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51. Polymorphisms in the interleukin 4, interleukin 13 and corresponding receptor genes are not associated with systemic sclerosis and do not influence gene expression

Author

Broen, J C A, Dieude, P, Vonk, M C, Beretta, L, Rueda, B, Herrick, A, Worthington, J, Hunzelmann, N, Riemekasten, G, Kiener, H, Scorza, R, Simeon, C P, Fonollosa, V, Carreira, P, Ortego-Centeno, N, Gonzalez-Gay, M A, Airoʼ, P, Coenen, M J H, Aliprantis, A, Martin, J, Allanore, Y, and Radstake, T R D J

Published
2011
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52. Variants of PBEF predispose to systemic sclerosis and pulmonary arterial hypertension development

Author

Broen, J C A, Gourh, P, Vonk, M C, Beretta, L, Niederer, F, Rueda, B, Geurts-van Bon, L, Brouwer, C, Hesselstrand, R, Herrick, A, Worthington, J, Hunzelman, N, Fonseca, Denton C, Riemekasten, G, Kiener, H, Scorza, R, Simeon, C P, Fonollosa, V, Carreira, P, Ortego-Centeno, N, Gonzalez-Gay, M A, Airoʼ, P, Coenen, M J H, Mayes, M, Kyburz, D, Arnett, F C, Martin, J, and Radstake, T R D J

Published
2011
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53. Analysis of the influence of PTPN22 gene polymorphisms in systemic sclerosis

Author

Diaz-Gallo, LM, Gourh, P, Broen, J, Simeon, C, Fonollosa, V, Ortego-Centeno, N, Agarwal, S, Vonk, MC, Coenen, M, Riemekasten, G, Hunzelmann, N, Hesselstrand, R, Tan, FK, Reveille, JD, Assassi, S, García-Hernandez, FJ, Carreira, P, Camps, MT, Fernandez-Nebro, A, de la Peña, P Garcia, Nearney, T, Hilda, D, González-Gay, MA, Airo, P, Beretta, L, Scorza, R, Herrick, A, Worthington, J, Pros, A, Gómez-Gracia, I, Trapiella, L, Espinosa, G, Castellvi, I, Witte, T, de Keyser, F, Vanthuyne, M, Mayes, MD, Radstake, TRDJ, Arnett, FC, Martin, J, and Rueda, B

Published
2011
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55. BANK1 functional variants are associated with susceptibility to diffuse systemic sclerosis in Caucasians

Author

Rueda, B, Gourh, P, Broen, J, Agarwal, S K, Simeon, C, Ortego-Centeno, N, Vonk, M C, Coenen, M, Riemekasten, G, Hunzelmann, N, Hesselstrand, R, Tan, F K, Reveille, J D, Assassi, S, Garcia-Hernandez, F J, Carreira, P, Camps, M, Fernandez-Nebro, A, de la Peña, P Garcia, Nearney, T, Hilda, D, Gónzalez-Gay, M A, Airo, P, Beretta, L, Scorza, R, Radstake, T R, Mayes, M D, Arnett, F C, and Martin, J

Published
2010
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56. Serum Jo-1 Autoantibody and Isolated Arthritis in the Antisynthetase Syndrome: Review of the Literature and Report of the Experience of AENEAS Collaborative Group

Author

Cavagna, L, Nuno, L, Scire, C, Govoni, M, Longo, F, Franceschini, F, Neri, R, Castaneda, S, Sifuentes Giraldo, W, Caporali, R, Iannone, F, Fusaro, E, Paolazzi, G, Pellerito, R, Schwarting, A, Saketkoo, L, Ortego-Centeno, N, Quartuccio, L, Bartoloni, E, Specker, C, Pina Murcia, T, La Corte, R, Furini, F, Foschi, V, Bachiller Corral, J, Airo, P, Cavazzana, I, Martinez-Barrio, J, Hinojosa, M, Giannini, M, Barsotti, S, Menke, J, Triantafyllias, K, Vitetta, R, Russo, A, Bogliolo, L, Bajocchi, G, Bravi, E, Barausse, G, Bortolotti, R, Selmi, C, Parisi, S, Salaffi, F, Montecucco, C, Gonzalez-Gay, M, Cavagna L., Nuno L., Scire C. A., Govoni M., Longo F. J. L., Franceschini F., Neri R., Castaneda S., Sifuentes Giraldo W. A., Caporali R., Iannone F., Fusaro E., Paolazzi G., Pellerito R., Schwarting A., Saketkoo L. A., Ortego-Centeno N., Quartuccio L., Bartoloni E., Specker C., Pina Murcia T., La Corte R., Furini F., Foschi V., Bachiller Corral J., Airo P., Cavazzana I., Martinez-Barrio J., Hinojosa M., Giannini M., Barsotti S., Menke J., Triantafyllias K., Vitetta R., Russo A., Bogliolo L., Bajocchi G., Bravi E., Barausse G., Bortolotti R., Selmi C., Parisi S., Salaffi F., Montecucco C., Gonzalez-Gay M. A., Cavagna, L, Nuno, L, Scire, C, Govoni, M, Longo, F, Franceschini, F, Neri, R, Castaneda, S, Sifuentes Giraldo, W, Caporali, R, Iannone, F, Fusaro, E, Paolazzi, G, Pellerito, R, Schwarting, A, Saketkoo, L, Ortego-Centeno, N, Quartuccio, L, Bartoloni, E, Specker, C, Pina Murcia, T, La Corte, R, Furini, F, Foschi, V, Bachiller Corral, J, Airo, P, Cavazzana, I, Martinez-Barrio, J, Hinojosa, M, Giannini, M, Barsotti, S, Menke, J, Triantafyllias, K, Vitetta, R, Russo, A, Bogliolo, L, Bajocchi, G, Bravi, E, Barausse, G, Bortolotti, R, Selmi, C, Parisi, S, Salaffi, F, Montecucco, C, Gonzalez-Gay, M, Cavagna L., Nuno L., Scire C. A., Govoni M., Longo F. J. L., Franceschini F., Neri R., Castaneda S., Sifuentes Giraldo W. A., Caporali R., Iannone F., Fusaro E., Paolazzi G., Pellerito R., Schwarting A., Saketkoo L. A., Ortego-Centeno N., Quartuccio L., Bartoloni E., Specker C., Pina Murcia T., La Corte R., Furini F., Foschi V., Bachiller Corral J., Airo P., Cavazzana I., Martinez-Barrio J., Hinojosa M., Giannini M., Barsotti S., Menke J., Triantafyllias K., Vitetta R., Russo A., Bogliolo L., Bajocchi G., Bravi E., Barausse G., Bortolotti R., Selmi C., Parisi S., Salaffi F., Montecucco C., and Gonzalez-Gay M. A.

Abstract

Anti-Jo-1 is the most frequently detectable antibody in the antisynthetase syndrome (ASSD), an autoimmune disease characterized by the occurrence of arthritis, myositis, and interstitial lung disease (ILD). Recently, we organized an international collaborative group called American and European NEtwork of Antisynthetase Syndrome (AENEAS) for the study of this rare and fascinating disease. The group collected and published one of the largest series of ASSD patients ever described and with one of the longer follow-up ever reported. The number of participating centers is steadily increasing, as well as the available cohort. In the first paper, we showed that arthritis, myositis, and ILD may be frequently the only feature at disease onset, raising problems to reach a correct diagnosis of this syndrome. Nevertheless, we first observed that the ex novo appearance of further manifestations is common during the follow-up, strengthening the importance of a correct diagnosis. In our cohort, the 24 % of the 243 patients up to now collected had isolated arthritis as a presenting feature. These patients represent the most intriguing group in terms of differential diagnosis and clinical time course. Furthermore, data on this aspect are scanty, the reason that lead us to evaluate these aspects in our cohort of patients, reviewing also available literature. In fact, the most relevant aspect is that ASSD is rarely suspected in this setting of patients, in particular in case of poliarticular involvement, positive rheumatoid factor (RF), or anti-cyclic citrullinated peptide antibodies (ACPA) or evidence of joint erosions at plain radiographs. These findings were not rare in our cohort, and they have been also described in other series. Furthermore, manifestations such as Raynaud’s phenomenon, mechanic’s hands, and fever that may lead to the suspect of ASSD are observed only in a third of cases. If we consider the high rate of clinical picture progression in these patients, we fee

Published
2017

57. Clinical follow-up predictors of disease pattern change in anti-Jo1 positive anti-synthetase syndrome: Results from a multicenter, international and retrospective study

Author

Bartoloni, E, Gonzalez-Gay, M, Scire, C, Castaneda, S, Gerli, R, Lopez-Longo, F, Martinez-Barrio, J, Govoni, M, Furini, F, Pina, T, Iannone, F, Giannini, M, Nuno, L, Quartuccio, L, Ortego-Centeno, N, Alunno, A, Specker, C, Montecucco, C, Triantafyllias, K, Balduzzi, S, Sifuentes-Giraldo, W, Paolazzi, G, Bravi, E, Schwarting, A, Pellerito, R, Russo, A, Selmi, C, Saketkoo, L, Fusaro, E, Parisi, S, Pipitone, N, Franceschini, F, Cavazzana, I, Neri, R, Barsotti, S, Codullo, V, Cavagna, L, Bartoloni E., Gonzalez-Gay M. A., Scire CA., Castaneda S., Gerli R., Lopez-Longo F. J., Martinez-Barrio J., Govoni M., Furini F., Pina T., Iannone F., Giannini M., Nuno L., Quartuccio L., Ortego-Centeno N., Alunno A., Specker C., Montecucco C., Triantafyllias K., Balduzzi S., Sifuentes-Giraldo W. A., Paolazzi G., Bravi E., Schwarting A., Pellerito R., Russo A., Selmi C., Saketkoo L. -A., Fusaro E., Parisi S., Pipitone N., Franceschini F., Cavazzana I., Neri R., Barsotti S., Codullo V., Cavagna L., Bartoloni, E, Gonzalez-Gay, M, Scire, C, Castaneda, S, Gerli, R, Lopez-Longo, F, Martinez-Barrio, J, Govoni, M, Furini, F, Pina, T, Iannone, F, Giannini, M, Nuno, L, Quartuccio, L, Ortego-Centeno, N, Alunno, A, Specker, C, Montecucco, C, Triantafyllias, K, Balduzzi, S, Sifuentes-Giraldo, W, Paolazzi, G, Bravi, E, Schwarting, A, Pellerito, R, Russo, A, Selmi, C, Saketkoo, L, Fusaro, E, Parisi, S, Pipitone, N, Franceschini, F, Cavazzana, I, Neri, R, Barsotti, S, Codullo, V, Cavagna, L, Bartoloni E., Gonzalez-Gay M. A., Scire CA., Castaneda S., Gerli R., Lopez-Longo F. J., Martinez-Barrio J., Govoni M., Furini F., Pina T., Iannone F., Giannini M., Nuno L., Quartuccio L., Ortego-Centeno N., Alunno A., Specker C., Montecucco C., Triantafyllias K., Balduzzi S., Sifuentes-Giraldo W. A., Paolazzi G., Bravi E., Schwarting A., Pellerito R., Russo A., Selmi C., Saketkoo L. -A., Fusaro E., Parisi S., Pipitone N., Franceschini F., Cavazzana I., Neri R., Barsotti S., Codullo V., and Cavagna L.

Abstract

Objective Arthritis, myositis and interstitial lung disease (ILD) constitute the classic clinical triad of anti-synthetase syndrome (ASSD). These patients experience other accompanying features, such as Raynaud's phenomenon, fever or mechanic's hands. Most ASSD patients develop the complete triad during the follow-up. In the present study we aimed to determine whether the subsequent appearance of accompanying features may suggest the development of triad findings lacking at the onset in anti-Jo1 positive ASSD patients. Methods Anti-Jo1 positive patients presenting with incomplete ASSD (no > 2 classic triad features) were assessed. Clinical characteristics and clusters of disease manifestations were retrospectively collected and analyzed in a large international multicenter cohort of ASSD patients. Results 165 patients (123 women) with incomplete ASSD were identified. Ninety-five patients (57.5%) developed new classic triad manifestations after 15 months median (IQR 9–51) and 40 (24%) developed new accompanying features after 19 months median (IQR 6–56) from disease onset. During the follow-up, the ex-novo occurrence of triad features was observed in 32 out of 40 patients (80%) with new accompanying findings and in 63 out of 125 patients (50.5%) without new accompanying findings (p = 0.002). In patients with at least one new accompanying feature the odds ratio for the occurrence of new triad manifestations was 3.94 with respect to patients not developing ex-novo accompanying findings (95% CI 1.68–9.21, p = 0.002). Conclusion Anti-Jo1 ASSD patients with incomplete forms at disease onset are at high risk for the subsequent occurrence of lacking classic triad findings. Although all ASSD patients should be carefully assessed for the occurrence of new triad features, a closer follow-up should be considered in the subgroup of patients developing ex novo accompanying findings. These patients, indeed, have near four-fold increased risk f

Published
2017

58. STAT4 associates with systemic lupus erythematosus through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk

Author

Abelson, A-K, Delgado-Vega, A M, Kozyrev, S V, Sánchez, E, Velázquez-Cruz, R, Eriksson, N, Wojcik, J, Linga Reddy, M V P, Lima, G, D’Alfonso, S, Migliaresi, S, Baca, V, Orozco, L, Witte, T, Ortego-Centeno, N, Abderrahim, H, Pons-Estel, B A, Gutiérrez, C, Suárez, A, González-Escribano, M F, Martin, J, and Alarcón-Riquelme, M E

Published
2009
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59. A large multicentre analysis of CTGF −945 promoter polymorphism does not confirm association with systemic sclerosis susceptibility or phenotype

Author

Rueda, B, Simeon, C, Hesselstrand, R, Herrick, A, Worthington, J, Ortego-Centeno, N, Riemekasten, G, Fonollosa, V, Vonk, M C, van den Hoogen, F H J, Sanchez-Román, J, Aguirre-Zamorano, M A, García-Portales, R, Pros, A, Camps, M T, Gonzalez-Gay, M A, Gonzalez-Escribano, M F, Coenen, M J, Lambert, N, Nelson, J L, Radstake, T R D J, and Martin, J

Published
2009
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60. The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype

Author

Rueda, B, Broen, J, Simeon, C, Hesselstrand, R, Diaz, B, Suárez, H, Ortego-Centeno, N, Riemekasten, G, Fonollosa, V, Vonk, MC, van den Hoogen, FHJ, Sanchez-Román, J, Aguirre-Zamorano, MA, García-Portales, R, Pros, A, Camps, MT, Gonzalez-Gay, MA, Coenen, MJH, Airo, P, Beretta, L, Scorza, R, van Laar, J, Gonzalez-Escribano, MF, Nelson, JL, Radstake, TRDJ, and Martin, J

Published
2009

63. ¿Qué opinan los internistas españoles de la osteoporosis?

Author

Sosa Henríquez, M., Filgueira Rubio, J., López-Harce Cid, J.A., Díaz Curiel, M., Lozano Tonkin, C., del Castillo Rueda, A., Sánchez Molini, P., Montes Santiago, J., Serrano Fernández, C., Díaz López, B., Pérez Cano, R., Blázquez, J.A., Ortego Centeno, N., Tirado Miranda, R., Sánchez Linares, J.R., Nogués Solán, X., Farrerons Minguela, J., Escobar Jiménez, F., del Pino del Montes, J., González-Macías, J., and Gómez Alonso, C.

Published
2005
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68. GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways

Author

López-Isac, E., Acosta-Herrera, M., Kerick, M., Assassi, S., Satpathy, A.T., Granja, J., Mumbach, M.R., Beretta, L., Simeón, C.P., Carreira, P., Ortego-Centeno, N., Castellvi, I., Bossini-Castillo, L., Carmona, F.D., Orozco, G., Hunzelmann, N., Distler, J.H.W., Franke, A., Lunardi, C., Moroncini, G., Gabrielli, A., de Vries-Bouwstra, J., Wijmenga, C., Koeleman, B.P.C., Nordin, A., Padyukov, L., Hoffmann-Vold, A.-M., Lie, B., Ríos, R., Callejas, J.L., Vargas-Hitos, J.A., García-Portales, R., Camps, M.T., Fernández-Nebro, A., González-Escribano, M.F., García-Hernández, F.J., Castillo, M.J., Aguirre, M.A., Gómez-Gracia, I., Fernández-Gutiérrez, B., Rodríguez-Rodríguez, L., García de la Peña, P., Vicente, E., Andreu, J.L., Fernández de Castro, M., López-Longo, F.J., Martínez, L., Fonollosa, V., Guillén, A., Espinosa, G., Tolosa, C., Pros, A., Rodríguez-Carballeira, M., Narváez, F.J., Rubio-Rivas, M., Ortiz-Santamaría, V, Madroñero, A.B., González-Gay, M.A., Díaz, B., Trapiella, L., Sousa, A., Egurbide, M.V., Fanlo-Mateo, P., Sáez-Comet, L., Díaz, F., Hernández, V, Beltrán, E., Román-Ivorra, J.A., Grau E., Alegre-Sancho, J.J., Freire, M., Blanco-García, F.J., Oreiro, N., Witte, T., Kreuter, A., Riemekasten, G., Airó P., Magro, C., Voskuyl, A.E., Vonk, M.C., Hesselstrand, R., Proudman S., Stevens, W., Nikpour, M., Zochling, J., Sahhar, J., Roddy, J., Nash, P., Tymms, K., Rischmueller, M., Lester, S., Vyse, T., Herrick, A.L., Worthington, J., Denton C.P., Allanore, Y., Brown, M.A., Radstake, T.R.D.J., Fonseca, C., Chang H.Y., Mayes, M.D., Martin, J., European Scleroderma Group, Australian Scleroderma Interest Group (ASIG), Universidad de Salamanca, Ministerio de Economía y Competitividad (España), Junta de Andalucía, Ministerio de Educación, Cultura y Deporte (España), Instituto de Salud Carlos III, Howard Hughes Medical Institute, Federal Ministry of Education and Research (Germany), Universidad de Cantabria, [López-Isac E, Acosta-Herrera M, Kerick M] Institute of Parasitology and Biomedicine López-Neyra, IPBLN-CSIC, Granada, Spain. [Assassi S] The University of Texas Health Science Center-Houston, Houston, USA. [Satpathy AT, Granja J] Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, USA. Howard Hughes Medical Institute, Stanford University, Stanford, USA. [Simeón CP] Servei de Medicina Interna, Vall d'Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Rheumatology, and AII - Inflammatory diseases

Subjects
0301 basic medicine, Chemistry(all), AUTOIMMUNITY, Àcids nucleics, General Physics and Astronomy, Genome-wide association study, Disease, VARIANTS, Biochemistry, ANNOTATION, 0302 clinical medicine, Phosphopantothenoylcysteine decarboxylase, Single nucleotide, Non-U.S. Gov't, lcsh:Science, skin and connective tissue diseases, características del estudio::metaanálisis [CARACTERÍSTICAS DE PUBLICACIONES], Multidisciplinary, Nucleid acid conformation, integumentary system, Research Support, Non-U.S. Gov't, High-Throughput Nucleotide Sequencing, Genètica - Tècnica, 3. Good health, Nucleic acids, Sequence analysis DNA, Medical genetics, medicine.medical_specialty, Chromatin Immunoprecipitation, GENES, Investigative Techniques::Epidemiologic Methods::Epidemiologic Research Design::Genome-Wide Association Study [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Science, Non-P.H.S, Single-nucleotide polymorphism, Scleroderma systemic, Computational biology, Physics and Astronomy(all), Biology, Research Support, Study Characteristics::Meta-Analysis [PUBLICATION CHARACTERISTICS], Genetic polymorphisms, enfermedades de la piel y tejido conjuntivo::enfermedades del tejido conjuntivo::esclerodermia sistémica [ENFERMEDADES], Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Functional genomics, Genome-wide association studies, Systemic sclerosis, Rheumatic diseases, CLASSIFICATION, N.I.H, 03 medical and health sciences, Research Support, N.I.H., Extramural, Diacylglycerol kinase theta, Molecular genetics, REVEALS, Journal Article, medicine, Humans, Vascular Diseases, Risk factor, Polymorphism, Genomes, GENOME-WIDE ASSOCIATION, METAANALYSIS, 030203 arthritis & rheumatology, Scleroderma, Systemic, Biochemistry, Genetics and Molecular Biology(all), Polimorfisme genètic, HUMAN-CELLS, Extramural, Bayes Theorem, General Chemistry, Sequence Analysis, DNA, Fibrosis, 030104 developmental biology, Scleroderma (Disease), Skin and Connective Tissue Diseases::Connective Tissue Diseases::Scleroderma, Systemic [DISEASES], técnicas de investigación::métodos epidemiológicos::diseño de la investigación epidemiológica::estudio de asociación genómica completa [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Nucleic Acid Conformation, VISUALIZATION, lcsh:Q, U.S. Gov't, Esclerodèrmia, Research Support, U.S. Gov't, Non-P.H.S, Metaanàlisi, Genetics and Molecular Biology(all), Genome-Wide Association Study
Abstract

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments., We thank Sofia Vargas, Sonia García, and Gema Robledo for their excellent technical assistance and all the patients and control donors for their essential collaboration. We thank National DNA Bank Carlos III (University of Salamanca, Spain) that supplied part of the control DNA samples from Spain, WTCCC and EIRA Consortiums, and PopGen 2.0 network. This work was supported by Spanish Ministry of Economy and Competitiveness (grant ref. SAF2015-66761-P), Consejeria de Innovacion, Ciencia y Tecnologia, Junta de Andalucía (P12-BIO-1395), Ministerio de Educación, Cultura y Deporte through the program FPU, Juan de la Cierva fellowship (FJCI-2015-24028), Red de Investigación en Inflamación y Enfermadades Reumaticas (RIER) from Instituto de Salud Carlos III (RD16/0012/0013), and Scleroderma Research Foundation and NIH P50- HG007735 (to H.Y.C.). H.Y.C. is an Investigator of the Howard Hughes Medical Institute. PopGen 2.0 is supported by a grant from the German Ministry for Education and Research (01EY1103). M.D.M and S.A. are supported by grant DoD W81XWH-18-1- 0423 and DoD W81XWH-16-1-0296, respectively

Published
2019
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71. THE ROLE OF KLOTHO IN RHEUMATOID ARTHRITIS

Author

Alvarez de Cienfuegos, Antonio, Cantero-Nieto, Lucía, García-Gómez, José Alberto, Robledo, Gema, Sánchez-Cano, Daniel, Martín, J., González-Gay, M. A., and Ortego-Centeno, N.

Published
2019

72. Endothelin-1 serum levels in women with Rheumatoid Arthritis

Author

Alvarez-Cienfuegos A, Cantero-Nieto L, Ja, García-Gómez, Raquel Rios-Fernández, Martin J, Ma, González-Gay, and Ortego-Centeno N

Subjects
Adult, rheumatoid arthritis, nt-probnp, lcsh:Immunologic diseases. Allergy, lcsh:Internal medicine, Endothelin-1, Rheumatoid Arthritis, Middle Aged, Arthritis, Rheumatoid, Cross-Sectional Studies, Cardiovascular Diseases, NT-proBNP, endothelin-1, prednisone, Humans, Prednisone, Female, Prospective Studies, CRP, lcsh:RC31-1245, lcsh:RC581-607, crp, Biomarkers
Abstract

Objective: The purpose of this study was to evaluate serum Endothelin-1(ET-1) levels in female Rheumatoid Arthritis (RA) patients compared with healthy controls, examine possible associations between ET-1 with different characteristic of the disease and investigate possible associations between ET-1 with surrogate markers of cardiovascular disease (CVD). Methods: This cross-sectional study was performed in Vega-Baja I Iospital, Orihuela (Spain) from November 2016 to May 2018. Sixty-three women with RA and sixty-five age and sex healthy controls were included in this study. Serum ET-1 was analyzed using ELISA. Results: Serum levels of ET-1 in RA female patients were higher than those in healthy controls (p 0.001). Serum levels of ET-1 were positively associated with N-terminal pro-brain natriuretic peptide (NT-proBNP) (r = 0.27, p < 0.05) and with C-reactive protein (CRP) (r = 0.36, p < 0.05). ET-1 levels in women with RA were higher in smokers. Prednisone use was associated with lower ET-1 levels. No association with carotid intima media thickness was found. Conclusions: we observed the presence of higher levels of serum ET-1 in RA women patients compared with healthy controls. These increased levels of ET-1 are associated with inflammation and smoking and reduced by prednisone intake.

Published
2019

73. IDENTIFICATION OF FOUR NEW SHARED SUSCEPTIBILITY GENES IN SYSTEMIC SCLEROSIS AND CROHN¿S DISEASE THROUGH A CROSS-DISEASE META-GWAS

Author

González-Serna, David, Ochoa, Eguzkine, López-Isac, Elena, Julià, A, Degenhardt, Frauke, van Beelen Granlund, A, Carreira, PE, Simeon, CP, Ortego-Centeno, N., González-Gay, M. A., Vicente, Esther, Beltran, E, Alegre-Sancho, Juan-José, Spanish Scleroderma Group, Beretta, L., Santaniello, A, Lunardi, C., Hunzelmann, Nicolas, Riemekasten, G, Witte, T, Distler, J.H.W., Kreuter, A., Airó, P, Koeleman, B. P., Voskuyl, AE, de Vries-Bouwstra, Jeska, Radstake, TRDJ, Wijmenga, C, Assassi, S., Franke, Andre, Marsal, Sara, Mayes, Maureen D., Martín, J., and Márquez A

Published
2019

74. A CROSS-DISEASE META-GWAS IDENTIFIES IRF1, STAT3 AND ZBTB9-BAK1 AS NEW SHARED SUSCEPTIBILITY LOCI IN SYSTEMIC SCLEROSIS AND CROHN¿S DISEASE

Author

González-Serna, David, Ochoa, Eguzkine, López-Isac, Elena, Julià, A, Degenhardt, Frauke, van Beelen Granlund, A., Carreira, P.E., Simeon, C.P., Ortego-Centeno, N., González-Gay, M. A., Vicente, Esther, Beltran, E., Alegre-Sancho, Juan-José, Beretta, L., Santaniello, A., Lunardi, C., Hunzelmann, Nicolas, Riemekasten, .G, Witte, T., Distler, J.H.W., Kreuter, A., Airó, P., Koeleman, BPC, Voskuyl, T..A.E., de Vries-Bouwstra, Jeska, Radstake TRDJ, Wijmenga, C., Assassi, S.., Franke, Andre, Marsal, Sara, Mayes, Maureen D., Martin, J., and Márquez, A.

Published
2019

75. Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases

Author

Acosta-Herrera, Marialbert, Kerick, Martin, González-Serna, David, Wijmenga, Cisca, Franke, Andre, Gregersen, Peter K., Padyukov, Leonid, Worthington, J., Vyse, T. J., Alarcón-Riquelme, M. E., Mayes, M. D., Martín, J., Miller, Frederick W., Chen, Wei, O'Hanlon, Terrance P., Cooper, Robert G., Vencovsky, Jiri, Rider, Lisa G, Danko, Katalin, Wedderburn, Lucy R., Lundberg, Ingrid E., Pachman, Lauren M., Reed, Ann M., Ytterberg, Steven R, Selva-O'Callaghan, Alber, Radstake, Timothy R., Isenberg, David A, Chinoy, Hector, Ollier, William E. R, Scheet, Paul, Peng, Bo, Lee, Annette, Lamb, Janine A., Amos, Christopher I., Denton, Christopher, Hilton-Jones, David, Plotz, Paul H., Varsani, Hemlata, Radstake, Timothy R. D. J., Gorlova, Olga, Rueda, B., Martín, J. E., Alizadeh, B. Z., Palomino-Morales, Rogelio, Coenen, Marieke J. H., Vonk, Madelon C., Voskuyl, Alexandre E., Scheurwegh, Annemie J., Broen, Jasper C., van Riel, Piet L. C. M., van 't Slot, Rubén, Italiaander, Annet, Ophoff, Roel A., Riemekasten, Gabriela, Hunzelmann, Nicolas, Simeon, Carmen P., Ortego-Centeno, N., González-Gay, M. A., González-Escribano, María Francisca, Airó, Paolo, van Laar, Jaap, Herrick, Ariane L., Hesselstrand, Roger, Smith, Vanessa, de Keyser, Filip, Houssiau, Fredric, Chee, Meng May, Madhok, Rajan, Shiels, Paul, Westhovens, Rene, Kreuter, A., Kiener, Hans, de Baere, Elfride, Witte, Torsten, Klareskog, Lars, Beretta, Lorenzo, Scorza, Rafaella, Lie, Benedicte A., Hoffman-Vold, A. M., Carreira, P., Varga, John, Hinchcliff, Monique, Lee, Annette T., Ying, Jun, Han, Younghun, Weng, Shih-Feng, Wigley, Fredrick M., Hummers, L. K., Nelson, J. Lee, Agarwal, Sandeep K., Assassi, S., Gourh, Pravitt, Tan, Filemon K., Koeleman, B. P., Arnett, Frank C., Myositis Genetics Consortium, Scleroderma Genetics Consortium., Innovative Medicines Initiative, Ministerio de Economía, Industria y Competitividad (España), Junta de Andalucía, National Institute of Environmental Health Sciences (US), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Polymer Chemistry and Bioengineering, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Myositis Genetics Consortium, and Scleroderma Genetics Consortium

Subjects
0301 basic medicine, Male, Lydia Becker Institute, PATHOGENESIS, PROTEIN, Arthritis, VARIANTS, medicine.disease_cause, Myositis Genetics Consortium, Autoimmunity, Scleroderma, Arthritis, Rheumatoid, 0302 clinical medicine, Scleroderma Genetics Consortium, Rheumatoid, MULTIPLE, Lupus Erythematosus, Systemic, Immunology and Allergy, Medicine, 2.1 Biological and endogenous factors, Aetiology, Genetics, autoimmunity, Family aggregation, Lim Kinases, ASSOCIATION, Single Nucleotide, Public Health and Health Services, Female, ARTHRITIS, Life Sciences & Biomedicine, alpha Karyopherins, Adult, medicine.medical_specialty, GENETICS, gene polymorphism, Quantitative Trait Loci, Clinical Sciences, Immunology, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Autoimmune Disease, General Biochemistry, Genetics and Molecular Biology, White People, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], 03 medical and health sciences, Immune system, Rheumatology, Internal medicine, Rheumatic Diseases, ResearchInstitutes_Networks_Beacons/lydia_becker_institute_of_immunology_and_inflammation, Humans, Genetic Predisposition to Disease, autoimmune diseases, Polymorphism, SCLEROSIS, COMMON, 030203 arthritis & rheumatology, Science & Technology, Scleroderma, Systemic, COMPLEX, Myositis, Lupus Erythematosus, business.industry, Inflammatory and immune system, Systemic, Human Genome, Membrane Proteins, medicine.disease, Arthritis & Rheumatology, Repressor Proteins, 030104 developmental biology, Expression quantitative trait loci, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Human medicine, Gene polymorphism, business, Genome-Wide Association Study
Abstract

ObjectiveImmune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies.MethodsWe meta-analysed ~6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases.ResultsOur analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study.ConclusionsWe have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs.

Published
2019
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76. Pulmonary hypertension in Spanish patients with systemic sclerosis. Data from the RESCLE registry

Author

Garcia-Hernandez, FJ, Castillo-Palma, MJ, Tolosa-Vilella, C, Guillen-del Castillo, A, Rubio-Rivas, M, Freire, M, Vargas-Hitos, JA, Todoli-Parra, JA, Rodriguez-Carballeira, M, Espinosa-Garriga, G, Colunga-Arguelles, D, Ortego-Centeno, N, Trapiella-Martinez, L, Rodero-Roldan, MM, Pla-Salas, X, Perales-Fraile, I, del Campo, IPM, Chamorro, AJ, Gimenez, RAFD, Madronero-Vuelta, AB, Ruiz-Munoz, M, Fonollosa-Pla, V, Simeon-Aznar, CP, SSSG, Autoimmune Dis Study Grp GEAS, and Spanish Soc Internal Med SEMI

Subjects
Anti-centromere antibodies, Systemic sclerosis, Pulmonary hypertension
Abstract

IntroductionOur objective was to evaluate the pulmonary hypertension (PH) data for Spanish patients with systemic sclerosis (SSc), define the PH types and determine the associated factors.MethodDescriptive study of PH-related data from the multicentre RESCLE registry. Estimated systolic pulmonary artery pressure (esPAP), measured via echocardiogram was considered elevated if 35mmHg. Left heart disease (LHD) and interstitial lung disease (ILD) were identified. When performed, data from right heart catheterisation (RHC) were collected.ResultsesPAP was elevated in 350 of 808 patients (43.3%). One hundred and forty-four patients (17.8%) were considered to have PH (88 via RHC and the rest due to elevated esPAP along with evidence of significant LHD or ILD): PAH 3.7%, secondary to ILD 8.3%, secondary to LHD 2.8% and unclassified 3%. Prevalence of elevated esPAP was greater in diffuse SSc (dSSc) than in limited scleroderma (lSSc) (50.5 vs. 42.2%, p 0.046). In the group with elevated esPAP, a lower prevalence of anti-centromere antibodies (41.9% vs. 52.3%, p 0.006) and a greater prevalence of anti-topoisomerase-1 antibodies (ATA) (25.1% vs. 18.6%, p 0.04) were observed compared to the group with normal esPAP. Patients with elevated esPAP had a lower rate of digital ulcers (50.6% vs. 60.2%, p 0.007) and esophageal involvement (83.6% vs. 88.7%, p 0.07) and higher rate of renal crisis (4.6% vs. 1.8%, p 0.066).ConclusionsPrevalence of PAH was lower than expected (3.7%). Probability of having elevated esPAP was higher among patients with dSSc and among those with ATA.

Published
2019

84. GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways.

Author

Vicente E., Mumbach M.R., Granja J., Beretta L., Simeon C.P., Carreira P., Ortego-Centeno N., Castellvi I., Bossini-Castillo L., Carmona F.D., Orozco G., Hunzelmann N., Distler J.H.W., Franke A., Lunardi C., Moroncini G., Gabrielli A., de Vries-Bouwstra J., Wijmenga C., Koeleman B.P.C., Nordin A., Padyukov L., Hoffmann-Vold A.-M., Lie B., Rios R., Callejas J.L., Vargas-Hitos J.A., Garcia-Portales R., Camps M.T., Fernandez-Nebro A., Gonzalez-Escribano M.F., Garcia-Hernandez F.J., Castillo M.J., Aguirre M.A., Gomez-Gracia I., Fernandez-Gutierrez B., Rodriguez-Rodriguez L., Garcia de la Pena P., Andreu J.L., Fernandez de Castro M., Lopez-Longo F.J., Martinez L., Fonollosa, Guillen A., Espinosa G., Tolosa C., Pros A., Rodriguez-Carballeira M., Narvaez F.J., Rubio-Rivas M., Ortiz-Santamaria, Madronero A.B., Gonzalez-Gay M.A., Diaz B., Trapiella L., Sousa A., Egurbide M.V., Fanlo-Mateo P., Saez-Comet L., Diaz F., Hernandez, Beltran E., Roman-Ivorra J.A., Grau E., Alegre-Sancho J.J., Freire M., Blanco-Garcia F.J., Oreiro N., Witte T., Kreuter A., Riemekasten G., Airo P., Magro C., Voskuyl A.E., Vonk M.C., Hesselstrand R., Proudman S., Stevens W., Nikpour M., Zochling J., Sahhar J., Roddy J., Nash P., Tymms K., Rischmueller M., Lester S., Vyse T., Herrick A.L., Worthington J., Denton C.P., Allanore Y., Brown M.A., Radstake T.R.D.J., Fonseca C., Chang H.Y., Mayes M.D., Martin J., Lopez-Isac E., Acosta-Herrera M., Kerick M., Assassi S., Satpathy A.T., Vicente E., Mumbach M.R., Granja J., Beretta L., Simeon C.P., Carreira P., Ortego-Centeno N., Castellvi I., Bossini-Castillo L., Carmona F.D., Orozco G., Hunzelmann N., Distler J.H.W., Franke A., Lunardi C., Moroncini G., Gabrielli A., de Vries-Bouwstra J., Wijmenga C., Koeleman B.P.C., Nordin A., Padyukov L., Hoffmann-Vold A.-M., Lie B., Rios R., Callejas J.L., Vargas-Hitos J.A., Garcia-Portales R., Camps M.T., Fernandez-Nebro A., Gonzalez-Escribano M.F., Garcia-Hernandez F.J., Castillo M.J., Aguirre M.A., Gomez-Gracia I., Fernandez-Gutierrez B., Rodriguez-Rodriguez L., Garcia de la Pena P., Andreu J.L., Fernandez de Castro M., Lopez-Longo F.J., Martinez L., Fonollosa, Guillen A., Espinosa G., Tolosa C., Pros A., Rodriguez-Carballeira M., Narvaez F.J., Rubio-Rivas M., Ortiz-Santamaria, Madronero A.B., Gonzalez-Gay M.A., Diaz B., Trapiella L., Sousa A., Egurbide M.V., Fanlo-Mateo P., Saez-Comet L., Diaz F., Hernandez, Beltran E., Roman-Ivorra J.A., Grau E., Alegre-Sancho J.J., Freire M., Blanco-Garcia F.J., Oreiro N., Witte T., Kreuter A., Riemekasten G., Airo P., Magro C., Voskuyl A.E., Vonk M.C., Hesselstrand R., Proudman S., Stevens W., Nikpour M., Zochling J., Sahhar J., Roddy J., Nash P., Tymms K., Rischmueller M., Lester S., Vyse T., Herrick A.L., Worthington J., Denton C.P., Allanore Y., Brown M.A., Radstake T.R.D.J., Fonseca C., Chang H.Y., Mayes M.D., Martin J., Lopez-Isac E., Acosta-Herrera M., Kerick M., Assassi S., and Satpathy A.T.

Abstract

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.Copyright © 2019, The Author(s).

Published
2019

85. Influence of Antisynthetase Antibodies Specificities on Antisynthetase Syndrome Clinical Spectrum Time Course

Author

Cavagna, L, Trallero-Araguás, E, Meloni, F, Cavazzana, I, Rojas-Serrano, J, Feist, E, Zanframundo, G, Morandi, V, Meyer, A, Pereira da Silva, J, Matos Costa, C, Molberg, O, Andersson, H, Codullo, V, Mosca, M, Barsotti, S, Neri, R, Scirè, C, Govoni, M, Furini, F, Lopez-Longo, F, Martinez-Barrio, J, Schneider, U, Lorenz, H, Doria, A, Ghirardello, A, Ortego-Centeno, N, Confalonieri, M, Tomietto, P, Pipitone, N, Rodriguez Cambron, A, Blázquez Cañamero, M, Voll, R, Wendel, S, Scarpato, S, Maurier, F, Limonta, M, Colombelli, P, Giannini, M, Geny, B, Arrigoni, E, Bravi, E, Migliorini, P, Mathieu, A, Piga, M, Drott, U, Delbrueck, C, Bauhammer, J, Cagnotto, G, Vancheri, C, Sambataro, G, De Langhe, E, Sainaghi, P, Monti, C, Gigli Berzolari, F, Romano, M, Bonella, F, Specker, C, Schwarting, A, Villa Blanco, I, Selmi, C, Ceribelli, A, Nuno, L, Mera-Varela, A, Perez Gomez, N, Fusaro, E, Parisi, S, Sinigaglia, L, Del Papa, N, Benucci, M, Cimmino, M, Riccieri, V, Conti, F, Sebastiani, G, Iuliano, A, Emmi, G, Cammelli, D, Sebastiani, M, Manfredi, A, Bachiller-Corral, J, Sifuentes Giraldo, W, Paolazzi, G, Saketkoo, L, Giorgi, R, Salaffi, F, Cifrian, J, Caporali, R, Locatelli, F, Marchioni, E, Pesci, A, Dei, G, Pozzi, M, Claudia, L, Distler, J, Knitza, J, Schett, G, Iannone, F, Fornaro, M, Franceschini, F, Quartuccio, L, Gerli, R, Bartoloni, E, Bellando Randone, S, Zampogna, G, Gonzalez Perez, M, Mejia, M, Vicente, E, Triantafyllias, K, Lopez-Mejias, R, Matucci-Cerinic, M, Selva-O'Callaghan, A, Castañeda, S, Montecucco, C, Gonzalez-Gay, M, Cavagna, Lorenzo, Trallero-Araguás, Ernesto, Meloni, Federica, Cavazzana, Ilaria, Rojas-Serrano, Jorge, Feist, Eugen, Zanframundo, Giovanni, Morandi, Valentina, Meyer, Alain, Pereira da Silva, Jose Antonio, Matos Costa, Carlo Jorge, Molberg, Oyvind, Andersson, Helena, Codullo, Veronica, Mosca, Marta, Barsotti, Simone, Neri, Rossella, Scirè, Carlo, Govoni, Marcello, Furini, Federica, Lopez-Longo, Francisco Javier, Martinez-Barrio, Julia, Schneider, Udo, Lorenz, Hanns-Martin, Doria, Andrea, Ghirardello, Anna, Ortego-Centeno, Norberto, Confalonieri, Marco, Tomietto, Paola, Pipitone, Nicolò, Rodriguez Cambron, Ana Belen, Blázquez Cañamero, María Ángeles, Voll, Reinhard Edmund, Wendel, Sarah, Scarpato, Salvatore, Maurier, Francois, Limonta, Massimiliano, Colombelli, Paolo, Giannini, Margherita, Geny, Bernard, Arrigoni, Eugenio, Bravi, Elena, Migliorini, Paola, Mathieu, Alessandro, Piga, Matteo, Drott, Ulrich, Delbrueck, Christiane, Bauhammer, Jutta, Cagnotto, Giovanni, Vancheri, Carlo, Sambataro, Gianluca, De Langhe, Ellen, Sainaghi, Pier Paolo, Monti, Cristina, Gigli Berzolari, Francesca, Romano, Mariaeva, Bonella, Francesco, Specker, Christof, Schwarting, Andreas, Villa Blanco, Ignacio, Selmi, Carlo, Ceribelli, Angela, Nuno, Laura, Mera-Varela, Antonio, Perez Gomez, Nair, Fusaro, Enrico, Parisi, Simone, Sinigaglia, Luigi, Del Papa, Nicoletta, Benucci, Maurizio, Cimmino, Marco Amedeo, Riccieri, Valeria, Conti, Fabrizio, Sebastiani, Gian Domenico, Iuliano, Annamaria, Emmi, Giacomo, Cammelli, Daniele, Sebastiani, Marco, Manfredi, Andreina, Bachiller-Corral, Javier, Sifuentes Giraldo, Walter Alberto, Paolazzi, Giuseppe, Saketkoo, Lesley Ann, Giorgi, Roberto, Salaffi, Fausto, Cifrian, Jose, Caporali, Roberto, Locatelli, Francesco, Marchioni, Enrico, Pesci, Alberto, Dei, Giulia, Pozzi, Maria Rosa, Claudia, Lomater, Distler, Jorg, Knitza, Johannes, Schett, George, Iannone, Florenzo, Fornaro, Marco, Franceschini, Franco, Quartuccio, Luca, Gerli, Roberto, Bartoloni, Elena, Bellando Randone, Silvia, Zampogna, Giuseppe, Gonzalez Perez, Montserrat I, Mejia, Mayra, Vicente, Esther, Triantafyllias, Konstantinos, Lopez-Mejias, Raquel, Matucci-Cerinic, Marco, Selva-O'Callaghan, Albert, Castañeda, Santos, Montecucco, Carlomaurizio, Gonzalez-Gay, Miguel Angel, Cavagna, L, Trallero-Araguás, E, Meloni, F, Cavazzana, I, Rojas-Serrano, J, Feist, E, Zanframundo, G, Morandi, V, Meyer, A, Pereira da Silva, J, Matos Costa, C, Molberg, O, Andersson, H, Codullo, V, Mosca, M, Barsotti, S, Neri, R, Scirè, C, Govoni, M, Furini, F, Lopez-Longo, F, Martinez-Barrio, J, Schneider, U, Lorenz, H, Doria, A, Ghirardello, A, Ortego-Centeno, N, Confalonieri, M, Tomietto, P, Pipitone, N, Rodriguez Cambron, A, Blázquez Cañamero, M, Voll, R, Wendel, S, Scarpato, S, Maurier, F, Limonta, M, Colombelli, P, Giannini, M, Geny, B, Arrigoni, E, Bravi, E, Migliorini, P, Mathieu, A, Piga, M, Drott, U, Delbrueck, C, Bauhammer, J, Cagnotto, G, Vancheri, C, Sambataro, G, De Langhe, E, Sainaghi, P, Monti, C, Gigli Berzolari, F, Romano, M, Bonella, F, Specker, C, Schwarting, A, Villa Blanco, I, Selmi, C, Ceribelli, A, Nuno, L, Mera-Varela, A, Perez Gomez, N, Fusaro, E, Parisi, S, Sinigaglia, L, Del Papa, N, Benucci, M, Cimmino, M, Riccieri, V, Conti, F, Sebastiani, G, Iuliano, A, Emmi, G, Cammelli, D, Sebastiani, M, Manfredi, A, Bachiller-Corral, J, Sifuentes Giraldo, W, Paolazzi, G, Saketkoo, L, Giorgi, R, Salaffi, F, Cifrian, J, Caporali, R, Locatelli, F, Marchioni, E, Pesci, A, Dei, G, Pozzi, M, Claudia, L, Distler, J, Knitza, J, Schett, G, Iannone, F, Fornaro, M, Franceschini, F, Quartuccio, L, Gerli, R, Bartoloni, E, Bellando Randone, S, Zampogna, G, Gonzalez Perez, M, Mejia, M, Vicente, E, Triantafyllias, K, Lopez-Mejias, R, Matucci-Cerinic, M, Selva-O'Callaghan, A, Castañeda, S, Montecucco, C, Gonzalez-Gay, M, Cavagna, Lorenzo, Trallero-Araguás, Ernesto, Meloni, Federica, Cavazzana, Ilaria, Rojas-Serrano, Jorge, Feist, Eugen, Zanframundo, Giovanni, Morandi, Valentina, Meyer, Alain, Pereira da Silva, Jose Antonio, Matos Costa, Carlo Jorge, Molberg, Oyvind, Andersson, Helena, Codullo, Veronica, Mosca, Marta, Barsotti, Simone, Neri, Rossella, Scirè, Carlo, Govoni, Marcello, Furini, Federica, Lopez-Longo, Francisco Javier, Martinez-Barrio, Julia, Schneider, Udo, Lorenz, Hanns-Martin, Doria, Andrea, Ghirardello, Anna, Ortego-Centeno, Norberto, Confalonieri, Marco, Tomietto, Paola, Pipitone, Nicolò, Rodriguez Cambron, Ana Belen, Blázquez Cañamero, María Ángeles, Voll, Reinhard Edmund, Wendel, Sarah, Scarpato, Salvatore, Maurier, Francois, Limonta, Massimiliano, Colombelli, Paolo, Giannini, Margherita, Geny, Bernard, Arrigoni, Eugenio, Bravi, Elena, Migliorini, Paola, Mathieu, Alessandro, Piga, Matteo, Drott, Ulrich, Delbrueck, Christiane, Bauhammer, Jutta, Cagnotto, Giovanni, Vancheri, Carlo, Sambataro, Gianluca, De Langhe, Ellen, Sainaghi, Pier Paolo, Monti, Cristina, Gigli Berzolari, Francesca, Romano, Mariaeva, Bonella, Francesco, Specker, Christof, Schwarting, Andreas, Villa Blanco, Ignacio, Selmi, Carlo, Ceribelli, Angela, Nuno, Laura, Mera-Varela, Antonio, Perez Gomez, Nair, Fusaro, Enrico, Parisi, Simone, Sinigaglia, Luigi, Del Papa, Nicoletta, Benucci, Maurizio, Cimmino, Marco Amedeo, Riccieri, Valeria, Conti, Fabrizio, Sebastiani, Gian Domenico, Iuliano, Annamaria, Emmi, Giacomo, Cammelli, Daniele, Sebastiani, Marco, Manfredi, Andreina, Bachiller-Corral, Javier, Sifuentes Giraldo, Walter Alberto, Paolazzi, Giuseppe, Saketkoo, Lesley Ann, Giorgi, Roberto, Salaffi, Fausto, Cifrian, Jose, Caporali, Roberto, Locatelli, Francesco, Marchioni, Enrico, Pesci, Alberto, Dei, Giulia, Pozzi, Maria Rosa, Claudia, Lomater, Distler, Jorg, Knitza, Johannes, Schett, George, Iannone, Florenzo, Fornaro, Marco, Franceschini, Franco, Quartuccio, Luca, Gerli, Roberto, Bartoloni, Elena, Bellando Randone, Silvia, Zampogna, Giuseppe, Gonzalez Perez, Montserrat I, Mejia, Mayra, Vicente, Esther, Triantafyllias, Konstantinos, Lopez-Mejias, Raquel, Matucci-Cerinic, Marco, Selva-O'Callaghan, Albert, Castañeda, Santos, Montecucco, Carlomaurizio, and Gonzalez-Gay, Miguel Angel

Abstract

Antisynthetase syndrome (ASSD) is a rare clinical condition that is characterized by the occurrence of a classic clinical triad, encompassing myositis, arthritis, and interstitial lung disease (ILD), along with specific autoantibodies that are addressed to different aminoacyl tRNA synthetases (ARS). Until now, it has been unknown whether the presence of a different ARS might affect the clinical presentation, evolution, and outcome of ASSD. In this study, we retrospectively recorded the time of onset, characteristics, clustering of triad findings, and survival of 828 ASSD patients (593 anti-Jo1, 95 anti-PL7, 84 anti-PL12, 38 anti-EJ, and 18 anti-OJ), referring to AENEAS (American and European NEtwork of Antisynthetase Syndrome) collaborative group's cohort. Comparisons were performed first between all ARS cases and then, in the case of significance, while using anti-Jo1 positive patients as the reference group. The characteristics of triad findings were similar and the onset mainly began with a single triad finding in all groups despite some differences in overall prevalence. The "ex-novo" occurrence of triad findings was only reduced in the anti-PL12-positive cohort, however, it occurred in a clinically relevant percentage of patients (30%). Moreover, survival was not influenced by the underlying anti-aminoacyl tRNA synthetase antibodies' positivity, which confirmed that antisynthetase syndrome is a heterogeneous condition and that antibody specificity only partially influences the clinical presentation and evolution of this condition.

Published
2019

86. GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways

Author

Lopez-Isac, E, Acosta-Herrera, M, Kerick, M, Assassi, S, Satpathy, AT, Granja, J, Mumbach, MR, Beretta, L, Simeon, CP, Carreira, P, Ortego-Centeno, N, Castellvi, I, Bossini-Castillo, L, David Carmona, F, Orozco, G, Hunzelmann, N, Distler, JHW, Franke, A, Lunardi, C, Moroncini, G, Gabrielli, A, de Vries-Bouwstra, J, Wijmenga, C, Koeleman, BPC, Nordin, A, Padyukov, L, Hoffmann-Vold, A-M, Lie, B, Rios, R, Callejas, JL, Vargas-Hitos, JA, Garcia-Portales, R, Camps, MT, Fernandez-Nebro, A, Gonzalez-Escribano, MF, Garcia-Hernandez, FJ, Castillo, MJ, Aguirre, MA, Gomez-Gracia, I, Fernandez-Gutierrez, B, Rodriguez-Rodriguez, L, Garcia de la Pena, P, Vicente, E, Andreu, JL, Fernandez de Castro, M, Lopez-Longo, FJ, Martinez, L, Fonollosa, V, Guillen, A, Espinosa, G, Tolosa, C, Pros, A, Rodriguez-Carballeira, M, Narvaez, FJ, Rubio-Rivas, M, Ortiz-Santamaria, V, Madronero, AB, Gonzalez-Gay, MA, Diaz, B, Trapiella, L, Sousa, A, Egurbide, MV, Fanlo-Mateo, P, Saez-Comet, L, Diaz, F, Hernandez, V, Beltran, E, Roman-Ivorra, JA, Grau, E, Alegre-Sancho, JJ, Freire, M, Blanco-Garcia, FJ, Oreiro, N, Witte, T, Kreuter, A, Riemekasten, G, Airo, P, Magro, C, Voskuyl, AE, Vonk, MC, Hesselstrand, R, Proudman, S, Stevens, W, Nikpour, M, Zochling, J, Sahhar, J, Roddy, J, Nash, P, Tymms, K, Rischmueller, M, Lester, S, Vyse, T, Herrick, AL, Worthington, J, Denton, CP, Allanore, Y, Brown, MA, Radstake, TRDJ, Fonseca, C, Chang, HY, Mayes, MD, Martin, J, Lopez-Isac, E, Acosta-Herrera, M, Kerick, M, Assassi, S, Satpathy, AT, Granja, J, Mumbach, MR, Beretta, L, Simeon, CP, Carreira, P, Ortego-Centeno, N, Castellvi, I, Bossini-Castillo, L, David Carmona, F, Orozco, G, Hunzelmann, N, Distler, JHW, Franke, A, Lunardi, C, Moroncini, G, Gabrielli, A, de Vries-Bouwstra, J, Wijmenga, C, Koeleman, BPC, Nordin, A, Padyukov, L, Hoffmann-Vold, A-M, Lie, B, Rios, R, Callejas, JL, Vargas-Hitos, JA, Garcia-Portales, R, Camps, MT, Fernandez-Nebro, A, Gonzalez-Escribano, MF, Garcia-Hernandez, FJ, Castillo, MJ, Aguirre, MA, Gomez-Gracia, I, Fernandez-Gutierrez, B, Rodriguez-Rodriguez, L, Garcia de la Pena, P, Vicente, E, Andreu, JL, Fernandez de Castro, M, Lopez-Longo, FJ, Martinez, L, Fonollosa, V, Guillen, A, Espinosa, G, Tolosa, C, Pros, A, Rodriguez-Carballeira, M, Narvaez, FJ, Rubio-Rivas, M, Ortiz-Santamaria, V, Madronero, AB, Gonzalez-Gay, MA, Diaz, B, Trapiella, L, Sousa, A, Egurbide, MV, Fanlo-Mateo, P, Saez-Comet, L, Diaz, F, Hernandez, V, Beltran, E, Roman-Ivorra, JA, Grau, E, Alegre-Sancho, JJ, Freire, M, Blanco-Garcia, FJ, Oreiro, N, Witte, T, Kreuter, A, Riemekasten, G, Airo, P, Magro, C, Voskuyl, AE, Vonk, MC, Hesselstrand, R, Proudman, S, Stevens, W, Nikpour, M, Zochling, J, Sahhar, J, Roddy, J, Nash, P, Tymms, K, Rischmueller, M, Lester, S, Vyse, T, Herrick, AL, Worthington, J, Denton, CP, Allanore, Y, Brown, MA, Radstake, TRDJ, Fonseca, C, Chang, HY, Mayes, MD, and Martin, J

Abstract

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.

Published
2019

87. Endothelin-1 serum levels in women with Rheumatoid Arthritis

Author

Álvarez-Cienfuegos, A., Cantero-Nieto, Lucía, García-Gómez, José Alberto, Ríos-Fernández, Raquel, Martín, J., González-Gay, M. A., Ortego-Centeno, N., Álvarez-Cienfuegos, A., Cantero-Nieto, Lucía, García-Gómez, José Alberto, Ríos-Fernández, Raquel, Martín, J., González-Gay, M. A., and Ortego-Centeno, N.

Abstract

Objective: The purpose of this study was to evaluate serum Endothelin-1(ET-1) levels in female Rheumatoid Arthritis (RA) patients compared with healthy controls, examine possible associations between ET-1 with different characteristic of the disease and investigate possible associations between ET-1 with surrogate markers of cardiovascular disease (CVD). Methods: This cross-sectional study was performed in Vega-Baja Hospital, Orihuela (Spain) from November 2016 to May 2018. Sixty-three women with RA and sixty-five age and sex healthy controls were included in this study. Serum ET-1 was analyzed using ELISA. Results: Serum levels of ET-1 in RA female patients were higher than those in healthy controls (p ??0.001). Serum le vels of ET-1 were positively associated with Nterminal pro-brain natriuretic peptide (NT-proBNP) (r = 0.27, p < 0.05) and with C-reactive protein (CRP) (r = 0.36, p < 0.05). ET-1 levels in women with RA were higher in smokers. Pre dnisone use was associated with lower ET-1 levels. No association with carotid intima media thickness was found. Conclusions: we observed the presence of higher le - vels of serum ET-1 in RA women patients compared with healthy controls. These increased levels of ET-1 are associated with inflammation and smoking and reduced by prednisone intake.

Published
2019

88. GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways.

Author

Universidad de Salamanca, Ministerio de Economía y Competitividad (España), Junta de Andalucía, Ministerio de Educación, Cultura y Deporte (España), Instituto de Salud Carlos III, Howard Hughes Medical Institute, Federal Ministry of Education and Research (Germany), López-Isac, Elena, Acosta-Herrera, Marialbert, Kerick M, Assassi, S., Satpathy AT, Granja J, Mumbach, Maxwell R., Beretta L, Simeón, Carmen P., Carreira P, Ortego-Centeno, N., Castellví, I., Bossini-Castillo, L., Carmona, F.D., Orozco, Gisela, Hunzelmann, Nicolas, Distler, J.H.W., Franke, Andre, Lunardi, C., Moroncini, G, Gabrielli, Armando, de Vries-Bouwstra, Jeska, Wijmenga, C, Koeleman, B. P., Nordin, A, Padyukov, L, Hoffmann-Vold, A. M., Lie, B, European Scleroderma Group¿, Proudman, S, Stevens, W, Nikpour, M, Australian Scleroderma Interest Group (ASIG), Vyse, T, Herrick, Ariane L., Worthington, J, Denton, CP, Allanore, Y, Brown, MA, Radstake, Timothy R. D. J., Fonseca, C., Chang, HY, Mayes, Maureen D., Martín, J., Universidad de Salamanca, Ministerio de Economía y Competitividad (España), Junta de Andalucía, Ministerio de Educación, Cultura y Deporte (España), Instituto de Salud Carlos III, Howard Hughes Medical Institute, Federal Ministry of Education and Research (Germany), López-Isac, Elena, Acosta-Herrera, Marialbert, Kerick M, Assassi, S., Satpathy AT, Granja J, Mumbach, Maxwell R., Beretta L, Simeón, Carmen P., Carreira P, Ortego-Centeno, N., Castellví, I., Bossini-Castillo, L., Carmona, F.D., Orozco, Gisela, Hunzelmann, Nicolas, Distler, J.H.W., Franke, Andre, Lunardi, C., Moroncini, G, Gabrielli, Armando, de Vries-Bouwstra, Jeska, Wijmenga, C, Koeleman, B. P., Nordin, A, Padyukov, L, Hoffmann-Vold, A. M., Lie, B, European Scleroderma Group¿, Proudman, S, Stevens, W, Nikpour, M, Australian Scleroderma Interest Group (ASIG), Vyse, T, Herrick, Ariane L., Worthington, J, Denton, CP, Allanore, Y, Brown, MA, Radstake, Timothy R. D. J., Fonseca, C., Chang, HY, Mayes, Maureen D., and Martín, J.

Abstract

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.

Published
2019

89. Association of Functional Polymorphisms of KIR3DL1/DS1 With Behçet's Disease.

Author

Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Castaño-Núñez, Á, Montes-Cano, Marco-Antonio, García-Lozano, José Raúl, Ortego-Centeno, N., García-Hernández, Francisco José, Espinosa, Gerard, Graña-Gil, Genaro, Sánchez-Bursón, J, Julià, María Rosa, Solans, R, Blanco, Ricardo, Barnosi-Marín, AC, Gómez de la Torre, Ricardo, Fanlo, P., Rodríguez-Carballeira, M., Rodríguez-Rodríguez, L., Camps, Teresa, Castañeda, Santos, Alegre-Sancho, Juan-José, Martín, J., González-Escribano, María Francisca, Instituto de Salud Carlos III, European Commission, Junta de Andalucía, Castaño-Núñez, Á, Montes-Cano, Marco-Antonio, García-Lozano, José Raúl, Ortego-Centeno, N., García-Hernández, Francisco José, Espinosa, Gerard, Graña-Gil, Genaro, Sánchez-Bursón, J, Julià, María Rosa, Solans, R, Blanco, Ricardo, Barnosi-Marín, AC, Gómez de la Torre, Ricardo, Fanlo, P., Rodríguez-Carballeira, M., Rodríguez-Rodríguez, L., Camps, Teresa, Castañeda, Santos, Alegre-Sancho, Juan-José, Martín, J., and González-Escribano, María Francisca

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

90. Association of TNFSF4 (OX40L) polymorphisms with systemic sclerosis-related calcinosis

Author

Duffus, Kate, López-Isac, Elena, Teruel, M., Simeón, Carmen P., Carreria, P., Ortego-Centeno, N., Vicente, Esther, Worthington, J., Herrick, Ariane L., Martín, J., Duffus, Kate, López-Isac, Elena, Teruel, M., Simeón, Carmen P., Carreria, P., Ortego-Centeno, N., Vicente, Esther, Worthington, J., Herrick, Ariane L., and Martín, J.

Abstract

descripción no proporcionada por scopus

Published
2019

91. Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases

Author

Innovative Medicines Initiative, Ministerio de Economía, Industria y Competitividad (España), Junta de Andalucía, National Institute of Environmental Health Sciences (US), Acosta-Herrera, Marialbert, Kerick, Martin, González-Serna, David, Wijmenga, Cisca, Franke, Andre, Gregersen, Peter K., Padyukov, Leonid, Worthington, J., Vyse, T. J., Alarcón-Riquelme, M. E., Mayes, Maureen D., Martín, J., Miller, Frederick W., Chen, Wei, O'Hanlon, Terrance P., Cooper, Robert G., Vencovsky, Jiri, Rider, Lisa G, Danko, Katalin, Wedderburn, Lucy R., Lundberg, Ingrid E., Pachman, Lauren M., Reed, Ann M., Ytterberg, Steven R, Selva-O'Callaghan, Alber, Radstake, Timothy R., Isenberg, David A, Chinoy, Hector, Ollier, William E. R, Scheet, Paul, Peng, Bo, Lee, Annette T., Lamb, Janine A., Amos, Christopher I., Denton, Christopher, Hilton-Jones, David, Plotz, Paul H., Varsani, Hemlata, Radstake, Timothy R. D. J., Gorlova, Olga, Rueda, B., Martín, J. E., Alizadeh, B. Z., Palomino-Morales, Rogelio, Coenen, Marieke J. H., Vonk, Madelon C., Voskuyl, Alexandre E., Scheurwegh, Annemie J., Broen, Jasper C., van Riel, Piet L. C. M., van 't Slot, Rubén, Italiaander, Annet, Ophoff, Roel A., Riemekasten, Gabriela, Hunzelmann, Nicolas, Simeón, Carmen P., Ortego-Centeno, N., González-Gay, M. A., González-Escribano, María Francisca, Airó, Paolo, van Laar, Jaap, Herrick, Ariane L., Hesselstrand, Roger, Smith, Vanessa, de Keyser, Filip, Houssiau, Fredric, Chee, Meng May, Madhok, Rajan, Shiels, Paul, Westhovens, Rene, Kreuter, A., Kiener, Hans, de Baere, Elfride, Witte, Torsten, Klareskog, Lars, Beretta, Lorenzo, Scorza, Rafaella, Lie, Benedicte A., Hoffman-Vold, A. M., Carreira, P., Varga, John, Hinchcliff, Monique, Ying, Jun, Han, Younghun, Weng, Shih-Feng, Wigley, Fredrick M., Hummers, L. K., Nelson, J. Lee, Agarwal, Sandeep K., Assassi, S., Gourh, Pravitt, Tan, Filemon K., Koeleman, B. P., Arnett, Frank C., Myositis Genetics Consortium, Scleroderma Genetics Consortium., Innovative Medicines Initiative, Ministerio de Economía, Industria y Competitividad (España), Junta de Andalucía, National Institute of Environmental Health Sciences (US), Acosta-Herrera, Marialbert, Kerick, Martin, González-Serna, David, Wijmenga, Cisca, Franke, Andre, Gregersen, Peter K., Padyukov, Leonid, Worthington, J., Vyse, T. J., Alarcón-Riquelme, M. E., Mayes, Maureen D., Martín, J., Miller, Frederick W., Chen, Wei, O'Hanlon, Terrance P., Cooper, Robert G., Vencovsky, Jiri, Rider, Lisa G, Danko, Katalin, Wedderburn, Lucy R., Lundberg, Ingrid E., Pachman, Lauren M., Reed, Ann M., Ytterberg, Steven R, Selva-O'Callaghan, Alber, Radstake, Timothy R., Isenberg, David A, Chinoy, Hector, Ollier, William E. R, Scheet, Paul, Peng, Bo, Lee, Annette T., Lamb, Janine A., Amos, Christopher I., Denton, Christopher, Hilton-Jones, David, Plotz, Paul H., Varsani, Hemlata, Radstake, Timothy R. D. J., Gorlova, Olga, Rueda, B., Martín, J. E., Alizadeh, B. Z., Palomino-Morales, Rogelio, Coenen, Marieke J. H., Vonk, Madelon C., Voskuyl, Alexandre E., Scheurwegh, Annemie J., Broen, Jasper C., van Riel, Piet L. C. M., van 't Slot, Rubén, Italiaander, Annet, Ophoff, Roel A., Riemekasten, Gabriela, Hunzelmann, Nicolas, Simeón, Carmen P., Ortego-Centeno, N., González-Gay, M. A., González-Escribano, María Francisca, Airó, Paolo, van Laar, Jaap, Herrick, Ariane L., Hesselstrand, Roger, Smith, Vanessa, de Keyser, Filip, Houssiau, Fredric, Chee, Meng May, Madhok, Rajan, Shiels, Paul, Westhovens, Rene, Kreuter, A., Kiener, Hans, de Baere, Elfride, Witte, Torsten, Klareskog, Lars, Beretta, Lorenzo, Scorza, Rafaella, Lie, Benedicte A., Hoffman-Vold, A. M., Carreira, P., Varga, John, Hinchcliff, Monique, Ying, Jun, Han, Younghun, Weng, Shih-Feng, Wigley, Fredrick M., Hummers, L. K., Nelson, J. Lee, Agarwal, Sandeep K., Assassi, S., Gourh, Pravitt, Tan, Filemon K., Koeleman, B. P., Arnett, Frank C., Myositis Genetics Consortium, and Scleroderma Genetics Consortium.

Published
2019

92. Behcet's disease and genetic interactions between HLA-B*51 and variants in genes of autoinflammatory syndromes

Author

Instituto de Salud Carlos III, Junta de Andalucía, European Commission, Burillo Sanz, Sergio [0000-0002-6895-7875], Blanco, Ricardo [0000-0003-2344-2285], Martín, J. [0000-0002-2202-0622], Burillo-Sanz, Sergio, Montes-Cano, Marco-Antonio, García-Lozano, José Raúl, Olivas-Martínez, Israel, Ortego-Centeno, N., García-Hernández, Francisco José, Espinosa, Gerard, Graña-Gil, Genaro, Sánchez-Bursón, Juan, Julià, María Rosa, Solans, Roser, Blanco, Ricardo, Barnosi-Marín, Ana C., Gómez de la Torre, Ricardo, Fanlo, Patricia, Rodríguez-Carballeira, Mónica, Rodríguez-Rodríguez, Luis, Camps, Teresa, Castañeda, Santos, Alegre-Sancho, Juan-José, Martín, J., González-Escribano, María Francisca, Instituto de Salud Carlos III, Junta de Andalucía, European Commission, Burillo Sanz, Sergio [0000-0002-6895-7875], Blanco, Ricardo [0000-0003-2344-2285], Martín, J. [0000-0002-2202-0622], Burillo-Sanz, Sergio, Montes-Cano, Marco-Antonio, García-Lozano, José Raúl, Olivas-Martínez, Israel, Ortego-Centeno, N., García-Hernández, Francisco José, Espinosa, Gerard, Graña-Gil, Genaro, Sánchez-Bursón, Juan, Julià, María Rosa, Solans, Roser, Blanco, Ricardo, Barnosi-Marín, Ana C., Gómez de la Torre, Ricardo, Fanlo, Patricia, Rodríguez-Carballeira, Mónica, Rodríguez-Rodríguez, Luis, Camps, Teresa, Castañeda, Santos, Alegre-Sancho, Juan-José, Martín, J., and González-Escribano, María Francisca

Abstract

Behcet's disease (BD) is an immune-mediated systemic disorder with a well-established genetic base. In a previous study, using a next generation sequencing approach, we found many rare variants and some functional polymorphisms in genes related to autoinflammatory syndromes (AID): CECR1, MEFV, MVK, NLRP3, NOD2, PSTPIP1 and TNFRSF1A in our BD cohort. Our strategy did not allow us to establish either number of patients with variants, proportion of individuals accumulating them or relationship with other genetic factors. With the goal to answer these questions, the individual samples were sequenced. Additionally, three functional polymorphisms: NLRP3 p.Gln703Lys, NOD2 p.Arg702Trp and p. Val955Ile were genotyped using TaqMan assays. A total of 98 patients (27.6%) carried at least one rare variant and 13 of them (3.7%) accumulated two or three. Functional regression model analysis suggests epistatic interaction between B51 and MEFV (P=0.003). A suggestive protective association of the minor allele of NOD2 p.Arg702Trp (P=0.01) was found in both, B51 positive and negative individuals. Therefore, a high percentage of patients with BD have rare variants in AID genes. Our results suggest that the association of MEFV with BD could be modulated by the HLA molecules; whereas the protective effect of NOD2 p.Arg702Trp would be independent of HLA.

Published
2019

94. 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

Lopez-Isac, E., Martin, J.E., Assassi, S., Simeon, C.P., Carreira, P., Ortego-Centeno, N., Freire, M., Beltran, E., Narvaez, J., Alegre-Sancho, J.J., Fernandez-Gutierrez, B., Balsa, A., Ortiz, A.M., Gonzalez-Gay, M.A., Beretta, L., Santaniello, A., Bellocchi, C., Lunardi, C., Moroncini, G., Gabrielli, A., Witte, T. de, Hunzelmann, N., Distler, J.H., Riekemasten, G., Mil, A.H.V. van der Helm-va, Vries-Bouwstra, J. de, Magro-Checa, C., Voskuyl, A.E., Vonk, M.C., Molberg, O., Merriman, T., Hesselstrand, R., Nordin, A., Padyukov, L., Herrick, A., Eyre, S., Koeleman, B.P.C., Denton, C.P., Fonseca, C., Radstake, T.R., Worthington, J., Mayes, M.D., and Martin, J.

Subjects
Scleroderma, Systemic, integumentary system, Rheumatoid Arthritis, Systemic Sclerosis, Arthritis, Rheumatoid, Genetic Loci, Risk Factors, IRF4, Interferon Regulatory Factors, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Humans, Genetic Predisposition to Disease, Systemic Sclerosis, Rheumatoid Arthritis, IRF4, skin and connective tissue diseases, Genome-Wide Association Study
Abstract

Contains fulltext : 172048.pdf (Publisher’s version ) (Closed access) 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 < 5 x 10(-6) ) that also showed evidence of association in the disease-specific GWAS scans. These loci included several genomic regions not previously reported as shared loci, as well as several risk factors that were previously found to be associated with both diseases. Follow-up analyses of the putatively new SSc-RA loci identified IRF4 as a shared risk factor for these 2 diseases (Pcombined = 3.29 x 10(-12) ). Analysis of the biologic relevance of the known SSc-RA shared loci identified the type I interferon and interleukin-12 signaling pathways as the main common etiologic factors. CONCLUSION: This study identified a novel shared locus, IRF4, for the risk of SSc and RA, and highlighted the usefulness of a cross-disease GWAS meta-analysis strategy in the identification of common risk loci.

Published
2016
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95. Tocilizumab as an Adjuvant Therapy for Hemophagocytic Lymphohistiocytosis Associated With Visceral Leishmaniasis

Author

Sancho, Jaime [0000-0003-3852-7951], Zubiaur, Mercedes [0000-0002-4127-3027], Ortego-Centeno, N. [0000-0003-2325-0937], Ríos-Fernández, Raquel, Callejas-Rubio, J. L., García-Rodríguez, Sonia, Sancho, Jaime, Zubiaur, Mercedes, Ortego-Centeno, N., Sancho, Jaime [0000-0003-3852-7951], Zubiaur, Mercedes [0000-0002-4127-3027], Ortego-Centeno, N. [0000-0003-2325-0937], Ríos-Fernández, Raquel, Callejas-Rubio, J. L., García-Rodríguez, Sonia, Sancho, Jaime, Zubiaur, Mercedes, and Ortego-Centeno, N.

Abstract

Leishmaniasis is important as a cause of hemophagocytic lymphohistiocytosis (HLH) and must be considered and excluded in patients with HLH because it can cause severe or even fatal complications. When HLH is present, there is a deficient downregulation of the immune response, leading to an uncontrolled inflammation. We report a case of visceral leishmaniasis-HLH where the therapy with tocilizumab, targeting interleukin 6, help to regulate the immune response for the infection of Leishmania.

Published
2016

97. Effect of ethnicity on clinical presentation and risk of antiphospholipid syndrome in Roma and Caucasian patients with systemic lupus erythematosus: a multicenter cross-sectional study

Author

Manzano-Gamero, V, Pardo-Cabello, AJ, Vargas-Hitos, JA, Zamora-Pasadas, M, Navarrete-Navarrete, N, Sabio, JM, Jaimez-Gamiz, L, Rios-Fernandez, R, Ortego-Centeno, N, Ayala-Gutierrez, MM, de Ramon, E, Colodro-Ruiz, A, Mico-Giner, L, Castillo-Palma, MJ, Robles-Marhuenda, A, Luna-Del Castillo, JD, Jimenez-Alonso, J, and Spanish Autoimmune Diseases Study Group (GEAS)

Subjects
disease etiology and pathogenesis - human, drug treatment, clinical aspects, epidemiology, systemic lupus erythematous
Abstract

Aim To determine if there are ethnic differences in the prevalence of antiphospholipid syndrome (APS), clinical presentation and autoantibody profile between Roma and Caucasian patients with systemic lupus erythematosus (SLE). Method A cross-sectional study was conducted including data from Roma and Caucasian SLE patients consecutively attending six hospitals in Spain. Socio-demographic characteristics, prevalence of APS, clinical and analytical features of SLE and APS were compared between ethnic groups. Results Data from 52 Roma and 98 Caucasian SLE patients were included. Roma SLE patients had a higher risk (odds ratio 2.56, 95% CI 1.02-6.39) and prevalence of APS (28.8% vs. 13.3%, P = 0.027). Furthermore, Roma SLE patients had a statistically significant higher prevalence of abortions (23.5% vs. 10.2%, P = 0.049). In relation to other APS diagnostic criteria, Roma SLE patients had a non-statistically significant higher prevalence of fetal deaths (14.3% vs. 5.1%, P = 0.106) and thrombotic events (21.1% vs. 12.2%, P = 0.160). In relation to SLE clinical features, Roma patients had a significantly higher prevalence of arthritis (75% vs. 57.1%, P = 0.034) and non-significant higher prevalence of serositis (44.2% vs. 29.6%, P = 0.104), discoid lesions (11.5% vs. 5.1%, P = 0.191), oral ulcers (46.1% vs. 34.7%, P = 0.218) and livedo reticularis (21.1% vs. 15.3%, P = 0.374). No statistically significant differences were found in the Systemic Lupus International Collaborating Clinics Damage Index or the autoimmune serological profile. Conclusion Prevalence and risk of APS were significantly higher in Roma SLE patients. Furthermore, Roma patients had a significantly higher prevalence of abortions and a non-significant higher prevalence of fetal deaths and thrombotic events.

Published
2018

98. Anti-CD38 autoimmunity in patients with systemic lupus erythematosus

Author

Pavón, E. J., Zumaquero, Esther, Rosal-Vela, Antonio, Khoo, K. M., Cerezo-Wallis, Daniela, García-Rodríguez, S., Carrascal, M., Abian, J., Graeff, R., Callejas-Rubio, J. L., Ortego-Centeno, N., Malavasi, F., Zubiaur, Mercedes, and Sancho, Jaime

Subjects
immune system diseases, hemic and lymphatic diseases, hemic and immune systems, skin and connective tissue diseases
Abstract

CD38 is a multifunctional protein possessing ADP-ribosyl cyclase activity responsible for both the synthesis and the degradation of several Ca(2+)-mobilizing second messengers. In mammals, CD38 also functions as a receptor. In this study CD38 expression in CD4(+), CD8(+), or CD25(+) T cells was significantly higher in systemic lupus erythematosus (SLE) patients than in Normal controls. Increased CD38 expression in SLE T cells correlated with plasma levels of Th2 (IL-4, IL-10, IL-13) and Th1 (IL-1ß, IL-12, IFN-¿, TNF-¿) cytokines, and was more prevalent in clinically active SLE patients than in Normal controls. In contrast, elevated anti-CD38 IgG autoantibodies were more frequent in clinically quiescent SLE patients (SLEDAI=0) than in Normal controls, and correlated with moderate increased plasma levels of IL-10 and IFN-¿. However, clinically active SLE patients were mainly discriminated from quiescent SLE patients by increased levels of IL-10 and anti-dsDNA antibodies, with odds ratios (ORs) of 3.7 and 4.8, respectively. Increased frequency of anti-CD38 autoantibodies showed an inverse relationship with clinical activity (OR=0.43), and in particular with the frequency of anti-dsDNA autoantibodies (OR=0.21). Increased cell death occurred in CD38(+) Jurkat T cells treated with anti-CD38(+) SLE plasmas, and not in these cells treated with anti-CD38(-) SLE plasmas, or Normal plasmas. This effect did not occur in CD38-negative Jurkat T cells, suggesting that it could be attributed to anti-CD38 autoantibodies. These results support the hypothesis that anti-CD38 IgG autoantibodies or their associated plasma factors may dampen immune activation by affecting the viability of CD38(+) effector T cells and may provide protection from certain clinical SLE features.

Published
2018

99. Hepatobiliary involvement in systemic sclerosis and the cutaneous subsets: Characteristics and survival of patients from the Spanish RESCLE Registry

Author

Mari-Alfonso, B, Pilar Simeon-Aznar, Carmen, Guillen-Del Castillo, A, Rubio-Rivas, M, Trapiella-Martinez, L, Antonio Todoli-Parra, Jose, Rodriguez Carballeira, Monica, Marin-Ballve, A, Iniesta-Arandia, N, Colunga-Arguelles, D, Jesus Castillo-Palma, Maria, Saez-Comet, L, Victoria Egurbide-Arberas, Maria, Ortego-Centeno, N, Freire, M, Vargas Hitos, Jose Antonio, Chamorro, AJ, Belen Madronero-Vuelta, Ana, Perales-Fraile, I, Pla-Salas, X, Fernandez-De-La-Puebla, RA, Fonollosa-Pla, V, Tolosa-Vilella, C, RESCLE Investigators, and Systemic Autoimmune Dis Study Grp

Subjects
integumentary system, Hepatobiliary involvement, Survival, parasitic diseases, Primary biliary cholangitis, Systemic sclerosis, SSc sine scleroderma, skin and connective tissue diseases, Autoimmune hepatitis
Abstract

Objective: To assess the prevalence and causes of hepatobiliary involvement (HBI) in systemic sclerosis (SSc), to investigate the clinical characteristics and prognosis of SSc patients with HBI (SSc-HBI) and without HBI (SSc-non-HBI), and to compare both groups according to the cutaneous SSc subsets. Methods: In all, 1572 SSc patients were collected in the RESCLE registry up to January 2015, and all hepatobiliary disturbances were recorded. We investigated the HBI-related characteristics and survival from the entire SSc cohort and according to the following cutaneous subsets: diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc), and SSc sine scleroderma (ssSSc). Results: Out of 1572, 118 (7.5%) patients had HBI. Primary biliary cholangitis (PBC) was largely the main cause (n = 67, 4.3%), followed by autoimmune hepatitis (n = 19, 1.2%), and anti-mitochondrial negative PBC (n = 6, 0.4%). Other causes of HBI were as follows: secondary liver diseases (n = 11, 0.7%), SSc-related HBI (n = 7, 0.4%), nodular regenerative hyperplasia (n = 3, 0.2%), liver cirrhosis (n = 3, 0.2%), and HBI of unknown origin (n = 2, 0.1%). In multivariate analysis, HBI was independently associated to lesser risk of dcSSc (5.1% vs. 24.4%), and higher frequency of calcinosis (26% vs. 18%), left ventricular diastolic dysfunction (46% vs. 27%), sicca syndrome (51% vs. 29%), and anti-centromere antibodies (ACA, 73% vs. 44%). According to the cutaneous subsets, HBI was associated (1) in lcSSc, to longer time from SSc onset to diagnosis (10.8 +/- 12.5 vs. 7.2 +/- 9.3 years), sicca syndrome (54% vs. 33%), and ACA (80% vs. 56%); (2) in ssSSc, to sicca syndrome (44% vs. 19%), and (3) in dcSSc, no associations were found. HBI was the cause of death in 23% patients but the cumulative survival according to the presence or absence of HBI showed no differences. Conclusions: HBI prevalence in SSc is 7.5% and dcSSc is the least involved subset. PBC is the main cause of HBI. Patients with SSc-HBI exhibited specific clinical and immunologic profile. Survival is similar for SSc patients with HBI (C). 2017 Elsevier Inc. All rights reserved.

Published
2018

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