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

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 (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.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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1345-6) contains supplementary material, which is available to authorized users.

Recurrent oral ulceration: Etiology, classification, management, and diagnostic algorithm

“…Genotyping of 4001 patients for 16 loci associated with systemic lupus erythematous found an association with STAT4 and protection of systemic lupus erythematous patients from oral ulceration . Genotyping of 482 patients has implicated vascular endothelial growth factor in oral ulceration in the context of systemic lupus erythematous, suggesting a potential for targeted therapies . The lesions include areas of ulceration and lichenoid‐type lesions.…”

Expression of endocan and vascular endothelial growth factor in recurrent minor aphthous ulcers

“…This evident association linking VEGF to the ulcerative process identified in our study is consistent with former studies associating the levels of VEGF with oral aphthous ulceration and with proof from other ulcer-related disorders as Behçet Disease where clinical proof advocates that VEGF could be directly involved in oral ulcers formation in Behçet Disease (11,14,37,38). Finally, an association between the genetic pathway of VEGF and the occurrence of oral ulcers have been recognized and validated the in Systemic Lupus Erythematosus (39).…”

Genetic variation at the glycosaminoglycan metabolism pathway contributes to the risk of psoriatic arthritis but not psoriasis

“…Similar to previous studies, the HLA region genes were excluded from the GWPA (online supplementary material 1). 29 43 The statistical association between genetic pathways and disease risk was analysed using the set-based method implemented in PLINK, as described in online supplementary material 1 29 30…”

“…Additionally, using well-curated biological information in GWPA significantly accelerates the translation of the genetic association results 28. With this strategy, new genetic variation has been identified in different common diseases, including autoimmune diseases like Ps 29 30…”