patients.
    Full-text · Article · Aug 2015 · Clinical and experimental rheumatology
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    ABSTRACT: Background Systemic sclerosis (SSc) is a chronic connective tissue disorder with the highest mortality of any autoimmune disease. SSc is a complex disease with a clear genetic component. This genetic susceptibility has been supported by a number of well-powered genetic association studies. In this regard, it is remarkable that several SSc genetic markers have been reported in the IL-12 pathway (IL12A, STAT4, IL12RB2, IL12RB1). Furthermore, multiple clinical and experimental evidences have shown that this pathway is altered in SSc patients. TYK2 encodes the Tyrosine kinase 2 enzyme, which mediates the signaling of IL-12 receptor. Objectives We aimed to analyze the association of the TYK2 locus with SSc susceptibility. Methods The complete set of individuals included in this study reached 4,985 SSc patients and 11,621 healthy controls of European ancestry from Spain, Germany, The Netherlands, USA, Italy and United Kingdom. Initially, we analyzed all the polymorphisms located in the region that encompasses the TYK2 coding sequence and 20 kb up and downstream, in a previously published Immunochip-based dense genotyping study. We identified a common single nucleotide polymorphism (SNP), the V362F variant (rs2304256) and three rare variants: P1104A (rs34536443), A928V (rs35018800) and I684S (rs12720356), as the genetic markers that better explained the observed association in the region. Then, these variants were followed up in additional cohorts. Association and dependence relations were tested using logistic regression and conditional logistic regression, and pooled analyses were performed using the inverse variance method. Results Our pooled analysis showed that V362F variant reached the genome-wide significance level (P=2.00x10-10, OR =0.84), while P1104A (rs34536443), A928V (rs35018800) and I684S (rs12720356) remained significant (P=8.61x10-3, OR=0.79; P=1.95x10-4, OR=0.49; Prandom=0.016, OR=0.84, respectively). The analyses carried out for the main clinical features revealed that the observed association signals relied on the whole disease. Furthermore, our results revealed that the association of TYK2 with SSc was dependent on the interaction between the P1104A, A928V and I684S rare variants and that the previously observed association for the autoimmune related V362F variant, corresponded to a synthetic association dependent on the association of the three previously mentioned rare variants. Conclusions We report for the first time the association of TYK2 variants with SSc. Moreover, our data support that the highly significant association of a previously known autoimmune disease marker, the V362F variant (rs2304256), is dependent on the effect of three non-synonymous rare variants in this locus. Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Studies evaluating the difference between men and women diagnosed of scleroderma (SSc) are scarce (1-5) because of the shortage of male patients. Objectives Assessing the existence of differences in clinical presentation and mortality causes among men and women in a large cohort of Spanish patients diagnosed with SSc. Methods A registry of patients with SSc has been performed by the Spanish network for systemic sclerosis (RESCLE) since 2008, in which 90 clinical, immunological and capillaroscopic variables were collected prospectively. Data were collected until May 2014 for this study. Results 1506 patients (1341 women), were included. Overall ratio female/male was 8/1. By subtypes lcSSc and preSSc were more frequent in females [84 (51%) vs 808 (60%), p0.023; 6 (3.6%) vs100 (7.5%), p0.076, respectively] and dcSSc in males [62 (38%) vs 293 (22%), p<0.001]. Diagnostic delay was longer in women (2.92 yrs vs 1.30yrs, p<0.001) and smoking was more prevalent in men. Myositis, tendon rubs, interstitial lung disease (ILD), cardiac conduction disturbances and renal crisis were more frequent in males, while isolated pulmonary arterial hypertension (PAH) and sicca syndrome in women. Positivity for ANA, ACA and antiRo was more frequent in women and antiScl-70 and antiRNA pol III in men. There were no sex differences in capillaroscopic patterns. In the multivariate study remained significant in the male predominance in smoking (OR 2.33, CI 1.49 to 4.14, p=0.002) and ILD (OR 1.70, CI 1.11 to 2 60, p=0.015) and in women sicca syndrome (OR 3, 1.63 to 5.52) and ANA positivity (OR 2.67, 1.29 to 5.51).Follow-up time (years) since the onset of symptoms was in males 8.69 yrs vs women 11.79, p=0.001. Altogether, 261 patients died (17%). Although there was no difference in the age at death, this was more common in men (31% men vs 15% women), and time from the onset of symptoms to death was longer in women [14.06 yrs (5.95 to 24.29) vs 8.33 (3.87 to 12.66), p<0.001]. Death was related to SSc in 112 (46%) (22 males vs 90 in women, p ns) while 129 (54%) (31 males vs. 103 for females, p ns) were due to other causes. ILD was the most common cause of death in men (27,5%) and PH in women (28,6%). PAH was more frequently a cause of death in women 39 (19,9%) than in men 0 (0,0%), p<0,001. The cumulative survival at 20 years from onset was 90.9% in women versus 76.3% in men, p<0.001. Conclusions 1. In the RESCLE cohort, smoking and ILD were more frequent in males, and sicca syndrome and ANA positivity in women. 2. ILD was the most common cause of death in men and PAH in women. 3. PAH was more frequently a cause of death in women than in men. 4. Men had less survival since the onset of symptoms. References Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Objectives: To date, the diagnostic utility of anti-SSA/Ro52 autoantibodies in scleroderma and the association of them with certain clinical manifestations, particularly inflammatory myositis, are still controversial. This paper aims to assess the correlation between the presence of anti-SSA/Ro52 antibodies and the demographic, clinical and prognosis characteristics of patients with systemic sclerosis (SSc). Methods: This is a retrospective, cross-sectional and observational study in patients with SSc. Baseline demographic and clinical characteristics were recorded. Presence of anti-SSA/Ro52, anti-SSA/Ro, anti-SSB/La, snRNP/Sm, anti-centromere, anti-Scl-70 and anti-PM-Scl were analysed by immunoblot, and antinuclear antibodies (ANA) by indirect immunofluorescence. Statistical analysis was performed with PASW Statics 18 software. Results: A total of 132 consecutive patients with analysis of anti-SSA/Ro52 antibodies were selected from a Spanish cohort of 408 patients with SSc, 87.1% of them being women. About half of patients had the limited form (51.5%), followed by diffused form (18.9%), sclerosis sine scleroderma (22.7%), and pre-scleroderma (6.8%). Prevalence of anti-SSA/Ro52 was 35.6%. No association between anti-SSA/Ro52 and clinical manifestations was found, while detection of anti-SSA/Ro52 was significantly associated with the presence of anti-Ro. Conclusions: The results of our study show that anti-SSA/Ro52 antibodies are often found in SSc patients. No clinical manifestations, including inflammatory myopathy, were related with anti-SSA/Ro antibodies.
    No preview · Article · Nov 2014 · Clinical and experimental rheumatology
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    ABSTRACT: Objective To determine the mortality, survival and causes of death in patients with Systemic Sclerosis (SSc) through the meta-analysis of the observational studies published up to 2013. Methods We performed a systematic review and meta-analysis of the observational studies in patients with SSc and mortality data from entire cohorts, published in MEDLINE and SCOPUS up to July 2013. Results 17 studies were included in the mortality meta-analysis from 1964 and 2005 (mid-cohort years), with data from 9239 patients. The overall SMR was 2.72 (CI 95% 1.93-3.83). 43 studies have been included in the survival meta-analysis, reporting data from 13529 patients. Cumulative survival from onset (first Raynaud) has been estimated in 87.6% at 5 years and 74.2% at 10 years, from onset (non-Raynaud's first symptom)84.1% at 5 years and 75.5% at 10 years and from diagnosis 74.9% at 5 years and 62.5% at 10 years. Pulmonary involvement represented the main cause of death. Conclusions SSc presents a larger mortality than general population (SMR 2.72). Cumulative survival has been estimated from diagnosis in 74.9% at 5 years and 62.5% at 10 years. Pulmonary involvement represented the main cause of death.
    No preview · Article · Oct 2014 · Seminars in Arthritis and Rheumatism
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    ABSTRACT: Background Some authors postulate that systemic sclerosis's (SSc) heterogenic expression is mostly conditioned by the positivity to any of its specific auto-antibodies. Objectives To assess the prevalence of anti-RNA-polymerase III (RNA-pol III) and anti-Pm-Scl (Pm-Scl) antibodies in a large SSc patient cohort included in the Spanish Scleroderma Study Group (SSSG), and to correlate with the clinical manifestations. Methods From January 1996 to June 2013, 1399 patients fullfilling LeRoy and Medsger criteria for SSC were included in the SSSG database. Demographic, clinical (visceral involvement), immunological, and capillaroscopic data were compared, according to the serologic status of RNA-pol III and Pm-Scl. Results 34 out of 179 patients (18.9%) tested positive for RNA-pol III. Among RNA-pol III positive patients, female gender was less common (79% vs 93%, p=0.02) and diffuse cutaneous subtype of SSc was more frequent (39% vs 19%, p=0.02). We did not find any difference in terms of mean age at clinical onset, mean age at diagnosis, mean disease duration, first manifestation at disease onset or cumulative manifestations. Sclerodermic renal crisis (SRC) was similar in both groups (18% vs 6.3%, p=0.15). Survival at 5, and 10 years was not different in both groups (93% vs 94.2%, p=0.72 and 84% vs 88%, p=0.41, respectively). Regarding Pm-Scl, 53 out of 684 patients (7.7%) were positive. We did not find any differences in terms of mean age at clinical onset, mean age at diagnosis, mean disease duration, first manifestation at disease onset or cumulative manifestations. Pm-Scl positive patients had more frequently puffy fingers (10% vs 2.2%, p=0.009), and myositis (32% vs 8.4%, p<0.001). In addition, ground-glass pattern on computerized tomography lung scan was more common (61% vs 34%, p=0.001) and less forced vital capacity (%) (78±21 vs 85±23) (p=0.04). However, there was no difference in the prevalence of interstitial lung disease (57% vs 47%, p=0.19). There was a higher prevalence of SRC in the Pm-Scl group (11% vs 2.2%, p=0.03). There was no difference between Pm-Scl positive and negative patients in terms of survival at 5 and 10 years (93.4% vs 96.6%, p=0.24 and 89.5% vs 91.3%, p=0.59, respectively). We found other SSc specific antibodies in RNA-pol III patients (6 with anti-centromere and 4 with anti-topoisomerase antibodies). Among Pm-Scl positive patients, 6 of them also tested positive for anti-centromere and 8 for anti-topoisomerase antibodies. 5 patients had both RNA-pol III and Pm-Scl antibodies. Conclusions In Spanish SSc patients, seropositivity for RNA-pol III patients did not correlate with SRC. The presence of anti-Pm-Scl antibodies was associated with muscular involvement. Neither RNA-pol III nor Pm-Scl antibodies were related to worse prognosis. References Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4098
    No preview · Article · Jun 2014 · Annals of the Rheumatic Diseases

  • No preview · Article · Mar 2014 · Clinical and experimental rheumatology
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    ABSTRACT: Peak age at onset of systemic sclerosis (SSc) is between 20 and 50 years, although SSc is also described in both young and elderly patients. We conducted the present study to determine if age at disease onset modulates the clinical characteristics and outcome of SSc patients. The Spanish Scleroderma Study Group recruited 1037 patients with a mean follow-up of 5.2 ± 6.8 years. Based on the mean ± 1 standard deviation (SD) of age at disease onset (45 ± 15 yr) of the whole series, patients were classified into 3 groups: age ≤30 years (early onset), age between 31 and 59 years (standard onset), and age ≥60 years (late onset). We compared initial and cumulative manifestations, immunologic features, and death rates. The early-onset group included 195 patients; standard-onset group, 651; and late-onset, 191 patients. The early-onset group had a higher prevalence of esophageal involvement (72% in early-onset compared with 67% in standard-onset and 56% in late-onset; p = 0.004), and myositis (11%, 7.2%, and 2.9%, respectively; p = 0.009), but a lower prevalence of centromere antibodies (33%, 46%, and 47%, respectively; p = 0.007). In contrast, late-onset SSc was characterized by a lower prevalence of digital ulcers (54%, 41%, and 34%, respectively; p < 0.001) but higher rates of heart conduction system abnormalities (9%, 13%, and 21%, respectively; p = 0.004). Pulmonary hypertension was found in 25% of elderly patients and in 12% of the youngest patients (p = 0.010). After correction for the population effects of age and sex, standardized mortality ratio was shown to be higher in younger patients. The results of the present study confirm that age at disease onset is associated with differences in clinical presentation and outcome in SSc patients.
    Full-text · Article · Mar 2014 · Medicine

  • No preview · Article · Mar 2014 · Clinical and experimental rheumatology
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    ABSTRACT: Background Systemic sclerosis or scleroderma (SSc) is a connective tissue disease which frequently presents lung affectation, being the principal cause of death in these patients. Currently, only cyclophosphamide (CyC) has shown efficiency to treat this complication. However, this efficiency is modest and not kept through the time. Several medicines have been tested for the treatment of this complication with controversial results. Rituximab (RTX) seems to show improvement in patients with SSc and Interstitial Lung Disease (ILD) refractory to others treatments, but there are not pivotal assays in this regard and the experience is limited. Objectives To study the evolution of Pulmonary Function Test (PFT) in patients with SSc affected by ILD refractory to usual treatment and have made at least one cycle of Rituximab. Methods Multicenter observational prospective study in patients with ILD-SSc was performed. These patients had one cycle of two Rituximab infusions for ILD and previously had realized CyC, azathioprine or mycophenolic acid with treatment failure. We evaluated the following data: gender, age, onset age of Raynaud’s phenomenon, age at diagnosis of SSc, age at diagnosis of ILD, ILD type, total dose of CYC, use of concomitants steroids, and other immunosuppressive agents. PFT outcome after each therapy and after 4 months of treatment with RTX was included. Results We collected the data of four patients who realized one complete cycle of treatment with RTX. Patients were women and presented diffuse cutaneous shape with antitopoisomerase I antibodies. The radiologic affectation was Non-Specific Interstitial Pneumonia (NSIP) in all cases. Patient’s characteristics are showed in table 1. The patient who presented the best response to RTX (Patient 4) had the highest dose of CyC accumulated previously. As a whole, patients presented a worsening of the predicted value of FVC and DLCO after treatment with CyC. Four months later of RTX infusion, we did not observe any worsening in the values of FVC beside of a trend to improve the values of DLCO. The best response in concern to respiratory function parameters was not related with taking concomitant or accumulated dose of other drugs different to CYC. Conclusions Rituximab could be an alternative to the treatment and stabilization for interstitial lung disease in patients with SSc, however experience remains limited. Disclosure of Interest None Declared
    No preview · Article · Jan 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants using a follow-up strategy. Sixty six non-HLA SNPs showing a P-value < 10-4 in the discovery phase of the French SSc GWAS were analyzed in the first step of this study performing a meta-analysis which combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed using TaqMan SNP genotyping assays. We observed nominal associations for both PPARG rs310746 (PMH = 1.90 x 10-6, OR = 1.28) and CHRNA9 rs6832151 (PMH = 4.30 x 10-6, OR = 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P-value = 0.066, OR = 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome wide significant P-value (PMH = 5.00 x 10-7, OR = 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled-analysis. Our results suggest a role of PPARG gene in the development of SSc.
    Full-text · Article · Jan 2014 · Arthritis research & therapy
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    ABSTRACT: In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, pro- vided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.
    Full-text · Article · Jan 2014 · The American Journal of Human Genetics
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    ABSTRACT: Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are two archetypal systemic autoimmune diseases which have been shown to share multiple genetic susceptibility loci. In order to gain insight into the genetic basis of these diseases we performed a pan-meta-analysis of two genome-wide association studies (GWAS) together with a replication stage including additional SSc and SLE cohorts. This increased the sample size to a total of 21,109 (6,835 cases and 14,274 controls). We selected for replication 19 SNPs from the GWAS data. We were able to validate KIAA0319 L (P=3.31x10−11, OR=1.49) as novel susceptibility loci for SSc and SLE. Furthermore, we also determined that the previously described SLE susceptibility loci PXK (P=3.27x10−11, OR=1.20) and JAZF1 (P=1.11x10−8, OR=1.13) are shared with SSc. Supporting these new discoveries, we observed that KIAA0319 L was overexpressed in peripheral blood cells of SSc and SLE patients compared to healthy controls. With these, we add three (KIAA0319 L, PXK and JAZF1) and one (KIAA0319 L) new susceptibility loci for SSc and SLE, respectively, increasing significantly the knowledge of the genetic basis of autoimmunity.
    Full-text · Article · May 2013 · Human Molecular Genetics
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    ABSTRACT: Objective: To evaluate whether the systemic sclerosis (SSc)-associated IRAK1 non-synonymous single-nucleotide polymorphism rs1059702 is responsible for the Xq28 association with SSc or whether there are other independent signals in the nearby methyl-CpG-binding protein 2 gene (MECP2). Methods: We analysed a total of 3065 women with SSc and 2630 unaffected controls from five independent Caucasian cohorts. Four tag single-nucleotide polymorphisms of MECP2 (rs3027935, rs17435, rs5987201 and rs5945175) and the IRAK1 variant rs1059702 were genotyped using TaqMan predesigned assays. A meta-analysis including all cohorts was performed to test the overall effect of these Xq28 polymorphisms on SSc. Results: IRAK1 rs1059702 and MECP2 rs17435 were associated specifically with diffuse cutaneous SSc (PFDR=4.12×10(-3), OR=1.27, 95% CI 1.09 to 1.47, and PFDR=5.26×10(-4), OR=1.30, 95% CI 1.14 to 1.48, respectively), but conditional logistic regression analysis showed that the association of IRAK1 rs1059702 with this subtype was explained by that of MECP2 rs17435. On the other hand, IRAK1 rs1059702 was consistently associated with presence of pulmonary fibrosis (PF), because statistical significance was observed when comparing SSc patients PF+ versus controls (PFDR=0.039, OR=1.30, 95% CI 1.07 to 1.58) and SSc patients PF+ versus SSc patients PF- (p=0.025, OR=1.26, 95% CI 1.03 to 1.55). Conclusions: Our data clearly suggest the existence of two independent signals within the Xq28 region, one located in IRAK1 related to PF and another in MECP2 related to diffuse cutaneous SSc, indicating that both genes may have an impact on the clinical outcome of the disease.
    Full-text · Article · Feb 2013 · Annals of the Rheumatic Diseases
  • No preview · Article · Feb 2013 · Clinical and experimental rheumatology
  • No preview · Article · Feb 2013 · Clinical and experimental rheumatology
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    ABSTRACT: Table S1. Overall statistical power of the study for each analysed IRF5 genetic variant at the 5% significance level. Table S2. Independent analyses of IRF5 genetic variants in Caucasian SSc patients and unaffected controls from Europe. Table S3. Meta-analysis of IRF5 genetic variants comparing the main clinical phenotypes with unaffected controls. Table S4. Linkage disequilibrium structure of the IRF5 region analysed in this study. Table S5. Pooled-analysis of different allelic combinations of the IRF5 genomic region according to the presence/absence of specific clinical phenotypes. (DOC)
    Preview · Dataset · Jan 2013
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    ABSTRACT: Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE) susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP) of each block (rs10488631, rs2004640, and rs4728142) in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P = 1.34×10(-8), OR = 1.22, CI 95% = 1.14-1.30; rs2004640: P = 4.60×10(-7), OR = 0.84, CI 95% = 0.78-0.90; rs10488631: P = 7.53×10(-20), OR = 1.63, CI 95% = 1.47-1.81). However, the association of rs2004640 with SSc was not independent of rs4728142 (conditioned P = 0.598). The haplotype containing the risk alleles (rs4728142*A-rs2004640*T-rs10488631*C: P = 9.04×10(-22), OR = 1.75, CI 95% = 1.56-1.97) better explained the observed association (likelihood P-value = 1.48×10(-4)), suggesting an additive effect of the three haplotypic blocks. No statistical significance was observed in the comparisons amongst SSc patients with and without the main clinical characteristics. Our data clearly indicate that the SLE risk haplotype also influences SSc predisposition, and that this association is not sub-phenotype-specific.
    Full-text · Article · Jan 2013 · PLoS ONE
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    ABSTRACT: Introduction Potassium voltage-gated channel shaker-related subfamily member 5 (KCNA5) is implicated in vascular tone regulation, and its inhibition during hypoxia produces pulmonary vasoconstriction. Recently, a protective association of the KCNA5 locus with systemic sclerosis (SSc) patients with pulmonary arterial hypertension (PAH) was reported. Hence, the aim of this study was to replicate these findings in an independent multicenter Caucasian SSc cohort. Methods The 2,343 SSc cases (179 PAH positive, confirmed by right-heart catheterization) and 2,690 matched healthy controls from five European countries were included in this study. Rs10744676 single-nucleotide polymorphism (SNP) was genotyped by using a TaqMan SNP genotyping assay. Results Individual population analyses of the selected KCNA5 genetic variant did not show significant association with SSc or any of the defined subsets (for example, limited cutaneous SSc, diffuse cutaneous SSc, anti-centromere autoantibody positive and anti-topoisomerase autoantibody positive). Furthermore, pooled analyses revealed no significant evidence of association with the disease or any of the subsets, not even the PAH-positive group. The comparison of PAH-positive patients with PAH-negative patients showed no significant differences among patients. Conclusions Our data do not support an important role of KCNA5 as an SSc-susceptibility factor or as a PAH-development genetic marker for SSc patients.
    No preview · Article · Dec 2012 · Arthritis research & therapy

Publication Stats

2k Citations
500.85 Total Impact Points

Institutions

  • 2009-2015
    • Hospital Valle Del Nalon
      Rianxo, Galicia, Spain
  • 2011-2014
    • Autonomous University of Barcelona
      • Department of Medicine
      Cerdanyola del Vallès, Catalonia, Spain
    • Instituto de Biomedicina de Sevilla (IBIS)
      Hispalis, Andalusia, Spain
    • Spanish National Research Council
      • Institute of Parasitology and Biomedicine "López-Neyra"
      Madrid, Madrid, Spain
  • 1990-2014
    • University Hospital Vall d'Hebron
      • Department of Internal Medicine
      Barcino, Catalonia, Spain
  • 2010-2011
    • Vall d’Hebron Institute of Oncology
      Barcino, Catalonia, Spain
    • University of Milan
      Milano, Lombardy, Italy