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Genome-wide association study meta-analysis identifies five new loci for systemic lupus erythematosus.

ABSTRACT: BACKGROUND:Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with a complex genetic inheritance. Genome-wide association studies (GWAS) have significantly increased the number of significant loci associated with SLE risk. To date, however, established loci account for less than 30% of the disease heritability and additional risk variants have yet to be identified. Here we performed a GWAS followed by a meta-analysis to identify new genome-wide significant loci for SLE. METHODS:We genotyped a cohort of 907 patients with SLE (cases) and 1524 healthy controls from Spain and performed imputation using the 1000 Genomes reference data. We tested for association using logistic regression with correction for the principal components of variation. Meta-analysis of the association results was subsequently performed on 7,110,321 variants using genetic data from a large cohort of 4036 patients with SLE and 6959 controls of Northern European ancestry. Genetic association was also tested at the pathway level after removing the effect of known risk loci using PASCAL software. RESULTS:We identified five new loci associated with SLE at the genome-wide level of significance (p?

SUBMITTER: Julia A

PROVIDER: S-EPMC5977506 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Genome-wide association study meta-analysis identifies five new loci for systemic lupus erythematosus.

Julià Antonio A López-Longo Francisco Javier FJ Pérez Venegas José J JJ Bonàs-Guarch Silvia S Olivé Àlex À Andreu José Luís JL Aguirre-Zamorano Mª Ángeles MÁ Vela Paloma P Nolla Joan M JM de la Fuente José Luís Marenco JLM Zea Antonio A Pego-Reigosa José María JM Freire Mercedes M Díez Elvira E Rodríguez-Almaraz Esther E Carreira Patricia P Blanco Ricardo R Taboada Víctor Martínez VM López-Lasanta María M Corbeto Mireia López ML Mercader Josep M JM Torrents David D Absher Devin D Marsal Sara S Fernández-Nebro Antonio A

Arthritis research & therapy 20180530 1

<h4>Background</h4>Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with a complex genetic inheritance. Genome-wide association studies (GWAS) have significantly increased the number of significant loci associated with SLE risk. To date, however, established loci account for less than 30% of the disease heritability and additional risk variants have yet to be identified. Here we performed a GWAS followed by a meta-analysis to identify new genome-wide significant loci fo ...[more]

PMID: 29848360

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Project description: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.

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Genome-wide association study meta-analysis identifies five new loci for systemic lupus erythematosus.

Publications

Genome-wide association study meta-analysis identifies five new loci for systemic lupus erythematosus.

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