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Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus

Authors
  • Aterido, Adrià1, 2
  • Julià, Antonio1
  • Carreira, Patricia3
  • Blanco, Ricardo4
  • López-Longo, José Javier5
  • Venegas, José Javier Pérez6
  • Olivé, Àlex7
  • Andreu, José Luís8
  • Aguirre-Zamorano, Maria Ángeles9
  • Vela, Paloma10
  • Nolla, Joan M.11
  • Marenco-de la Fuente, José Luís12
  • Zea, Antonio13
  • Pego, José María14
  • Freire, Mercedes15
  • Díez, Elvira16
  • López-Lasanta, María1
  • López-Corbeto, Mireia1
  • Palau, Núria1
  • Tortosa, Raül1
  • And 5 more
  • 1 Vall d’Hebron Research Institute, Rheumatology Research Group, Barcelona, 08035, Spain , Barcelona (Spain)
  • 2 Universitat Pompeu Fabra, Department of Experimental and Health Sciences, Barcelona, 08005, Spain , Barcelona (Spain)
  • 3 Hospital Universitario 12 de Octubre, Rheumatology Department, Madrid, 28041, Spain , Madrid (Spain)
  • 4 Hospital Universitario Marqués de Valdecilla, Rheumatology Department, Santander, 39008, Spain , Santander (Spain)
  • 5 Hospital Universitario Gregorio Marañón, Rheumatology Department, Madrid, 28007, Spain , Madrid (Spain)
  • 6 Hospital del SAS de Jerez de la Frontera, Rheumatology Department, Cádiz, 11407, Spain , Cádiz (Spain)
  • 7 Hospital Universitari Germans Trias i Pujol, Rheumatology Department, Badalona, 08916, Spain , Badalona (Spain)
  • 8 Hospital Universitario Puerta de Hierro, Rheumatology Department, Madrid, 28222, Spain , Madrid (Spain)
  • 9 Hospital Universitario Reina Sofía, Rheumatology Department, Córdoba, 14004, Spain , Córdoba (Spain)
  • 10 Hospital General Universitario de Alicante, Rheumatology Department, Alicante, 03010, Spain , Alicante (Spain)
  • 11 Hospital Universitari de Bellvitge, Rheumatology Department, Barcelona, 08907, Spain , Barcelona (Spain)
  • 12 Hospital de Valme, Rheumatology Department, Sevilla, 41014, Spain , Sevilla (Spain)
  • 13 Hospital Universitario Ramón y Cajal, Rheumatology Department, Madrid, 28034, Spain , Madrid (Spain)
  • 14 Instituto de Investigación Biomédica de Vigo, Ourense y Pontevedra, 36204, Spain , Ourense y Pontevedra (Spain)
  • 15 Hospital Universitario A Coruña, Rheumatology Department, A Coruña, 15006, Spain , A Coruña (Spain)
  • 16 Hospital Complejo Asistencial Universitario de León, Rheumatology Department, León, 24001, Spain , León (Spain)
  • 17 Life Sciences, Barcelona Supercomputing Centre, Barcelona, 08034, Spain , Barcelona (Spain)
  • 18 HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, 35806, USA , Huntsville (United States)
  • 19 Hospital Regional Universitario de Málaga, Rheumatology Department, Málaga, 29010, Spain , Málaga (Spain)
  • 20 Universidad de Málaga, Instituto de Investigación Biomédica de Málaga, Málaga, 29010, Spain , Málaga (Spain)
Type
Published Article
Journal
Arthritis Research & Therapy
Publisher
Springer Science and Business Media LLC
Publication Date
Jun 15, 2017
Volume
19
Issue
1
Identifiers
DOI: 10.1186/s13075-017-1345-6
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundSystemic 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.MethodsA 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.ResultsIn 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 (PFDR) < 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 (PFDR < 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.ConclusionsThe 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.

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