title: Evidence of epistasis between TNFRSF14 and TNFRSF6B polymorphisms in patients with rheumatoid arthritis.
abstract: OBJECTIVE
  Genetic variants located close to 2 genes codifying for members of the tumor necrosis factor receptor superfamily (TNFRSF), TNFRSF14 and TNFRSF6B, have recently been associated with rheumatoid arthritis (RA) and with inflammatory bowel disease susceptibility, respectively. The TNFRSF6B protein has been related to osteoclastic activity, apoptosis inhibition, and modulation of T cell activation and differentiation. Interestingly, peptides encoded by both genes bind a common ligand called LIGHT, which is overexpressed in RA synovium. The aim of this study was to investigate the combined effect of the TNFRSF14 rs6684865 and TNFRSF6B rs4809330 polymorphisms in RA predisposition.
  
  
  METHODS
  TaqMan genotyping of these polymorphisms was conducted in 649 patients with RA and 553 ethnically matched control subjects (first study). To validate the results, an independent replication cohort with 211 patients and 255 control subjects was additionally studied (replication study).
  
  
  RESULTS
  The frequency of the rs6684865 G allele in the RA subgroup with the rs4809330 GG susceptibility genotype was significantly higher than that in the other patients with RA (74% versus 65%; P = 0.002) or in control subjects (74% versus 67%; P = 0.003). Because no significant differences between the control and patient groups in the first and replication studies were observed, the data were pooled. When compared with control subjects overall, the effect of the rs6684865 G allele in the group with the rs4809330 GG genotype (odds ratio [OR] 1.49) was significantly different from the effect observed in the group carrying the rs4809330 A allele (OR 0.97; P = 0.0015 by Breslow-Day test of homogeneity).
  
  
  CONCLUSIONS
  We have identified and replicated a novel gene-gene interaction between 2 polymorphisms of TNFRSF members in Spanish patients with RA, based on the hypothesis of shared pathogenic pathways in complex diseases.
authors.affiliation: Immunology Department, Hospital Clínico San Carlos, C/Profesor Martín Lagos, s/n 28040 Madrid, Spain. nievich@hotmail.com
authors.forename: Nieves
authors.initials: N
authors.lastname: Perdigones
authors.forename: Ana G
authors.initials: AG
authors.lastname: Vigo
authors.forename: José R
authors.initials: JR
authors.lastname: Lamas
authors.forename: Alfonso
authors.initials: A
authors.lastname: Martínez
authors.forename: Alejandro
authors.initials: A
authors.lastname: Balsa
authors.forename: Dora
authors.initials: D
authors.lastname: Pascual-Salcedo
authors.forename: Emilio G
authors.initials: EG
authors.lastname: de la Concha
authors.forename: Benjamín
authors.initials: B
authors.lastname: Fernández-Gutiérrez
authors.forename: Elena
authors.initials: E
authors.lastname: Urcelay
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic