[Show abstract][Hide abstract] 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.
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Annals of the rheumatic diseases 09/2015; DOI:10.1136/annrheumdis-2015-208154 · 10.38 Impact Factor
[Show abstract][Hide abstract] 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.
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.
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.
Our work confirms the association of CCR6 gene and ATA+ SSc patients.
Clinical and experimental rheumatology 08/2015; 33(4). · 2.72 Impact Factor
[Show abstract][Hide abstract] 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
Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):116.2-116. DOI:10.1136/annrheumdis-2015-eular.3859 · 10.38 Impact Factor
[Show abstract][Hide abstract] 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.
Disclosure of Interest None declared
Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):602.1-602. DOI:10.1136/annrheumdis-2015-eular.5644 · 10.38 Impact Factor
[Show abstract][Hide abstract] 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.
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.
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.
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.
Seminars in Arthritis and Rheumatism 10/2014; 44(2). DOI:10.1016/j.semarthrit.2014.05.010 · 3.93 Impact Factor
[Show abstract][Hide abstract] 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.
Disclosure of Interest None declared
Annals of the Rheumatic Diseases 06/2014; 73(Suppl 2):1014-1014. DOI:10.1136/annrheumdis-2014-eular.4098 · 10.38 Impact Factor
[Show abstract][Hide abstract] 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.
Medicine 03/2014; 93(2):73-81. DOI:10.1097/MD.0000000000000018 · 5.72 Impact Factor
[Show abstract][Hide abstract] 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
Annals of the Rheumatic Diseases 01/2014; 71(Suppl 3):684-684. DOI:10.1136/annrheumdis-2012-eular.806 · 10.38 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
The American Journal of Human Genetics 01/2014; 94(1):47-61. DOI:10.1016/j.ajhg.2013.12.002. · 10.93 Impact Factor
[Show abstract][Hide abstract] 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.
Human Molecular Genetics 05/2013; 22(19):4021-4029. DOI:10.1093/hmg/ddt248 · 6.39 Impact Factor
[Show abstract][Hide abstract] 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).
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.
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).
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.
Annals of the Rheumatic Diseases 02/2013; 72(12):2032-8. DOI:10.1136/annrheumdis-2012-202742 · 10.38 Impact Factor
[Show abstract][Hide abstract] 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.
PLoS ONE 01/2013; 8(1):e54419. DOI:10.1371/journal.pone.0054419 · 3.23 Impact Factor
[Show abstract][Hide abstract] 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.
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.
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.
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.
[Show abstract][Hide abstract] ABSTRACT: Objective The interleukin 2 (IL-2) and interleukin 21 (IL-21) locus at chromosome 4q27 has been associated with several autoimmune diseases, and both genes are related to immune system functions. The aim of this study was to evaluate the role of the IL-2/IL-21 locus in systemic sclerosis (SSc).
Patients and methods The case control study included 4493 SSc Caucasian patients and 5856 healthy controls from eight Caucasian populations (Spain, Germany, The Netherlands, USA, Italy, Sweden, UK and Norway). Four single nucleotide polymorphisms (rs2069762, rs6822844, rs6835457 and rs907715) were genotyped using TaqMan allelic discrimination assays.
Results We observed evidence of association of the rs6822844 and rs907715 variants with global SSc (pc=6.6E-4 and pc=7.2E-3, respectively). Similar statistically significant associations were observed for the limited cutaneous form of the disease. The conditional regression analysis suggested that the most likely genetic variation responsible for the association was the rs6822844 polymorphism. Consistently, the rs2069762A-rs6822844T-rs6835457G-rs907715T allelic combination showed evidence of association with SSc and limited cutaneous SSc subtype (pc=1.7E-03 and pc=8E-4, respectively).
Conclusions These results suggested that the IL-2/IL-21 locus influences the genetic susceptibility to SSc. Moreover, this study provided further support for the IL-2/IL-21 locus as a common genetic factor in autoimmune diseases.
Annals of the rheumatic diseases 11/2012; 72(7). DOI:10.1136/annrheumdis-2012-202357 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
Systemic sclerosis (SSc) is a genetically complex autoimmune disease; the genetic component has not been fully defined. Interleukin 6 (IL-6) plays a crucial role in immunity and fibrosis, both key aspects of SSc. We investigated the influence of IL6 gene in the susceptibility and phenotype expression of SSc.
We performed a large metaanalysis including a total of 2749 cases and 3189 controls from 6 white populations (Germany, The Netherlands, Norway, Spain, Sweden, and United Kingdom). Three IL6 single-nucleotide polymorphisms (SNP; rs2069827, rs1800795, and rs2069840) were selected by SNP tagging and genotyped using TaqMan(®) allele discrimination technology.
Individual SNP metaanalysis showed no evidence of association of the 3 IL6 genetic variants with the global disease. Phenotype analyses revealed a significant association between the minor allele of rs2069840 and the limited cutaneous SSc clinical form (Bonferroni p = 0.036, OR 1.14, 95% CI 1.04-1.25). A trend of association between the minor allele of the rs1800795 and the diffuse cutaneous SSc clinical form was also evident (Bonferroni p = 0.072, OR 0.86, 95% CI 0.77-0.96). In the IL6 allelic combination analyses, the GGC allelic combination rs2069827-rs1800795-rs2069840 showed an association with overall SSc (Bonferroni p = 0.016, OR 1.13, 95% CI 1.04-1.23).
Our results suggest that the IL6 gene may influence the development of SSc and its progression.
The Journal of Rheumatology 10/2012; 39(12). DOI:10.3899/jrheum.120506 · 3.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction:
A recent genome-wide association study in European systemic sclerosis (SSc) patients identified three loci (PSORS1C1, TNIP1 and RHOB) as novel genetic risk factors for the disease. The aim of this study was to replicate the previously mentioned findings in a large multicentre independent SSc cohort of Caucasian ancestry.
4389 SSc patients and 7611 healthy controls from different European countries and the USA were included in the study. Six single nucleotide polymorphisms (SNP): rs342070, rs13021401 (RHOB), rs2233287, rs4958881, rs3792783 (TNIP1) and rs3130573 (PSORS1C1) were analysed. Overall significance was calculated by pooled analysis of all the cohorts. Haplotype analyses and conditional logistic regression analyses were carried out to explore further the genetic structure of the tested loci.
Pooled analyses of all the analysed SNPs in TNIP1 revealed significant association with the whole disease (rs2233287 p(MH)=1.94×10(-4), OR 1.19; rs4958881 p(MH)=3.26×10(-5), OR 1.19; rs3792783 p(MH)=2.16×10(-4), OR 1.19). These associations were maintained in all the subgroups considered. PSORS1C1 comparison showed association with the complete set of patients and all the subsets except for the anti-centromere-positive patients. However, the association was dependent on different HLA class II alleles. The variants in the RHOB gene were not associated with SSc or any of its subsets.
These data confirmed the influence of TNIP1 on an increased susceptibility to SSc and reinforced this locus as a common autoimmunity risk factor.
Annals of the rheumatic diseases 08/2012; 72(4). DOI:10.1136/annrheumdis-2012-201888 · 10.38 Impact Factor
[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.