Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: Genome-wide association studies (GWASs) have revolutionized our understanding of the genetic component of complex autoimmune diseases (ADs) by the identification of thousands of susceptibility loci associated with autoimmunity. The vast majority of these loci are shared risk factors for at least two or more ADs, pointing to a common genetic background underlying autoimmune processes. One approach that has been developed for the identification of common loci is to perform a combined-phenotype GWAS, that is, to combine genome-wide genotype data from two autoimmune diseases. In the present study we applied this strategy to systematically search for new common loci for systemic sclerosis (SSc) and rheumatoid arthritis (RA), two complex traits that share clinical and immunological features, and a considerable proportion of its genetic background.
Methods: The complete set of individuals enrolled for this study comprised a total of 8,830 SSc patients, 16,870 RA patients and 43,393 controls of European ancestry. First, we performed a meta-analysis combining GWAS datasets of SSc and RA using a strategy that allowed identification of loci with both same-direction and opposing-direction allelic effects. Those SNPs that showed a P-value < 5 x 10-6 in the combined-phenotype analysis and nominal significance in the GWA study for each disease (P-value < 0.05) were followed-up in independent SSc and RA case-control replication cohorts. Subsequently, we performed a meta-analysis of the initial GWAS screening and replication stages. Association tests were performed by the means of logistic regression. Meta-analyses were performed with inverse-variance method based on population specific logistic regression results.
Results: The cross-disease meta-analysis of the GWAS datasets identified several loci with nominal association signals (P-value < 5 x 10-6), which also showed evidence of association in the disease-specific GWAS scan. These loci included several genomic regions not previously reported as shared loci, besides risk factors associated with both diseases in previous studies. The follow-up of the putatively new SSc-RA loci identified IRF4 as a shared risk factor for these two diseases (Pcombined = 3.29 x 10-12). In addition, the analysis of the biological relevance of the known SSc-RA shared loci pointed to the type I interferon and the interleukin 12 signaling pathways as the main common etiopathogenic factors.
Conclusion: The present study has identified a novel shared locus, IRF4, for SSc and RA. The identification of these pleiotropic autoimmunity loci may point to common pathogenic pathways, which ultimately may represent a clinical advantage, thus providing support for drug repositioning.
To cite this abstract in AMA style:Lopez-Isac E, Assassi S, Simeón CP, Carreira P, Ortego Centeno N, Fernandez Gutierrez B, Balsa A, González-Gay MA, Beretta L, Lunardi C, Moroncini G, Witte T, Hunzelmann N, Distler JH, Riekemasten G, van der Helm-van Mil AH, de Vries-Bouwstra JK, Magro-Checa C, Voskuyl AE, Vonk MC, Molberg Ø, Merriman T, Hesselstrand R, Nordin A, Padyukov L, Herrick AL, Eyre S, Denton C, Fonseca C, Radstake TRDJ, Worthington J, Mayes MD, Martín J. Combined-Phenotype Meta-GWAS in Systemic Sclerosis and Rheumatoid Arthritis Identifies IRF4 As a New Common Susceptibility Locus [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/combined-phenotype-meta-gwas-in-systemic-sclerosis-and-rheumatoid-arthritis-identifies-irf4-as-a-new-common-susceptibility-locus/. Accessed October 26, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/combined-phenotype-meta-gwas-in-systemic-sclerosis-and-rheumatoid-arthritis-identifies-irf4-as-a-new-common-susceptibility-locus/