IRF4 Newly Identified as a Common Susceptibility Locus for Systemic Sclerosis and Rheumatoid Arthritis in a Cross-Disease Meta-Analysis of Genome-Wide Association Studies

Autoría conjunta: Spanish Scleroderma GrpObjective. Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that have similar clinical and immunologic characteristics. To date, several shared SSc-RA genetic loci have been identified independently. The aim of the current study was to systematically search for new common SSc-RA loci through an interdisease meta-genome-wide association (meta-GWAS) strategy. Methods. The study was designed as a meta-analysis combining GWAS data sets of patients with SSc and patients with RA, using a strategy that allowed identification of loci with both same-direction and opposite-direction allelic effects. The top single-nucleotide polymorphisms were followed up in independent SSc and RA case-control cohorts. This allowed an increase in the sample size to a total of 8,830 patients with SSc, 16,870 patients with RA, and 43,393 healthy controls. Results. This cross-disease meta-analysis of the GWAS data sets identified several loci with nominal association signals (P<5 x 10(-6)) that also showed evidence of association in the disease-specific GWAS scans. These loci included several genomic regions not previously reported as shared loci, as well as several risk factors that were previously found to be associated with both diseases. Follow-up analyses of the putatively new SSc-RA loci identified IRF4 as a shared risk factor for these 2 diseases (P-combined=3.29 x 10(-12)). Analysis of the biologic relevance of the known SSc-RA shared loci identified the type I interferon and interleukin-12 signaling pathways as the main common etiologic factors. Conclusion. This study identified a novel shared locus, IRF4, for the risk of SSc and RA, and highlighted the usefulness of a cross-disease GWAS meta-analysis strategy in the identification of common risk loci.Supported by a grant from the Ministerio de Educacion, Cultura y Deporte through the program FPU (to Dr. Lopez-Isac), grant 115565 from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking PRECISESADS (ref. no. 115565) and BIO-1395 from the Junta de Andalucia, grant PI-0590-2010 from the Consejeria de Salud y Bienestar Social, Junta de Andalucia, Spain (to Dr. Ortego-Centeno), a VIDI laureate from the Dutch Association of Research and Dutch Arthritis Foundation (to Dr. Radstake), and grant SAF2012-34435 from the Spanish Ministry of Economy and Competitiveness (to Dr. J. Martin). Dr. Assassi's work was supported by grants KL2-RR-024149-04 and K23-AR-061436 from the NIH, grant 3-UL1-RR-024148 from the NIH National Center for Research Resources, and grant U01-1U01AI09090 from the NIH National Institute of Allergy and Infectious Diseases. Dr. Mayes' work was supported by grant P50-AR-054144 from the NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Centers of Research Translation, grant N01-AR-0-2251 from the NIAMS SSc Family Registry and DNA Repository, grant PR-1206877 from the Department of Defense, and grant R01-AR-055258 from the NIAMS.Peer reviewe

The forward physics facility at the high-luminosity LHC

High energy collisions at the High-Luminosity Large Hadron Collider (LHC) produce a large number of particles along the beam collision axis, outside of the acceptance of existing LHC experiments. The proposed Forward Physics Facility (FPF), to be located several hundred meters from the ATLAS interaction point and shielded by concrete and rock, will host a suite of experiments to probe standard model (SM) processes and search for physics beyond the standard model (BSM). In this report, we review the status of the civil engineering plans and the experiments to explore the diverse physics signals that can be uniquely probed in the forward region. FPF experiments will be sensitive to a broad range of BSM physics through searches for new particle scattering or decay signatures and deviations from SM expectations in high statistics analyses with TeV neutrinos in this low-background environment. High statistics neutrino detection will also provide valuable data for fundamental topics in perturbative and non-perturbative QCD and in weak interactions. Experiments at the FPF will enable synergies between forward particle production at the LHC and astroparticle physics to be exploited. We report here on these physics topics, on infrastructure, detector, and simulation studies, and on future directions to realize the FPF's physics potential