Lamana, AmaliaBalsa, AlejandroRueda, BlancaOrtiz, Ana MNuño, LauraMiranda-Carus, Maria EugeniaGonzalez-Escribano, Maria FLopez-Nevot, Miguel APascual-Salcedo, DoraMartin, JavierGonzález-Álvaro, Isidoro2013-12-042013-12-042012-08-24Lamana A, Balsa A, Rueda B, Ortiz AM, Nuño L, Miranda-Carus ME, et al. The TT genotype of the STAT4 rs7574865 polymorphism is associated with high disease activity and disability in patients with early arthritis. PLoS ONE. 2012; 7(8):e43661http://hdl.handle.net/10668/1408Journal Article; Research Support, Non-U.S. Gov't. The authors have read the journal’s policy and some authors have the following conflicts: Unrestricted research grants have been provided by Roche, UCB and Bristol-Myers Squibb to IG-A; and by Abbott Laboratories and Roche to LN. All these research projects have no relation with the present study. AB holds an advisory board membership with Pfizer and UCB. The following authors hold Honoraria for speaking: IG-A (Spanish Society of Rheumatology (SER), Rheumatology Society of Madrid (SORCOM), Roche, Abbott Laboratories and Bristol-Myers Squibb); AB (Roche, Schering-Plough, Wyeth, Abbott, BMS, Janssen and UCB); AMO (Spanish Society of Rheumatology (SER), Laboratorios Esteve, Abbott Laboratories and MSD); JM (Spanish Society of Rheumatology (SER)); and LN (Abbott Laboratories). The remaining authors have declared that no competing interests exist. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials, as detailed online on the guide for authors.BACKGROUND The number of copies of the HLA-DRB1 shared epitope, and the minor alleles of the STAT4 rs7574865 and the PTPN22 rs2476601 polymorphisms have all been linked with an increased risk of developing rheumatoid arthritis. In the present study, we investigated the effects of these genetic variants on disease activity and disability in patients with early arthritis. METHODOLOGY AND RESULTS We studied 640 patients with early arthritis (76% women; median age, 52 years), recording disease-related variables every 6 months during a 2-year follow-up. HLA-DRB1 alleles were determined by PCR-SSO, while rs7574865 and rs2476601 were genotyped with the Taqman 5' allelic discrimination assay. Multivariate analysis was performed using generalized estimating equations for repeated measures. After adjusting for confounding variables such as gender, age and ACPA, the TT genotype of rs7574865 in STAT4 was associated with increased disease activity (DAS28) as compared with the GG genotype (β coefficient [95% confidence interval] = 0.42 [0.01-0.83], p = 0.044). Conversely, the presence of the T allele of rs2476601 in PTPN22 was associated with diminished disease activity during follow-up in a dose-dependent manner (CT genotype = -0.27 [-0.56- -0.01], p = 0.042; TT genotype = -0.68 [-1.64- -0.27], p = 0.162). After adjustment for gender, age and disease activity, homozygosity for the T allele of rs7574865 in STAT4 was associated with greater disability as compared with the GG genotype. CONCLUSIONS Our data suggest that patients with early arthritis who are homozygous for the T allele of rs7574865 in STAT4 may develop a more severe form of the disease with increased disease activity and disability.enSTAT4 Transcription FactorPTPN22 protein, humanProtein Tyrosine Phosphatase, Non-Receptor Type 22HLA-DRB1 ChainsAncianoAlelosArtritisEvaluación de la DiscapacidadPredisposición Genética a la EnfermedadGenotipoMediana EdadPolimorfismo de Nucleótido SimpleFactor de Transcripción STAT4Índice de Severidad de la EnfermedadAdultoMedical Subject Headings::Named Groups::Persons::Age Groups::Adult::AgedMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::AllelesMedical Subject Headings::Diseases::Musculoskeletal Diseases::Joint Diseases::ArthritisMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Disability EvaluationMedical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Susceptibility::Genetic Predisposition to DiseaseMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::GenotypeMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Check Tags::MaleMedical Subject Headings::Named Groups::Persons::Age Groups::Adult::Middle AgedMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Polymorphism, Single NucleotideMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intracellular Signaling Peptides and Proteins::Adaptor Proteins, Signal Transducing::STAT Transcription Factors::STAT4 Transcription FactorMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Health Surveys::Health Status Indicators::Severity of Illness IndexMedical Subject Headings::Named Groups::Persons::Age Groups::AdultMedical Subject Headings::Check Tags::FemaleMedical Subject Headings::Chemicals and Drugs::Biological Factors::Antigens::Antigens, Surface::Histocompatibility Antigens::HLA Antigens::HLA-D Antigens::HLA-DR Antigens::HLA-DR beta-Chains::HLA-DRB1 ChainsMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Esterases::Phosphoric Monoester Hydrolases::Protein Tyrosine Phosphatases::Protein Tyrosine Phosphatases, Non-Receptor::Protein Tyrosine Phosphatase, Non-Receptor Type 22research article22937072open access10.1371/journal.pone.00436611932-6203PMC3427144