Patricia Carreira

Publications (26)178.49 Total impact

• Article: The role of NLRP1 gene in systemic sclerosis: a replication study.

  María Teruel, Carmen P Simeon, Jasper Broen, Patricia Carreira, Paloma García de la Peña, M Ángeles Aguirre, The Spanish Scleroderma Group, Lorenzo Beretta, Torsten Witte, Alexander Kreuter, Madelon C Vonk, Alexandre E Voskuyl, Annemie J Schuerwegh, Timothy R D J Radstake, Javier Martin
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  ABSTRACT: -
  Clinical and experimental rheumatology 02/2013; · 2.15 Impact Factor
• Article: KCNA5 gene is not confirmed as a systemic sclerosis-related pulmonary arterial hypertension genetic susceptibility factor.

  Lara Bossini-Castillo, Carmen P Simeon, Lorenzo Beretta, Jasper Broen, Madelon C Vonk, Jose L Callejas, Patricia Carreira, Luis Rodriguez-Rodriguez, Rosa Garcia-Portales, Miguel A Gonzalez-Gay, [......], Roger Hesselstrand, Claudio Lunardi, Jacob M van Laar, Paul Shiels, Ariane Herrick, Jane Worthington, Christopher Denton, Timothy Rdj Radstake, Carmen Fonseca, Javier Martin
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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 multicentre Caucasian SSc cohort. METHODS: 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 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 (e.g. 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 versus PAH negative patients showed no significant differences among patients. CONCLUSIONS: Our data do not support an important role of KCNA5 as a SSc susceptibility factor or as a PAH development genetic marker for SSc patients.
  Arthritis research & therapy 12/2012; 14(6):R273. · 4.27 Impact Factor
• Article: Influence of the IL6 Gene in Susceptibility to Systemic Sclerosis.

  Maria Carmen Cénit, Carmen P Simeón, Madelon C Vonk, Jose L Callejas-Rubio, Gerard Espinosa, Patricia Carreira, Francisco J Blanco, Javier Narvaez, Carlos Tolosa, José A Román-Ivorra, [......], Oyvind Palm, Jacob M van Laar, Nicolas Hunzelmann, Jörg H W Distler, Alexander Kreuter, Ariane Herrick, Jane Worthington, Bobby P Koeleman, Timothy R D J Radstake, Javier Martín
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  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. METHODS: 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. RESULTS: 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). CONCLUSION: Our results suggest that the IL6 gene may influence the development of SSc and its progression.
  The Journal of Rheumatology 10/2012; · 3.69 Impact Factor
• Article: Confirmation of TNIP1 but not RHOB and PSORS1C1 as systemic sclerosis risk factors in a large independent replication study.

  Lara Bossini-Castillo, Jose Ezequiel Martin, Jasper Broen, Carmen P Simeon, Lorenzo Beretta, Olga Y Gorlova, Madelon C Vonk, Norberto Ortego-Centeno, Gerard Espinosa, Patricia Carreira, [......], Jane Worthington, Carmen Fonseca, Christopher Denton, Filemon K Tan, Frank C Arnett, Shervin Assassi, Bobby P Koeleman, Maureen D Mayes, Timothy R D J Radstake, Javier Martin
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  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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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; · 8.11 Impact Factor
• Article: Analysis of the association between CD40 and CD40 ligand polymorphisms and systemic sclerosis.

  María Teruel, Carmen P Simeon, Jasper Broen, Madelon C Vonk, Patricia Carreira, Maria Teresa Camps, Rosa García-Portales, Esmeralda Delgado-Frías, Maria Gallego, Gerard Espinosa, [......], Thomas Krieg, Alexander Kreuter, Jörg Hw Distler, Nicolas Hunzelmann, Bobby P Koeleman, Alexandre E Voskuyl, Annemie J Schuerwegh, Miguel Angel González-Gay, Timothy Rdj Radstake, Javier Martin
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  ABSTRACT: INTRODUCTION: The aim of the present study was to investigate the possible role of CD40 and CD40 ligand (CD40LG) genes in the susceptibility and phenotype expression of systemic sclerosis (SSc). METHODS: In total, 2,670 SSc patients and 3,245 healthy individuals from four European populations (Spain, Germany, The Netherlands, and Italy) were included in the study. Five single-nucleotide polymorphisms (SNPs) of CD40 (rs1883832, rs4810485, rs1535045) and CD40LG (rs3092952, rs3092920) were genotyped by using a predesigned TaqMan allele-discrimination assay technology. Meta-analysis was assessed to determine whether an association exists between the genetic variants and SSc or its main clinical subtypes. RESULTS: No evidence of association between CD40 and CD40LG genes variants and susceptibility to SSc was observed. Similarly, no significant statistical differences were observed when SSc patients were stratified by the clinical subtypes, the serologic features, and pulmonary fibrosis. CONCLUSIONS: Our results do not suggest an important role of CD40 and CD40LG gene polymorphisms in the susceptibility to or clinical expression of SSc.
  Arthritis research & therapy 06/2012; 14(3):R154. · 4.27 Impact Factor
• Article: Evaluation of a shared autoimmune disease-associated polymorphism of TRAF6 in systemic sclerosis and giant cell arteritis.

  F David Carmona, Aurora Serrano, Luis Rodríguez-Rodríguez, José Luis Callejas, Carmen P Simeón, Patricia Carreira, Santos Castañeda, Roser Solans, Ricardo Blanco, Miguel A González-Gay, Javier Martín
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  ABSTRACT: We evaluated whether a single-nucleotide polymorphism (SNP) of the TRAF6 gene previously associated with systemic lupus erythematosus and rheumatoid arthritis may be a common risk factor for systemic sclerosis (SSc) and giant cell arteritis (GCA). A total of 1185 patients with SSc, 479 patients with biopsy-proven GCA, and 1442 unrelated healthy controls of white Spanish origin were genotyped for the rs540386 variant using a specifically designed TaqMan(©) allele discrimination assay. No significant associations of this SNP with global SSc or GCA were found. This was also the case when the potential associations of the TRAF6 polymorphism with the main clinical phenotypes of the 2 diseases (e.g., limited cutaneous and diffuse cutaneous SSc, or presence of polymyalgia rheumatica and visual ischemic manifestations in GCA) were assessed. Our data do not support a role of the rs540386 TRAF6 variant as a key component of the genetic network underlying SSc and GCA.
  The Journal of Rheumatology 05/2012; 39(6):1275-9. · 3.69 Impact Factor
• Article: Bias in effect size of systemic lupus erythematosus susceptibility loci across Europe: a case-control study.

  Elisa Alonso-Perez, Marian Suarez-Gestal, Manuel Calaza, Gian Domenico Sebastiani, Rudolf Pullmann, Chryssa Papasteriades, Attila Kovacs, Fotini N Skopouli, Marc Bijl, Ana Suarez, [......], Patricia Carreira, Josep Ordi-Ros, Torsten Witte, Sarka Ruzickova, Maria Jose Santos, Nadia Barizzone, Francisco J Blanco, Bernard R Lauwerys, Juan J Gomez-Reino, Antonio Gonzalez
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  ABSTRACT: INTRODUCTION: We aimed to investigate whether the effect size of the systemic lupus erythematosus (SLE) risk alleles varies across European subpopulations. METHODS: European SLE patients (n = 1,742) and ethnically matched healthy controls (n = 2,101) were recruited at 17 centres from 10 different countries. Only individuals with self-reported ancestry from the country of origin were included. In addition, participants were genotyped for top ancestry informative markers and for 25 SLE associated SNPs. The results were used to compare effect sizes between the Central Eureopan and Southern European subgroups. RESULTS: Twenty of the 25 SNPs showed independent association with SLE, These SNPs showed a significant bias to larger effect sizes in the Southern subgroup, with 15/20 showing this trend (P = 0.019) and a larger mean odds ratio of the 20 SNPs (1.46 vs. 1.34, P = 0.02) as well as a larger difference in the number of risk alleles (2.06 vs. 1.63, P = 0.027) between SLE patients and controls than for Central Europeans. This bias was reflected in a very significant difference in the cumulative genetic risk score (4.31 vs. 3.48, P = 1.8 × 10-32). Effect size bias was accompanied by a lower number of SLE risk alleles in the Southern subjects, both patients and controls, the difference being more marked between the controls (P = 1.1 × 10-8) than between the Southern and Central European patients (P = 0.016). Seven of these SNPs showed significant allele frequency clines. CONCLUSION: Our findings showed a bias to larger effect sizes of SLE loci in the Southern Europeans relative to the Central Europeans together with clines of SLE risk allele frequencies. These results indicate the need to study risk allele clines and the implications of the polygenic model of inheritance in SLE.
  Arthritis research & therapy 04/2012; 14(2):R94. · 4.27 Impact Factor
• Article: A multicenter study confirms CD226 gene association with systemic sclerosis-related pulmonary fibrosis.

  Lara Bossini-Castillo, Carmen P Simeon, Lorenzo Beretta, Jasper C Broen, Madelon C Vonk, Raquel Ríos-Fernández, Gerard Espinosa, Patricia Carreira, María T Camps, Maria J Castillo, [......], Roger Hesselstrand, Claudio Lunardi, Jacob M van Laar, Meng May Chee, Ariane Herrick, Bobby Pc Koeleman, Christopher P Denton, Carmen Fonseca, Timothy Rdj Radstake, Javier Martin
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  ABSTRACT: INTRODUCTION: CD226 genetic variants have been associated with a number of autoimmune diseases and recently with systemic sclerosis (SSc). The aim of this study was to test the influence of CD226 loci in SSc susceptibility, clinical phenotypes and autoantibody status in a large multicenter European population. METHODS: A total of seven European populations of Caucasian ancestry were included, comprising 2,131 patients with SSc and 3,966 healthy controls. Three CD226 single nucleotide polymorphisms (SNPs), rs763361, rs3479968 and rs727088, were genotyped using Taqman 5'allelic discrimination assays. RESULTS: Pooled analyses showed no evidence of association of the three SNPs, neither with the global disease nor with the analyzed subphenotypes. However, haplotype block analysis revealed a significant association for the TCG haplotype (SNP order: rs763361, rs34794968, rs727088) with lung fibrosis positive patients (PBonf = 3.18E-02 OR 1.27 (1.05 to 1.54)). CONCLUSION: Our data suggest that the tested genetic variants do not individually influence SSc susceptibility but a CD226 three-variant haplotype is related with genetic predisposition to SSc-related pulmonary fibrosis.
  Arthritis research & therapy 04/2012; 14(2):R85. · 4.27 Impact Factor
• Article: Identification of CSK as a systemic sclerosis genetic risk factor through Genome Wide Association Study follow-up.

  Jose-Ezequiel Martin, Jasper C Broen, F David Carmona, Maria Teruel, Carmen P Simeon, Madelon C Vonk, Ruben van 't Slot, Luis Rodriguez-Rodriguez, Esther Vicente, Vicente Fonollosa, [......], Ariane Herrick, Christopher Denton, Filemon K Tan, Frank C Arnett, Shervin Assassi, Carmen Fonseca, Maureen D Mayes, Timothy R D J Radstake, Bobby P C Koeleman, Javier Martin
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  ABSTRACT: Systemic sclerosis (SSc) is complex autoimmune disease affecting the connective tissue; influenced by genetic and environmental components. Recently, we performed the first successful genome-wide association study (GWAS) of SSc. Here, we perform a large replication study to better dissect the genetic component of SSc. We selected 768 polymorphisms from the previous GWAS and genotyped them in seven replication cohorts from Europe. Overall significance was calculated for replicated significant SNPs by meta-analysis of the replication cohorts and replication-GWAS cohorts (3237 cases and 6097 controls). Six SNPs in regions not previously associated with SSc were selected for validation in another five independent cohorts, up to a total of 5270 SSc patients and 8326 controls. We found evidence for replication and overall genome-wide significance for one novel SSc genetic risk locus: CSK [P-value = 5.04 × 10(-12), odds ratio (OR) = 1.20]. Additionally, we found suggestive association in the loci PSD3 (P-value = 3.18 × 10(-7), OR = 1.36) and NFKB1 (P-value = 1.03 × 10(-6), OR = 1.14). Additionally, we strengthened the evidence for previously confirmed associations. This study significantly increases the number of known putative genetic risk factors for SSc, including the genes CSK, PSD3 and NFKB1, and further confirms six previously described ones.
  Human Molecular Genetics 03/2012; 21(12):2825-35. · 7.64 Impact Factor
• Article: Further evidence of subphenotype association with systemic lupus erythematosus susceptibility Loci: a European cases only study.

  Elisa Alonso-Perez, Marian Suarez-Gestal, Manuel Calaza, Josep Ordi-Ros, Eva Balada, Marc Bijl, Chryssa Papasteriades, Patricia Carreira, Fotini N Skopouli, Torsten Witte, [......], Gian Domenico Sebastiani, Maria Jose Santos, Ana Suarez, Francisco J Blanco, Nadia Barizzone, Rudolf Pullmann, Sarka Ruzickova, Bernard R Lauwerys, Juan J Gomez-Reino, Antonio Gonzalez
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  ABSTRACT: Systemic Lupus Erythematosus (SLE) shows a spectrum of clinical manifestations that complicate its diagnosis, treatment and research. This variability is likely related with environmental exposures and genetic factors among which known SLE susceptibility loci are prime candidates. The first published analyses seem to indicate that this is the case for some of them, but results are still inconclusive and we aimed to further explore this question. European SLE patients, 1444, recruited at 17 centres from 10 countries were analyzed. Genotypes for 26 SLE associated SNPs were compared between patients with and without each of 11 clinical features: ten of the American College of Rheumatology (ACR) classification criteria (except ANAs) and age of disease onset. These analyses were adjusted for centre of recruitment, top ancestry informative markers, gender and time of follow-up. Overlap of samples with previous studies was excluded for assessing replication. THERE WERE THREE NEW ASSOCIATIONS: the SNPs in XKR6 and in FAM167A-BLK were associated with lupus nephritis (OR = 0.76 and 1.30, P(corr) = 0.007 and 0.03, respectively) and the SNP of MECP2, which is in chromosome X, with earlier age of disease onset in men. The previously reported association of STAT4 with early age of disease onset was replicated. Some other results were suggestive of the presence of additional associations. Together, the association signals provided support to some previous findings and to the characterization of lupus nephritis, autoantibodies and age of disease onset as the clinical features more associated with SLE loci. Some of the SLE loci shape the disease phenotype in addition to increase susceptibility to SLE. This influence is more prominent for some clinical features than for others. However, results are only partially consistent between studies and subphenotype specific GWAS are needed to unravel their genetic component.
  PLoS ONE 01/2012; 7(9):e45356. · 4.09 Impact Factor
• Article: Analysis of Class II human leucocyte antigens in Italian and Spanish systemic sclerosis.

  Lorenzo Beretta, Blanca Rueda, Maurizio Marchini, Alessandro Santaniello, Carmen P Simeón, Vicente Fonollosa, Monica Caronni, Raquel Rios-Fernandez, Patricia Carreira, Luis Rodriguez-Rodriguez, Antonia Moreno, Miguel A López-Nevot, Ana Escalera, Maria F González-Escribano, Javier Martin, Raffaella Scorza
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  ABSTRACT: To determine the role of Class II HLAs in SSc patients from Italy and Spain and in SSc patients of Caucasian ancestry. Nine hundred and forty-four SSc patients (Italy 392 patients; Spain 452 patients) and 1320 ethnically matched healthy controls (Italy 398 patients; Spain 922 patients) were genotyped up to the fourth digit by PCR with sequence-specific oligonucleotides for HLA-DRB1, DQA1 and DQB1 loci. Patients included 390 ACA-positive and 254 anti-topo I-positive subjects. Associations between SSc or SSc-specific antibodies and HLA alleles or HLA haplotypes were sought via the chi-square test after 10 000-fold permutation testing. A meta-analysis including this study cohort and other Caucasoids samples was also conducted. In both the cohorts, the strongest association was observed between the HLA-DRB1*1104 allele and SSc or anti-topo I antibodies. The HLA-DRB1*1104 -DQA1*0501 -DQB1*0301 haplotype was overrepresented in Italian [odds ratio (OR) = 2.069, 95% asymptotic CIs (CI(95)) 1.486, 2.881; P < 0.001] and in Spanish patients (OR = 6.707, CI(95) 3.974, 11.319; P < 0.001) as well as in anti-topo-positive patients: Italy (OR = 2.642, CI(95) 1.78, 3.924; P < 0.001) and Spain (OR = 20.625, CI(95) 11.536, 36.876; P < 0.001). In both the populations we also identified an additional risk allele (HLA-DQB1*03) and a protective allele (HLA-DQB1*0501) in anti-topo-positive patients. The meta-analysis showed different statistically significant associations, the most interesting being the differential association between HLA-DRB1*01 alleles and ACAs (OR = 1.724, CI(95) 1.482, 2.005; P < 0.001) or topo I antibodies (OR = 0.5, CI(95) 0.384, 0.651; P < 0.001). We describe multiple robust associations between SSc and HLA Class II antigens in Caucasoids that may help to understand the genetic architecture of SSc.
  Rheumatology (Oxford, England) 11/2011; 51(1):52-9. · 4.24 Impact Factor
• Article: A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations.

  Lara Bossini-Castillo, Jose-Ezequiel Martin, Jasper Broen, Olga Gorlova, Carmen P Simeón, Lorenzo Beretta, Madelon C Vonk, Jose Luis Callejas, Ivan Castellví, Patricia Carreira, [......], Jane Worthington, Christopher Denton, Filemon K Tan, Frank C Arnett, Sandeep K Agarwal, Shervin Assassi, Carmen Fonseca, Maureen D Mayes, Timothy R D J Radstake, Javier Martin
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  ABSTRACT: A single-nucleotide polymorphism (SNP) at the IL12RB2 locus showed a suggestive association signal in a previously published genome-wide association study (GWAS) in systemic sclerosis (SSc). Aiming to reveal the possible implication of the IL12RB2 gene in SSc, we conducted a follow-up study of this locus in different Caucasian cohorts. We analyzed 10 GWAS-genotyped SNPs in the IL12RB2 region (2309 SSc patients and 5161 controls). We then selected three SNPs (rs3790567, rs3790566 and rs924080) based on their significance level in the GWAS, for follow-up in an independent European cohort comprising 3344 SSc and 3848 controls. The most-associated SNP (rs3790567) was further tested in an independent cohort comprising 597 SSc patients and 1139 controls from the USA. After conditional logistic regression analysis of the GWAS data, we selected rs3790567 [P(MH)= 1.92 × 10(-5) odds ratio (OR) = 1.19] as the genetic variant with the firmest independent association observed in the analyzed GWAS peak of association. After the first follow-up phase, only the association of rs3790567 was consistent (P(MH)= 4.84 × 10(-3) OR = 1.12). The second follow-up phase confirmed this finding (P(χ2) = 2.82 × 10(-4) OR = 1.34). After performing overall pooled-analysis of all the cohorts included in the present study, the association found for the rs3790567 SNP in the IL12RB2 gene region reached GWAS-level significant association (P(MH)= 2.82 × 10(-9) OR = 1.17). Our data clearly support the IL12RB2 genetic association with SSc, and suggest a relevant role of the interleukin 12 signaling pathway in SSc pathogenesis.
  Human Molecular Genetics 11/2011; 21(4):926-33. · 7.64 Impact Factor
• Article: Polymorphisms in the interleukin 4, interleukin 13, and corresponding receptor genes are not associated with systemic sclerosis and do not influence gene expression.

  Jasper C A Broen, Phillipe Dieude, Madelon C Vonk, Lorenzo Beretta, Francisco D Carmona, Ariane Herrick, Jane Worthington, Nicholas Hunzelmann, Gabriela Riemekasten, Hans Kiener, [......], Patricia Carreira, Norberto Ortego-Centeno, Miguel A Gonzalez-Gay, Paolo Airo, Marieke J Coenen, Kelly Tsang, Antonios O Aliprantis, Javier Martin, Yannick Allanore, Timothy R D J Radstake
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  ABSTRACT: Polymorphisms in the genes encoding interleukin 4 (IL4), interleukin 13 (IL13), and their corresponding receptors have been associated with multiple immune-mediated diseases. Our aim was to validate these previous observations in patients with systemic sclerosis (SSc) and scrutinize the effect of the polymorphisms on gene expression in various populations of peripheral blood leukocytes. We genotyped a cohort of 2488 patients with SSc and 2246 healthy controls from The Netherlands, Spain, United Kingdom, Italy, Germany, and France. Taqman assays were used to genotype single-nucleotide polymorphisms (SNP) in the following genes: (1) IL4 (-590C>T/rs2243250); (2) IL4 receptor alpha (IL4RA) (Q576R/rs1801275); (3) IL13 (R130Q/rs20541 and -1112C>T/rs1800925); and (4) IL13RA1 (43163G>A/rs6646259). The effect of these polymorphisms on expression of the corresponding genes was assessed using quantitative RT-PCR on RNA derived from peripheral blood B cells, T cells, plasmacytoid dendritic cells, monocytes, and myeloid dendritic cells. We investigated whether these polymorphisms influenced development of pulmonary complications over 15 years in patients with SSc. None of the investigated polymorphisms was associated with SSc or any SSc clinical subtype. We did not observe any effect on transcript levels in the cell subtypes or on development of pulmonary complications. Our data showed that polymorphisms in IL4, IL13, and their receptors do not play a role in SSc and do not influence the expression of their corresponding transcript in peripheral blood cells.
  The Journal of Rheumatology 11/2011; 39(1):112-8. · 3.69 Impact Factor
• Article: Novel identification of the IRF7 region as an anticentromere autoantibody propensity locus in systemic sclerosis.

  F David Carmona, Ramana Gutala, Carmen P Simeón, Patricia Carreira, Norberto Ortego-Centeno, Esther Vicente-Rabaneda, Francisco J García-Hernández, Paloma García de la Peña, Mónica Fernández-Castro, Lina Martínez-Estupiñán, María Victoria Egurbide, Betty P Tsao, Pravitt Gourh, Sandeep K Agarwal, Shervin Assassi, Maureen D Mayes, Frank C Arnett, Filemon K Tan, Javier Martín
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  ABSTRACT: Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are related chronic autoimmune diseases of complex aetiology in which the interferon (IFN) pathway plays a key role. Recent studies have reported an association between IRF7 and SLE which confers a risk to autoantibody production. A study was undertaken to investigate whether the IRF7 genomic region is also involved in susceptibility to SSc and the main clinical features. Two case-control sets of Caucasian origin from the USA and Spain, comprising a total of 2316 cases of SSc and 2347 healthy controls, were included in the study. Five single nucleotide polymorphisms (SNPs) in the PHRF1-IRF7-CDHR5 locus were genotyped using TaqMan allelic discrimination technology. A meta-analysis was performed to test the overall effect of these genetic variants on SSc. Four out of five analysed SNPs were significantly associated with the presence of anticentromere autoantibodies (ACA) in the patients with SSc in the combined analysis (rs1131665: p(FDR)=6.14 × 10(-4), OR=0.78; rs4963128: p(FDR)=6.14 × 10(-4), OR=0.79; rs702966: p(FDR)=3.83 × 10(-3), OR=0.82; and rs2246614: p(FDR)=3.83 × 10(-3), OR=0.83). Significant p values were also obtained when the disease was tested globally; however, the statistical significance was lost when the ACA-positive patients were excluded from the study, suggesting that these associations rely on ACA positivity. Conditional logistic regression and allelic combination analyses suggested that the functional IRF7 SNP rs1131665 is the most likely causal variant. The results show that variation in the IRF7 genomic region is associated with the presence of ACA in patients with SSc, supporting other evidence that this locus represents a common risk factor for autoantibody production in autoimmune diseases.
  Annals of the rheumatic diseases 09/2011; 71(1):114-9. · 8.11 Impact Factor
• Article: No evidence for association between the CCR5/Delta32CCR5 polymorphism and systemic sclerosis.

  F David Carmona, Aurora Serrano-Lopera, Elena López-Isac, Carmen P Simeón, Patricia Carreira, Raquel Rios-Fernandez, Gerard Espinosa, María Teresa Camps, Nuria Navarrete, María F González-Escribano, [......], Rosa García-Portales, María Victoria Egurbide, Vicente Fonollosa, Paloma García de la Peña, Ana Pros, Mónica Rodríguez-Carballeira, Federico Díaz-Gónzalez, Luis Sáez-Comet, Miguel A González-Gay, Javier Martín
  Clinical and experimental rheumatology 09/2011; 29(5):895-6. · 2.15 Impact Factor
• Article: Confirmation of association of the macrophage migration inhibitory factor gene with systemic sclerosis in a large European population.

  Lara Bossini-Castillo, Carmen P Simeon, Lorenzo Beretta, Madelon C Vonk, José Luis Callejas-Rubio, Gerard Espinosa, Patricia Carreira, María T Camps, Luis Rodríguez-Rodríguez, Mónica Rodríguez-Carballeira, [......], Paul Shiels, Jacob M van Laar, Carmen Fonseca, Christopher Denton, Ariane Herrick, Jane Worthington, Bobby P Koeleman, Blanca Rueda, Timothy R D J Radstake, Javier Martin
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  ABSTRACT: The aim of this study was to confirm the implication of macrophage migration inhibitory factor (MIF) gene in SSc susceptibility or clinical phenotypes in a large European population. A total of 3800 SSc patients and 4282 healthy controls of white Caucasian ancestry from eight different European countries were included in the study. The MIF -173 single nucleotide polymorphism (SNP) was selected as genetic marker and genotyped using Taqman 5' allelic discrimination assay. The MIF -173 SNP showed association with SSc [P = 0.04, odds ratio (OR) = 1.10, 95% CI 1.00, 1.19]. Analysis of the MIF -173 polymorphism according to SSc clinical phenotype revealed that the frequency of the -173*C allele was significantly higher in the dcSSc group compared with controls (P = 5.30E-03, OR = 1.21, 95% CI 1.07, 1.38). Conversely, the frequency of the MIF -173*C allele was significantly underrepresented in the lcSSc group compared with dcSSc patients, supporting previous findings [(P = 0.04, OR = 0.86, 95% CI 0.75, 0.99); meta-analysis including previous results (P = 0.005, OR = 0.83, 95% CI 0.73, 0.94)]. Our results confirm the role of MIF -173 promoter polymorphism in SSc, and provide evidence of a strong association with the dcSSc subgroup of patients. Hence, the MIF -173 variant is confirmed as a promising clinical phenotype genetic marker.
  Rheumatology (Oxford, England) 08/2011; 50(11):1976-81. · 4.24 Impact Factor
• Source

  Available from: Jose-Ezequiel Martin

  Article: Correction: Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy.

  Olga Gorlova, Jose-Ezequiel Martin, Blanca Rueda, Bobby P C Koeleman, Jun Ying, Maria Teruel, Lina-Marcela Diaz-Gallo, Jasper C Broen, Madelon C Vonk, Carmen P Simeon, [......], Carmen Fonseca, Christopher P Denton, Peter K Gregersen, Sandeep Agarwal, Shervin Assassi, Filemon K Tan, Frank C Arnett, Timothy R D J Radstake, Maureen D Mayes, Javier Martin
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  ABSTRACT: [This corrects the article on p. e1002178 in vol. 7.].
  PLoS Genetics 08/2011; 7(8). · 8.69 Impact Factor
• Source

  Available from: Alexander Kreuter

  Article: Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy.

  Olga Gorlova, Jose-Ezequiel Martin, Blanca Rueda, Bobby P C Koeleman, Jun Ying, Maria Teruel, Lina-Marcela Diaz-Gallo, Jasper C Broen, Madelon C Vonk, Carmen P Simeon, [......], Carmen Fonseca, Christopher P Denton, Peter K Gregersen, Sandeep Agarwal, Shervin Assassi, Filemon K Tan, Frank C Arnett, Timothy R D J Radstake, Maureen D Mayes, Javier Martin
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  ABSTRACT: The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32×10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 × 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39×10(-7), OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79×10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57×10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84×10(-21), OR = 0.55) and ATA (P = 1.14×10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.
  PLoS Genetics 07/2011; 7(7):e1002178. · 8.69 Impact Factor
• Article: Association of a non-synonymous functional variant of the ITGAM gene with systemic sclerosis.

  F David Carmona, Carmen P Simeon, Lorenzo Beretta, Patricia Carreira, Madelon C Vonk, Raquel Ríos-Fernández, Gerard Espinosa, Nuria Navarrete, Esther Vicente-Rabaneda, Luis Rodríguez-Rodríguez, [......], Raffaella Scorza, Claudio Lunardi, Jacob M van Laar, Nicolas Hunzelmann, Alexander Kreuter, Ariane Herrick, Jane Worthington, Bobby P C Koeleman, Timothy R D J Radstake, Javier Martín
  Annals of the rheumatic diseases 05/2011; 70(11):2050-2. · 8.11 Impact Factor
• Source

  Available from: Manuel Calaza

  Article: Association of systemic lupus erythematosus clinical features with European population genetic substructure.

  Elisa Alonso-Perez, Marian Suarez-Gestal, Manuel Calaza, Torsten Witte, Chryssa Papasteriades, Maurizio Marchini, Sergio Migliaresi, Attila Kovacs, Josep Ordi-Ros, Marc Bijl, [......], Sarka Ruzickova, Rudolf Pullmann, Patricia Carreira, Fotini N Skopouli, Sandra D'Alfonso, Gian Domenico Sebastiani, Ana Suarez, Francisco J Blanco, Juan J Gomez-Reino, Antonio Gonzalez
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  ABSTRACT: Systemic Lupus Erythematosus (SLE) is an autoimmune disease with a very varied spectrum of clinical manifestations that could be partly determined by genetic factors. We aimed to determine the relationship between prevalence of 11 clinical features and age of disease onset with European population genetic substructure. Data from 1413 patients of European ancestry recruited in nine countries was tested for association with genotypes of top ancestry informative markers. This analysis was done with logistic regression between phenotypes and genotypes or principal components extracted from them. We used a genetic additive model and adjusted for gender and disease duration. Three clinical features showed association with ancestry informative markers: autoantibody production defined as immunologic disorder (P = 6.8×10(-4)), oral ulcers (P = 6.9×10(-4)) and photosensitivity (P = 0.002). Immunologic disorder was associated with genotypes more common in Southern European ancestries, whereas the opposite trend was observed for photosensitivity. Oral ulcers were specifically more common in patients of Spanish and Portuguese self-reported ancestry. These results should be taken into account in future research and suggest new hypotheses and possible underlying mechanisms to be investigated. A first hypothesis linking photosensitivity with variation in skin pigmentation is suggested.
  PLoS ONE 01/2011; 6(12):e29033. · 4.09 Impact Factor