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

• Published in: Arthritis research & therapy Vol. 19; no. 1; p. 138
• Main Authors: Aterido, Adrià, Julià, Antonio, Carreira, Patricia, Blanco, Ricardo, López-Longo, José Javier, Venegas, José Javier Pérez, Olivé, Àlex, Andreu, José Luís, Aguirre-Zamorano, Maria Ángeles, Vela, Paloma, Nolla, Joan M, Marenco-de la Fuente, José Luís, Zea, Antonio, Pego, José María, Freire, Mercedes, Díez, Elvira, López-Lasanta, María, López-Corbeto, Mireia, Palau, Núria, Tortosa, Raül, Gelpí, Josep Lluís, Absher, Devin, Myers, Richard M, Fernández-Nebro, Antonio, Marsal, Sara
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 15.06.2017; BioMed Central; BMC
• Subjects: Adult; Analysis; Arthritis; Autoimmune diseases; Clinical phenotypes; Consortia; Development and progression; Disease; Factor de creixement de l'endoteli vascular; Female; Fenotip; Genealogy; Genes; Genetic aspects; Genetic Predisposition to Disease - genetics; Genetic Variation; Genetics; Genoma humà; Genome-wide association studies; Genome-Wide Association Study; Genome-wide pathway analysis; Genomes; Genotype; Human genome; Humans; Identification; Lupus; Lupus eritematós; Lupus erythematosus; Lupus Erythematosus, Systemic - complications; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - pathology; Malalties autoimmunitàries; Male; Oral Ulcer - genetics; Oral ulceration; Phenotype; Physiological aspects; Psoriasis; Rheumatology; Systemic lupus erythematosus; Ulcers; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular endothelial growth factors; Úlceres; Oral ulceration; Genetics; Systemic lupus erythematosus; Clinical phenotypes; Genome-wide pathway analysis
• ISSN: 1478-6362; 1478-6354; 1478-6362
• DOI: 10.1186/s13075-017-1345-6

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. 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. 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 ) < 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  < 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. 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.