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Arthritis Research and Therapy

, 19:138

First Online: 15 June 2017Received: 26 January 2017Accepted: 22 May 2017DOI: 10.1186-s13075-017-1345-6

Cite this article as: Aterido, A., Julià, A., Carreira, P. et al. Arthritis Res Ther 2017 19: 138. doi:10.1186-s13075-017-1345-6


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.

KeywordsGenome-wide pathway analysis Genetics Systemic lupus erythematosus Oral ulceration Clinical phenotypes AbbreviationsACRAmerican College of Rheumatology

BDBehçet disease

CEUCaucasian European


CIConfidence interval

ETS1ETS Proto-Oncogene 1 gene

FDRFalse discovery rate

FDRDFalse discovery rate discovery cohort

FDRVFalse discovery rate validation cohort

FLI1Fli-1 Proto-Oncogene gene

GEOGene Expression Omnibus

GWASGenome-wide association study

GWPAGenome-wide pathway analysis

IKZF2Zinc finger DNA binding protein helios, subfamily 1A, 2 gene

IL10Interleukin-10 gene

IMIDImmune-mediated inflammatory disease

KEGGKyoto Encyclopedia of Genes and Genomes


MDA5Melanoma differentiation-associated protein 5 gene

MHCMajor histocompatibility complex

NSample size

NSample size of negative individuals for a particular clinical variable

NSample size of positive individuals for a particular clinical variable

OROdds ratio

PP value

PCP value combined

PDP value discovery cohort

POSsingle nucleotide polymorphism base pair in build GRCh37-hg19

PTPN22Protein tyrosine phosphatase, non-receptor type 22 gene

PVP value validation cohort

RADisease risk allele

RAURecurrent aphtosus ulceration

RIG-IRetinoic acid-inducible gene 1 gene

SDStandard deviation

SH2B3Lymphocyte-specific adapter protein Lnk 3 gene

SLC15A4Solute carrier family 15 member 4 gene

SLESystemic lupus erythematosus

SNPSingle nucleotide polymorphism

UHRF1BP1Ubiquitin-like containing PHD and RING finger domains 1-binding protein 1 gene

VEGFVascular endothelial growth factor

λsSibling recurrence rate

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

Autor: Adrià Aterido - Antonio Julià - Patricia Carreira - Ricardo Blanco - José Javier López-Longo - José Javier Pérez Ve


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