Carmona, F DavidMartín, José-EzequielBeretta, LorenzoSimeón, Carmen PCarreira, Patricia ECallejas, José LuisFernández-Castro, MónicaSáez-Comet, LuisBeltrán, EmmaCamps, María TeresaEgurbide, María VictoriaAiró, PaoloScorza, RaffaellaLunardi, ClaudioHunzelmann, NicolasRiemekasten, GabrielaWitte, TorstenKreuter, AlexanderDistler, Jörg H WMadhok, RajanShiels, Paulvan Laar, Jacob MFonseca, CarmenDenton, ChristopherHerrick, ArianeWorthington, JaneSchuerwegh, Annemie JVonk, Madelon CVoskuyl, Alexandre ERadstake, Timothy R D JMartín, Javier2015-08-042015-08-042013-08Carmona FD, Martín JE, Beretta L, Simeón CP, Carreira PE, Callejas JL, et al. The systemic lupus erythematosus IRF5 risk haplotype is associated with systemic sclerosis. PLoS ONE. 2013; 8(1):e54419http://hdl.handle.net/10668/1942Journal Article; Research Support, Non-U.S. Gov't;Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE) susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP) of each block (rs10488631, rs2004640, and rs4728142) in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P  = 1.34×10(-8), OR  = 1.22, CI 95%  = 1.14-1.30; rs2004640: P  = 4.60×10(-7), OR  = 0.84, CI 95%  = 0.78-0.90; rs10488631: P  = 7.53×10(-20), OR  = 1.63, CI 95%  = 1.47-1.81). However, the association of rs2004640 with SSc was not independent of rs4728142 (conditioned P  = 0.598). The haplotype containing the risk alleles (rs4728142*A-rs2004640*T-rs10488631*C: P  = 9.04×10(-22), OR  = 1.75, CI 95%  = 1.56-1.97) better explained the observed association (likelihood P-value  = 1.48×10(-4)), suggesting an additive effect of the three haplotypic blocks. No statistical significance was observed in the comparisons amongst SSc patients with and without the main clinical characteristics. Our data clearly indicate that the SLE risk haplotype also influences SSc predisposition, and that this association is not sub-phenotype-specific.enFactores reguladores del interferónPredisposición genética a la enfermedadHaplotiposPolimorfismo de nucleótido simpleLupus eritematoso sistémicoDesequilibrio de ligamientoGrupo de ascendencia continental europeaFactores de riesgoMedical Subject Headings::Named Groups::Persons::Population Groups::Continental Population Groups::European Continental Ancestry GroupMedical Subject Headings::Check Tags::FemaleMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Gene FrequencyMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genetic LociMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genotype::Genetic Predisposition to DiseaseMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genotype::HaplotypesMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intracellular Signaling Peptides and Proteins::Adaptor Proteins, Signal Transducing::Interferon Regulatory FactorsMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Linkage::Linkage DisequilibriumMedical Subject Headings::Diseases::Immune System Diseases::Autoimmune Diseases::Lupus Erythematosus, SystemicMedical Subject Headings::Check Tags::MaleMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::PhenotypeMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, GeneticMedical Subject Headings::Health Care::Environment and Public Health::Public Health::Epidemiologic Factors::Causality::Risk FactorsMedical Subject Headings::Diseases::Skin and Connective Tissue Diseases::Skin Diseases::Scleroderma, SystemicMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Allelesresearch article23372721open access10.1371/journal.pone.00544191932-6203PMC3553151