المؤلفون: Ortiz Fernández, Lourdes, Carmona, Elio G., Kerick, Martin, Carmona López, Francisco David, Callejas Rubio, José Luis, Martín, Javier, Márquez, Ana

الوصف: Objectives The number of susceptibility loci currently associated with vasculitis is lower than in other immune-mediated diseases due in part to small cohort sizes, a consequence of the low prevalence of vasculitides. This study aimed to identify new genetic risk loci for the main systemic vasculitides through a comprehensive analysis of their genetic overlap. Methods Genome-wide data from 8467 patients with any of the main forms of vasculitis and 29 795 healthy controls were meta-analysed using ASSET. Pleiotropic variants were functionally annotated and linked to their target genes. Prioritised genes were queried in DrugBank to identify potentially repositionable drugs for the treatment of vasculitis. Results Sixteen variants were independently associated with two or more vasculitides, 15 of them representing new shared risk loci. Two of these pleiotropic signals, located close to CTLA4 and CPLX1, emerged as novel genetic risk loci in vasculitis. Most of these polymorphisms appeared to affect vasculitis by regulating gene expression. In this regard, for some of these common signals, potential causal genes were prioritised based on functional annotation, including CTLA4, RNF145, IL12B, IL5, IRF1, IFNGR1, PTK2B, TRIM35, EGR2 and ETS2, each of which has key roles in inflammation. In addition, drug repositioning analysis showed that several drugs, including abatacept and ustekinumab, could be potentially repurposed in the management of the analysed vasculitides. Conclusions We identified new shared risk loci with functional impact in vasculitis and pinpointed potential causal genes, some of which could represent promising targets for the treatment of vasculitis. ; HELICAL Innovative Training Network ; European Commission funded-under the Marie Sklodowska-Curie 813545 ; Cooperative Research Thematic Network programme RD16/0012/0013 ; Redes de Investigacion Cooperativa Orientadas a Resultados en Salud (RICORS) RD21/0002/0039 ; Instituto de Salud Carlos III PI18/00040 ; Juan de la Cierva Incorporacion fellowship ...

العلاقة: info:eu-repo/grantAgreement/EC/H2020/813545; Ortiz-Fernández L. [et al.]. Identification of new risk loci shared across systemic vasculitides points towards potential target genes for drug repurposingAnnals of the Rheumatic Diseases Published Online First: 16 February 2023. doi: [10.1136/ard-2022-223697]; https://hdl.handle.net/10481/80813Test

الإتاحة: https://doi.org/10.1136/ard-2022-223697Test
https://hdl.handle.net/10481/80813Test

المؤلفون: Martínez-López, Javier, Kerick, Martin, Ortiz-Fernández, Lourdes, Acosta-Herrera, Marialbert, Márquez, Ana, Martín, Javier

مصطلحات موضوعية: SSc, low-frequency variant, seropositive immune-mediated diseases, Humans, Genetic Predisposition to Disease, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Scleroderma, Systemic, Genotype, Autoimmune Diseases, Case-Control Studies, fms-Like Tyrosine Kinase 3

الوصف: rs76428106-C, a low frequency polymorphism that affects the splicing of the FLT3 gene, has recently been associated with several seropositive autoimmune diseases. Here, we aimed to evaluate the potential implication of rs76428106-C in the susceptibility to systemic sclerosis (SSc). We analysed a total of 26 598 European ancestry individuals, 9063 SSc and 17 535 healthy controls, to test the association between FLT3 rs76428106-C and SSc and its different subphenotypes. Genotype data of rs76428106 were obtained by imputation of already available genome-wide association study data and analysed by logistic regression analysis. In accordance with that observed in other autoimmune disorders, the FLT3 rs76428106-C allele was significantly increased [P-value = 2.03 × 10-3, odds ratio (OR) = 1.34] in SSc patients compared with healthy controls. A similar risk effect was found when the main SSc clinical and serological subgroups were compared with controls. When comparing SSc patients with and without digital ulcers (DU), the rs76428106-C frequency was significantly increased in DU-positive SSc patients in comparison with DU-negative patients (P-value = 0.036, OR = 2.16). This study is the first to report an association between rs76428176-C and SSc. Our results support the role of FLT3 as a relevant gene in seropositive immune-mediated diseases and a potential biomarker for SSc microangiopathy.

وصف الملف: application/pdf

العلاقة: http://hdl.handle.net/10668/19834Test; PMC9910569; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9910569/pdfTest

الإتاحة: https://doi.org/10.1093/rheumatology/keac406Test
http://hdl.handle.net/10668/19834Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9910569/pdfTest

المؤلفون: Martínez López, Javier, Márquez, Ana, Pegoraro, Francesco, Ortiz-Fernández, Lourdes, Acosta-Herrera, Marialbert, Kerick, Martin, Gelain, Elena, Diamond, Eli L., Durham, Benjamin H., Abdel-Wahab, Omar, Go, Ronald S., Koster, Matthew J., Dagna, Lorenzo, Campochiaro, Corrado, Collin, Matthew, Milne, Paul, Estrada-Veras, Juvianee I., O'Brien, Kevin, Papo, Matthias, Cohen-Aubar, Fleur, Amoura, Zahir, Haroche, Julien, Martín, Javier, Vaglio, Augusto

المساهمون: Histio UK, National Human Genome Research Institute (US), Redes de Investigación Cooperativa Orientadas a Resultados en Salud (España) RICORS, Instituto de Salud Carlos III, Agencia Estatal de Investigación (España), Ministerio de Ciencia e Innovación (España)

مصطلحات موضوعية: Genome- wide association study, Germline genetic variant, Histiocytosis, Myeloid disorders, Erdheim-Chester Disease

الوصف: [Objective] Erdheim-Chester disease (ECD) is rare histiocytosis with a wide range of clinical manifestations. Somatic mutations are key to the pathogenesis of the disease; however, the relationship between germline genetic variants and ECD has not been examined so far. The present study aims to explore the inherited genetic component of ECD by performing the first genome-wide association study. ; [Methods] After quality controls, a cohort of 255 ECD patients and 7,471 healthy donors was included in this study. Afterwards, a logistic regression followed by in silico functional annotation was performed. ; [Results] A signal at the 18q12.3 genomic region was identified as a new susceptibility locus for ECD (p-value=2.75x10-11; OR=2.09). This association was annotated to the SETBP1 gene, which is involved in clonal haematopoiesis. Functional annotation of this region and of the identified suggestive signals revealed additional genes that could be potentially involved in the pathogenesis of the disease. ; [Conclusion] Overall, this work demonstrates that germline genetic variants can impact on the development of ECD and suggests new pathways with a potential pathogenic role. ; This work was supported by the project “Genome-wide and epigenome-wide association study in patients with Erdheim-Chester Disease”, funded by by Histio UK, and supported in part by the Intramural Research Program of the National Human Genome Research Institute and Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) (RD21/0002/0039). M.A.H. is a recipient of a Miguel Servet fellows hip (CP21/00132) from Instituto de Salud Carlos III. L.O.F. was supported by a Juan de la Cierva Incorporación fellowship (IJC2019-040746-I) funded by MCIN/AEI/10.13039/501100011033. ; Peer reviewed

وصف الملف: application/pdf

العلاقة: #PLACEHOLDER_PARENT_METADATA_VALUE#; info:eu-repo/grantAgreement/AEI//IJC2019-040746-I; Postprint; https://doi.org/10.1002/art.42673Test; Sí; Arthritis & Rheumatology (2023); http://hdl.handle.net/10261/334198Test

الإتاحة: https://doi.org/10.1002/art.42673Test
http://hdl.handle.net/10261/334198Test

المؤلفون: Martínez-López, Javier, Márquez, Ana, Pegoraro, Francesco, Ortiz-Fernández, Lourdes, Acosta-Herrera, Marialbert, Kerick, Martin, Gelain, Elena, Diamond, Eli L, Durham, Benjamin H, Abdel-Wahab, Omar, Go, Ronald S, Koster, Matthew J, Dagna, Lorenzo, Campochiaro, Corrado, Collin, Matthew, Milne, Paul, Estrada-Veras, Juvianee I, O'Brien, Kevin, Papo, Matthias, Cohen-Aubar, Fleur, Amoura, Zahir, Haroche, Julien, Martín, Javier, Vaglio, Augusto

المصدر: Arthritis Rheumatol ; ISSN:2326-5205 ; Volume:76 ; Issue:1

الوصف: Erdheim-Chester disease (ECD) is rare histiocytosis with a wide range of clinical manifestations. Somatic mutations are key to the pathogenesis of the disease; however, the relationship between germline genetic variants and ECD has not been examined so far. The present study aims to explore the inherited genetic component of ECD by performing the first genome-wide association study.

العلاقة: https://doi.org/10.1002/art.42673Test; https://pubmed.ncbi.nlm.nih.gov/37561109Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10841187Test/

الإتاحة: https://doi.org/10.1002/art.42673Test
https://pubmed.ncbi.nlm.nih.gov/37561109Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10841187Test/

المؤلفون: Estupiñán-Moreno, Elkyn, Hernández-Rodríguez, José, Li, Tianlu, Ciudad, Laura, Andrés-León, Eduardo, Terron-Camero, Laura Carmen, Prieto-González, Sergio, Espígol-Frigolé, Georgina, Cid, Maria C, Márquez, Ana, Martin, Javier, Ballestar, Esteban, Ortiz-Fernández, Lourdes

المصدر: J Autoimmun ; ISSN:1095-9157 ; Volume:146

مصطلحات موضوعية: CD4(+) T cells, Cross-talk, Giant cell arteritis, Transcriptomic

الوصف: Giant cell arteritis (GCA) is an immune-mediated large-vessels vasculitis with complex etiology. Although the pathogenic mechanisms remain poorly understood, a central role for CD4+ T cells has been demonstrated. In this context, understanding the transcriptome dysregulation in GCA CD4+ T cells will yield new insights into its pathogenesis.

العلاقة: https://doi.org/10.1016/j.jaut.2024.103240Test; https://pubmed.ncbi.nlm.nih.gov/38754238Test

الإتاحة: https://doi.org/10.1016/j.jaut.2024.103240Test
https://pubmed.ncbi.nlm.nih.gov/38754238Test

المؤلفون: Ortiz Fernandez, Lourdes Patricia

المساهمون: Rodriguez Pañora, Patricia Elizabeth, 030166658-2

المصدر: Universidad Católica de Cuenca ; Extension Cañar

مصطلحات موضوعية: Evaluación de respuesta epidemiológica durante la pandemia covid-19. Una revisión Sistemática

الوقت: Cañar Ecuador

الوصف: Introducción: La epidemiología estudia la distribución, la gravedad de los problemas de salud y la etiología de los mismos, en 2019 surge el COVID-19, que luego se convirtió en una pandemia, trayendo consigo cambios a nivel social, económico y sanitario, conllevando a la respuesta rápida de los sistemas sanitarios. Objetivo: Describir la respuesta epidemiológica durante la pandemia COVID 19 y con ello, aportar con un estudio que pueda servir de antecedente para futuros trabajos investigativos. Material y método: Se planteó una revisión sistemática de la literatura mediante el método PRISMA para selección de artículos. Los criterios de búsqueda se basaron en las palabras clave: respuesta epidemiológica, nivel de atención, COVID-19 y pandemia, concatenadas con conectores lógicos AND. Se filtraron archivos publicados en los últimos cinco años en idioma inglés y español, para analizar un total de 33 artículos orientados a la temática planteada. Resultados: Existe concordancia en las investigaciones en cuanto a la aparición y evolución del COVID -19, así como la activación de las respuestas epidemiológicas de organismos internacionales, como a nivel país cuyo objetivo fundamental era contener la expansión de la enfermedad. Conclusión: La pandemia del COVID-19, es una enfermedad emergente que apareció en 2019 en Wuhan, causando cambios en todas las esferas de la vida de las personas, sobre todo en el sanitario, ya que, a nivel mundial, así como a nivel país no se tenían estrategias de contención frente a emergencias sanitarias como la actual, lo cual acarreo estrategias de prevención en base a respuestas epidemiológicas. Palabras Clave: respuesta epidemiológica, nivel de atención, covid-19 y pandemia. ; Epidemiology studies the distribution, health problems severity, and their etiology. In 2019, COVID-19 emerged, which later became a pandemic bringing with it social, economic, and health changes, leading to the speedy response of health systems around the world. Objective: To evaluate the epidemiological response ...

وصف الملف: application/pdf; 53.p

العلاقة: articulo cientifico; https://dspace.ucacue.edu.ec/handle/ucacue/11574Test

الإتاحة: https://dspace.ucacue.edu.ec/handle/ucacue/11574Test

المؤلفون: Estupiñán-Moreno, Elkyn, Ortiz-Fernández, Lourdes, Li, Tianlu, Hernández-Rodríguez, José, Ciudad, Laura, Andrés-León, Eduardo, Terron-Camero, Laura Carmen, Prieto-González, Sergio, Espígol-Frigolé, Georgina, Cid, María Cinta, Márquez, Ana, Ballestar, Esteban, Martín, Javier

الوصف: Objectives Giant cell arteritis (GCA) is a complex systemic vasculitis mediated by the interplay between both genetic and epigenetic factors. Monocytes are crucial players of the inflammation occurring in GCA. Therefore, characterisation of the monocyte methylome and transcriptome in GCA would be helpful to better understand disease pathogenesis. Methods We performed an integrated epigenome-and transcriptome-wide association study in CD14+ monocytes from 82 patients with GCA, cross-sectionally classified into three different clinical statuses (active, in remission with or without glucocorticoid (GC) treatment), and 31 healthy controls. Results We identified a global methylation and gene expression dysregulation in GCA monocytes. Specifically, monocytes from active patients showed a more proinflammatory phenotype compared with healthy controls and patients in remission. In addition to inflammatory pathways known to be involved in active GCA, such as response to IL-6 and IL-1, we identified response to IL-11 as a new pathway potentially implicated in GCA. Furthermore, monocytes from patients in remission with treatment showed downregulation of genes involved in inflammatory processes as well as overexpression of GC receptor-target genes. Finally, we identified changes in DNA methylation correlating with alterations in expression levels of genes with a potential role in GCA pathogenesis, such as ITGA7 and CD63, as well as genes mediating the molecular response to GC, including FKBP5, ETS2, ZBTB16 and ADAMTS2. Conclusion Our results revealed profound alterations in the methylation and transcriptomic profiles of monocytes from GCA patients, uncovering novel genes and pathways involved in GCA pathogenesis and in the molecular response to GC treatment.

وصف الملف: application/pdf

العلاقة: European Commission 813545; Ministerio de Economía y Competitividad RD16/0012/0013; Instituto de Salud Carlos III CP17/00008; Agencia Estatal de Investigación IJC2019-040746-I; Annals of the rheumatic diseases; Vol. 81 Núm. 9 (january 2022), p. 1290-1300; https://ddd.uab.cat/record/270655Test; urn:10.1136/annrheumdis-2022-222156; urn:oai:ddd.uab.cat:270655; urn:scopus_id:85132577322; urn:articleid:14682060v81n9p1290; urn:pmid:35705375; urn:pmc-uid:9380516; urn:pmcid:PMC9380516; urn:oai:pubmedcentral.nih.gov:9380516

الإتاحة: https://ddd.uab.cat/record/270655Test

المؤلفون: Jo, Yun Gun, Ortiz-Fernandez, Lourdes, Coit, Patrick, Yilmaz, Vuslat, Yentur, Sibel P., Alibaz-Oner, Fatma, Aksu, Kenan, Erken, Eren, Duzgun, Nursen, Keser, Gokhan, Cefle, Ayse, Yazici, Ayten, Ergen, Andac, Alpsoy, Erkan, Salvarani, Carlo, Kisacik, Bunyamin, Koetter, Ina, Henes, Joerg, Cinar, Muhammet, Schaefer, Arne, Nohutcu, Rahime M., Takeuchi, Fujio, Harihara, Shinji, Kaburaki, Toshikatsu, Messedi, Meriam, Song, Yeong-Wook, Kasifoglu, Timucin, Martin, Javier, Gonzalez Escribano, Maria Francisca, Saruhan-Direskeneli, Guher, Direskeneli, Haner, Sawalha, Amr H.

المساهمون: Song, Yeong-Wook

الوصف: Objectives: Behcet's disease tends to be more severe in men than women. This study was undertaken to investigate sex-specific genetic effects in Behcet's disease. Methods: A total of 1762 male and 1216 female patients with Behcet's disease from six diverse populations were studied, with the majority of patients of Turkish origin. Genotyping was performed using an Infinium ImmunoArray-24 BeadChip, or extracted from available genotyping data. Following imputation and extensive quality control measures, genome-wide association analysis was performed comparing male to female patients in the Turkish cohort, followed by a meta-analysis of significant results in all six populations. In addition, a weighted genetic risk score for Behcet's disease was calculated and compared between male and female patients. Results: Genetic association analysis comparing male to female patients with Behcet's disease from Turkey revealed an association with male sex in HLA-B/MICA within the HLA region with a GWAS level of significance (rs2848712, OR = 1.46, P = 1.22 x 10-8). Meta-analysis of the effect in rs2848712 across six populations confirmed these results. Genetic risk score for Behcet's disease was significantly higher in male compared to female patients from Turkey. Higher genetic risk for Behcet's disease was observed in male patients in HLA-B/ MICA (rs116799036, OR = 1.45, P = 1.95 x 10-8), HLA-C (rs12525170, OR = 1.46, P = 5.66 x 10-7), and KLRC4 (rs2617170, OR = 1.20, P = 0.019). In contrast, IFNGR1 (rs4896243, OR = 0.86, P = 0.011) was shown to confer higher genetic risk in female patients. Conclusions: Male patients with Behcet's disease are characterized by higher genetic risk compared to female patients. This genetic difference, primarily derived from our Turkish cohort, is largely explained by risk within the HLA region. These data suggest that genetic factors might contribute to differences in disease presentation between men and women with Behcet's disease. ; N ; 1

العلاقة: Journal of Autoimmunity, Vol.132, p. 102882; https://hdl.handle.net/10371/186154Test; 000860622100005; 2-s2.0-85135992329; 172639

الإتاحة: https://doi.org/10.1016/j.jaut.2022.102882Test
https://hdl.handle.net/10371/186154Test

المؤلفون: Martínez-López, Javier, Kerick, Martin, Ortiz-Fernández, Lourdes, Acosta-Herrera, Marialbert, Márquez, Ana, Martin, Javier

المساهمون: Ministerio de Ciencia e Innovación (España), FEDER, Instituto de Salud Carlos III, Juan de la Cierva Incorporación

مصطلحات موضوعية: SSc, low-frequency variant, seropositive immune-mediated diseases

الوصف: OBJECTIVES: rs76428106-C, a low frequency polymorphism that affects the splicing of the FLT3 gene, has recently been associated with several seropositive autoimmune diseases. Here, we aimed to evaluate the potential implication of rs76428106-C in the susceptibility to systemic sclerosis (SSc). METHODS: We analysed a total of 26 598 European ancestry individuals, 9063 SSc and 17 535 healthy controls, to test the association between FLT3 rs76428106-C and SSc and its different subphenotypes. Genotype data of rs76428106 were obtained by imputation of already available genome-wide association study data and analysed by logistic regression analysis. RESULTS: In accordance with that observed in other autoimmune disorders, the FLT3 rs76428106-C allele was significantly increased [P-value = 2.03 × 10-3, odds ratio (OR) = 1.34] in SSc patients compared with healthy controls. A similar risk effect was found when the main SSc clinical and serological subgroups were compared with controls. When comparing SSc patients with and without digital ulcers (DU), the rs76428106-C frequency was significantly increased in DU-positive SSc patients in comparison with DU-negative patients (P-value = 0.036, OR = 2.16). CONCLUSION: This study is the first to report an association between rs76428176-C and SSc. Our results support the role of FLT3 as a relevant gene in seropositive immune-mediated diseases and a potential biomarker for SSc microangiopathy. ; This work was supported by grant RTI2018101332-B-100 funded by MCIN/AEI/10.13039/501100011033 and ‘ERDF A way of making Europe’, Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) (RD21/0002/0039), Red de Investigación en Inflamación y Enfermedades Reumáticas (RIER) from Instituto de Salud Carlos III (RD16/0012/0013). M.A.-H. is a recipient of a Miguel Servet fellowship (CP21/00132) from Instituto de Salud Carlos III. L.O.-F. was supported by Juan de la Cierva Incorporación fellowship (IJC2019-040746-I) funded by MCIN/AEI/10.13039/501100011033.

العلاقة: Publisher's version; http://dx.doi.org/10.1093/rheumatology/keac406Test; Sí; Rheumatology 62: SI138- SI142 (2023); http://hdl.handle.net/10261/351308Test

الإتاحة: https://doi.org/10.1093/rheumatology/keac406Test
http://hdl.handle.net/10261/351308Test

المؤلفون: Martínez‐López, Javier, Márquez, Ana, Pegoraro, Francesco, Ortiz‐Fernández, Lourdes, Acosta‐Herrera, Marialbert, Kerick, Martin, Gelain, Elena, Diamond, Eli L., Durham, Benjamin H., Abdel‐Wahab, Omar, Go, Ronald S., Koster, Matthew J., Dagna, Lorenzo, Campochiaro, Corrado, Collin, Matthew, Milne, Paul, Estrada‐Veras, Juvianee I., O'Brien, Kevin, Papo, Matthias, Cohen‐Aubar, Fleur

المصدر: Arthritis & Rheumatology; Jan2024, Vol. 76 Issue 1, p141-145, 5p

مصطلحات موضوعية: GENETIC mutation, CONFIDENCE intervals, GENOME-wide association studies, CELLULAR signal transduction, GENE expression, DESCRIPTIVE statistics, DATA analysis software, ODDS ratio, HEMATOPOIESIS, LOGISTIC regression analysis, ERDHEIM-Chester disease

مستخلص: Objective: Erdheim‐Chester disease (ECD) is rare histiocytosis with a wide range of clinical manifestations. Somatic mutations are key to the pathogenesis of the disease; however, the relationship between germline genetic variants and ECD has not been examined so far. The present study aims to explore the inherited genetic component of ECD by performing the first genome‐wide association study. Methods: After quality controls, a cohort of 255 patients with ECD and 7,471 healthy donors was included in this study. Afterward, a logistic regression followed by in silico functional annotation was performed. Results: A signal at the 18q12.3 genomic region was identified as a new susceptibility locus for ECD (P = 2.75 × 10−11; Odds Ratio = 2.09). This association was annotated to the SETBP1 gene, which is involved in clonal haematopoiesis. Functional annotation of this region and of the identified suggestive signals revealed additional genes that could be potentially involved in the pathogenesis of the disease. Conclusion: Overall, this work demonstrates that germline genetic variants can impact on the development of ECD and suggests new pathways with a potential pathogenic role. [ABSTRACT FROM AUTHOR]

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