Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus
Background: Systemic lupus erythematosus (SLE) is a genetically complex rheumatic disease characterized by heterogeneous clinical manifestations of unknown etiology. Recent studies have suggested the existence of a genetic basis for SLE heterogeneity. The objective of the present study was to identi...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2017 |
| País: | España |
| Recursos: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:2445/119659 |
| Acesso em linha: | https://hdl.handle.net/2445/119659 |
| Access Level: | acceso abierto |
| Palavra-chave: | Malalties autoimmunitàries Genoma humà Factor de creixement de l'endoteli vascular Lupus eritematós Úlceres Fenotip Autoimmune diseases Human genome Vascular endothelial growth factors Lupus erythematosus Ulcers Phenotype |
| id |
ES_be2bb6ff551c94ef193fb95986d8a7ee |
|---|---|
| oai_identifier_str |
oai:recercat.cat:2445/119659 |
| network_acronym_str |
ES |
| network_name_str |
España |
| repository_id_str |
|
| spelling |
Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosusAterido, AdriàJulià, AntonioCarreira, PatriciaBlanco, RicardoLópez-Longo, José JavierPérez Venegas, José JavierOlivé, ÀlexAndreu, José LuisAguirre-Zamorano, Maria ÁngelesVela, PalomaNolla Solé, Joan MiquelMarenco de la Fuente, José LuisZea, AntonioPego Reigosa, José MaríaFreire, MercedesDíez, ElviraLópez Lasanta, MaríaLópez Corbeto, MireiaPalau, NúriaTortosa, RaülGelpí Buchaca, Josep LluísAbsher, DevinMyers, Richard M.Fernández-Nebro, AntonioMarsal Barril, SaraMalalties autoimmunitàriesGenoma humàFactor de creixement de l'endoteli vascularLupus eritematósÚlceresFenotipAutoimmune diseasesHuman genomeVascular endothelial growth factorsLupus erythematosusUlcersPhenotypeBackground: Systemic lupus erythematosus (SLE) is a genetically complex rheumatic disease characterized by heterogeneous clinical manifestations of unknown etiology. Recent studies have suggested the existence of a genetic basis for SLE heterogeneity. The objective of the present study was to identify new genetic variation associated with the clinically relevant phenotypes in SLE. Methods: A two-stage pathway-based approach was used to identify the genetic variation associated with the main clinical phenotypes in SLE. In the discovery stage, 482 SLE patients were genotyped using Illumina Human Quad610 microarrays. Association between 798 reference genetic pathways from the Molecular Signatures Database and 11 SLE phenotypes was tested using the set-based method implemented in PLINK software. Pathways significantly associated after multiple test correction were subsequently tested for replication in an independent cohort of 425 SLE patients. Using an in silico approach, we analyzed the functional effects of common SLE therapies on the replicated genetic pathways. The association of known SLE risk variants with the development of the clinical phenotypes was also analyzed. Results: In the discovery stage, we found a significant association between the vascular endothelial growth factor (VEGF) pathway and oral ulceration (P value for false discovery rate (P FDR) < 0.05), and between the negative regulation signaling pathway of retinoic acid inducible gene-I/melanoma differentiation associated gene 5 and the production of antinuclear antibodies (P FDR < 0.05). In the replication stage, we validated the association between the VEGF pathway and oral ulceration. Therapies commonly used to treat mucocutaneous phenotypes in SLE were found to strongly influence VEGF pathway gene expression (P = 4.60e-4 to 5.38e-14). Analysis of known SLE risk loci identified a strong association between PTPN22 and the risk of hematologic disorder and with the development of antinuclear antibodies. Conclusions: The present study has identified VEGF genetic pathway association with the risk of oral ulceration in SLE. New therapies targeting the VEGF pathway could be more effective in reducing the severity of this phenotype. These findings represent a first step towards the understanding of the genetic basis of phenotype heterogeneity in SLE.BioMed Central2018201820172018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion11 p.application/pdfhttps://hdl.handle.net/2445/119659Articles publicats en revistes (Ciències Clíniques)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1186/s13075-017-1345-6Arthritis Research & Therapy, 2017, vol. 19, num. 1, p. 138https://doi.org/10.1186/s13075-017-1345-6cc-by (c) Aterido, Adrià et al., 2017http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:recercat.cat:2445/1196592026-05-29T05:05:01Z |
| dc.title.none.fl_str_mv |
Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus |
| title |
Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus |
| spellingShingle |
Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus Aterido, Adrià Malalties autoimmunitàries Genoma humà Factor de creixement de l'endoteli vascular Lupus eritematós Úlceres Fenotip Autoimmune diseases Human genome Vascular endothelial growth factors Lupus erythematosus Ulcers Phenotype |
| title_short |
Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus |
| title_full |
Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus |
| title_fullStr |
Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus |
| title_full_unstemmed |
Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus |
| title_sort |
Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus |
| dc.creator.none.fl_str_mv |
Aterido, Adrià Julià, Antonio Carreira, Patricia Blanco, Ricardo López-Longo, José Javier Pérez Venegas, José Javier Olivé, Àlex Andreu, José Luis Aguirre-Zamorano, Maria Ángeles Vela, Paloma Nolla Solé, Joan Miquel Marenco de la Fuente, José Luis Zea, Antonio Pego Reigosa, José María Freire, Mercedes Díez, Elvira López Lasanta, María López Corbeto, Mireia Palau, Núria Tortosa, Raül Gelpí Buchaca, Josep Lluís Absher, Devin Myers, Richard M. Fernández-Nebro, Antonio Marsal Barril, Sara |
| author |
Aterido, Adrià |
| author_facet |
Aterido, Adrià Julià, Antonio Carreira, Patricia Blanco, Ricardo López-Longo, José Javier Pérez Venegas, José Javier Olivé, Àlex Andreu, José Luis Aguirre-Zamorano, Maria Ángeles Vela, Paloma Nolla Solé, Joan Miquel Marenco de la Fuente, José Luis Zea, Antonio Pego Reigosa, José María Freire, Mercedes Díez, Elvira López Lasanta, María López Corbeto, Mireia Palau, Núria Tortosa, Raül Gelpí Buchaca, Josep Lluís Absher, Devin Myers, Richard M. Fernández-Nebro, Antonio Marsal Barril, Sara |
| author_role |
author |
| author2 |
Julià, Antonio Carreira, Patricia Blanco, Ricardo López-Longo, José Javier Pérez Venegas, José Javier Olivé, Àlex Andreu, José Luis Aguirre-Zamorano, Maria Ángeles Vela, Paloma Nolla Solé, Joan Miquel Marenco de la Fuente, José Luis Zea, Antonio Pego Reigosa, José María Freire, Mercedes Díez, Elvira López Lasanta, María López Corbeto, Mireia Palau, Núria Tortosa, Raül Gelpí Buchaca, Josep Lluís Absher, Devin Myers, Richard M. Fernández-Nebro, Antonio Marsal Barril, Sara |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Malalties autoimmunitàries Genoma humà Factor de creixement de l'endoteli vascular Lupus eritematós Úlceres Fenotip Autoimmune diseases Human genome Vascular endothelial growth factors Lupus erythematosus Ulcers Phenotype |
| topic |
Malalties autoimmunitàries Genoma humà Factor de creixement de l'endoteli vascular Lupus eritematós Úlceres Fenotip Autoimmune diseases Human genome Vascular endothelial growth factors Lupus erythematosus Ulcers Phenotype |
| description |
Background: Systemic lupus erythematosus (SLE) is a genetically complex rheumatic disease characterized by heterogeneous clinical manifestations of unknown etiology. Recent studies have suggested the existence of a genetic basis for SLE heterogeneity. The objective of the present study was to identify new genetic variation associated with the clinically relevant phenotypes in SLE. Methods: A two-stage pathway-based approach was used to identify the genetic variation associated with the main clinical phenotypes in SLE. In the discovery stage, 482 SLE patients were genotyped using Illumina Human Quad610 microarrays. Association between 798 reference genetic pathways from the Molecular Signatures Database and 11 SLE phenotypes was tested using the set-based method implemented in PLINK software. Pathways significantly associated after multiple test correction were subsequently tested for replication in an independent cohort of 425 SLE patients. Using an in silico approach, we analyzed the functional effects of common SLE therapies on the replicated genetic pathways. The association of known SLE risk variants with the development of the clinical phenotypes was also analyzed. Results: In the discovery stage, we found a significant association between the vascular endothelial growth factor (VEGF) pathway and oral ulceration (P value for false discovery rate (P FDR) < 0.05), and between the negative regulation signaling pathway of retinoic acid inducible gene-I/melanoma differentiation associated gene 5 and the production of antinuclear antibodies (P FDR < 0.05). In the replication stage, we validated the association between the VEGF pathway and oral ulceration. Therapies commonly used to treat mucocutaneous phenotypes in SLE were found to strongly influence VEGF pathway gene expression (P = 4.60e-4 to 5.38e-14). Analysis of known SLE risk loci identified a strong association between PTPN22 and the risk of hematologic disorder and with the development of antinuclear antibodies. Conclusions: The present study has identified VEGF genetic pathway association with the risk of oral ulceration in SLE. New therapies targeting the VEGF pathway could be more effective in reducing the severity of this phenotype. These findings represent a first step towards the understanding of the genetic basis of phenotype heterogeneity in SLE. |
| publishDate |
2017 |
| dc.date.none.fl_str_mv |
2017 2018 2018 2018 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/2445/119659 |
| url |
https://hdl.handle.net/2445/119659 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Reproducció del document publicat a: https://doi.org/10.1186/s13075-017-1345-6 Arthritis Research & Therapy, 2017, vol. 19, num. 1, p. 138 https://doi.org/10.1186/s13075-017-1345-6 |
| dc.rights.none.fl_str_mv |
cc-by (c) Aterido, Adrià et al., 2017 http://creativecommons.org/licenses/by/3.0/es info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
cc-by (c) Aterido, Adrià et al., 2017 http://creativecommons.org/licenses/by/3.0/es |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
11 p. application/pdf |
| dc.publisher.none.fl_str_mv |
BioMed Central |
| publisher.none.fl_str_mv |
BioMed Central |
| dc.source.none.fl_str_mv |
Articles publicats en revistes (Ciències Clíniques) reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| instname_str |
Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| reponame_str |
Recercat. Dipósit de la Recerca de Catalunya |
| collection |
Recercat. Dipósit de la Recerca de Catalunya |
| repository.name.fl_str_mv |
|
| repository.mail.fl_str_mv |
|
| _version_ |
1869418263122804736 |
| score |
15,812429 |