Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus
Abstract 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 t...
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| Format: | Article |
| Language: | English |
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BMC
2017-06-01
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| Series: | Arthritis Research & Therapy |
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| Online Access: | http://link.springer.com/article/10.1186/s13075-017-1345-6 |
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| author | Adrià Aterido Antonio Julià Patricia Carreira Ricardo Blanco José Javier López-Longo José Javier Pérez Venegas Àlex Olivé José Luís Andreu Maria Ángeles Aguirre-Zamorano Paloma Vela Joan M. Nolla José Luís Marenco-de la Fuente Antonio Zea José María Pego Mercedes Freire Elvira Díez María López-Lasanta Mireia López-Corbeto Núria Palau Raül Tortosa Josep Lluís Gelpí Devin Absher Richard M Myers Antonio Fernández-Nebro Sara Marsal |
| author_facet | Adrià Aterido Antonio Julià Patricia Carreira Ricardo Blanco José Javier López-Longo José Javier Pérez Venegas Àlex Olivé José Luís Andreu Maria Ángeles Aguirre-Zamorano Paloma Vela Joan M. Nolla José Luís Marenco-de la Fuente Antonio Zea José María Pego Mercedes Freire Elvira Díez María López-Lasanta Mireia López-Corbeto Núria Palau Raül Tortosa Josep Lluís Gelpí Devin Absher Richard M Myers Antonio Fernández-Nebro Sara Marsal |
| author_sort | Adrià Aterido |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-21T02:04:33Z |
| format | Article |
| id | doaj.art-462ceb3ec4e54a95a3eaec684b37d99b |
| institution | Directory Open Access Journal |
| issn | 1478-6362 |
| language | English |
| last_indexed | 2024-12-21T02:04:33Z |
| publishDate | 2017-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Arthritis Research & Therapy |
| spelling | doaj.art-462ceb3ec4e54a95a3eaec684b37d99b2022-12-21T19:19:32ZengBMCArthritis Research & Therapy1478-63622017-06-0119111110.1186/s13075-017-1345-6Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosusAdrià Aterido0Antonio Julià1Patricia Carreira2Ricardo Blanco3José Javier López-Longo4José Javier Pérez Venegas5Àlex Olivé6José Luís Andreu7Maria Ángeles Aguirre-Zamorano8Paloma Vela9Joan M. Nolla10José Luís Marenco-de la Fuente11Antonio Zea12José María Pego13Mercedes Freire14Elvira Díez15María López-Lasanta16Mireia López-Corbeto17Núria Palau18Raül Tortosa19Josep Lluís Gelpí20Devin Absher21Richard M Myers22Antonio Fernández-Nebro23Sara Marsal24Rheumatology Research Group, Vall d’Hebron Research InstituteRheumatology Research Group, Vall d’Hebron Research InstituteRheumatology Department, Hospital Universitario 12 de OctubreRheumatology Department, Hospital Universitario Marqués de ValdecillaRheumatology Department, Hospital Universitario Gregorio MarañónRheumatology Department, Hospital del SAS de Jerez de la FronteraRheumatology Department, Hospital Universitari Germans Trias i PujolRheumatology Department, Hospital Universitario Puerta de HierroRheumatology Department, Hospital Universitario Reina SofíaRheumatology Department, Hospital General Universitario de AlicanteRheumatology Department, Hospital Universitari de BellvitgeRheumatology Department, Hospital de ValmeRheumatology Department, Hospital Universitario Ramón y CajalInstituto de Investigación Biomédica de VigoRheumatology Department, Hospital Universitario A CoruñaRheumatology Department, Hospital Complejo Asistencial Universitario de LeónRheumatology Research Group, Vall d’Hebron Research InstituteRheumatology Research Group, Vall d’Hebron Research InstituteRheumatology Research Group, Vall d’Hebron Research InstituteRheumatology Research Group, Vall d’Hebron Research InstituteLife Sciences, Barcelona Supercomputing CentreHudsonAlpha Institute for BiotechnologyHudsonAlpha Institute for BiotechnologyRheumatology Department, Hospital Regional Universitario de MálagaRheumatology Research Group, Vall d’Hebron Research InstituteAbstract 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.http://link.springer.com/article/10.1186/s13075-017-1345-6Genome-wide pathway analysisGeneticsSystemic lupus erythematosusOral ulcerationClinical phenotypes |
| spellingShingle | Adrià Aterido Antonio Julià Patricia Carreira Ricardo Blanco José Javier López-Longo José Javier Pérez Venegas Àlex Olivé José Luís Andreu Maria Ángeles Aguirre-Zamorano Paloma Vela Joan M. Nolla José Luís Marenco-de la Fuente Antonio Zea José María Pego Mercedes Freire Elvira Díez María López-Lasanta Mireia López-Corbeto Núria Palau Raül Tortosa Josep Lluís Gelpí Devin Absher Richard M Myers Antonio Fernández-Nebro Sara Marsal Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus Arthritis Research & Therapy Genome-wide pathway analysis Genetics Systemic lupus erythematosus Oral ulceration Clinical phenotypes |
| title | 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_short | 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 |
| topic | Genome-wide pathway analysis Genetics Systemic lupus erythematosus Oral ulceration Clinical phenotypes |
| url | http://link.springer.com/article/10.1186/s13075-017-1345-6 |
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