title: STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus.
abstract: BACKGROUND
  Rheumatoid arthritis is a chronic inflammatory disease with a substantial genetic component. Susceptibility to disease has been linked with a region on chromosome 2q.
  
  
  METHODS
  We tested single-nucleotide polymorphisms (SNPs) in and around 13 candidate genes within the previously linked chromosome 2q region for association with rheumatoid arthritis. We then performed fine mapping of the STAT1-STAT4 region in a total of 1620 case patients with established rheumatoid arthritis and 2635 controls, all from North America. Implicated SNPs were further tested in an independent case-control series of 1529 patients with early rheumatoid arthritis and 881 controls, all from Sweden, and in a total of 1039 case patients and 1248 controls from three series of patients with systemic lupus erythematosus.
  
  
  RESULTS
  A SNP haplotype in the third intron of STAT4 was associated with susceptibility to both rheumatoid arthritis and systemic lupus erythematosus. The minor alleles of the haplotype-defining SNPs were present in 27% of chromosomes of patients with established rheumatoid arthritis, as compared with 22% of those of controls (for the SNP rs7574865, P=2.81x10(-7); odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.32). The association was replicated in Swedish patients with recent-onset rheumatoid arthritis (P=0.02) and matched controls. The haplotype marked by rs7574865 was strongly associated with lupus, being present on 31% of chromosomes of case patients and 22% of those of controls (P=1.87x10(-9); odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.55). Homozygosity of the risk allele, as compared with absence of the allele, was associated with a more than doubled risk for lupus and a 60% increased risk for rheumatoid arthritis.
  
  
  CONCLUSIONS
  A haplotype of STAT4 is associated with increased risk for both rheumatoid arthritis and systemic lupus erythematosus, suggesting a shared pathway for these illnesses.
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA.
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Remmers
authors.forename: Robert M
authors.initials: RM
authors.lastname: Plenge
authors.forename: Annette T
authors.initials: AT
authors.lastname: Lee
authors.forename: Robert R
authors.initials: RR
authors.lastname: Graham
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Hom
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Behrens
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.forename: Julie M
authors.initials: JM
authors.lastname: Le
authors.forename: Hye-Soon
authors.initials: HS
authors.lastname: Lee
authors.forename: Franak
authors.initials: F
authors.lastname: Batliwalla
authors.forename: Wentian
authors.initials: W
authors.lastname: Li
authors.forename: Seth L
authors.initials: SL
authors.lastname: Masters
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Booty
authors.forename: John P
authors.initials: JP
authors.lastname: Carulli
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.forename: Wei V
authors.initials: WV
authors.lastname: Chen
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
authors.forename: Michael F
authors.initials: MF
authors.lastname: Seldin
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D050797:STAT4 Transcription Factor / Q000235:genetics*