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1. The complex HLA-E-nonapeptide in Behçet disease

Author

Ángel Luís Castaño-Núñez, Marco-Antonio Montes-Cano, José-Raúl García-Lozano, Norberto Ortego-Centeno, Francisco José García-Hernández, Gerard Espinosa, Genaro Graña-Gil, Juan Sánchez-Bursón, María Rosa Juliá, Roser Solans, Ricardo Blanco, Ana-Celia Barnosi-Marín, Ricardo Gómez de la Torre, Patricia Fanlo, Mónica Rodríguez-Carballeira, Luis Rodríguez-Rodríguez, Teresa Camps, Santos Castañeda, Juan-Jose Alegre-Sancho, Javier Martín, and María Francisca González-Escribano

Subjects
Behçet disease, gene association, classical HLA Class I molecules, HLA-E, NK cells, Immunologic diseases. Allergy, RC581-607
Abstract

IntroductionThe knowledge of the aetiology of Behçet disease (BD), an immune-mediated vasculitis, is limited. HLA-B, mainly HLA-B51, and HLA-A molecules are associated with disease, but the ultimate cause of this association remains obscure. There is evidence that NK cells participate in the etiopathology of BD. NK cells have activator and inhibitor surface receptors, like the KIR and the NKG2 families. Classical HLA-class I molecules (A, B and C) are keys in the activity control of the NK because they are KIR ligands. Most NKG2 receptors bind HLA-E, which presents only nonapeptides derived from the signal peptide of other class-I molecules.ObjectiveThis study investigates the contribution of the pair HLA-E and ligand, nonapeptide derived from the 3-11 sequence of the signal peptides of class I classical molecules, to the susceptibility to BD.MethodsWe analyzed the frequency of the HLA-derivated nonapeptide forms in 466 BD patients and 444 controls and an HLA-E functional dimorphism in a subgroup of patients and controls. Results: In B51 negative patients, the frequency of VMAPRTLLL was lower (70.4% versus 80.0% in controls; P=0.006, Pc=0.04, OR=0.60, 95%CI 0.41-0.86), and the frequency of VMAPRTLVL was higher (81.6% versus 71.4% in controls; P=0.004, Pc=0.03, OR=1.78, 95%CI 1.20-2.63). In homozygosity, VMAPRTLLL is protective, and VMAPRTLVL confers risk. The heterozygous condition is neutral. There were no significant differences in the distribution of the HLA-E dimorphism.DiscussionOur results explain the association of BD with diverse HLA-A molecules, reinforce the hypothesis of the involvement of the NK cells in the disease and do not suggest a significant contribution of the HLA-E polymorphism to disease susceptibility.

Published
2023
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2. Long-term follow-up of certolizumab pegol in uveitis due to immune-mediated inflammatory diseases: multicentre study of 80 patients

Author

Ricardo Blanco, Alfredo Adan, Ignacio Torre, Vega Jovani, Susana Romero-Yuste, Arantxa Conesa, Vanesa Calvo-Río, Cristina Fernández-Carballido, Emma Beltrán-Catalán, Patricia Fanlo, Miguel Cordero-Coma, Alvaro Garcia Martos, Ines Hernanz, Angel Garcia-Aparicio, Patricia Moya Alvarado, José Luis Martín-Varillas, Lara Sanchez-Bilbao, Adela Gallego-Flores, Sonia Castro-Oreiro, Juan Ramon De Dios, Marisa Hernández-Garfella, Amalia Sánchez-Andrade, Andrea García-Valle, Olga Maiz, Roberto Miguélez, Sergio Rodríguez-Montero, Ana Urruticoechea, Raúl Veroz, Jose J Mondejar, Olga Martínez González, Paula Rubio-Muñoz, Eva Peña-Sainz-Pardo, Marta Garijo-Bufort, Rosalía Demetrio-Pablo, and José L Hernández

Subjects
Medicine
Abstract

Objectives To evaluate effectiveness and safety of certolizumab pegol (CZP) in uveitis due to immune-mediated inflammatory diseases (IMID).Methods Multicentre study of CZP-treated patients with IMID uveitis refractory to conventional immunosuppressant. Effectiveness was assessed through the following ocular parameters: best-corrected visual acuity, anterior chamber cells, vitritis, macular thickness and retinal vasculitis. These variables were compared between the baseline, and first week, first, third, sixth months, first and second year.Results We studied 80 (33 men/47 women) patients (111 affected eyes) with a mean age of 41.6±11.7 years. The IMID included were: spondyloarthritis (n=43), Behçet’s disease (n=10), psoriatic arthritis (n=8), Crohn’s disease (n=4), sarcoidosis (n=2), juvenile idiopathic arthritis (n=1), reactive arthritis (n=1), rheumatoid arthritis (n=1), relapsing polychondritis (n=1),Conclusions CZP seems to be effective and safe in uveitis related to different IMID, even in patients refractory to previous biological drugs.

Published
2022
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3. Methylprednisolone Pulses in Hospitalized COVID-19 Patients Without Respiratory Failure: A Randomized Controlled Trial

Author

Iñigo Les, Jose Loureiro-Amigo, Ferran Capdevila, Isabel Oriol, Iñaki Elejalde, Judit Aranda-Lobo, Joao Modesto, Elena Güell-Farré, Ruth García, Anna Murgadella-Sancho, Javier Anniccherico, Miguel Martín-Fernández, José Javier Lorza, Joan-Pol Monteys-Montblanch, Julián Librero, Sara Pintado-Lalueza, Marina Delgado, Berta Gracia-García, Julio Sánchez-Álvarez, Melani Pestaña-Fernández, Patricia Fanlo, Gisela Funalleras-Puig, Maite Sarobe, Eduardo Mediavilla, and Carlos Ibero

Subjects
corticosteroids, methylprednisolone, COVID-19, SARS-CoV-2, hospitalized patients, randomized controlled trial, Medicine (General), R5-920
Abstract

BackgroundCorticosteroids are the cornerstone of the treatment of patients with COVID-19 admitted to hospital. However, whether corticosteroids can prevent respiratory worsening in hospitalized COVID-19 patients without oxygen requirements is currently unknown.AimsTo assess the efficacy of methylprednisolone pulses (MPP) in hospitalized COVID-19 patients with increased levels of inflammatory markers not requiring oxygen at baseline.MethodsMulticenter, parallel, randomized, double-blind, placebo-controlled trial conducted in Spain. Patients admitted for confirmed SARS-CoV-2 pneumonia with raised inflammatory markers (C-reactive protein >60 mg/L, interleukin-6 >40 pg/ml, or ferritin >1,000 μg/L) but without respiratory failure after the first week of symptom onset were randomized to receive a 3-day course of intravenous MPP (120 mg/day) or placebo. The primary outcome was treatment failure at 14 days, a composite variable including mortality, the need for ICU admission or mechanical ventilation, and clinical worsening, this last parameter defined as a PaO2/FiO2 ratio below 300; or a 15% decrease in the PaO2 from baseline, together with an increase in inflammatory markers or radiological progression. If clinical worsening occurred, patients received tocilizumab and unmasked corticosteroids. The secondary outcomes were 28-day mortality, adverse events, need for ICU admission or high-flow oxygen, length of hospital stay, SARS-CoV-2 clearance, and changes in laboratory parameters.ResultsA total of 72 patients were randomized and 71 patients were analyzed (34 in the MPP group and 37 in the placebo group). Twenty patients presented with treatment failure (29.4 in the MPP group vs. 27.0% in the placebo group, p = 0.82), with no differences regarding the time to treatment failure between groups. There were no cases of death or mechanical ventilation requirements at 14 days post-randomization. The secondary outcomes were similar in MPP and placebo groups.ConclusionsA 3-day course of MPP after the first week of disease onset did not prevent respiratory deterioration in hospitalized COVID-19 patients with an inflammatory phenotype who did not require oxygen.

Published
2022
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4. COVID GEAS: COVID-19 National Survey in Patients With Systemic Autoimmune Diseases

Author

Borja Del Carmelo Gracia, Luis Sáez, Lucio Pallarés, Jose Velilla, Adela Marín, Luis Martinez-Lostao, Carmen Pilar Simeón, and Patricia Fanlo

Subjects
COVID-19 infection, SARS-CoV-2, systemic autoimmune disease, survey, systemic erythematosus lupus, corticosteroids, Medicine (General), R5-920
Abstract

ObjectivesCOVID-19 outcomes in population with systemic autoimmune diseases (SAD) remain poorly understood. The aim was to examine demographic and clinical factors associated with COVID-19 infection in people with rheumatic disease.MethodsTwo phases cross-sectional survey of individuals with rheumatic disease in April 2020 and October 2020. COVID infection, severity of disease, age, sex, smoking status, underlying rheumatic disease diagnosis, comorbidities and rheumatic disease medications taken immediately prior to infection were analyzed.ResultsA total of 1,529 individuals with autoimmunity disease diagnosis were included. Out of 50 positive patients, 21 required telephone medical assistance, 16 received assessment by primary care physician, 9 were evaluated in Emergency Department and 4 patient required hospitalization. Multivariate analysis was performed without obtaining differences in any of the systemic autoimmune diseases. Regarding the treatments, significant differences were found (p 0.011) in the treatment with anti-TNF-alpha agents with OR 3.422 (1.322–8.858) and a trend to significance (p 0.094) was observed in patients receiving mycophenolate treatment [OR 2.016 (0.996–4-081)].ConclusionsAnti-TNF-alpha treatment was associated with more than 3-fold risk of suffering from SARS-CoV-2 infection, although in all cases infection was mild. Cumulative incidence in patients with SAD was up to 5 times higher than general population but with great differences between autoimmune diseases.

Published
2022
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5. Mutational profile of rare variants in inflammasome-related genes in Behçet disease: A Next Generation Sequencing approach

Author

Sergio Burillo-Sanz, Marco-Antonio Montes-Cano, José-Raúl García-Lozano, Lourdes Ortiz-Fernández, Norberto Ortego-Centeno, Francisco-José García-Hernández, Gerard Espinosa, Genaro Graña-Gil, Juan Sánchez-Bursón, María Rosa Juliá, Roser Solans, Ricardo Blanco, Ana-Celia Barnosi-Marín, Ricardo Gómez De la Torre, Patricia Fanlo, Mónica Rodríguez-Carballeira, Luis Rodríguez-Rodríguez, Teresa Camps, Santos Castañeda, Juan-Jose Alegre-Sancho, Javier Martín, and María Francisca González-Escribano

Subjects
Medicine, Science
Abstract

Abstract Behçet’s disease (BD) is an immune-mediated systemic disorder with a well-established association with HLA class I and other genes. BD has clinical overlap with many autoinflammatory diseases (AIDs). The aim of this study was to investigate the role of rare variants in seven genes involved in AIDs: CECR1, MEFV, MVK, NLRP3, NOD2, PSTPIP1 and TNFRSF1A using a next generation sequencing (NGS) approach in 355 BD patients. To check global association of each gene, 4 tests: SKAT, CollapseBt, C(α) and weighted KBAC were used. Databases: 1000 Genomes Project Phase 3, Infevers, HGMD and ClinVar and algorithms: PolyPhen2 and SIFT were consulted to collect information of the 62 variants found. All the genes resulted associated using SKAT but only 3 (MVK, NOD2 and PSTPIP1) with C(α) and weighted KBAC. When all the genes are considered, 40 variants were associated to AIDs in clinical databases and 25 were predicted as pathogenic at least by one of the algorithms. Including only MVK, NOD2 and PSTPIP1, the associated to AIDs variants found in BD were 20 and the predicted as pathogenic, 12. The maxima contribution corresponds to NOD2. This study supports influence of rare variants in genes involved in AIDs in the pathogenesis of BD.

Published
2017
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6. Characterization and risk estimate of cancer in patients with primary Sjögren syndrome

Author

Pilar Brito-Zerón, Belchin Kostov, Guadalupe Fraile, Daniel Caravia-Durán, Brenda Maure, Francisco-Javier Rascón, Mónica Zamora, Arnau Casanovas, Miguel Lopez-Dupla, Mar Ripoll, Blanca Pinilla, Eva Fonseca, Miriam Akasbi, Gloria de la Red, Miguel-Angel Duarte-Millán, Patricia Fanlo, Pablo Guisado-Vasco, Roberto Pérez-Alvarez, Antonio J. Chamorro, César Morcillo, Iratxe Jiménez-Heredia, Isabel Sánchez-Berná, Armando López-Guillermo, Manuel Ramos-Casals, and on behalf of the SS Study Group GEAS-SEMI

Subjects
Sjögren syndrome, Cancer, Lymphoma, Diseases of the blood and blood-forming organs, RC633-647.5, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background The purpose of this study is to characterize the risk of cancer in a large cohort of patients with primary Sjögren syndrome (SjS). Methods We had analyzed the development of cancer in 1300 consecutive patients fulfilling the 2002 SjS classification criteria. The baseline clinical and immunological characteristics and systemic activity (ESSDAI scores) were assessed at diagnosis as predictors of cancer using Cox proportional hazards regression analysis adjusted for age at diagnosis and gender. The sex-and age-specific standardized incidence ratios (SIR) of cancer were estimated from 2012 Spanish mortality data. Results After a mean follow-up of 91 months, 127 (9.8%) patients developed 133 cancers. The most frequent type of cancer was B-cell lymphoma (including 27 MALT and 19 non-MALT B-cell lymphomas). Systemic activity at diagnosis of primary SjS correlated with the risk of hematological neoplasia and cryoglobulins with a high risk of either B-cell or non-B-cell lymphoma subtypes. Patients with cytopenias had a high risk of non-MALT B-cell and non-B-cell cancer, while those with low C3 levels had a high risk of MALT lymphomas and those with monoclonal gammopathy and low C4 levels had a high risk of non-MALT lymphomas. The estimated SIR for solid cancer was 1.13 and 11.02 for hematological cancer. SIRs for specific cancers were 36.17 for multiple myeloma and immunoproliferative diseases, 19.41 for Hodgkin lymphoma, 6.04 for other non-Hodgkin lymphomas, 5.17 for thyroid cancer, 4.81 for cancers of the lip and oral cavity, and 2.53 for stomach cancer. Conclusions One third of cancers developed by patients with primary SjS are B-cell lymphomas. The prognostic factors identified at SjS diagnosis differed according to the subtype of B-cell lymphoma developed. Primary SjS is also associated with the development of some non-hematological cancers (thyroid, oral cavity, and stomach).

Published
2017
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7. Association of Functional Polymorphisms of KIR3DL1/DS1 With Behçet's Disease

Author

Ángel Castaño-Núñez, Marco-Antonio Montes-Cano, José-Raúl García-Lozano, Norberto Ortego-Centeno, Francisco-José García-Hernández, Gerard Espinosa, Genaro Graña-Gil, Juan Sánchez-Bursón, María-Rosa Juliá, Roser Solans, Ricardo Blanco, Ana-Celia Barnosi-Marín, Ricardo Gómez de la Torre, Patricia Fanlo, Mónica Rodríguez-Carballeira, Luis Rodríguez-Rodríguez, Teresa Camps, Santos Castañeda, Juan-Jose Alegre-Sancho, Javier Martín, and María-Francisca González-Escribano

Subjects
Behçet's disease, HLA, KIR, NK cells, functional polymorphisms, Immunologic diseases. Allergy, RC581-607
Abstract

Behçet's disease (BD) is an immune-mediated vasculitis related to imbalances between the innate and adaptive immune response. Infectious agents or environmental factors may trigger the disease in genetically predisposed individuals. HLA-B51 is the genetic factor stronger associated with the disease, although the bases of this association remain elusive. NK cells have also been implicated in the etiopathogenesis of BD. A family of NK receptors, Killer-cell Immunoglobulin-like Receptor (KIR), with a very complex organization, is very important in the education and control of the NK cells by the union to their ligands, most of them, HLA class I molecules. This study aimed to investigate the contribution of certain KIR functional polymorphisms to the susceptibility to BD. A total of 466 BD patients and 444 healthy individuals were genotyped in HLA class I (A, B, and C). The set of KIR genes and the functional variants of KIR3DL1/DS1 and KIR2DS4 were also determined. Frequency of KIR3DL1*004 was lower in patients than in controls (0.15 vs. 0.20, P = 0.005, Pc = 0.015; OR = 0.70; 95% CI 0.54–0.90) in both B51 positive and negative individuals. KIR3DL1*004, which encodes a misfolded protein, is included in a common telomeric haplotype with only one functional KIR gene, KIR3DL2. Both, KIR3DL1 and KIR3DL2 sense pathogen-associated molecular patterns but they have different capacities to eliminate them. The education of the NK cells depending on the HLA, the balance of KIR3DL1/KIR3DL2 licensed NK cells and the different capacities of these receptors to eliminate pathogens could be involved in the etiopathogenesis of BD.

Published
2019
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8. Genetic Analysis with the Immunochip Platform in Behçet Disease. Identification of Residues Associated in the HLA Class I Region and New Susceptibility Loci.

Author

Lourdes Ortiz-Fernández, Francisco-David Carmona, Marco-Antonio Montes-Cano, José-Raúl García-Lozano, Marta Conde-Jaldón, Norberto Ortego-Centeno, María Jesús Castillo, Gerard Espinosa, Genaro Graña-Gil, Juan Sánchez-Bursón, María Rosa Juliá, Roser Solans, Ricardo Blanco, Ana-Celia Barnosi-Marín, Ricardo Gómez de la Torre, Patricia Fanlo, Mónica Rodríguez-Carballeira, Luis Rodríguez-Rodríguez, Teresa Camps, Santos Castañeda, Juan-Jose Alegre-Sancho, Javier Martín, and María Francisca González-Escribano

Subjects
Medicine, Science
Abstract

Behcet's disease (BD) is an immuno-mediated vasculitis in which knowledge of its etiology and genetic basis is limited. To improve the current knowledge, a genetic analysis performed with the Immunochip platform was carried out in a population from Spain. A discovery cohort comprising 278 BD cases and 1,517 unaffected controls were genotyped using the Immunochip platform. The validation step was performed on an independent replication cohort composed of 130 BD cases and 600 additional controls. The strongest association signals were observed in the HLA class I region, being HLA-B*51 the highest peak (overall P = 6.82E-32, OR = 3.82). A step-wise conditional logistic regression with classical alleles identified HLA-B*57 and HLA-A*03 as additional independent markers. The amino acid model that best explained the association, includes the position 97 of the HLA-B molecule and the position 66 of the HLA-A. Among the non-HLA loci, the most significant in the discovery analysis were: IL23R (rs10889664: P = 3.81E-12, OR = 2.00), the JRKL/CNTN5 region (rs2848479: P = 5.00E-08, OR = 1.68) and IL12A (rs1874886: P = 6.67E-08, OR = 1.72), which were confirmed in the validation phase (JRKL/CNTN5 rs2848479: P = 3.29E-10, OR = 1.66; IL12A rs1874886: P = 1.62E-08, OR = 1.61). Our results confirm HLA-B*51 as a primary-association marker in predisposition to BD and suggest additional independent signals within the class I region, specifically in the genes HLA-A and HLA-B. Regarding the non-HLA genes, in addition to IL-23R, previously reported in our population; IL12A, described in other populations, was found to be a BD susceptibility factor also in Spaniards; finally, a new associated locus was found in the JRKL/CNTN5 region.

Published
2016
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9. Epistatic interaction of ERAP1 and HLA-B in Behçet disease: a replication study in the Spanish population.

Author

Marta Conde-Jaldón, Marco Antonio Montes-Cano, José Raul García-Lozano, Lourdes Ortiz-Fernández, Norberto Ortego-Centeno, Rocío González-León, Gerard Espinosa, Genaro Graña-Gil, Juan Sánchez-Bursón, Miguel Angel González-Gay, Ana Celia Barnosi-Marín, Roser Solans, Patricia Fanlo, Mónica Rodríguez Carballeira, Teresa Camps, Santos Castañeda, Javier Martín, and María Francisca González-Escribano

Subjects
Medicine, Science
Abstract

Behçet's disease (BD) is a multifactorial disorder associated with the HLA region. Recently, the ERAP1 gene has been proposed as a susceptibility locus with a recessive model and with epistatic interaction with HLA-B51. ERAP1 trims peptides in the endoplasmic reticulum to optimize their length for MHC-I binding. Polymorphisms in this gene have been related with the susceptibility to other immune-mediated diseases associated to HLA class I. Our aim was, the replication in the Spanish population of the association described in the Turkish population between ERAP1 (rs17482078) and BD. Additionally, in order to improve the understanding of this association we analyzed four additional SNPs (rs27044, rs10050860, rs30187 and rs2287987) associated with other diseases related to HLA class I and the haplotype blocks in this gene region. According to our results, frequencies of the homozygous genotypes for the minor alleles of all the SNPs were increased among patients and the OR values were higher in the subgroup of patients with the HLA-B risk factors, although differences were not statistically significant. Moreover, the presence of the same mutation in both chromosomes increased the OR values from 4.51 to 10.72 in individuals carrying the HLA-B risk factors. Therefore, although they were not statistically significant, our data were consistent with an association between ERAP1 and BD as well as with an epistatic interaction between ERAP1 and HLA-B in the Spanish population.

Published
2014
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15. Anticoagulation Strategies in Non-Critically Ill Patients Hospitalized with COVID-19: A Randomized Clinical Trial

Author

Stone, Gregg W., primary, Farkouh, Michael E., additional, Lala, Anuradha, additional, Tinuoye, Elizabeth, additional, Dressler, Ovidiu, additional, Moreno, Pedro R., additional, Palacios, Igor F., additional, Goodman, Shaun G., additional, Esper, Rodrigo B., additional, Abizaid, Alexandre, additional, Varade, Deepak, additional, Betancur, Juan F., additional, Ricalde, Alejandro, additional, Payro, Gerardo, additional, Castellano, José María, additional, Hung, Ivan FN, additional, Nadkarni, Girish N., additional, Giustino, Gennaro, additional, Godoy, Lucas C., additional, Feinman, Jason, additional, Camaj, Anton, additional, Bienstock, Solomon W., additional, Furtado, Remo H.M., additional, Granada, Carlos, additional, Bustamante, Jessica, additional, Peyra, Carlos, additional, Contreras, Johanna, additional, Owen, Ruth, additional, Bhatt, Deepak L., additional, Pocock, Stuart J., additional, Fuster, Valentin, additional, Lala, Anu, additional, Paul, Jonathan, additional, Pyo, Robert, additional, Baber, Usman, additional, Suh, Jason, additional, Saggar, Suraj, additional, Srivatsa, Sanjay, additional, Coylewright, Megan, additional, Chapparo, Sandra, additional, Melo, Jairo, additional, Keller, Norma, additional, Llanos, Alexander, additional, Chiu, Edwin, additional, Fahid, Ibrahim, additional, The, Angela, additional, Esper, Rodrigo Barbosa, additional, Ghetti Cabral, Ricardo Mauro, additional, Pompilio, Mauricio Antonio, additional, Cordeiro de Paula, Leonardo Jorge, additional, Airton de Arruda, Jose, additional, Filho, Roberto Kalil, additional, Faillace, Bruno, additional, Avancini Caramori, Paulo Ricardo, additional, da Silva Junior, Delcio Goncalves, additional, Neto, Eduardo Kowalski, additional, Nascif, Gibran Bhering, additional, Baccaro, Bruno Mendonca, additional, Cesar Cavalcanti, Rafael Rebelo, additional, Moraes Junior, Joao Batista, additional, Betancur, Juan Felipe, additional, Echeverri, Dario, additional, Beltran, Fernan Mendoza, additional, Renowistki Zabarain, Carlos Ramon, additional, Martinez Bula, Eduardo Antonio, additional, Fernandez, Angela María, additional, Melendez Flórez, Hector Julio, additional, Osorio, Wilder Castano, additional, Clavijo Moldón, Absalon Antonio, additional, Moreno, Antonio Figueredo, additional, Wong, Chun-Ka, additional, Varma, Madhumati, additional, Khanna, Aman, additional, Nikam, Prasad, additional, Bangi, Ashpak, additional, Gupta, Jugal Bihari, additional, Bhandari, Sudhir, additional, Sengupta, Shantanu, additional, Bhattacharya, Meenakshi, additional, Mehta, Nihar, additional, Aggarwal, Deepesh, additional, Uppe, Abhay, additional, Calcagno, Andrea, additional, Querini, Patrizia Rovere, additional, Narducci, Maria Lucia, additional, Guerrero, Jessica Paola, additional, Elizalde, Ivan, additional, Bello, Hector Herrera, additional, Cabrera, Otto Tavera, additional, Portano, Julieta Morales, additional, Riedel, Patricia Aubanel, additional, Llamas Esperon, Guillermo Antonio, additional, Guarena Casillas, Jorge Armando, additional, Azpiri, Jose Ramon, additional, Calvillo, Jorge Carrillo, additional, Lopez, Roberto Dominguez, additional, Barreto, Nancy Quezada, additional, Jaramillo, Ricardo, additional, Sokolski, Mateusz, additional, Fernandez, Paula Villares, additional, Moya Mateo, Eva Maria, additional, Varona Arche, Jose Felipe, additional, Mateo, Patricia Fanlo, additional, and Garcia Lomas, Mercedes Villareal, additional

Published
2023
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17. External clinical validation of automated software to identify structural abnormalities and microhaemorrhages in nailfold videocapillaroscopy images

Author

Borja C. Gracia Tello, Eduardo Ramos Ibañez, Luis Saez Comet, Alfredo Guillén Del Castillo, Carmen Pilar Simeón Aznar, Albert Selva O'Callaghan, Gerard Espinosa, Gema Lledó, Mayka Freire Dapena, Elena Martinez Robles, Juan José Ríos, José Antonio Todolí Parra, Begoña Marí Alfonso, Norberto Ortego Centeno, Adela Marín Ballvé, José Luis Callejas Rubio, Vicent Fonollosa Plá, and Patricia Fanlo

Subjects
Rheumatology, Immunology, Immunology and Allergy
Published
2022
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18. Long-term follow-up of certolizumab pegol in uveitis due to immune-mediated inflammatory diseases: multicentre study of 80 patients

Author

José Luis Martín-Varillas, Lara Sanchez-Bilbao, Vanesa Calvo-Río, Alfredo Adán, Inés Hernanz, Adela Gallego-Flores, Emma Beltran-Catalan, Sonia Castro-Oreiro, Patricia Fanlo, Alvaro Garcia Martos, Ignacio Torre, Miguel Cordero-Coma, Juan Ramon De Dios, Ángel García-Aparicio, Marisa Hernández-Garfella, Amalia Sánchez-Andrade, Andrea García-Valle, Olga Maiz, Roberto Miguélez, Sergio Rodríguez-Montero, Ana Urruticoechea, Raúl Veroz, Arantxa Conesa, Cristina Fernández-Carballido, Vega Jovaní, Jose J Mondejar, Olga Martínez González, Patricia Moya Alvarado, Susana Romero-Yuste, Paula Rubio-Muñoz, Eva Peña-Sainz-Pardo, Marta Garijo-Bufort, Rosalía Demetrio-Pablo, José L Hernández, Ricardo Blanco, and Universidad de Cantabria

Subjects
Male, Adult, Autoimmune diseases, Immunology, Middle Aged, Uveitis, Treatment Outcome, Rheumatology, Certolizumab pegol, Systemic vasculitis, Immunology and Allergy, Humans, Female, Biological therapy, Immunosuppressive Agents, Follow-Up Studies
Abstract

ObjectivesTo evaluate effectiveness and safety of certolizumab pegol (CZP) in uveitis due to immune-mediated inflammatory diseases (IMID).MethodsMulticentre study of CZP-treated patients with IMID uveitis refractory to conventional immunosuppressant. Effectiveness was assessed through the following ocular parameters: best-corrected visual acuity, anterior chamber cells, vitritis, macular thickness and retinal vasculitis. These variables were compared between the baseline, and first week, first, third, sixth months, first and second year.ResultsWe studied 80 (33 men/47 women) patients (111 affected eyes) with a mean age of 41.6±11.7 years. The IMID included were: spondyloarthritis (n=43), Behçet’s disease (n=10), psoriatic arthritis (n=8), Crohn’s disease (n=4), sarcoidosis (n=2), juvenile idiopathic arthritis (n=1), reactive arthritis (n=1), rheumatoid arthritis (n=1), relapsing polychondritis (n=1),ConclusionsCZP seems to be effective and safe in uveitis related to different IMID, even in patients refractory to previous biological drugs.

Published
2022

19. Methylprednisolone Pulses in Hospitalized COVID-19 Patients Without Respiratory Failure: A Randomized Controlled Trial

Author

Iñigo Les, Jose Loureiro-Amigo, Ferran Capdevila, Isabel Oriol, Iñaki Elejalde, Judit Aranda-Lobo, Joao Modesto, Elena Güell-Farré, Ruth García, Anna Murgadella-Sancho, Javier Anniccherico, Miguel Martín-Fernández, José Javier Lorza, Joan-Pol Monteys-Montblanch, Julián Librero, Sara Pintado-Lalueza, Marina Delgado, Berta Gracia-García, Julio Sánchez-Álvarez, Melani Pestaña-Fernández, Patricia Fanlo, Gisela Funalleras-Puig, Maite Sarobe, Eduardo Mediavilla, and Carlos Ibero

Subjects
General Medicine
Abstract

BackgroundCorticosteroids are the cornerstone of the treatment of patients with COVID-19 admitted to hospital. However, whether corticosteroids can prevent respiratory worsening in hospitalized COVID-19 patients without oxygen requirements is currently unknown.AimsTo assess the efficacy of methylprednisolone pulses (MPP) in hospitalized COVID-19 patients with increased levels of inflammatory markers not requiring oxygen at baseline.MethodsMulticenter, parallel, randomized, double-blind, placebo-controlled trial conducted in Spain. Patients admitted for confirmed SARS-CoV-2 pneumonia with raised inflammatory markers (C-reactive protein >60 mg/L, interleukin-6 >40 pg/ml, or ferritin >1,000 μg/L) but without respiratory failure after the first week of symptom onset were randomized to receive a 3-day course of intravenous MPP (120 mg/day) or placebo. The primary outcome was treatment failure at 14 days, a composite variable including mortality, the need for ICU admission or mechanical ventilation, and clinical worsening, this last parameter defined as a PaO2/FiO2 ratio below 300; or a 15% decrease in the PaO2 from baseline, together with an increase in inflammatory markers or radiological progression. If clinical worsening occurred, patients received tocilizumab and unmasked corticosteroids. The secondary outcomes were 28-day mortality, adverse events, need for ICU admission or high-flow oxygen, length of hospital stay, SARS-CoV-2 clearance, and changes in laboratory parameters.ResultsA total of 72 patients were randomized and 71 patients were analyzed (34 in the MPP group and 37 in the placebo group). Twenty patients presented with treatment failure (29.4 in the MPP group vs. 27.0% in the placebo group, p = 0.82), with no differences regarding the time to treatment failure between groups. There were no cases of death or mechanical ventilation requirements at 14 days post-randomization. The secondary outcomes were similar in MPP and placebo groups.ConclusionsA 3-day course of MPP after the first week of disease onset did not prevent respiratory deterioration in hospitalized COVID-19 patients with an inflammatory phenotype who did not require oxygen.

Published
2021

20. Capilaroscopia periungueal en el Grupo Español de Enfermedades Autoinmunes Sistémicas (GEAS). Resultados de una encuesta electrónica

Author

Luis Sáez-Comet, Patricia Fanlo-Mateo, Borja Gracia-Tello, José Antonio Todolí Parra, Mayka Freire-Dapena, Gerard Espinosa-Garriga, Begoña Marí Alfonso, Francisco García-Hernández, Alfredo Guillén del Castillo, Norberto Ortego Centeno, Juan José Ríos Blanco, Albert Selva-O’Callaghan, and Vicens Fonollosa Pla

Subjects
business.industry, Medicine, General Medicine, business, Humanities
Published
2020
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21. Nailfold capillaroscopy in the Spanish Group of Systemic Autoimmune Diseases (GEAS). Results of an electronic survey

Author

Luis Sáez-Comet, Patricia Fanlo-Mateo, Borja Gracia-Tello, José Antonio Todolí Parra, Mayka Freire-Dapena, Gerard Espinosa-Garriga, Begoña Marí Alfonso, Francisco García-Hernández, Alfredo Guillén del Castillo, Norberto Ortego Centeno, Juan José Ríos Blanco, Albert Selva-O’Callaghan, and Vicens Fonollosa Pla

Subjects
medicine.medical_specialty, business.industry, medicine, MEDLINE, business, Dermatology, Nailfold Capillaroscopy
Published
2020
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23. Corrigendum: Analysis of the common genetic component of large-vessel vasculitides through a meta-Immunochip strategy (Scientific Reports (2017) 7 (43953) DOI: 10.1038/srep43953)

Author

Martínez Berriochoa, Agustín, Unzurrunzaga, Ainhoa, Hidalgo Conde, Ana, Vuelta, Ana Belén Madroñero, Fernández Nebro, Antonio, Carmen Ordóñez Cañizares, M., Fernández Gutiérrez, Benjamín, Rodríguez Rodríguez, Luis, Escalante, Begoña, Alfonso, Begoña Marí, Sopeña, Bernardo, Gómez Vaquero, Carmen, Raya, Enrique, Grau, Elena, Román, José A., Vicente, Esther F., Miguel, Eugenio de, López Longo, Francisco J., Martínez, Lina, Morado, Inmaculada C., Bernardino Díaz López, J., Caminal Montero, Luis, Martínez Zapico, Aleida, Narváez, Javier, Monfort, Jordi, Tío, Laura, Filloy, José A. Miranda, Sánchez Martín, Julio, Alegre Sancho, Juan J., Sáez Comet, Luis, Conesa, Mercedes Pérez, Corbera Bellalta, Marc, Ramentol Sintas, Marc, García Villanueva, María Jesús, Rojas, Mercedes Guijarro, Ortego Centeno, Norberto, Fernández, Raquel Ríos, Callejas, José Luis, Pernaute, Olga Sanchez, Mateo, Patricia Fanlo, Blanco, Ricardo, González, Sergio Prieto, Soriano, Víctor Manuel Martínez T.a.b.o.a.d.a.1.1. Alessandra, Lunardi, Claudio, Gianfreda, Davide, Santilli, Daniele, Bonatti, Francesco, Muratore, Francesco, Pazzola, Giulia, ADDIMANDA, OLGA, Emmi, Giacomo, Ramirez, Giuseppe A., Beretta, Lorenzo, Govoni, Marcello, Onat, Marco A. C.i.m.m.i.n.o.5.2. Ahmet Mesut, Cefle, Ayse, Yazici, Ayten, Kısacık, Bünyamin, Dalkilic, Ediz, Seyahi, Emire, Fresko, Izzet, Tunc, Ercan, Erken, Eren, Ozer, Hüseyin TE, Aksu, Kenan, Keser, Gokhan, Ozturk, Mehmet A., Bıcakcıgil, Muge, Duzgun, Nurşen, Karadag, Omer, Kiraz, Sedat, Pamuk, Ömer N., Akar, Servet, Onen, Fatos, Akkoc, Nurullah, Kamali, Sevil, Inanc, Murat, Yentür, Sibel P., Aydin, Sibel Z., Alibaz Oner, Fatma, Kaşifoğlu, Timuçin, Cobankara, Veli, Ozbalkan, Zeynep, Ates, Askin, Carette, Yasar K.a.r.a.a.s.l.a.n.7.3. Simon, Chung, Sharon A., Cuthbertson, David, Forbess, Lindsay J., Hoffman, Gary S., Khalidi, Nader A., Koening, Curry L., Langford, Carol A., Mcalear, Carol A., McKinnon Maksimowicz, Kathleen, Monach, Paul A., Moreland, Larry, Pagnoux, Christian, Seo, Philip, Spiera, Robert, Sreih, Antoine G., Warrington, Kenneth J., Ytterberg87, Steven R. ., Martínez-Berriochoa, Agustín, Unzurrunzaga, Ainhoa, Hidalgo-Conde, Ana, Vuelta, Ana Belén Madroñero, Fernández-Nebro, Antonio, Carmen Ordóñez-Cañizares, M., Fernández-Gutiérrez, Benjamín, Rodríguez-Rodríguez, Lui, Escalante, Begoña, Alfonso, Begoña Marí, Sopeña, Bernardo, Gómez-Vaquero, Carmen, Raya, Enrique, Grau, Elena, Román, José A., Vicente, Esther F., Miguel, Eugenio de, López-Longo, Francisco J., Martínez, Lina, Morado, Inmaculada C., Bernardino Díaz-López, J., Caminal-Montero, Lui, Martínez-Zapico, Aleida, Narváez, Javier, Monfort, Jordi, Tío, Laura, Filloy, José A. Miranda, Sánchez-Martín, Julio, Alegre-Sancho, Juan J., Sáez-Comet, Lui, Conesa, Mercedes Pérez, Corbera-Bellalta, Marc, Ramentol-Sintas, Marc, García-Villanueva, María Jesú, Rojas, Mercedes Guijarro, Ortego-Centeno, Norberto, Fernández, Raquel Río, Callejas, José Lui, Pernaute, Olga Sanchez, Mateo, Patricia Fanlo, Blanco, Ricardo, González, Sergio Prieto, Soriano, Víctor Manuel Martínez-Taboada11.Alessandra, Lunardi, Claudio, Gianfreda, Davide, Santilli, Daniele, Bonatti, Francesco, Muratore, Francesco, Pazzola, Giulia, Addimanda, Olga, Emmi, Giacomo, Ramirez, Giuseppe A., Beretta, Lorenzo, Govoni, Marcello, Onat, Marco A. Cimmino52. Ahmet Mesut, Cefle, Ayse, Yazici, Ayten, Kısacık, Bünyamin, Dalkilic, Ediz, Seyahi, Emire, Fresko, Izzet, Tunc, Ercan, Erken, Eren, Ozer, Hüseyin TE, Aksu, Kenan, Keser, Gokhan, Ozturk, Mehmet A., Bıcakcıgil, Muge, Duzgun, Nurşen, Karadag, Omer, Kiraz, Sedat, Pamuk, Ömer N., Akar, Servet, Onen, Fato, Akkoc, Nurullah, Kamali, Sevil, Inanc, Murat, Yentür, Sibel P., Aydin, Sibel Z., Alibaz-Oner, Fatma, Kaşifoğlu, Timuçin, Cobankara, Veli, Ozbalkan, Zeynep, Ates, Askin, Carette, Yasar Karaaslan73. Simon, Chung, Sharon A., Cuthbertson, David, Forbess, Lindsay J., Hoffman, Gary S., Khalidi, Nader A., Koening, Curry L., Langford, Carol A., Mcalear, Carol A., McKinnon-Maksimowicz, Kathleen, Monach, Paul A., Moreland, Larry, Pagnoux, Christian, Seo, Philip, Spiera, Robert, Sreih, Antoine G., Warrington, Kenneth J., and Ytterberg87, Steven R. .

Subjects
Multidisciplinary, skin and connective tissue diseases
Abstract

Giant cell arteritis (GCA) and Takayasu’s arteritis (TAK) are major forms of large-vessel vasculitis (LVV) that share clinical features. To evaluate their genetic similarities, we analysed Immunochip genotyping data from 1,434 LVV patients and 3,814 unaffected controls. Genetic pleiotropy was also estimated. The HLA region harboured the main disease-specific associations. GCA was mostly associated with class II genes (HLA-DRB1/HLA-DQA1) whereas TAK was mostly associated with class I genes (HLA-B/ MICA). Both the statistical significance and effect size of the HLA signals were considerably reduced in the cross-disease meta-analysis in comparison with the analysis of GCA and TAK separately. Consequently, no significant genetic correlation between these two diseases was observed when HLA variants were tested. Outside the HLA region, only one polymorphism located nearby the IL12B gene surpassed the study-wide significance threshold in the meta-analysis of the discovery datasets (rs755374, P = 7.54E-07; ORGCA = 1.19, ORTAK = 1.50). This marker was confirmed as novel GCA risk factor using four additional cohorts (PGCA = 5.52E-04, ORGCA = 1.16). Taken together, our results provide evidence of strong genetic differences between GCA and TAK in the HLA. Outside this region, common susceptibility factors were suggested, especially within the IL12B locus.

Published
2017

24. Analysis of the common genetic component of large-vessel vasculitides through a meta-Immunochip strategy

Author

Martínez Berriochoa, Agustín, Unzurrunzaga, Ainhoa, Hidalgo Conde, Ana, Vuelta, Ana Belén Madroñero, Fernández Nebro, Antonio, Carmen Ordóñez Cañizares, M., Fernández Gutiérrez, Benjamín, Rodríguez Rodríguez, Luis, Escalante, Begoña, Alfonso, Begoña Marí, Sopeña, Bernardo, Gómez Vaquero, Carmen, Raya, Enrique, Grau, Elena, Román, José A., Vicente, Esther F., Miguel, Eugenio de, López Longo, Francisco J., Martínez, Lina, Morado, Inmaculada C., Bernardino Díaz López, J., Caminal Montero, Luis, Martínez Zapico, Aleida, Narváez, Javier, Monfort, Jordi, Tío, Laura, Filloy, José A. Miranda, Sánchez Martín, Julio, Alegre Sancho, Juan J., Sáez Comet, Luis, Conesa, Mercedes Pérez, Corbera Bellalta, Marc, Ramentol Sintas, Marc, García Villanueva, María Jesús, Rojas, Mercedes Guijarro, Ortego Centeno, Norberto, Fernández, Raquel Ríos, Callejas, José Luis, Pernaute, Olga Sanchez, Mateo, Patricia Fanlo, Blanco, Ricardo, González, Sergio Prieto, Soriano, Víctor Manuel Martínez T.a.b.o.a.d.a.1.1. Alessandra, Lunardi, Claudio, Gianfreda, Davide, Santilli, Daniele, Bonatti, Francesco, Muratore, Francesco, Pazzola, Giulia, ADDIMANDA, OLGA, Emmi, Giacomo, Ramirez, Giuseppe A., Beretta, Lorenzo, Govoni, Marcello, Onat, Marco A. Cimmino52 Ahmet Mesut, Cefle, Ayse, Yazici, Ayten, Kısacık, Bünyamin, Dalkilic, Ediz, Seyahi, Emire, Fresko, Izzet, Tunc, Ercan, Erken, Eren, Ozer, Hüseyin TE, Aksu, Kenan, Keser, Gokhan, Ozturk, Mehmet A., Bıcakcıgil, Muge, Duzgun, Nurşen, Karadag, Omer, Kiraz, Sedat, Pamuk, Ömer N., Akar, Servet, Onen, Fatos, Akkoc, Nurullah, Kamali, Sevil, Inanc, Murat, Yentür, Sibel P., Aydin, Sibel Z., Alibaz Oner, Fatma, Kaşifoğlu, Timuçin, Cobankara, Veli, Ozbalkan, Zeynep, Ates, Askin, Carette, Yasar Karaaslan73 Simon, Chung, Sharon A., Cuthbertson, David, Forbess, Lindsay J., Hoffman, Gary S., Khalidi, Nader A., Koening, Curry L., Langford, Carol A., Mcalear, Carol A., McKinnon Maksimowicz, Kathleen, Monach, Paul A., Moreland, Larry, Pagnoux, Christian, Seo, Philip, Spiera, Robert, Sreih, Antoine G., Warrington, Kenneth J., Ytterberg87, Steven R. ., Universidad de Cantabria, David Carmona, F., Coit, Patrick, Saruhan-Direskeneli, Guher, Hernandez-Rodriguez, Jose, Cid, Maria C., Solans, Roser, Castaneda, Santos, Vaglio, Augusto, Direskeneli, Haner, Merkel, Peter A., Boiardi, Luigi, Salvarani, Carlo, Gonzalez-Gay, Miguel A., Martin, Javier, Sawalha, Amr H., Institut Català de la Salut, [Carmona FD] Instituto de Parasitología y Biomedicina ‘López-Neyra’, IPBLN-CSIC, PTS Granada, Granada, Spain. Departamento de Genética e Instituto de Biotecnología, Universidad de Granada, Granada 18016, Spain. [Coit P] Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. [Saruhan-Direskeneli G] Department of Physiology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey. [Hernández-Rodríguez J, Cid MC] Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. [Solans R] Unitat de Malalties Autoimmunes Sistèmiques, Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain, Vall d'Hebron Barcelona Hospital Campus, Martínez-Berriochoa, Agustín, Unzurrunzaga, Ainhoa, Hidalgo-Conde, Ana, Vuelta, Ana Belén Madroñero, Fernández-Nebro, Antonio, Carmen Ordóñez-Cañizares, M., Fernández-Gutiérrez, Benjamín, Rodríguez-Rodríguez, Lui, Escalante, Begoña, Alfonso, Begoña Marí, Sopeña, Bernardo, Gómez-Vaquero, Carmen, Raya, Enrique, Grau, Elena, Román, José A., Vicente, Esther F., Miguel, Eugenio de, López-Longo, Francisco J., Martínez, Lina, Morado, Inmaculada C., Bernardino Díaz-López, J., Caminal-Montero, Lui, Martínez-Zapico, Aleida, Narváez, Javier, Monfort, Jordi, Tío, Laura, Filloy, José A. Miranda, Sánchez-Martín, Julio, Alegre-Sancho, Juan J., Sáez-Comet, Lui, Conesa, Mercedes Pérez, Corbera-Bellalta, Marc, Ramentol-Sintas, Marc, García-Villanueva, María Jesú, Rojas, Mercedes Guijarro, Ortego-Centeno, Norberto, Fernández, Raquel Río, Callejas, José Lui, Pernaute, Olga Sanchez, Mateo, Patricia Fanlo, Blanco, Ricardo, González, Sergio Prieto, Soriano, Víctor Manuel Martínez-Taboada11.Alessandra, Lunardi, Claudio, Gianfreda, Davide, Santilli, Daniele, Bonatti, Francesco, Muratore, Francesco, Pazzola, Giulia, Addimanda, Olga, Emmi, Giacomo, Ramirez, Giuseppe A., Beretta, Lorenzo, Govoni, Marcello, Onat, Marco A. Cimmino52 Ahmet Mesut, Cefle, Ayse, Yazici, Ayten, Kısacık, Bünyamin, Dalkilic, Ediz, Seyahi, Emire, Fresko, Izzet, Tunc, Ercan, Erken, Eren, Ozer, Hüseyin TE, Aksu, Kenan, Keser, Gokhan, Ozturk, Mehmet A., Bıcakcıgil, Muge, Duzgun, Nurşen, Karadag, Omer, Kiraz, Sedat, Pamuk, Ömer N., Akar, Servet, Onen, Fato, Akkoc, Nurullah, Kamali, Sevil, Inanc, Murat, Yentür, Sibel P., Aydin, Sibel Z., Alibaz-Oner, Fatma, Kaşifoğlu, Timuçin, Cobankara, Veli, Ozbalkan, Zeynep, Ates, Askin, Carette, Yasar Karaaslan73 Simon, Chung, Sharon A., Cuthbertson, David, Forbess, Lindsay J., Hoffman, Gary S., Khalidi, Nader A., Koening, Curry L., Langford, Carol A., Mcalear, Carol A., McKinnon-Maksimowicz, Kathleen, Monach, Paul A., Moreland, Larry, Pagnoux, Christian, Seo, Philip, Spiera, Robert, Sreih, Antoine G., Warrington, Kenneth J., Ytterberg87, Steven R. ., and Universitat de Barcelona

Subjects
Male, 0301 basic medicine, PATHOGENESIS, enfermedades cardiovasculares::enfermedades vasculares::vasculitis [ENFERMEDADES], Genome-wide association study, Cardiovascular Diseases::Vascular Diseases::Vasculitis [DISEASES], 0302 clinical medicine, vasculitides, Immunochip strategy, HLA Antigens, RHEUMATOLOGY 1990 CRITERIA, Medicine, skin and connective tissue diseases, Genetics, RISK, Multidisciplinary, Nervous System Diseases::Autoimmune Diseases of the Nervous System::Vasculitis, Central Nervous System::Giant Cell Arteritis [DISEASES], TAKAYASU ARTERITIS, ASSOCIATION, Genomics, Corrigenda, predisposición, 3. Good health, enfermedades del sistema nervioso::enfermedades autoinmunitarias del sistema nervioso::vasculitis del sistema nervioso central::arteritis de células gigantes [ENFERMEDADES], Female, meta-Immunochip strategy, Vasculitis, Genotype, SUSCEPTIBILITY LOCI, Giant Cell Arteritis, Locus (genetics), POLYMYALGIA-RHEUMATICA, Human leukocyte antigen, Genetic correlation, 03 medical and health sciences, GIANT-CELL ARTERITIS, Genetic Pleiotropy, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Arteritis, Genotyping, Arteritis de cèl·lules gegants, 030203 arthritis & rheumatology, Polymorphism, Genetic, IDENTIFICATION, business.industry, medicine.disease, common genetic component, Takayasu Arteritis, Giant cell arteritis, Genòmica, 030104 developmental biology, business, INFLAMMATORY-BOWEL-DISEASE, arge-vessel vasculitides
Abstract

Giant cell arteritis (GCA) and Takayasu's arteritis (TAK) are major forms of large-vessel vasculitis (LVV) that share clinical features. To evaluate their genetic similarities, we analysed Immunochip genotyping data from 1,434 LVV patients and 3,814 unaffected controls. Genetic pleiotropy was also estimated. The HLA region harboured the main disease-specific associations. GCA was mostly associated with class II genes (HLA-DRB1/HLA-DQA1) whereas TAK was mostly associated with class I genes (HLA-B/MICA). Both the statistical significance and effect size of the HLA signals were considerably reduced in the cross-disease meta-analysis in comparison with the analysis of GCA and TAK separately. Consequently, no significant genetic correlation between these two diseases was observed when HLA variants were tested. Outside the HLA region, only one polymorphism located nearby the IL12B gene surpassed the study-wide significance threshold in the meta-analysis of the discovery datasets (rs755374, P = 7.54E-07; ORGCA = 1.19, ORTAK = 1.50). This marker was confirmed as novel GCA risk factor using four additional cohorts (PGCA = 5.52E-04, ORGCA = 1.16). Taken together, our results provide evidence of strong genetic differences between GCA and TAK in the HLA. Outside this region, common susceptibility factors were suggested, especially within the IL12B locus., This work was supported by SAF2012– 34435 from the Spanish Ministry of Economy and Competitiveness, BIO-1395 from Junta de Andalucía, and RD12/0009/0004 from the RETICS Program (RIER) of Instituto de Salud Carlos III (ISCIII). FDC was recipient of a grant from the ‘Ramón y Cajal’ programme of the Spanish Ministry of Economy and Competitiveness (RYC-2014–16458). MCC and JHR are supported by Ministerio de Economía y Competitividad (SAF 14/57708R), cofunded by “Fondo Europeo de Desarrollo Regional, Unión Europea, Una manera de hacer Europa” [Instituto de Salud Carlos III and Fondo Europeo de desarrollo regional (FEDER) (PIE 13/00033)]. The Vasculitis Clinical Research Consortium has received support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54AR057319), the National Center for Research Resources (U54 RR019497), the Office of Rare Diseases Research, and the National Center for Advancing Translational Science. The VCRC is part of the Rare Diseases Clinical Research Network (RDCRN).

Published
2017

25. Delirium como síntoma de presentación atípico de lupus eritematoso sistémico

Author

Patricia Fanlo-Mateo, Vanesa Antoña-Sáenz, Amaia Redondo-Arriazu, Fernando Pérez-Nievas, and Laureano Menéndez-Ozcoidi

Abstract

El lupus eritematoso sistémico (LES) es una enfermedad autoinmune multisistémica que puede afectar al sistema nervioso central (SNC) y al sistema nervioso periférico (SNP) en forma de lupus neuropsiquiátrico (LES-NP). Hasta el 95% de los pacientes podrán desarrollar LES-NP en cualquier momento de la enfermedad. Múltiples factores (autoanticuerpos, microvasculopatía y citocinas proinflamatorias) se han asociado con su patogenia. El diagnóstico de LES-NP supone un reto para el clínico, ya que sólo se conseguirá el diagnóstico una vez que se hayan descartado otras causas. El manejo de esta patología se basa en el tratamiento sintomático asociado o no a inmunosupresores.

Published
2017
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26. Severe, life-threatening phenotype of primary Sjögren's syndrome: clinical characterisation and outcomes in 1580 patients (GEAS-SS Registry)

Author

Alejandra, Flores-Chávez, Belchin, Kostov, Roser, Solans, Guadalupe, Fraile, Brenda, Maure, Carlos, Feijoo-Massó, Francisco-Javier, Rascón, Roberto, Pérez-Alvarez, Mónica, Zamora-Pasadas, Alicia, García-Pérez, Miguel, Lopez-Dupla, Miguel-Ángel, Duarte-Millán, Mar, Ripoll, Eva, Fonseca-Aizpuru, Pablo, Guisado-Vasco, Blanca, Pinilla, Gloria, de-la-Red, Antonio-J, Chamorro, César, Morcillo, Patricia, Fanlo, Mª José, Soto-Cárdenas, Soledad, Retamozo, Manuel, Ramos-Casals, and Pilar, Brito-Zerón

Subjects
Adult, Male, Middle Aged, Risk Assessment, Severity of Illness Index, Decision Support Techniques, Phenotype, Sjogren's Syndrome, Treatment Outcome, Predictive Value of Tests, Risk Factors, Spain, Disease Progression, Humans, Female, Registries, Glucocorticoids, Immunosuppressive Agents, Aged
Abstract

To analyse the clinical features and outcomes of patients presenting with life-threatening systemic disease in a large cohort of Spanish patients with primary Sjögren's syndrome (SS).The GEAS-SS multicentre registry was formed in 2005 with the aim of collecting a large series of Spanish patients with primary SS, and included more than 20 Spanish reference centres with substantial experience in the management of SS patients. By January 2018, the database included 1580 consecutive patients fulfilling the 2002 classification criteria for primary SS. Severe, life-threatening systemic disease was defined as an activity level scored as "high" in at least one ESSDAI domain.Among 1580 patients, 208 (13%) were classified as presenting a severe, potentially life-threatening systemic disease: 193 presented one ESSDAI domain classified as high, 14 presented two high scored domains and only one presented three high activity domains. The ESSDAI domains involved consisted of lymphadenopathy in 78 (37%) cases, CNS in 28 (13%), PNS in 25 (12%), pulmonary in 25 (12%), renal in 21 (10%), cutaneous in 19 (9%), articular in 18 (9%), haematological in 7 (3%) and muscular in 4 (2%). Patients with severe systemic disease were more frequently men (p=0.001) and had a higher frequency of anaemia (p0.001), lymphopenia (p0.001), rheumatoid factor (p=0.021), low C3 levels (p=0.015), low C4 levels (p0.001) and cryoglobulins (p0.001). From a therapeutic point of view, systemic patients received more frequently glucocorticoids (p0.001), immunosuppressants (p0.001), intravenous immunoglobulins (p=0.008) and rituximab (p0.001). We found an overall mortality rate of 20% in severe systemic patients, a rate that reached to 33% in patients presenting two or more high systemic involvements; these patients had a higher frequency of low C4 levels (p=0.012) and cryoglobulins (p=0.001) in comparison with those with a single severe organ involved.13% of patients with primary SS develop a potentially life-threatening systemic disease (mainly lymphoma, but also severe internal organ involvements including nervous system, the lungs and the kidneys). This subset of patients requires intensive therapeutic management with a mortality rate of nearly 20% of cases.

Published
2018

27. Brief Report: IRF4 Newly Identified as a Common Susceptibility Locus for Systemic Sclerosis and Rheumatoid Arthritis in a Cross-Disease Meta-Analysis of Genome-Wide Association Studies

Author

López-Isac, Elena, Martín, Jose Ezequiel, Assassi, Shervin, Simeón, Carmen P., Carreira, Patricia, Ortego-Centeno, Norberto, Freire, Mayka, Beltrán, Emma, Narváez, Javier, Alegre-Sancho, Juan J., Fernández-Gutiérrez, Benjamín, Balsa, Alejandro, Ortiz, Ana M., González-Gay, Miguel A., Beretta, Lorenzo, Santaniello, Alessandro, Bellocchi, Chiara, Lunardi, Claudio, Moroncini, Gianluca, Gabrielli, Armando, Witte, Torsten, Hunzelmann, Nicolas, Distler, Jörg H W, Riekemasten, Gabriella, van der Helm-van Mil, Annette H., de Vries-Bouwstra, Jeska, Magro-Checa, Cesar, Voskuyl, Alexandre E., Vonk, Madelon C., Molberg, Øyvind, Merriman, Tony, Hesselstrand, Roger, Nordin, Annika, Padyukov, Leonid, Herrick, Ariane, Eyre, Steve, Koeleman, Bobby P C, Denton, Christopher P., Fonseca, Carmen, Radstake, Timothy R D J, Worthington, Jane, Mayes, Maureen D., Martín, Javier, Ríos, Raquel, Callejas, Jose Luis, Hitos, José Antonio Vargas, Portales, Rosa García, Camps, María Teresa, Fernández-Nebro, Antonio, González-Escribano, María F., García-Hernández, Francisco José, Castillo, Ma Jesús, Ángeles Aguirre, Ma, Gómez-Gracia, Inmaculada, Rodríguez-Rodríguez, Luis, Peña, Paloma García de la, Vicente, Esther, Andreu, José Luis, de Castro, Mónica Fernández, López-Longo, Francisco Javier, Martínez, Lina, Fonollosa, Vicente, Guillén, Alfredo, Castellví, Iván, Espinosa, Gerard, Tolosa, Carlos, Pros, Anna, Carballeira, Mónica Rodríguez, Narváez, Francisco Javier, Rivas, Manel Rubio, Ortiz-Santamaría, Vera, Madroñero, Ana Belén, Díaz, Bernardino, Trapiella, Luis, Sousa, Adrián, Egurbide, María Victoria, Mateo, Patricia Fanlo, Sáez-Comet, Luis, Díaz, Federico, Hernández, Vanesa, Román-Ivorra, José Andrés, Grau, Elena, Alegre-Sancho, Juan José, Blanco García, Francisco J., and Oreiro, Natividad

Subjects
Rheumatology, Immunology, Journal Article, Immunology and Allergy, skin and connective tissue diseases
Abstract

Objective: Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that have similar clinical and immunologic characteristics. To date, several shared SSc–RA genetic loci have been identified independently. The aim of the current study was to systematically search for new common SSc–RA loci through an interdisease meta–genome-wide association (meta-GWAS) strategy. Methods: The study was designed as a meta-analysis combining GWAS data sets of patients with SSc and patients with RA, using a strategy that allowed identification of loci with both same-direction and opposite-direction allelic effects. The top single-nucleotide polymorphisms were followed up in independent SSc and RA case–control cohorts. This allowed an increase in the sample size to a total of 8,830 patients with SSc, 16,870 patients with RA, and 43,393 healthy controls. Results: This cross-disease meta-analysis of the GWAS data sets identified several loci with nominal association signals (P

Published
2016

28. PTPN22 is not associated with Behçet's disease. Study spanning the complete gene region in the Spanish population and meta-analysis of the functional variant R620W

Author

Lourdes, Ortiz-Fernández, Marco Antonio, Montes-Cano, José-Raúl, García-Lozano, Marta, Conde-Jaldón, Norberto, Ortego-Centeno, Rocio, González-Leon, Gerard, Espinosa, Genaro, Graña-Gil, Juan, Sánchez-Bursón, Maria Rosa, Juliá, Roser, Solans, Ricardo, Blanco, Ana-Celia, Barnosi-Marín, Patricia, Fanlo, Monica, Rodríguez Carballeira, Maria Teresa, Camps, Santos, Castañeda, Javier, Martín, and María Francisca, González-Escribano

Subjects
Genetic Markers, Male, Chi-Square Distribution, Behcet Syndrome, Protein Tyrosine Phosphatase, Non-Receptor Type 22, Polymorphism, Single Nucleotide, Phenotype, Risk Factors, Spain, Case-Control Studies, Odds Ratio, Humans, Female, Genetic Predisposition to Disease, Promoter Regions, Genetic, Genetic Association Studies
Abstract

The functional variant R620W of the protein tyrosine phosphatase non receptor-22 (PTPN22) gene plays an important role in susceptibility to several immuno-mediated pathologies. Behçet's disease (BD) is a complex disease related to the immune system with a demonstrated genetic base. The HLA class I genes are the most important genetic factors in BD although other genes are also involved in the susceptibility to this disease. The PTPN22 has been proposed as a candidate gene in BD but this association has not been clearly demonstrated yet. The aim of this study was to assess the association of PTPN22 with BD.A cohort composed of 404 Spanish BD patients and 1517 unrelated healthy individuals ethnically matched was genotyped in rs2476601 (R620W). Five tag SNPs: rs1217412, rs2476599, rs3789607, rs3765598 and rs1217419 (spanning a 57 Kb region between 3'UTR and 5'UTR) and rs2488457 (located at the promoter region) were also studied in order to perform a screening of the complete gene. Genotyping was performed using TaqMan® assays. The rs2476601 data were included in a meta-analysis together with those published till the date. The rest of SNPs were used in a case-control study.No evidence of the association of rs2476601 with BD in the meta-analysis (P = 0.504 in the model of alleles) was found. In the case-control study, no statistically significant differences were observed when comparing the distribution of variants in patients and controls.Our results do not support a major role of the PTPN22 gene in BD.

Published
2015

29. Association of CCR5Δ32 and Behçet's disease: new data from a case-control study in the Spanish population and meta-analysis

Author

Lourdes, Ortiz-Fernández, Jose-Raul, García-Lozano, Marco-Antonio, Montes-Cano, Marta, Conde-Jaldón, Norberto, Ortego-Centeno, Maria-Jesus, Castillo-Palma, Gerard, Espinosa, Genaro, Graña-Gil, Juan, Sánchez-Bursón, Maria Rosa, Juliá, Ricardo, Blanco, Ana-Celia, Barnosi-Marín, Roser, Solans, Patricia, Fanlo, Monica, Rodríguez-Carballeira, Teresa, Camps, Santos, Castañeda, Javier, Martín, and Maria-Francisca, González-Escribano

Subjects
Adult, Male, Chi-Square Distribution, Receptors, CCR5, Behcet Syndrome, Middle Aged, Risk Assessment, Phenotype, Gene Frequency, Risk Factors, Spain, Case-Control Studies, Odds Ratio, Humans, Female, Genetic Predisposition to Disease, Genetic Association Studies
Abstract

Behçet's disease (BD) is an immune-mediated and complex disease associated with HLA class I and other genes. The aim of this study was to contribute to a better understanding of the relationship of the 32-bp deletion in the CCR5 gene (CCR5Δ32) and this disease by conducting a case-control study in the Spanish population and also a meta-analysis including all the studies available to date.A cohort composed of 348 BD Spanish patients and 477 unrelated healthy and ethnically matched individuals were genotyped in CCR5Δ32 using polymerase chain reaction (PCR) and capillary electrophoresis with fluorescent detection. In the meta-analysis, data from a total of seven populations extracted from four previous studies along with data of the present study were included.Regarding the case-control study, no statistically significant differences were observed when the patient and control groups were compared (allelic model: 0.07 in patients vs. 0.06 in controls, p=0.303). In the meta-analysis, no evidence of association of the CCR5Δ32 polymorphism with BD was observed (pMH=0.091; OR=1.22; 95%CI 0.98 to 1.52 in the allelic model).The results of this meta-analysis discard a major role of the CCR5Δ32 polymorphism in BD.

Published
2015

30. Brief Report: IRF4 Newly Identified as a Common Susceptibility Locus for Systemic Sclerosis and Rheumatoid Arthritis in a Cross-Disease Meta-Analysis of Genome-Wide Association Studies

Author

Genetica Groep Koeleman, Circulatory Health, Brain, Child Health, Translationele immunologie, Infection & Immunity, López-Isac, Elena, Martín, Jose Ezequiel, Assassi, Shervin, Simeón, Carmen P., Carreira, Patricia, Ortego-Centeno, Norberto, Freire, Mayka, Beltrán, Emma, Narváez, Javier, Alegre-Sancho, Juan J., Fernández-Gutiérrez, Benjamín, Balsa, Alejandro, Ortiz, Ana M., González-Gay, Miguel A., Beretta, Lorenzo, Santaniello, Alessandro, Bellocchi, Chiara, Lunardi, Claudio, Moroncini, Gianluca, Gabrielli, Armando, Witte, Torsten, Hunzelmann, Nicolas, Distler, Jörg H W, Riekemasten, Gabriella, van der Helm-van Mil, Annette H., de Vries-Bouwstra, Jeska, Magro-Checa, Cesar, Voskuyl, Alexandre E., Vonk, Madelon C., Molberg, Øyvind, Merriman, Tony, Hesselstrand, Roger, Nordin, Annika, Padyukov, Leonid, Herrick, Ariane, Eyre, Steve, Koeleman, Bobby P C, Denton, Christopher P., Fonseca, Carmen, Radstake, Timothy R D J, Worthington, Jane, Mayes, Maureen D., Martín, Javier, Ríos, Raquel, Callejas, Jose Luis, Hitos, José Antonio Vargas, Portales, Rosa García, Camps, María Teresa, Fernández-Nebro, Antonio, González-Escribano, María F., García-Hernández, Francisco José, Castillo, Ma Jesús, Ángeles Aguirre, Ma, Gómez-Gracia, Inmaculada, Rodríguez-Rodríguez, Luis, Peña, Paloma García de la, Vicente, Esther, Andreu, José Luis, de Castro, Mónica Fernández, López-Longo, Francisco Javier, Martínez, Lina, Fonollosa, Vicente, Guillén, Alfredo, Castellví, Iván, Espinosa, Gerard, Tolosa, Carlos, Pros, Anna, Carballeira, Mónica Rodríguez, Narváez, Francisco Javier, Rivas, Manel Rubio, Ortiz-Santamaría, Vera, Madroñero, Ana Belén, Díaz, Bernardino, Trapiella, Luis, Sousa, Adrián, Egurbide, María Victoria, Mateo, Patricia Fanlo, Sáez-Comet, Luis, Díaz, Federico, Hernández, Vanesa, Román-Ivorra, José Andrés, Grau, Elena, Alegre-Sancho, Juan José, Blanco García, Francisco J., Oreiro, Natividad, Genetica Groep Koeleman, Circulatory Health, Brain, Child Health, Translationele immunologie, Infection & Immunity, López-Isac, Elena, Martín, Jose Ezequiel, Assassi, Shervin, Simeón, Carmen P., Carreira, Patricia, Ortego-Centeno, Norberto, Freire, Mayka, Beltrán, Emma, Narváez, Javier, Alegre-Sancho, Juan J., Fernández-Gutiérrez, Benjamín, Balsa, Alejandro, Ortiz, Ana M., González-Gay, Miguel A., Beretta, Lorenzo, Santaniello, Alessandro, Bellocchi, Chiara, Lunardi, Claudio, Moroncini, Gianluca, Gabrielli, Armando, Witte, Torsten, Hunzelmann, Nicolas, Distler, Jörg H W, Riekemasten, Gabriella, van der Helm-van Mil, Annette H., de Vries-Bouwstra, Jeska, Magro-Checa, Cesar, Voskuyl, Alexandre E., Vonk, Madelon C., Molberg, Øyvind, Merriman, Tony, Hesselstrand, Roger, Nordin, Annika, Padyukov, Leonid, Herrick, Ariane, Eyre, Steve, Koeleman, Bobby P C, Denton, Christopher P., Fonseca, Carmen, Radstake, Timothy R D J, Worthington, Jane, Mayes, Maureen D., Martín, Javier, Ríos, Raquel, Callejas, Jose Luis, Hitos, José Antonio Vargas, Portales, Rosa García, Camps, María Teresa, Fernández-Nebro, Antonio, González-Escribano, María F., García-Hernández, Francisco José, Castillo, Ma Jesús, Ángeles Aguirre, Ma, Gómez-Gracia, Inmaculada, Rodríguez-Rodríguez, Luis, Peña, Paloma García de la, Vicente, Esther, Andreu, José Luis, de Castro, Mónica Fernández, López-Longo, Francisco Javier, Martínez, Lina, Fonollosa, Vicente, Guillén, Alfredo, Castellví, Iván, Espinosa, Gerard, Tolosa, Carlos, Pros, Anna, Carballeira, Mónica Rodríguez, Narváez, Francisco Javier, Rivas, Manel Rubio, Ortiz-Santamaría, Vera, Madroñero, Ana Belén, Díaz, Bernardino, Trapiella, Luis, Sousa, Adrián, Egurbide, María Victoria, Mateo, Patricia Fanlo, Sáez-Comet, Luis, Díaz, Federico, Hernández, Vanesa, Román-Ivorra, José Andrés, Grau, Elena, Alegre-Sancho, Juan José, Blanco García, Francisco J., and Oreiro, Natividad

Published
2016

31. Lack of association of TNFAIP3 and JAK1 with Behçet's disease in the European population

Author

Lourdes, Ortiz-Fernández, José-Raul, García-Lozano, Marco-Antonio, Montes-Cano, Marta, Conde-Jaldón, Norberto, Ortego-Centeno, Francisco-Jose, García-Hernández, Gerard, Espinosa, Genaro, Graña-Gil, Juan, Sánchez-Bursón, Maria Rosa, Juliá, Ricardo, Blanco, Ana-Celia, Barnosi-Marín, Roser, Solans, Patricia, Fanlo, Monica, Rodríguez Carballeira, Teresa, Camps, Santos, Castañeda, Javier, Martín, and Maria-Francisca, González-Escribano

Subjects
Adult, Genetic Markers, Male, Behcet Syndrome, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, Janus Kinase 1, Middle Aged, Polymorphism, Single Nucleotide, White People, DNA-Binding Proteins, Phenotype, Gene Frequency, Risk Factors, Spain, Case-Control Studies, Humans, Female, Genetic Predisposition to Disease, Tumor Necrosis Factor alpha-Induced Protein 3
Abstract

Behçet's disease (BD) is an immune-mediated and complex disease which has been associated with HLA class I molecules although other genes such as IL23R and IL10 have also been involved in the susceptibility to BD. Recently, an association of variants of the JAK1 and TNFAIP3 genes with the disease has been reported in the Chinese Han population. The aim of the present work was to asses whether the association described in Asian populations is replicated in Europeans.This study includes a total of 1155 Spanish subjects of European origin (372 BD and 783 unrelated healthy individuals). Patients were recruited from different hospitals and controls were collected in the same geographic regions and they matched with patients in age and gender. A total of five SNPs, two in the JAK1 gene: rs2780815 and rs310241 and the other three in the TNFAIP3: rs10499194, rs9494885 and rs610604, were included in this study. The genotyping of these SNPs was performed using a real time PCR system (TaqMan® SNP Genotyping Assays).No statistically significant differences were found when the patient and control groups were compared. The distribution of the risk alleles was similar in patients with and without eye manifestations and in patients with and without HLA-B*51.The association of variants of the genes JAK1 and the TNFAIP3 with BD which has been described in the Chinese population was not replicated in Europeans.

Published
2014

32. GIMAP and Behçet disease: no association in the European population

Author

Lourdes, Ortiz-Fernández, Marta, Conde-Jaldón, José Raul, García-Lozano, Marco Antonio, Montes-Cano, Norberto, Ortego-Centeno, María Jesús, Castillo-Palma, Gerard, Espinosa, Genaro, Graña-Gil, Juan, Sánchez-Bursón, Miguel Angel, González-Gay, Ana Celia, Barnosi-Marín, Roser, Solans, Patricia, Fanlo, Mónica, Rodríguez Carballeira, Teresa, Camps, Santos, Castañeda, Javier, Martín, and María Francisca, González-Escribano

Subjects
Male, Genotype, Behcet Syndrome, Membrane Proteins, Polymorphism, Single Nucleotide, White People, GTP Phosphohydrolases, Asian People, GTP-Binding Proteins, HLA-B Antigens, Case-Control Studies, HLA-B51 Antigen, Humans, Female, Genetic Predisposition to Disease
Published
2014

33. Immunochip Analysis Identifies Multiple Susceptibility Loci for Systemic Sclerosis

Author

Maureen D. Mayes, Lara Bossini-Castillo, Olga Gorlova, José Ezequiel Martin, Xiaodong Zhou, Wei V. Chen, Shervin Assassi, Jun Ying, Filemon K. Tan, Frank C. Arnett, John D. Reveille, Sandra Guerra, María Teruel, Francisco David Carmona, Peter K. Gregersen, Annette T. Lee, Elena López-Isac, Eguzkine Ochoa, Patricia Carreira, Carmen Pilar Simeón, Iván Castellví, Miguel Ángel González-Gay, Alexandra Zhernakova, Leonid Padyukov, Marta Alarcón-Riquelme, Cisca Wijmenga, Matthew Brown, Lorenzo Beretta, Gabriela Riemekasten, Torsten Witte, Nicolas Hunzelmann, Alexander Kreuter, Jörg H.W. Distler, Alexandre E. Voskuyl, Annemie J. Schuerwegh, Roger Hesselstrand, Annika Nordin, Paolo Airó, Claudio Lunardi, Paul Shiels, Jacob M. van Laar, Ariane Herrick, Jane Worthington, Christopher Denton, Fredrick M. Wigley, Laura K. Hummers, John Varga, Monique E. Hinchcliff, Murray Baron, Marie Hudson, Janet E. Pope, Daniel E. Furst, Dinesh Khanna, Kristin Phillips, Elena Schiopu, Barbara M. Segal, Jerry A. Molitor, Richard M. Silver, Virginia D. Steen, Robert W. Simms, Robert A. Lafyatis, Barri J. Fessler, Tracy M. Frech, Firas AlKassab, Peter Docherty, Elzbieta Kaminska, Nader Khalidi, Henry Niall Jones, Janet Markland, David Robinson, Jasper Broen, Timothy R.D.J. Radstake, Carmen Fonseca, Bobby P. Koeleman, Javier Martin, Norberto Ortego-Centeno, Raquel Ríos, José Luis Callejas, Nuria Navarrete, Rosa García Portales, María Teresa Camps, Antonio Fernández-Nebro, María F. González-Escribano, Julio Sánchez-Román, Francisco José García-Hernández, María Jesús Castillo, María Ángeles Aguirre, Inmaculada Gómez-Gracia, Benjamín Fernández-Gutiérrez, Luis Rodríguez-Rodríguez, Esther Vicente, José Luis Andreu, Mónica Fernández de Castro, Paloma García de la Peña, Francisco Javier López-Longo, Lina Martínez, Vicente Fonollosa, Gerard Espinosa, Carlos Tolosa, Anna Pros, Mónica Rodríguez Carballeira, Francisco Javier Narváez, Manel Rubio Rivas, Vera Ortiz Santamaría, Bernardino Díaz, Luis Trapiella, María del Carmen Freire, Adrián Sousa, María Victoria Egurbide, Patricia Fanlo Mateo, Luis Sáez-Comet, Federico Díaz, Vanesa Hernández, Emma Beltrán, José Andrés Román-Ivorra, Elena Grau, Juan José Alegre Sancho, Francisco J. Blanco García, Natividad Oreiro, Luis Fernández Sueiro, Rheumatology, CCA - Disease profiling, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Translational Immunology Groningen (TRIGR)

Subjects
Male, Linkage disequilibrium, systemic sclerosis, Genome-wide association study, immunochip array, DNASE-GAMMA, Linkage Disequilibrium, DISEASE, Autophagy-Related Protein 5, DEAD-box RNA Helicases, FUNCTIONAL POLYMORPHISM, 0302 clinical medicine, HLA Antigens, Risk Factors, Genetics(clinical), Genetics (clinical), Genetics, 0303 health sciences, HLA, Female, Chromosomes, Human, Pair 3, Microtubule-Associated Proteins, SNPs, GENETIC RISK-FACTOR, Genotype, Single-nucleotide polymorphism, Locus (genetics), Human leukocyte antigen, Biology, Polymorphism, Single Nucleotide, Article, Interleukin-12 Subunit p35, White People, 03 medical and health sciences, Proto-Oncogene Proteins, Microchip Analytical Procedures, LUPUS-ERYTHEMATOSUS, Humans, Genetic Predisposition to Disease, JAPANESE POPULATION, Allele, GENOME-WIDE ASSOCIATION, Alleles, 030304 developmental biology, Genetic association, 030203 arthritis & rheumatology, PRIMARY BILIARY-CIRRHOSIS, Endodeoxyribonucleases, Scleroderma, Systemic, Chromosomes, Human, Pair 11, Haplotype, DNASE1L3, RHEUMATOID-ARTHRITIS, Logistic Models, Genetic Loci, Case-Control Studies, Carrier Proteins, FOLLOW-UP, Genome-Wide Association Study
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, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.

Published
2014
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