title: Replication of the tumor necrosis factor receptor-associated factor 1/complement component 5 region as a susceptibility locus for rheumatoid arthritis in a European family-based study.
abstract: OBJECTIVE
  We recently showed, using a candidate gene approach in a case-control association study, that a 65-kb block encompassing tumor necrosis factor receptor-associated factor 1 (TRAF1) and C5 is strongly associated with rheumatoid arthritis (RA). Compared with case-control association studies, family-based studies have the added advantage of controlling potential differences in population structure and are not likely to be hampered by variation in population allele frequencies, as is seen for many genetic polymorphisms, including the TRAF1/C5 locus. The aim of this study was to confirm this association in populations of European origin by using a family-based approach.
  
  
  METHODS
  A total of 1,356 western European white individuals from 452 "trio" families were genotyped for the rs10818488 polymorphism, using the TaqMan allelic discrimination assay.
  
  
  RESULTS
  We observed evidence for association, demonstrating departure from Mendel's law, with an overtransmission of the rs10818488 A allele (A = 55%; P = 0.036). By taking into consideration parental phenotypes, we also observed an increased A allele frequency in affected versus unaffected parents (A = 64%; combined P = 0.015). Individuals carrying the A allele had a 1.2-fold increased risk of developing RA (allelic odds ratio 1.24, 95% confidence interval 1.04-1.50).
  
  
  CONCLUSIONS
  Using a family-based study that is robust against population stratification, we provide evidence for the association of the TRAF1/C5 rs10818488 A allele and RA in populations of European descent, further substantiating our previous findings. Future functional studies should yield insight into the biologic relevance of this locus to the pathways involved in RA.
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: F A S
authors.initials: FA
authors.lastname: Kurreeman
authors.forename: D
authors.initials: D
authors.lastname: Rocha
authors.forename: J
authors.initials: J
authors.lastname: Houwing-Duistermaat
authors.forename: S
authors.initials: S
authors.lastname: Vrijmoet
authors.forename: V H
authors.initials: VH
authors.lastname: Teixeira
authors.forename: P
authors.initials: P
authors.lastname: Migliorini
authors.forename: A
authors.initials: A
authors.lastname: Balsa
authors.forename: R
authors.initials: R
authors.lastname: Westhovens
authors.forename: P
authors.initials: P
authors.lastname: Barrera
authors.forename: H
authors.initials: H
authors.lastname: Alves
authors.forename: C
authors.initials: C
authors.lastname: Vaz
authors.forename: M
authors.initials: M
authors.lastname: Fernandes
authors.forename: D
authors.initials: D
authors.lastname: Pascual-Salcedo
authors.forename: L
authors.initials: L
authors.lastname: Michou
authors.forename: S
authors.initials: S
authors.lastname: Bombardieri
authors.forename: T
authors.initials: T
authors.lastname: Radstake
authors.forename: P
authors.initials: P
authors.lastname: van Riel
authors.forename: L
authors.initials: L
authors.lastname: van de Putte
authors.forename: A
authors.initials: A
authors.lastname: Lopes-Vaz
authors.forename: B
authors.initials: B
authors.lastname: Prum
authors.forename: T
authors.initials: T
authors.lastname: Bardin
authors.forename: I
authors.initials: I
authors.lastname: Gut
authors.forename: F
authors.initials: F
authors.lastname: Cornelis
authors.forename: T W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: E
authors.initials: E
authors.lastname: Petit-Teixeira
authors.forename: R E M
authors.initials: RE
authors.lastname: Toes