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341 results on '"Ortego Centeno N"'

1. Metabolismo mineral óseo en la enfermedad inflamatoria intestinal

Author

Sánchez Cano D, Callejas Rubio JL, Ríos Fernández R, and Ortego Centeno N

Subjects
Colitis ulcerosa, Enfermedad de Crohn, Enfermedad inflamatoria intestinal, Medicine, Osteopathy, RZ301-397.5
Abstract

La colitis ulcerosa y la enfermedad de Crohn constituyen los principales exponenentes de la enfermedad inflamatoria intestinal (EII). La osteoporosis es una complicación bien conocida de la EII, presentando una etiología multifactorial, aunque la importancia del papel del proceso inflamatorio en sí parece ser cada vez mayor. El fin de este artículo es revisar los datos existentes en cuanto al metabolismo mineral óseo en estos pacientes, tanto en relación a la prevalencia de la pérdida de masa ósea como la situación de los marcadores de recambio óseo, los factores implicados, así como del riesgo de fractura. De este modo, se pretende aportar luz sobre la importancia de la osteoporosis en la EII.

Published
2009

2. Contribution of Telomere Length to Systemic Sclerosis Onset: A Mendelian Randomization Study

Author

Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Ministerio de Universidades (España), Rodríguez-Martín, Inmaculada, Villanueva-Martín, Gonzalo, Guillén del Castillo, Alfredo, Ortego-Centeno, N., Callejas-Rubio, J. L., Simeón, Carmen P., Martín, Javier, Acosta-Herrera, Marialbert, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Ministerio de Universidades (España), Rodríguez-Martín, Inmaculada, Villanueva-Martín, Gonzalo, Guillén del Castillo, Alfredo, Ortego-Centeno, N., Callejas-Rubio, J. L., Simeón, Carmen P., Martín, Javier, and Acosta-Herrera, Marialbert

Abstract

Although previous studies have suggested a relationship between telomere shortening and systemic sclerosis (SSc), the association between these two traits remains poorly understood. The objective of this study was to assess the causal relationship between telomere length in leukocytes (LTL) and SSc using the two-sample Mendelian randomization approach, with the genome-wide association study data for both LTL and SSc. The results of inverse-variance weighted regression (OR = 0.716 [95% CI 0.528–0.970], p = 0.031) and the Mendelian randomization pleiotropy residual sum and outlier method (OR = 0.716 [95% CI 0.563–0.911], p = 0.035) indicate an association between telomere length and SSc. Specifically, longer genetically predicted LTL is associated with a reduced risk of SSc. Sensitivity tests highlight the significant roles of the variants rs10936599 and rs2736100 annotated to the TERC and TERT genes, respectively. Our findings suggest an influence of telomere length in leukocytes on the development of SSc.

Published
2023

3. Cranial and extracranial large-vessel giant cell arteritis share a genetic pattern of interferon-gamma pathway

Author

Prieto-Peña, Diana, Genre, Fernanda, Pulito-Cueto, Verónica, Ocejo-Vinyals, J. Gonzalo, Atienza-Mateo, Belén, Muñoz Jiménez, Alejandro, Ortiz-Sanjuán, Francisco, Romero-Yuste, Susana, Moriano, Clara, Galíndez-Agirregoikoa, E., Calvo, I., Ortego-Centeno, N., Álvarez-Rivas, Noelia, Miranda-Filloy, J. A., Baldivieso-Achá, J. P., Blanco, R., Gualillo, Oreste, Martin, Javier, Castañeda, S., López-Mejías, Raquel, Remuzgo-Martínez, S., González-Gay, M. A., Prieto-Peña, Diana, Genre, Fernanda, Pulito-Cueto, Verónica, Ocejo-Vinyals, J. Gonzalo, Atienza-Mateo, Belén, Muñoz Jiménez, Alejandro, Ortiz-Sanjuán, Francisco, Romero-Yuste, Susana, Moriano, Clara, Galíndez-Agirregoikoa, E., Calvo, I., Ortego-Centeno, N., Álvarez-Rivas, Noelia, Miranda-Filloy, J. A., Baldivieso-Achá, J. P., Blanco, R., Gualillo, Oreste, Martin, Javier, Castañeda, S., López-Mejías, Raquel, Remuzgo-Martínez, S., and González-Gay, M. A.

Abstract

OBJECTIVES: Two main different clinical phenotypes of giant cell arteritis (GCA) have been described, the classic cranial pattern and the extracranial large-vessel (LV) pattern. Since interferon gamma (IFNG) has shown to be a pivotal cytokine in the pathophysiology of GCA, our aim was to evaluate for the first time the influence of IFNG and IFNG receptor 1 (IFNGR1) polymorphisms in the different clinical phenotypes of GCA. METHODS: Two IFNG polymorphisms (rs2069718 G/A and rs1861493 A/G) and one polymorphism in IFNGR1 (rs1327474 G/A) were genotyped in 191 patients with biopsy-proven cranial GCA, 109 with extracranial LV-GCA and 490 healthy controls. A comparative study was conducted between patients with cranial and extracranial LV-GCA. RESULTS: No significant differences in genotype, allele, and haplotype frequencies of IFNG polymorphisms were found between GCA patients with the classic cranial pattern and the extracranial LV-GCA pattern. Similar results were found for genotype and allele frequencies of IFNGR1 polymorphism. It was also the case when patients with extracranial LV-GCA were compared with healthy controls. CONCLUSIONS: Our results show that IFNG and IFNGR1 polymorphisms do not influence the clinical phenotype of expression of GCA. Classic cranial GCA and extracranial LV-GCA seem to share a genetic pattern of IFNG pathway.

Published
2023

4. IgA Vasculitis: Influence of CD40, BLK and BANK1 Gene Polymorphisms

Author

European Commission, Instituto de Salud Carlos III, Xunta de Galicia, Batista-Liz, Joao Carlos, Genre, Fernanda, Pulito-Cueto, Verónica, Remuzgo-Martínez, Sara, Prieto-Peña, Diana, Márquez, Ana, Ortego-Centeno, N., Leonardo, María Teresa, Peñalba, Ana, Narváez, Javier, Martín-Penagos, Luis, Belmar, Lara, Gómez Fernández, Cristina, Miranda-Filloy, J. A., Caminal-Montero, Luis, Collado, Paz, Árgila, Diego de, Quiroga, Patricia, Vicente, Esther, Triguero-Martínez, Ana, Rubio, Esteban, León Luque, Manuel, Blanco-Madrigal, Juan María, Galíndez-Agirregoikoa, E., Martín, Javier, Gualillo, Oreste, Blanco, Ricardo, Castañeda, Santos, González-Gay, M. A., López-Mejías, Raquel, European Commission, Instituto de Salud Carlos III, Xunta de Galicia, Batista-Liz, Joao Carlos, Genre, Fernanda, Pulito-Cueto, Verónica, Remuzgo-Martínez, Sara, Prieto-Peña, Diana, Márquez, Ana, Ortego-Centeno, N., Leonardo, María Teresa, Peñalba, Ana, Narváez, Javier, Martín-Penagos, Luis, Belmar, Lara, Gómez Fernández, Cristina, Miranda-Filloy, J. A., Caminal-Montero, Luis, Collado, Paz, Árgila, Diego de, Quiroga, Patricia, Vicente, Esther, Triguero-Martínez, Ana, Rubio, Esteban, León Luque, Manuel, Blanco-Madrigal, Juan María, Galíndez-Agirregoikoa, E., Martín, Javier, Gualillo, Oreste, Blanco, Ricardo, Castañeda, Santos, González-Gay, M. A., and López-Mejías, Raquel

Abstract

CD40, BLK and BANK1 genes involved in the development and signaling of B-cells are identified as susceptibility loci for numerous inflammatory diseases. Accordingly, we assessed the potential influence of CD40, BLK and BANK1 on the pathogenesis of immunoglobulin-A vasculitis (IgAV), predominantly a B-lymphocyte inflammatory condition. Three genetic variants within CD40 (rs1883832, rs1535045, rs4813003) and BLK (rs2254546, rs2736340, rs2618476) as well as two BANK1 polymorphisms (rs10516487, rs3733197), previously associated with inflammatory diseases, were genotyped in 382 Caucasian patients with IgAV and 955 sex- and ethnically matched healthy controls. No statistically significant differences were observed in the genotype and allele frequencies of CD40, BLK and BANK1 when IgAV patients and healthy controls were compared. Similar results were found when CD40, BLK and BANK1 genotypes or alleles frequencies were compared between patients with IgAV stratified according to the age at disease onset or to the presence/absence of gastrointestinal or renal manifestations. Moreover, no CD40, BLK and BANK1 haplotype differences were disclosed between patients with IgAV and healthy controls and between patients with IgAV stratified according to the clinical characteristics mentioned above. Our findings indicate that CD40, BLK and BANK1 do not contribute to the genetic background of IgAV.

Published
2022

6. Corrigendum to 'Spanish scleroderma risk score (RESCLESCORE) to predict 15-year all-cause mortality in scleroderma patients at the time of diagnosis based on the RESCLE cohort: Derivation and internal validation' [AUTREV 19-5 (2020) 102507]

Author

Rubio-Rivas M, Corbella X, Guillén-Del-Castillo A, Tolosa Vilella C, Colunga Argüelles D, Argibay A, Vargas Hitos JA, Todolí Parra JA, González-Echávarri C, Ortego-Centeno N, Trapiella Martínez L, Rodríguez Carballeira M, Marín Ballvé A, Pla Salas X, Perales Fraile I, Chamorro AJ, Madroñero Vuelta AB, Freire M, Ruiz Muñoz M, González García A, Pons Martín Del Campo I, Sánchez García ME, Bernal Bello D, Espinosa G, García Hernández FJ, Sáez Comet L, Ríos Blanco JJ, Fernández de la Puebla Giménez RÁ, Sánchez Trigo S, Fonollosa Pla V, and Simeón Aznar CP

Published
2021

7. The challenge of comprehensive nailfold videocapillaroscopy practice: a further contribution

Author

Gracia Tello B, Ramos Ibañez E, Fanlo Mateo P, Sáez Cómet L, Martínez Robles E, Ríos Blanco JJ, Marí Alfonso B, Espinosa Garriga G, Todolí Parra J, Ortego Centeno N, Callejas Rubio JL, Freire Dapena M, Marín Ballvé A, Selva-O'Callaghan A, Guillén Del Castillo A, Simeón Aznar CP, and Fonollosa Pla V

Abstract

OBJECTIVES: Although classification systems and scores for capillaroscopy interpretation have been published, there is a lack of homogenization for the procedure, especially in the way and place the images are taken, the counting of the capillaries and the measuring of their size. Our objective is to provide a deep learning-based software to obtain objective and exhaustive data for the whole nailfold without increasing the time or effort needed to do the examination, or requiring expensive equipment. METHODS: An automated software to count nailfold capillaries has been designed, through an exploratory image dataset of 2,713 images with 18,000 measurements of 3 different types. Subsequently, application rules have been created to detect the morphology of nailfold videocapillaroscopy images, through a training set of images. The software reliability has been evaluated with standard metrics used in the machine learning field for object detection tasks, comparing automatic and manual counting on the same NVC images. RESULTS: A mean average precision (mAP) of 0.473 is achieved for detecting and classifying capillaries and haemorrhages by their shape, and a mAP of 0.515 is achieved for detecting and classifying capillaries by their size. A precision of 83.84% and a recall of 92.44% in the identification of capillaries was estimated. CONCLUSIONS: Deep learning is a useful tool in nailfold videocapillaroscopy that allows to analyse objectively and homogeneously images taken with multiple devices. It should make the assessment of the capillary morphology in nailfold video capillaroscopy easier, quicker, more complete and accessible to everyone.

Published
2021

8. Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases

Author

Barturen, Guillermo, Babaei, Sepideh, Català-Moll, Francesc, Martínez-Bueno, Manuel, Makowska, Zuzanna, Martorell-Marugán, Jordi, Carmona-Sáez, Pedro, Toro-Domínguez, Daniel, Carnero-Montoro, Elena, Teruel, María, Kerick, Martin, Acosta-Herrera, Marialbert, Le Lann, Lucas, Jamin, Christophe, Rodríguez-Ubreva, Javier, García-Gómez, Antonio, Kageyama, Jorge, Buttgereit, Anne, Hayat, Sikander, Mueller, Joerg, Lesche, Ralf, Hernández-Fuentes, María, Juárez, María, Rowley, Tania, López-Pedrera, Rosario, Ortega-Castro, Rafaela, Ortego-Centeno, N., Raya, Enrique, Artusi, Carolina, Benschop, Robert J., Chamberlain, Chris, Dow, Ernst R., Ioannou, Yiannis, Laigle, Laurence, Marovac, Jacqueline, Wojcik, Jerome, Renaudineau, Yves, Orietta Borghi, Maria, Frostegård, Johan, Martín, J., Beretta, Lorenzo, Ballestar, Estéban, McDonald, Fiona, Pers, J.O., and Alarcón-Riquelme, M. E.

Abstract

Objective Clinical heterogeneity, a hallmark of systemic autoimmune diseases, impedes early diagnosis and effective treatment, issues that may be addressed if patients could be classified into groups defined by molecular pattern. This study was undertaken to identify molecular clusters for reclassifying systemic autoimmune diseases independently of clinical diagnosis. Methods Unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data on 955 patients with 7 systemic autoimmune diseases and 267 healthy controls was undertaken. In addition, an inception cohort was prospectively followed up for 6 or 14 months to validate the results and analyze whether or not cluster assignment changed over time. Results Four clusters were identified and validated. Three were pathologic, representing “inflammatory,” “lymphoid,” and “interferon” patterns. Each included all diagnoses and was defined by genetic, clinical, serologic, and cellular features. A fourth cluster with no specific molecular pattern was associated with low disease activity and included healthy controls. A longitudinal and independent inception cohort showed a relapse–remission pattern, where patients remained in their pathologic cluster, moving only to the healthy one, thus showing that the molecular clusters remained stable over time and that single pathogenic molecular signatures characterized each individual patient. Conclusion Patients with systemic autoimmune diseases can be jointly stratified into 3 stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of nonresponse to therapy, marking a paradigm shift in our view of systemic autoimmune diseases.

Published
2021

9. The presence of both HLA-DRB1[*]04:01 and HLA-B[*]15:01 increases the susceptibility to cranial and extracranial giant cell arteritis.

Author

Instituto de Salud Carlos III, Gobierno de Cantabria, European Commission, Xunta de Galicia, Prieto-Peña, Diana, Remuzgo-Martínez, Sara, Ocejo-Vinyals, J. Gonzalo, Atienza-Mateo, B., Genre, Fernanda, Muñoz-Jiménez, Alejandro, Ortiz-Sanjuán, Francisco, Romero-Yuste, Susana, Moriano, Clara, Galíndez-Agirregoikoa, E., Calvo, Itziar, Ortego-Centeno, N., Álvarez-Rivas, Noelia, Miranda-Filloy, J. A., Llorente, Irene, García-García, Javier, Blanco, R., Gualillo, Oreste, Martín, J., Castañeda, Santos, López-Mejías, Raquel, González-Gay, M. A., Instituto de Salud Carlos III, Gobierno de Cantabria, European Commission, Xunta de Galicia, Prieto-Peña, Diana, Remuzgo-Martínez, Sara, Ocejo-Vinyals, J. Gonzalo, Atienza-Mateo, B., Genre, Fernanda, Muñoz-Jiménez, Alejandro, Ortiz-Sanjuán, Francisco, Romero-Yuste, Susana, Moriano, Clara, Galíndez-Agirregoikoa, E., Calvo, Itziar, Ortego-Centeno, N., Álvarez-Rivas, Noelia, Miranda-Filloy, J. A., Llorente, Irene, García-García, Javier, Blanco, R., Gualillo, Oreste, Martín, J., Castañeda, Santos, López-Mejías, Raquel, and González-Gay, M. A.

Abstract

Objectives: To determine if patients with the predominant extracranial large-vessel-vasculitis (LVV) pattern of giant cell arteritis (GCA) have a distinctive HLA-B association, different from that reported in biopsy-proven cranial GCA patients. In a further step we assessed if the combination of HLA-B and HLA-DRB1 alleles confers an increased risk for GCA susceptibility, either for the cranial and extracranial LVV phenotypes. Methods: A total of 184 patients with biopsy-proven cranial GCA, 105 with LVV-GCA and 486 healthy controls were included in our study. We compared HLA-B phenotype frequencies between the three groups. Results: HLA-B*15 phenotype was significantly increased in patients with classic cranial GCA compared to controls (14.7% versus 5.8%, respectively; p<0.01; OR [95% CI] =2.81 [1.54-5.11]). It was mainly due to the HLA-B*15:01 allele (12.5% versus 4.0%, respectively; p<0.01; OR [95% CI] =3.51 [1.77-6.99]) and remained statistically significant after Bonferroni correction. Similar HLA-B*15 association was observed in patients with the LVV-GCA (11.4% versus 5.8%, p=0.04, OR [95% CI] =2.11 [1.04-4.30]). This association was also mainly due to the HLA-B*15:01 allele (10.5% versus 4.0%, respectively; p=0.0054; OR [95% CI] =2.88 [1.19-6.59]). Noteworthy, the presence of HLA-B*15:01 together with HLA-DRB1*04:01 led to an increased risk of developing both cranial and extracranial LVV-GCA. Conclusions: Susceptibility to GCA is strongly related to the HLA region, regardless of the clinical phenotype of expression of the disease.

Published
2021

10. Comprehensive analysis of the major histocompatibility complex in systemic sclerosis identifies differential HLA associations by clinical and serological subtypes

Author

Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, National Institutes of Health (US), Manchester Biomedical Research Centre, Acosta-Herrera, Marialbert, Kerick, Martin, López-Isac, Elena, Assassi, S., Beretta, L., Simeón, Carmen P., Ortego-Centeno, N., International SSc Group, Proudman, SM, Australian Scleroderma Interest Group (ASIG), Hunzelmann, Nicolas, Moroncini, G, de Vries-Bouwstra, Jeska, Orozco, Gisela, Barton, Anne, Herrick, A., Terao, Chikashi, Allanore, Yannick, Brown, Matthew A., Radstake, T. R., Fonseca, C., Denton, C., Mayes, Maureen D., Martín, Javier, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, National Institutes of Health (US), Manchester Biomedical Research Centre, Acosta-Herrera, Marialbert, Kerick, Martin, López-Isac, Elena, Assassi, S., Beretta, L., Simeón, Carmen P., Ortego-Centeno, N., International SSc Group, Proudman, SM, Australian Scleroderma Interest Group (ASIG), Hunzelmann, Nicolas, Moroncini, G, de Vries-Bouwstra, Jeska, Orozco, Gisela, Barton, Anne, Herrick, A., Terao, Chikashi, Allanore, Yannick, Brown, Matthew A., Radstake, T. R., Fonseca, C., Denton, C., Mayes, Maureen D., and Martín, Javier

Abstract

Objective The greatest genetic effect reported for systemic sclerosis (SSc) lies in the major histocompatibility complex (MHC) locus. Leveraging the largest SSc genome-wide association study, we aimed to fine-map this region to identify novel human leucocyte antigen (HLA) genetic variants associated with SSc susceptibility and its main clinical and serological subtypes. Methods 9095 patients with SSc and 17 584 controls genome-wide genotyped were used to impute and test single-nucleotide polymorphisms (SNPs) across the MHC, classical HLA alleles and their composite amino acid residues. Additionally, patients were stratified according to their clinical and serological status, namely, limited cutaneous systemic sclerosis (lcSSc), diffuse cutaneous systemic sclerosis (dcSSc), anticentromere (ACA), antitopoisomerase (ATA) and anti-RNApolIII autoantibodies (ARA). Results Sequential conditional analyses showed nine SNPs, nine classical alleles and seven amino acids that modelled the observed associations with SSc. This confirmed previously reported associations with HLA-DRB1*11:04 and HLA-DPB1*13:01, and revealed a novel association of HLA-B*08:01. Stratified analyses showed specific associations of HLA-DQA1*02:01 with lcSSc, and an exclusive association of HLA-DQA1*05:01 with dcSSc. Similarly, private associations were detected in HLA-DRB1*08:01 and confirmed the previously reported association of HLA-DRB1*07:01 with ACA-positive patients, as opposed to the HLA-DPA1*02:01 and HLA-DQB1*03:01 alleles associated with ATA presentation. Conclusions This study confirms the contribution of HLA class II and reveals a novel association of HLA class I with SSc, suggesting novel pathways of disease pathogenesis. Furthermore, we describe specific HLA associations with SSc clinical and serological subtypes that could serve as biomarkers of disease severity and progression.

Published
2021

11. Role of the IL33 and IL1RL1 pathway in the pathogenesis of Immunoglobulin A vasculitis

Author

European Commission, Instituto de Salud Carlos III, Xunta de Galicia, Prieto-Peña, Diana, Remuzgo-Martínez, Sara, Genre, Fernanda, Pulito-Cueto, Verónica, Atienza-Mateo, B., Llorca, Javier, Sevilla-Pérez, Belén, Ortego-Centeno, N., Márquez, Ana, Lera-Gómez, L., Leonardo, María Teresa, Peñalba, Ana, Narváez, Javier, Martín-Penagos, Luis, Rodrigo, Emilio, Miranda-Filloy, J. A., Caminal-Montero, Luis, Collado, Paz, Sánchez Pérez, J., Árgila, Diego de, Rubio, E., León Luque, Manuel, Blanco-Madrigal, Juan María, Galíndez-Agirregoikoa, E., Gualillo, Oreste, Martín, J., Castañeda, Santos, Blanco, Ricardo, González-Gay, M. A., López-Mejías, Raquel, European Commission, Instituto de Salud Carlos III, Xunta de Galicia, Prieto-Peña, Diana, Remuzgo-Martínez, Sara, Genre, Fernanda, Pulito-Cueto, Verónica, Atienza-Mateo, B., Llorca, Javier, Sevilla-Pérez, Belén, Ortego-Centeno, N., Márquez, Ana, Lera-Gómez, L., Leonardo, María Teresa, Peñalba, Ana, Narváez, Javier, Martín-Penagos, Luis, Rodrigo, Emilio, Miranda-Filloy, J. A., Caminal-Montero, Luis, Collado, Paz, Sánchez Pérez, J., Árgila, Diego de, Rubio, E., León Luque, Manuel, Blanco-Madrigal, Juan María, Galíndez-Agirregoikoa, E., Gualillo, Oreste, Martín, J., Castañeda, Santos, Blanco, Ricardo, González-Gay, M. A., and López-Mejías, Raquel

Abstract

Cytokines signalling pathway genes are crucial factors of the genetic network underlying the pathogenesis of Immunoglobulin-A vasculitis (IgAV), an inflammatory vascular condition. An influence of the interleukin (IL)33- IL1 receptor like (IL1RL)1 signalling pathway on the increased risk of several immune-mediated diseases has been described. Accordingly, we assessed whether the IL33-IL1RL1 pathway represents a novel genetic risk factor for IgAV. Three tag polymorphisms within IL33 (rs3939286, rs7025417 and rs7044343) and three within IL1RL1 (rs2310173, rs13015714 and rs2058660), that also were previously associated with several inflammatory diseases, were genotyped in 380 Caucasian IgAV patients and 845 matched healthy controls. No genotypes or alleles differences were observed between IgAV patients and controls when IL33 and IL1RL1 variants were analysed independently. Likewise, no statistically significant differences were found in IL33 or IL1RL1 genotype and allele frequencies when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when IL33 and IL1RL1 haplotypes were compared between IgAV patients and controls and between IgAV patients stratified according to the clinical characteristics mentioned above. Our results suggest that the IL33-IL1RL1 signalling pathway does not contribute to the genetic network underlying IgAV.

Published
2021

12. BAFF, APRIL and BAFFR on the pathogenesis of Immunoglobulin-A vasculitis

Author

European Commission, Instituto de Salud Carlos III, Gobierno de Cantabria, Xunta de Galicia, Prieto-Peña, Diana, Genre, Fernanda, Remuzgo-Martínez, Sara, Pulito-Cueto, Verónica, Atienza-Mateo, B., Llorca, Javier, Sevilla-Pérez, B., Ortego-Centeno, N., Lera-Gómez, Leticia, Leonardo, María Teresa, Peñalba, Ana, Narváez, Javier, Martín-Penagos, Luis, Rodrigo, E., Miranda-Filloy, J. A., Caminal-Montero, Luis, Collado, Paz, Sánchez Pérez, J., Árgila, Diego de, Rubio, E., León Luque, Manuel, Blanco-Madrigal, Juan María, Galíndez-Agirregoikoa, E., Gualillo, Oreste, Martín, J., Castañeda, Santos, Blanco, R., González-Gay, M. A., López-Mejías, Raquel, European Commission, Instituto de Salud Carlos III, Gobierno de Cantabria, Xunta de Galicia, Prieto-Peña, Diana, Genre, Fernanda, Remuzgo-Martínez, Sara, Pulito-Cueto, Verónica, Atienza-Mateo, B., Llorca, Javier, Sevilla-Pérez, B., Ortego-Centeno, N., Lera-Gómez, Leticia, Leonardo, María Teresa, Peñalba, Ana, Narváez, Javier, Martín-Penagos, Luis, Rodrigo, E., Miranda-Filloy, J. A., Caminal-Montero, Luis, Collado, Paz, Sánchez Pérez, J., Árgila, Diego de, Rubio, E., León Luque, Manuel, Blanco-Madrigal, Juan María, Galíndez-Agirregoikoa, E., Gualillo, Oreste, Martín, J., Castañeda, Santos, Blanco, R., González-Gay, M. A., and López-Mejías, Raquel

Abstract

BAFF, APRIL and BAFF-R are key proteins involved in the development of B-lymphocytes and autoimmunity. Additionally, BAFF, APRIL and BAFFR polymorphisms were associated with immune-mediated conditions, being BAFF GCTGT>A a shared insertion-deletion genetic variant for several autoimmune diseases. Accordingly, we assessed whether BAFF, APRIL and BAFFR represent novel genetic risk factors for Immunoglobulin-A vasculitis (IgAV), a predominantly B-lymphocyte inflammatory condition. BAFF rs374039502, which colocalizes with BAFF GCTGT>A, and two tag variants within APRIL (rs11552708 and rs6608) and BAFFR (rs7290134 and rs77874543) were genotyped in 386 Caucasian IgAV patients and 806 matched healthy controls. No genotypes or alleles differences were observed between IgAV patients and controls when BAFF, APRIL and BAFFR variants were analysed independently. Likewise, no statistically significant differences were found in the genotype and allele frequencies of BAFF, APRIL or BAFFR when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when APRIL and BAFFR haplotypes were compared between IgAV patients and controls and between IgAV patients stratified according to the clinical characteristics mentioned above. Our results suggest that BAFF, APRIL and BAFFR do not contribute to the genetic network underlying IgAV.

Published
2021

13. Association Between FGF-23 Levels and Risk of Fracture in Women With Systemic Sclerosis.

Author

Cantero-Nieto, Lucía, Álvarez-Cienfuegos, A., García-Gómez, José Alberto, Ríos-Fernández, Raquel, Robledo, G., Ortego-Centeno, N., Cantero-Nieto, Lucía, Álvarez-Cienfuegos, A., García-Gómez, José Alberto, Ríos-Fernández, Raquel, Robledo, G., and Ortego-Centeno, N.

Abstract

Introduction/Background: The purpose of this study was to evaluate the association between Fracture Risk Assessment Tool (FRAX) and serum fibroblast grow factor-23 (FGF-23) levels in SSc women patients compared with healthy controls. Methodology: This cross-sectional study was performed in San Cecilio Hospital, Granada (Spain) from November 2017 to May 2019. Sixty-two women with SSc and 62 age and sex matched healthy controls were included in this study. FGF-23 serum concentration was evaluated by indirect enzyme-linked immunosorbent assay. The FRAX scoring tool was applied using the on-line calculator (www.shef.ac.uk/FRAX). Results: Even though there was no significant difference in FGF-23 levels between SSc women patients and healthy controls (78.2 ± 60.5 vs 80.3 ± 56.3 pg/mL, p = 0.662). FGF-23 levels were positively associated with FRAX index within the study group. Conclusions: This study shows that FGF-23 status is associated with FRAX index in women with SSc. FGF-23 could be a promising biomarker for detecting risk fracture in SSc women patients.

Published
2021

14. A TNFSF13B Functional Variant Is Not Involved in Systemic Sclerosis and Giant Cell Arteritis Susceptibility

Author

Gonzalez-Serna, D, Carmona, EG, Ortego-Centeno, N, Simeon, CP, Solans, R, Hernandez-Rodriguez, J, Tolosa, C, Castaneda, S, Narvaez, J, Martinez-Valle, F, European GCA Consortium, European Scleroderma Group, Witte, T, Neumann, T, Holle, J, Beretta, L, Boiardi, L, Emmi, G, Cimmino, MA, Vaglio, A, Herrick, AL, Denton, CP, Salvarani, C, Cid, MC, Morgan, AW, Fonseca, C, Gonzalez-Gay, MA, Martin, J, Marquez, A, Márquez, Ana [0000-0001-9913-7688], Martín, Javier [0000-0002-2202-0622], Ortego-Centeno, N. [0000-0003-2325-0937], Universidad de Cantabria, Universitat de Barcelona, Márquez, Ana, Martín, Javier, and Ortego-Centeno, N.

Subjects
Male, 0301 basic medicine, Genetics and Molecular Biology (all), B Cells, Genotyping Techniques, Lydia Becker Institute, Physiology, Cooperative research, Biopsy, Autoimmunity, Biochemistry, Temporal Arteritis, Cohort Studies, White Blood Cells, Mathematical and Statistical Techniques, 0302 clinical medicine, INDEL Mutation, immune system diseases, Animal Cells, Biochemistry, Genetics and Molecular Biology (all), Agricultural and Biological Sciences (all), Immune Physiology, B-Cell Activating Factor, Medicine and Health Sciences, Gene Regulatory Networks, Molecular genetics, skin and connective tissue diseases, Aged, 80 and over, Innate Immune System, Multidisciplinary, Statistics, Middle Aged, Metaanalysis, TNFSF13B, Systemic Sclerosis, Giant Cell Arteritis, Europe, Thematic network, Physical Sciences, Cytokines, Medicine, Female, Christian ministry, Cellular Types, Research Article, Adult, Immune Cells, Science, Cèl·lules B, Giant Cell Arteritis, Immunology, Library science, Research and Analysis Methods, Genetic Predisposition, Polymorphism, Single Nucleotide, Genètica molecular, Autoimmune Diseases, 03 medical and health sciences, Political science, ResearchInstitutes_Networks_Beacons/lydia_becker_institute_of_immunology_and_inflammation, Genetics, medicine, Humans, Genetic Predisposition to Disease, Statistical Methods, Antibody-Producing Cells, Aged, 030203 arthritis & rheumatology, B cells, Scleroderma, Systemic, Blood Cells, Biology and Life Sciences, Human Genetics, Cell Biology, Molecular Development, medicine.disease, Giant cell arteritis, 030104 developmental biology, Case-Control Studies, Immune System, Genetics of Disease, Clinical Immunology, Clinical Medicine, Mathematics, Developmental Biology
Abstract

BACKGROUND: The TNFSF13B (TNF superfamily member 13b) gene encodes BAFF, a cytokine with a crucial role in the differentiation and activation of B cells. An insertion-deletion variant (GCTGT→A) of this gene, leading to increased levels of BAFF, has been recently implicated in the genetic predisposition to several autoimmune diseases, including multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis. Based on the elevated levels of this cytokine found in patients with giant cell arteritis (GCA) and systemic sclerosis (SSc), we aimed to assess whether this functional variant also represents a novel genetic risk factor for these two disorders. METHODS: A total of 1,728 biopsy-proven GCA patients from 4 European cohorts, 4,584 SSc patients from 3 European cohorts and 5,160 ethnically-matched healthy controls were included in the study. The single nucleotide polymorphism (SNP) rs374039502, which colocalizes with the genetic variant previously implicated in autoimmunity, was genotyped using a custom TaqMan assay. First, association analysis was conducted in each independent cohort using χ2 test in Plink (v1.9). Subsequently, different case/control sets were meta-analyzed by the inverse variance method. RESULTS: No statistically significant differences were found when allele distributions were compared between cases and controls for any of the analyzed cohorts. Similarly, combined analysis of the different sets evidenced a lack of association of the rs374039502 variant with GCA (P = 0.421; OR (95% CI) = 0.92 (0.75-1.13)) and SSc (P = 0.500; OR (95% CI) = 1.05 (0.91-1.22)). The stratified analysis considering the main clinical subphenotypes of these diseases yielded similar negative results. CONCLUSION: Our data suggest that the TNFSF13B functional variant does not contribute to the genetic network underlying GCA and SSc., Funding: This work was supported by the following grants: P12-BIO-1395 from Consejería de Innovación, Ciencia y Tecnología, Junta de Andalucía (Spain) (JM), and the Cooperative Research Thematic Network (RETICS) programme (RD16/0012/0013) (RIER) (JM), from Instituto de Salud Carlos III (ISCIII, Spanish Ministry of Economy, Industry and Competitiveness). AM is recipient of a Miguel Servet fellowship (CP17/00008) from ISCIII (Spanish Ministry of Economy, Industry and Competitiveness) (AM).

Published
2018
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15. Role of IRF5 in the pathogenesis of immunoglobulin-A vasculitis

Author

Genre, F., Remuzgo-Martínez, S., Prieto-Peña, D., Atienza-Mateo, B., Pulito-Cueto, V., Llorca, J., Sevilla-Pérez, B., Ortego-Centeno, N., Lera-Gómez, L., Leonardo, M. T., Peñalba, A., Cabero, M. J., Martín-Penagos, L., Miranda-Filloy, J. A., Navas Parejo, A., Sánchez Pérez, J., Argila, D., Rubio, E., León Luque, M., Blanco-Madrigal, J. M., Galíndez-Agirregoikoa, E., Blanco, R., Gualillo, O., Martín, J., Castañeda, S., González-Gay, M. A., and López-Mejías, R.

Subjects
Vasculitis, Genotype, Haplotypes, Case-Control Studies, Interferon Regulatory Factors, Humans, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Immunoglobulin A
Abstract

OBJECTIVES: Interferon regulatory factor 5 (IRF5) is a major regulator of type I interferon induction and is also critical to produce pro-inflammatory cytokines. An influence of IRF5 genetic variants on the increased risk of immune-mediated diseases has been described. Accordingly, we aimed to evaluate the implication of IRF5 in the pathogenesis of Immunoglobulin-A vasculitis (IgAV), an inflammatory vascular pathology. METHODS: Three tag genetic variants (rs2004640, rs2070197 and rs10954213), representative of 3 different haplotype blocks within IRF5, were genotyped in 372 Caucasian patients with IgAV and 876 sex and ethnically matched healthy controls by TaqMan assays. RESULTS: No significant differences in the genotype and allele frequencies between patients with IgAV and healthy controls were observed when each IRF5 polymorphism was evaluated independently. Likewise, no significant differences between patients with IgAV and healthy controls were found when we assessed the three IRF5 polymorphisms combined, conforming haplotypes. In addition, there were no significant differences in genotype, allele and haplotype frequencies of IRF5 when patients with IgAV were stratified according to the age at disease onset or to the presence/absence of gastrointestinal or renal manifestations. CONCLUSIONS: Our results do not support an influence of IRF5 on the pathogenesis of IgAV.

Published
2020

16. Spanish scleroderma risk score (RESCLESCORE) to predict 15-year all-cause mortality in scleroderma patients at the time of diagnosis based on the RESCLE cohort: Derivation and internal validation

Author

Rubio-Rivas, M, Corbella, X, Guillen-del-Castillo, A, Vilella, CT, Arguelles, DC, Argibay, A, Hitos, JAV, Parra, JAT, Gonzalez-Echavarri, C, Ortego-Centeno, N, Martinez, LT, Carballeira, MR, Ballve, AM, Salas, XP, Fraile, IP, Chamorro, AJ, Vuelta, ABM, Freire, M, Munoz, MR, Garcia, AG, del Campo, IPM, Garcia, MES, Bello, DB, Espinosa, G, Hernandez, FJG, Comet, LS, Blanco, JJR, Gimenez, RAFD, Trigo, SS, Pla, VF, and Aznar, CPS

Subjects
Score, Systemic sclerosis, Mortality, Prognosis
Abstract

A few scores predicting the short-term risk of mortality in Systemic sclerosis (SSc) have been reported to date. Our study aimed to create a predictive 15-year all-cause mortality score at the time of the diagnosis of SSc. The study was based on the Spanish Scleroderma Registry (RESCLE). The cohort was split up in derivation (DC) and validation cohort (VC). A multivariate analysis to detect variables related to all-cause mortality within the first 15 years from SSc diagnosis was performed, assigning points to the rounded beta values to create the score (RESCLESCORE). 1935 SSc patients were included. The variables in the final model were as follows: age at diagnosis (+2 points > 65 years-old), male gender (+1 point), lcSSc subset (-1 point), mode of onset other than Raynaud's (+1 point), cancer (+1 point) and visceral involvement, such as ILD (+1 point), PAH (+1 point), heart ( +1 point) and renal involvement ( +2 points). Autoantibodies did not achieve statistical significance in the multivariate analysis. The 3 categories of risk to predict 15-year all-cause mortality at the time of diagnosis were as follows: low risk (5% vs. 7%, p = .189), intermediate risk (26.5% vs. 25.5%, p = .911) and high risk (47.8% vs. 59%, p = .316). The AUC was 0.799 (DC) vs. 0.778 (VC) (p = .530). In conclusion, the RESCLESCORE demonstrated an excellent ability to categorize SSc patients at the time of diagnosis in separate 15-year all-cause mortality risk strata at the time of diagnosis.

Published
2020

17. Identificación de un locus de riesgo compartido entre la enfermedad de Kawasaki y la vasculitis IgA mediante un análisis combinado de datos de GWAS

Author

Carmona, Elio G., López-Mejías, Raquel, Khor, Chiea C., Ortego-Centeno, N., Castañeda, Santos, Sevilla-Pérez, B., Miranda-Filloy, J. A., Navas Parejo, A., Rubio, E., León Luque, Manuel, Blanco-Madrigal, Juan María, Galíndez-Agirregoikoa, E., Blanco, Ricardo, Burgner, David, González-Gay, M. A., Martín, J., and Márquez, Ana

Published
2020

18. Longterm Efficacy and Safety of Monotherapy versus Combination Therapy in Systemic Sclerosis-associated Pulmonary Arterial Hypertension: A Retrospective RESCLE Registry Study

Author

Pestaña-Fernández M, Rubio-Rivas M, Tolosa-Vilella C, Guillén-Del-Castillo A, Freire M, Vargas-Hitos JA, Todolí-Parra JA, Rodríguez-Carballeira M, Marín-Ballvé A, Espinosa G, Colunga-Argüelles D, Ortego-Centeno N, Trapiella-Martínez L, Carbonell-Muñoz C, Pla-Salas X, Perales-Fraile I, Corbella X, Fonollosa-Pla V, Simeón-Aznar CP, and RESCLE investigators, Autoimmune Diseases Study Group (GEAS)

Subjects
SYSTEMIC SCLEROSIS, PULMONARY ARTERIAL HYPERTENSION, SURVIVAL ANALYSIS
Abstract

Monotherapy is an option as first-line therapy for pulmonary arterial hypertension (PAH). However, combination therapy is a beneficial alternative. Our objective was to evaluate the efficacy of monotherapy versus combination therapy in patients with systemic sclerosis (SSc)-associated PAH.

Published
2020

19. A cross-disease meta-GWAS identifies four new susceptibility loci shared between systemic sclerosis and Crohn’s disease

Author

González-Serna, D., Ochoa, E., López-Isac, E., Julià, A., Degenhardt, F., Ortego-Centeno, N., Radstake, T.R.D.J., Franke, A., Marsal, S., Mayes, M.D., Martín, J., Márquez, A., Assassi, S., Zhou, X., Tan, F.K., Arnett, F.C., Reveille, J.D., Gorlova, O., Chen, W.V., Ying, J., Gregersen, P.K., Lee, A.T., Voskuyl, A.E., de Vries-Bouwstra, J., Magro-Checa, C., Broen, J., Koeleman, B.P.C., Simeón, C.P., Fonollosa, V., Guillén, A., Carreira, P., Castellví, I., González-Gay, M.A., Ríos, R., Callejas-Rubio, 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.Á., Gómez-Gracia, I., Rodríguez-Rodríguez, L., Fernández-Gutiérrez, B., de la Peña, P.G., Vicente, E., Andreu, J.L., Fernández de Castro, M., López-Longo, F.J., Martínez, L., Espinosa, G., Tolosa, C., Pros, A., Rodríguez-Carballeira, M., Narváez, F.J., Rubio-Rivas, M., Ortiz-Santamaría, V., Madroñero, A.B., Díaz, B., Trapiella, L., Sousa, A., Egurbide, M.V., Fanlo-Mateo, P., Sáez-Comet, L., Díaz-González, F., Hernández, V., Beltrán, E., Román-Ivorra, J.A., Grau, E., Alegre-Sancho, J.J., Blanco-García, F.J., Oreiro, N., Freire, M., Balsa, A., Ortiz, A.M., Hunzelmann, N., Riemekasten, G., Distler, J.H.W., Witte, T., Airó, P., Beretta, L., Santaniello, A., Bellocchi, C., Lunardi, C., Moroncini, G., Gabrielli, A., and Scleroderma, Genetic, Consortium

Abstract

Genome-wide association studies (GWASs) have identified a number of genetic risk loci associated with systemic sclerosis (SSc) and Crohn’s disease (CD), some of which confer susceptibility to both diseases. In order to identify new risk loci shared between these two immune-mediated disorders, we performed a cross-disease meta-analysis including GWAS data from 5, 734 SSc patients, 4, 588 CD patients and 14, 568 controls of European origin. We identified 4 new loci shared between SSc and CD, IL12RB2, IRF1/SLC22A5, STAT3 and an intergenic locus at 6p21.31. Pleiotropic variants within these loci showed opposite allelic effects in the two analysed diseases and all of them showed a significant effect on gene expression. In addition, an enrichment in the IL-12 family and type I interferon signaling pathways was observed among the set of SSc-CD common genetic risk loci. In conclusion, through the first cross-disease meta-analysis of SSc and CD, we identified genetic variants with pleiotropic effects on two clinically distinct immune-mediated disorders. The fact that all these pleiotropic SNPs have opposite allelic effects in SSc and CD reveals the complexity of the molecular mechanisms by which polymorphisms affect diseases.

Published
2020

20. Association between homocysteine levels and arterial stiffness in women with systemic sclerosis

Author

Alvarez-Cienfuegos, A., Cantero-Nieto, L., Garcia-Gomez, J. A., Sabio, J. M., González-Gay, M. A., and Ortego-Centeno, N.

Subjects
arterial stiffness, systemic sclerosis, pulse wave velocity, homocysteine, brain natriuretic peptide
Abstract

Objective. The purpose of this study was to evaluate homocysteine (Hcy) serum levels in women with systemic sclerosis (SSc) compared with healthy controls and to examine possible associations between Hcy and markers of arterial stiffness. Methods. A cross-sectional study was performed at a single hospital between November 2017 and May 2019: 62 women with SSc and 62 age- and sex-matched healthy controls were enrolled. Pulse wave velocity (PWV) was measured non-invasively along the carotidfemoral arterial segment. Serum Hcy was analysed using immunonephelometric method. Results. There was a significant difference in Hcy serum levels between SSc female patients and healthy controls (11.9 +/- 3.3 vs. 10.3 +/- 2.3 mu mol/ml, p=0.002). Serum levels of Hcy were positively correlated with PWV (r=0.28, p

Published
2020

22. A cross-disease meta-GWAS identifies four new susceptibility loci shared between systemic sclerosis and Crohn's disease.

Author

Universidad de Salamanca, Junta de Andalucía, Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad (España), Ministerio de Economía y Competitividad (España), González-Serna, David, Ochoa, Eguzkine, López-Isac, Elena, Julià, Antonio, Degenhardt, Frauke, Ortego-Centeno, N., Radstake, Timothy R. D. J., Franke, Andre, Marsal, Sara, Mayes, Maureen D., Martín, J., Márquez, Ana, Universidad de Salamanca, Junta de Andalucía, Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad (España), Ministerio de Economía y Competitividad (España), González-Serna, David, Ochoa, Eguzkine, López-Isac, Elena, Julià, Antonio, Degenhardt, Frauke, Ortego-Centeno, N., Radstake, Timothy R. D. J., Franke, Andre, Marsal, Sara, Mayes, Maureen D., Martín, J., and Márquez, Ana

Abstract

Genome-wide association studies (GWASs) have identified a number of genetic risk loci associated with systemic sclerosis (SSc) and Crohn’s disease (CD), some of which confer susceptibility to both diseases. In order to identify new risk loci shared between these two immune-mediated disorders, we performed a cross-disease meta-analysis including GWAS data from 5,734 SSc patients, 4,588 CD patients and 14,568 controls of European origin. We identified 4 new loci shared between SSc and CD, IL12RB2, IRF1/SLC22A5, STAT3 and an intergenic locus at 6p21.31. Pleiotropic variants within these loci showed opposite allelic effects in the two analysed diseases and all of them showed a significant effect on gene expression. In addition, an enrichment in the IL-12 family and type I interferon signaling pathways was observed among the set of SSc-CD common genetic risk loci. In conclusion, through the first cross-disease meta-analysis of SSc and CD, we identified genetic variants with pleiotropic effects on two clinically distinct immune-mediated disorders. The fact that all these pleiotropic SNPs have opposite allelic effects in SSc and CD reveals the complexity of the molecular mechanisms by which polymorphisms affect diseases.

Published
2020

23. Role of IRF5 in the pathogenesis of immunoglobulin-A vasculitis

Author

Genre, Fernanda, Remuzgo-Martínez, Sara, Prieto-Peña, Diana, Atienza-Mateo, B., Pulito-Cueto, Verónica, Llorca, J., Sevilla-Pérez, Belén, Ortego-Centeno, N., Lera-Gómez, L., Leonardo, María Teresa, Peñalba, Ana, Cabero, M.J., Martín-Penagos, Luis, Miranda-Filloy, J. A., Navas Parejo, A., Sánchez Pérez, J., Árgila, Diego de, Rubio, E., León Luque, Manuel, Blanco-Madrigal, Juan María, Galíndez-Agirregoikoa, E., Blanco, R., Gualillo, Oreste, Martín, J., Castañeda, Santos, González-Gay, M. A., López-Mejías, Raquel, Genre, Fernanda, Remuzgo-Martínez, Sara, Prieto-Peña, Diana, Atienza-Mateo, B., Pulito-Cueto, Verónica, Llorca, J., Sevilla-Pérez, Belén, Ortego-Centeno, N., Lera-Gómez, L., Leonardo, María Teresa, Peñalba, Ana, Cabero, M.J., Martín-Penagos, Luis, Miranda-Filloy, J. A., Navas Parejo, A., Sánchez Pérez, J., Árgila, Diego de, Rubio, E., León Luque, Manuel, Blanco-Madrigal, Juan María, Galíndez-Agirregoikoa, E., Blanco, R., Gualillo, Oreste, Martín, J., Castañeda, Santos, González-Gay, M. A., and López-Mejías, Raquel

Abstract

OBJECTIVES: Interferon regulatory factor 5 (IRF5) is a major regulator of type I interferon induction and is also critical to produce pro-inflammatory cytokines. An influence of IRF5 genetic variants on the increased risk of immune-mediated diseases has been described. Accordingly, we aimed to evaluate the implication of IRF5 in the pathogenesis of Immunoglobulin-A vasculitis (IgAV), an inflammatory vascular pathology. METHODS: Three tag genetic variants (rs2004640, rs2070197 and rs10954213), representative of 3 different haplotype blocks within IRF5, were genotyped in 372 Caucasian patients with IgAV and 876 sex and ethnically matched healthy controls by TaqMan assays. RESULTS: No significant differences in the genotype and allele frequencies between patients with IgAV and healthy controls were observed when each IRF5 polymorphism was evaluated independently. Likewise, no significant differences between patients with IgAV and healthy controls were found when we assessed the three IRF5 polymorphisms combined, conforming haplotypes. In addition, there were no significant differences in genotype, allele and haplotype frequencies of IRF5 when patients with IgAV were stratified according to the age at disease onset or to the presence/absence of gastrointestinal or renal manifestations. CONCLUSIONS: Our results do not support an influence of IRF5 on the pathogenesis of IgAV.

Published
2020

24. FGF23-Klotho axis in patients with rheumatoid arthritis

Author

Álvarez-Cienfuegos, A., Cantero-Nieto, Lucía, García-Gómez, José Alberto, Robledo, G., González-Gay, M. A., Ortego-Centeno, N., Álvarez-Cienfuegos, A., Cantero-Nieto, Lucía, García-Gómez, José Alberto, Robledo, G., González-Gay, M. A., and Ortego-Centeno, N.

Abstract

OBJECTIVES: We aimed to compare serum Klotho and fibroblast growth factor-23 (FGF-23) levels between rheumatoid arthritis (RA) patients and healthy controls. Possible association between FGF-23 and soluble Klotho with different characteristic of the disease as well as their potential role as surrogate markers of cardiovascular disease (CVD) were studied. METHODS: Sixty-three patients with RA recruited at Vega-Baja Hospital, Orihuela (Spain) from November 2016 to May 2018 and sixty-five age- and sex-matched healthy controls were included in this study. Serum Klotho and FGF-23 were analysed using ELISA. RESULTS: Patients had higher serum levels of Klotho than healthy controls (p˂0.0001). They were positively associated with the presence of anticitrullinated peptide antibody and rheumatic factor (p<0.05). Klotho serum levels were higher in RA patients treated with biologic agents than in those undergoing conventional therapy (p=0.008). However, no association with carotid intima media thickness was found. Although no significant differences in serum FGF-23 levels between patients and controls were found (p=0.43), FGF-23 levels were positively associated with low-density lipoprotein (LDL-c) level (p<0.05) and smoking (p=0.008) in patients with RA. CONCLUSIONS: The increased serum Klotho levels in RA patients, especially in those undergoing biologic therapy, may indicate a potential implication in the pathogenesis of the disease. Although levels of FGF-23 were related to LDL-c levels, the FGF-23-Klotho axis does not seem to be related to subclinical arteriosclerosis in RA.

Published
2020

25. Influence of IL17A gene on the pathogenesis of immunoglobulin-A vasculitis

Author

López-Mejías, Raquel, Genre, Fernanda, Remuzgo-Martínez, Sara, Pulito-Cueto, Verónica, Sevilla-Pérez, Belén, Llorca, J., Ortego-Centeno, N., Mijares, V., Lera-Gómez, L., Leonardo, María Teresa, Peñalba, Ana, Cabero, M.J., Martín-Penagos, Luis, Miranda-Filloy, J. A., Navas Parejo, A., Sánchez Pérez, J., Árgila, Diego de, Rubio, E., León Luque, Manuel, Blanco-Madrigal, Juan María, Galíndez-Agirregoikoa, E., Martín, J., Blanco, R., Castañeda, Santos, González-Gay, M. A., López-Mejías, Raquel, Genre, Fernanda, Remuzgo-Martínez, Sara, Pulito-Cueto, Verónica, Sevilla-Pérez, Belén, Llorca, J., Ortego-Centeno, N., Mijares, V., Lera-Gómez, L., Leonardo, María Teresa, Peñalba, Ana, Cabero, M.J., Martín-Penagos, Luis, Miranda-Filloy, J. A., Navas Parejo, A., Sánchez Pérez, J., Árgila, Diego de, Rubio, E., León Luque, Manuel, Blanco-Madrigal, Juan María, Galíndez-Agirregoikoa, E., Martín, J., Blanco, R., Castañeda, Santos, and González-Gay, M. A.

Abstract

OBJECTIVES: Cytokines signaling pathway genes represent a key component of the genetic network implicated in the pathogenesis of immunoglobulin-A vasculitis (IgAV), an inflammatory vascular pathology. Interleukin (IL)17A is described as a genetic risk locus for some autoimmune diseases, such as giant cell arteritis and spondyloarthritis. Accordingly, we aimed to determine the potential influence of IL17A on the pathogenesis of IgAV. METHODS: Five IL17A tag polymorphisms (rs4711998, rs8193036, rs3819024, rs2275913 and rs7747909), which cover the major variability of this gene, were genotyped in 360 Caucasian patients with IgAV and 1,003 sex and ethnically matched healthy controls using TaqMan probes. RESULTS: No statistically significant differences between patients with IgAV and healthy controls were observed when each IL17A genetic variant was analysed independently. Similarly, no statistically significant differences between patients with IgAV and healthy controls were found when the five IL17A polymorphisms were evaluated combined conforming haplotypes. In addition, there were no statistically significant differences in genotype, allele and haplotype frequencies of IL17A when patients with IgAV were stratified according to the age at disease onset or to the presence/absence of gastrointestinal or renal manifestations. CONCLUSIONS: Our results do not support an influence of IL17A on the pathogenesis of IgAV.

Published
2020

26. Variants of PBEF predispose to systemic sclerosis and pulmonary arterial hypertension development

Author

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

Subjects
Medicine
Published
2010
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27. A replication study confirms the association of TNFSF4 (OX40L) polymorphisms with Systemic Sclerosis in a large European cohort

Author

Airó P, Lie B A, Palm Ø, Nordin A, Padykov L, Claes K, Denton C, Fonseca C, Madhok R, Shiels P, Chee M M, Schuerwegh A J, Voskuyl A E, De Langhe E, Westhovens R, Smith V, De Keyser F, Houssiau F, Koeleman B P, Coenen MJH, Witte T, Riemekasten G, Hesselstrand R, González-Gay M A, Pros A, García de la Peña P, Follonosa V, Egurbide M V, Fernández-Nebro A, Gallego M, Castellví I, García-Hernández F J, Gómez-Gracia I, Román-Ivorra J A, Tolosa C, Rodríguez L, Vicente-Rabaneda E, González-Escribano M F, Navarrete N, Camps M T, Carreira P, Espinosa G, Ortego-Centeno N, Vonk M C, Beretta L, Simeon C P, Broen JCA, Bossini-Castillo L, Scorza R, van Laar J M, Hunzelmann N, Kreuter A, Herrick A, Worthington J, Radstake TRDJ, Martín J, and Rueda B

Subjects
Medicine
Published
2010
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30. S.12.1 Is H1N1 influenza vaccine safe and effective in patients with SSc?

Author

Carmona, F., Gutala, R., Simeón, C. P., Carreira, P., Ortego Centeno, N., Vicente Rabaneda, E., García Hernández, F. J., García De La Peña, P., Fernández Castro, M., Martínez Estupiñán, L., Egurbide, M. V., Tsao, B. P, Gourh, P., Agarwal, S. K., Assassi, S., Mayes, M. D., Arnett, F. C., Tan, F. K., and Martín, J.

Published
2012

31. A rare polymorphism in the gene for Toll-like receptor 2 is associated with systemic sclerosis phenotype and increases the production of inflammatory mediators

Author

Broen, J. C. A., Bossini-Castillo, L., van Bon, L., Vonk, M. C., Knaapen, H., Beretta, L., Rueda, B., Hesselstrand, R., Herrick, A., Worthington, J., Hunzelman, N., Denton, C. P., Fonseca, C., Riemekasten, G., Kiener, H. P., Scorza, R., Simeón, C. P., Ortego-Centeno, N., Gonzalez-Gay, M. A., Airò, P., Coenen, M. J. H., Martín, J., and Radstake, T. R. D. J.

Published
2012
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33. 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

34. 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

36. 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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39. 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

40. 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

41. 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

42. 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

43. 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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44. 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

48. 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

49. 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

50. 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

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