SUMMARY OF RESEARCH

Molecular basis of giant cell arteritis.

Our research line is focused on elucidating the molecular mechanisms involved in the development of giant cell arteritis. This autoimmune disease is characterized by the inflammation of medium and large-sized blood vessels. Accordingly, the clinical manifestations of this vasculitis include life-threatening complications, such as aortic dissection, aortic aneurysm, and irreversible blindness due to ischemia of the optic nerve.
The blood vessel wall represents an immune-privileged site and is, therefore, free of inflammatory cells. However, in giant cell arteritis, this immune privilege is lost and both innate and adaptive immune cells, mainly monocytes and CD4+ T lymphocytes, can gain access to the arterial wall, triggering an inflammatory process that leads to vessel occlusion.
Although the cause of this vasculitis is still unknown, giant cell arteritis has a complex etiology resulting from the interaction among environmental, genetic, and epigenetic factors. In recent years, our knowledge of the genetic landscape of this disorder has experienced a significant increase, mainly due to the development of large-scale genetic scans, including genome-wide association studies (GWAS) and Immunochip studies. However, the molecular pathways underlying its pathogenesis are still largely unknown.
Currently, our research group is carrying out several studies focused on elucidating genetic and epigenetic contribution to the pathogenesis of giant cell arteritis, using genomic (GWAS), epigenomic (DNA methylation) and transcriptomic (RNA sequencing and single-cell RNA sequencing) approaches in relevant cell types for the disease. In addition, one of our main objectives is to perform an integrative analysis of the different -omic data in order to have a clearer picture of the molecular network that predisposes an individual to develop this vasculitis as well as to assign a functional role to non-coding genetic variation associated with giant cell arteritis.

FUNDING AGENCIES LAST 5 YEARS

- CARACTERIZACION DEL PERFIL EPIGENOMICO DE LA ARTERITIS DE CELULAS GIGANTES. PROYECTO, PN2022 - PROY I+D GENERACION CONOC. - PID, Ref: PID2022-136416OB-I00, (2023 - 2026).

PUBLICATIONS LAST 5 YEARS

-Martínez-López, J.; Kerick, M.; Ortiz-Fernández, L.; Acosta-Herrera, M.; Márquez, A.; Martín, J., FLT3 functional low-frequency variant rs76428106-C is associated with susceptibility to systemic sclerosis, Rheumatology, 2023, Vol. 62: SI138-SI142, ARTÍCULO, Id:941877

-Joao Carlos Batista Liz; Fernanda Genre; Verónica Pulito-Cueto; Sara Remuzgo-Martínez; Diana Prieto-Peña; Ana Márquez; Norberto Ortego-Centeno; María Teresa Leonardo; Ana Peñalba; Javier Narváez; Luis Martín-Penagos; Lara Belmar-Vega; Cristina Gómez-Fernández; José A Miranda-Filloy; Luis Caminal-Montero; Paz Collado; Diego De Árgila; Patricia Quiroga-Colina; Esther F Vicente-Rabaneda; Ana Triguero-Martínez; Esteban Rubio; Manuel León Luque; Juan María Blanco-Madrigal; Eva Galíndez-Agirregoikoa; Javier Martín; Oreste Gualillo; Ricardo Blanco; Santos Castañeda; Miguel A González-Gay; Raquel López-Mejías, IgA Vasculitis: Influence of CD40, BLK and BANK1 Gene Polymorphisms, Journal of Clinical Medicine, 2022, Vol. 11: 55719-557, ARTÍCULO, Id:905420

-Giorgio Trivioli; Ana Márquez; Davide Martorana; Michelangelo Tesi; Andreas Kronbichler; Paul A Lyons; Augusto Vaglio, Genetics of ANCA-associated vasculitis: role in pathogenesis, classification and management, Nature Reviews, Rheumatology, 2022, Vol. 18: 559-574, ARTÍCULO DE REVISIÓN, Id:900183

-Elkyn Estupiñán-Moreno; Lourdes Ortiz-Fernández; Tianlu Li  3; Jose Hernández-Rodríguez; Laura Ciudad; Eduardo Andrés-León; Laura Carmen Terron-Camero; Sergio Prieto-González; Georgina Espígol-Frigolé; Maria Cinta Cid; Ana Márquez; Esteban Ballesta; Javier Martín, Methylome and transcriptome profiling of giant cell arteritis monocytes reveals novel pathways involved in disease pathogenesis and molecular response to glucocorticoids, Annals of the Rheumatic Diseases, 2022, Vol. 81: 1290-1300, ARTÍCULO, Id:900132

-Adela Madrid-Paredes; Javier Martín; Ana Márquez, 3-Omic Approaches and Treatment Response in Rheumatoid Arthritis, Pharmaceutics, 2022, Vol. 14: 16488-1648, ARTÍCULO DE REVISIÓN, Id:898609

-Prieto-Peña, D.; Remuzgo-Martínez, S.; Genre, F.; Ocejo-Vinyals, J.G.; Atienza-Mateo, B.; Muñoz-Jiménez, A.; Ortiz-Sanjuán, F.; Romero-Yuste, S.; Moriano, C.; Galíndez-Agirregoikoa, E.; Calvo, I.; Ortego-Centeno, N.; Álvarez-Rivas, N.; Miranda-Filloy, J.A.; Llorente, I.; Blanco, R.; Gualillo, O.; Martín, J.; Márquez, A.; Castañeda, S.; Ferraz-Amaro, I.; López-Mejías, R.; González-Gay, M.A., Vascular endothelial growth factor haplotypes are associated with severe ischaemic complications in giant cell arteritis regardless of the disease phenotype, Clinical and Experimental Rheumatology, 2022, Vol. 40: 727-733, ARTÍCULO, Id:896242

-Elio G Carmona; Jose A García-Giménez; Raquel López-Mejías; Chiea Chuen Khor; Jong-Keuk Lee; Ekim Taskiran; Seza Ozen; Alojzija Hocevar; Lili Liu; Mario Gorenjak; Uro? Poto¿nik; Krzysztof Kiryluk; Norberto Ortego-Centeno; María C Cid; José Hernández-Rodríguez; Santos Castañeda; Miguel A González-Gay; David Burgner; Javier Martín; Ana Márquez, Identification of a shared genetic risk locus for Kawasaki disease and immunoglobulin A vasculitis by a cross-phenotype meta-analysis, Rheumatology, 2022, Vol. 61: 1204-1210, ARTÍCULO, Id:892520

-Ana Márquez; Javier Martín, Genetic overlap between type 1 diabetes and other autoimmune diseases, Seminars in Immunopathology, 2022, Vol. 44: 81-97, ARTÍCULO DE REVISIÓN, Id:869923

-Diana Prieto-Peña; Sara Remuzgo-Martínez; Belén Atienza-Mateo; Raquel López-Mejias; Miguel Á González-Gay; Spanish collaborative group for the study of large-vessel vasculitis( Fernanda Genre; Javier Gonzalo Ocejo-Vinyals; Alejandro Muñoz Jiménez; Francisco Ortiz-Sanjuán, Susana Romero-Yuste; Clara Moriano; Eva Galíndez-Agirregoikoa; Itziar Calvo; Norberto Ortego-Centeno; Noelia Álvarez-Rivas; José A Miranda-Filloy; Irene Llorente; Ricardo Blanco; Oreste Gualillo; Javier Martín; Ana Márquez; Santos Castañeda; Iván Ferraz-Amaro ), Cranial and extracranial giant cell arteritis do not have different HLA-DRB1 and HLA-B association in Caucasian individuals., Arthritis Research and Therapy, 2021, Vol. 23: 268-268, CARTA AL EDITOR, Id:861243

-Remuzgo-Martínez, S.; Atienza-Mateo, B.; Ocejo-Vinyals, J.G.; Pulito-Cueto, V.; Prieto-Peña, D.; Genre, F.; Marquez, A.; Llorca, J.; Mora Cuesta, V.M.; Fernández, D.I.; Riesco, L.; Ortego-Centeno, N.; Gómez, N.P.; Mera, A.; Martínez-Barrio, J.; López-Longo, F.J.; Lera-Gómez, L.; Moriano, C.; Díez, E.; Tomero, E.; Calvo-Alén, J.; Romero-Bueno, F.; Sanchez-Pernaute, O.; Nuño, L.; Bonilla, G.; Grafia, I.; Prieto-González, S.; Narvaez, J.; Trallero-Araguas, E.; Selva-O'Callaghan, A.; Gualillo, O.; Martín, J.; Cavagna, L.; Castañeda, S.; Cifrian, J.M.; Renzoni, E.A.; López-Mejías, R.; González-Gay, M.A., HLA association with the susceptibility to anti-synthetase syndrome, JOINT BONE SPINE, 2021, Vol. 88: 3-105115, ARTÍCULO, Id:848691

-David González-Serna; Gonzalo Villanueva-Martin; Marialbert Acosta-Herrera; Ana Márquez; Javier Martín, Approaching Shared Pathophysiology in Immune-Mediated Diseases through Functional Genomics, GENES, 2020, Vol. 11: 148212-1482, ARTÍCULO, Id:818500

-Lamana, A.; Villares, R.; Seoane, I.V.; Andrés, N.; Lucas, P.; Emery, P.; Vital, E.M.; Triguero-Martínez, A.; Marquez, A.; Ortiz, A.M.; Maxime, R.; Martínez, C.; Martín, J.; Gomariz, R.P.; Ponchel, F.; González-Álvaro, I.; Mellado, M., Identification of a Human SOCS1 Polymorphism That Predicts Rheumatoid Arthritis Severity, Frontiers in Immunology, 2020, Vol. 11: 1336, ARTÍCULO, Id:811724

-González-Serna D; Ochoa E; López-Isac E; Julià A; Degenhardt F; Ortego-Centeno N; Radstake TRDJ; Franke A; Marsal S; Mayes MD; Martín J; Márquez A, A cross-disease meta-GWAS identifies four new susceptibility loci shared between systemic sclerosis and Crohn's disease., Scientific Reports, 2020, Vol. 10: 18621-1862, ARTÍCULO, Id:808314

-Oh, Y.J.; Shin, D.Y.; Hwang, S.M.; Kim, S.M.; Im, K.; Park, H.S.; Kim, J.A.; Song, Y.W.; Márquez, A.; Martín, J.; Lee, D.S.; Park, J.K., Mutation of ten-eleven translocation-2 is associated with increased risk of autoimmune disease in patients with myelodysplastic syndrome, Korean Journal of Internal Medicine, 2020, Vol. 35: 457-464, ARTÍCULO, Id:805429

-Acosta-Herrera M; González-Gay MA; Martín J; Márquez A, Leveraging Genetic Findings for Precision Medicine in Vasculitis., Frontiers in Immunology, 2019, Vol. 2: 1796-, ARTÍCULO DE REVISIÓN, Id:768968

-Carmona, F.D.; López-Mejías, R.; Márquez, A.; Martín, J.; González-Gay, M.A., Genetic Basis of Vasculitides with Neurologic Involvement, NEUROLOGIC CLINICS, 2019, Vol. : , ARTÍCULO DE REVISIÓN, Id:762309

-Ferreiro-Iglesias, A.; Montes, A.; Perez-Pampin, E.; Cañete, J.D.; Raya, E.; Magro-Checa, C.; Vasilopoulos, Y.; Caliz, R.; Ferrer, M.A.; Joven, B.; Carreira, P.; Balsa, A.; Salcedo, D.P.; Blanco, F.J.; Moreno-Ramos, M.J.; Manrique-Arija, S.; Del Carmen Ordonez, M.; Alegre-Sancho, J.J.; Narvaez, J.; Narvaez, J.; Navarro-Sarabia, F.; Moreira, V.; Valor, L.; Garcia-Portales, R.; Marquez, A.; Gomez-Reino, J.J.; Martin, J.; Gonzalez, A., Evaluation of 12 GWAS-drawn SNPs as biomarkers of rheumatoid arthritis response to TNF inhibitors. A potential SNP association with response to etanercept, PLoS ONE, 2019, Vol. 14: 2-e0213073, ARTÍCULO, Id:762086

-Montes, P.; Kerick, M.; Bernal, M.; Hernández, F.; Jiménez, P.; Garrido, P.; Márquez, A.; Jurado, M.; Martin, J.; Garrido, F.; Ruiz-Cabello, F., Genomic loss of HLA alleles may affect the clinical outcome in low-risk myelodysplastic syndrome patients, Oncotarget, 2018, Vol. 9: 36929-36944, ARTÍCULO, Id:739224

-Márquez A; Kerick M; Zhernakova A; Gutierrez-Achury J; Chen WM; Onengut-Gumuscu S; González-Álvaro I; Rodriguez-Rodriguez L; Rios-Fernández R; González-Gay MA; Coeliac Disease Immunochip Consortium, Rheumatoid Arthritis Consortium International for Immunochip (RACI),International Scleroderma Group,Type 1 Diabetes Genetics Consortium; Mayes MD11; Raychaudhuri S; Rich SS6, Wijmenga C; Martín J, Meta-analysis of Immunochip data of four autoimmune diseases reveals novel single-disease and cross-phenotype associations., Genome Medicine, 2018, Vol. 10: 97-, ARTÍCULO, Id:737400

-González-Serna D; Carmona EG; Ortego-Centeno N; Simeón CP; Solans R; Hernández-Rodríguez J; Tolosa C; Castañeda S; Narváez 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; González-Gay MA; Martín J; Márquez A., A TNFSF13B functional variant is not involved in systemic sclerosis and giant cell arteritis susceptibility., PLoS ONE, 2018, Vol. 13: e020934312-e0209343, ARTÍCULO, Id:737351

-Martorana, D.; Márquez, A.; Carmona, F.D.; Bonatti, F.; Adorni, A.; Urban, M.L.; Maritati, F.; Accorsi Buttini, E.; Marvisi, C.; Palmisano, A.; Rossi, G.M.; Trivioli, G.; Fenaroli, P.; Manenti, L.; Nicastro, M.; Incerti, M.; Gianfreda, D.; Bani, S.; Ferretti, S.; Corradi, D.; Alberici, F.; Emmi, G.; Di Scala, G.; Moroni, G.; Percesepe, A.; Scheel, P.J.; Vermeer, E.; van Bommel, E.F.; Martín, J.; Vaglio, A., A large-scale genetic analysis reveals an autoimmune origin of idiopathic retroperitoneal fibrosis, Journal of Allergy and Clinical Immunology, 2018, Vol. 142: 1662-1665, ARTÍCULO, Id:734446

-Kuiper JJW; Setten J; Devall M; Cretu-Stancu M; Hiddingh S; Ophoff RA; Missotten TOAR; Velthoven M; Den Hollander AI; Hoyng CB; James E; Reeves E; Cordero-Coma M; Fonollosa A; Adán A; Martín J; Koeleman BPC; Boer JH; Pulit SL; Márquez A; Radstake TRDJ, Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis., Human Molecular Genetics, 2018, Vol. 27: 4333-4343, ARTÍCULO, Id:731682

-Lopez-Rodriguez, R.; Perez-Pampin, E.; Marquez, A.; Blanco, F.J.; Joven, B.; Carreira, P.; Ferrer, M.A.; Caliz, R.; Valor, L.; Narvaez, J.; Cañete, J.D.; Del Carmen Ordoñez, M.; Manrique-Arija, S.; Vasilopoulos, Y.; Balsa, A.; Pascual-Salcedo, D.; Moreno-Ramos, M.J.; Alegre-Sancho, J.J.; Navarro-Sarabia, F.; Moreira, V.; Garcia-Portales, R.; Raya, E.; Magro-Checa, C.; Martin, J.; Gomez-Reino, J.J.; Gonzalez, A., Validation study of genetic biomarkers of response to TNF inhibitors in rheumatoid arthritis, PLoS ONE, 2018, Vol. 13: 5-e0196793, ARTÍCULO, Id:727100

DOCTORAL THESES LAST 5 YEARS