title: European genetic study on rheumatoid arthritis: is there a linkage of the interleukin-1 (IL-1), IL-10 or IL-4 genes to RA?
abstract: The genetic predisposition for rheumatoid arthritis (RA) is only partly explained by the HLA locus and most genetic factors involved in the susceptibility (and/or severity) of the disease await further identification. The first European genome scan in RA families provided suggestive evidence for linkage with a region (3.1/3q13) on chromosome 3, but many other potential RA susceptibility genes have yet to be analysed.
  
  
  OBJECTIVE
  To perform a linkage analysis with microsatellite markers located in the vicinity of the interleukin-1 (IL-1) gene superfamily, the IL-10 gene and the IL-4 gene cluster which might be considered putative candidate loci for RA.
  
  
  METHODS
  107 Caucasoid European RA sibpairs from 90 nuclear families were genotyped for markers flanking the genes for the IL-1 superfamily, IL-10 and the IL-4 gene cluster. Linkage analysis based on the identity by descent (IBD) in affected siblings was analysed with the program SIBPALNA. Affected sibpairs were stratified according to the identity by state (IBS) for three markers in the HLA region (DRB1 oligotyping, D6S276 and TNFa microsatellites) and to the presence/absence of erosive disease on X-ray examination.
  
  
  RESULTS
  Analysis of the whole family set showed an excess of allele sharing for markers of the IL-1 gene cluster (IBD 60%; P = 0.012) but not for IL-10 or IL-4. After stratification, the evidence of linkage to IL-1 was restricted to HLA concordant sibpairs (n = 32; IBD 70%; P = 0.006). Some evidence of linkage to IL-10 was also observed in HLA concordant sibpairs (IBD 66%; P = 0.03) and in sibpairs with erosive disease (n = 61; IBD 62%; P = 0.02).
  
  
  CONCLUSIONS
  We found suggestive evidence of linkage of RA to the IL-1 locus. The increased linkage to IL-1 and IL-10 in HLA-identical sibs suggests a possible interaction between these cytokines and the HLA loci. Moreover IL-10 could interact with HLA factors in predisposing to erosive disease. These results need to be tested in additional families for consistency and replication.
authors.affiliation: Department of Rheumatology, University Hospital, Nijmegen, The Netherlands. p.barrera@reuma.azn.nl
authors.forename: P
authors.initials: P
authors.lastname: Barrera
authors.forename: S
authors.initials: S
authors.lastname: Fauré
authors.forename: J F
authors.initials: JF
authors.lastname: Prud'homme
authors.forename: A
authors.initials: A
authors.lastname: Balsa
authors.forename: P
authors.initials: P
authors.lastname: Migliorini
authors.forename: D
authors.initials: D
authors.lastname: Chimenti
authors.forename: T R
authors.initials: TR
authors.lastname: Radstake
authors.forename: L B
authors.initials: LB
authors.lastname: van de Putte
authors.forename: D
authors.initials: D
authors.lastname: Pascual-Salcedo
authors.forename: R
authors.initials: R
authors.lastname: Westhovens
authors.forename: K
authors.initials: K
authors.lastname: Maenaut
authors.forename: H
authors.initials: H
authors.lastname: Alves
authors.forename: A
authors.initials: A
authors.lastname: Lopes-Vaz
authors.forename: C
authors.initials: C
authors.lastname: Stravopoulos
authors.forename: M
authors.initials: M
authors.lastname: Spyropoulou
authors.forename: P
authors.initials: P
authors.lastname: Fritz
authors.forename: T
authors.initials: T
authors.lastname: Bardin
authors.forename: D
authors.initials: D
authors.lastname: Charron
authors.forename: V
authors.initials: V
authors.lastname: Lepage
authors.lastname: Alibert
authors.forename: M
authors.initials: M
authors.lastname: Martinez
authors.forename: F
authors.initials: F
authors.lastname: Cornélis
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics*; D002893:Chromosomes, Human, Pair 3; D005060:Europe; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics; D007378:Interleukins / Q000235:genetics*; D008297:Male
chemical_list: D007375:Interleukin-1; D007378:Interleukins; D016753:Interleukin-10; D015847:Interleukin-4