title: The TT genotype of the STAT4 rs7574865 polymorphism is associated with high disease activity and disability in patients with early arthritis.
abstract: 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.
  
  
  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.
authors.affiliation: Rheumatology Service, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Madrid, Spain.
authors.forename: Amalia
authors.initials: A
authors.lastname: Lamana
authors.forename: Alejandro
authors.initials: A
authors.lastname: Balsa
authors.forename: Blanca
authors.initials: B
authors.lastname: Rueda
authors.forename: Ana M
authors.initials: AM
authors.lastname: Ortiz
authors.forename: Laura
authors.initials: L
authors.lastname: Nuño
authors.forename: Maria Eugenia
authors.initials: ME
authors.lastname: Miranda-Carus
authors.forename: Maria F
authors.initials: MF
authors.lastname: Gonzalez-Escribano
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Lopez-Nevot
authors.forename: Dora
authors.initials: D
authors.lastname: Pascual-Salcedo
authors.forename: Javier
authors.initials: J
authors.lastname: Martin
authors.forename: Isidoro
authors.initials: I
authors.lastname: González-Álvaro
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D001168:Arthritis / Q000235:genetics* / Q000276:immunology; D004185:Disability Evaluation; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059811:HLA-DRB1 Chains / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics; D050797:STAT4 Transcription Factor / Q000235:genetics*; D012720:Severity of Illness Index
chemical_list: D059811:HLA-DRB1 Chains; D050797:STAT4 Transcription Factor; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22