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.
Highlights
Systemic lupus erythematosus (SLE) is a genetically complex rheumatic disease characterized by heterogeneous clinical manifestations of unknown etiology
Identification of SLE risk genetic variants associated with SLE phenotypes In the discovery stage, we found that 19 out of the 43 Single nucleotide polymorphism (SNP) previously associated with SLE risk were significantly associated with one or more clinical phenotypes (PDiscovery < 0.05, Table 2)
Two genetic pathways were significantly associated with systemic lupus erythematosus (SLE) phenotypes in the discovery stage Abbreviations: SNP single-nucleotide polymorphism, PD P value discovery cohort, False discovery rate discovery cohort (FDRD) false discovery rate discovery cohort, PV P value validation cohort, False discovery rate validation cohort (FDRV) false discovery rate validation cohort, PC P value combined aThe association between the vascular endothelial growth factor (VEGF) pathway and oral ulcers was significantly replicated in the validation cohort
Summary
Systemic lupus erythematosus (SLE) is a genetically complex rheumatic disease characterized by heterogeneous clinical manifestations of unknown etiology. SLE is characterized by the dysregulation of the immune system and high phenotypical diversity [2] This phenotypical heterogeneity includes a wide range of clinical manifestations that are exemplified by the current use of multiple clinical phenotypes as criteria to diagnose the disease [3]. Nine genome-wide association studies (GWAS) of SLE risk have been performed in European and Asian populations [5]. Together these studies have led to the identification of >40 loci associated with SLE susceptibility Despite this extraordinary success, there is still a lack of understanding of the genetic variation that is relevant for the development of specific phenotypes within the disease. There is evidence, that the main clinical phenotypes in SLE aggregate in families [6], suggesting a genetic basis underlying disease heterogeneity
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