title: New classification of HLA-DRB1 alleles supports the shared epitope hypothesis of rheumatoid arthritis susceptibility.
abstract: OBJECTIVE
  The shared epitope hypothesis was formulated to explain the involvement of HLA-DRB1 in rheumatoid arthritis (RA). However, several studies, which considered only the HLA-DRB1 alleles shown to be associated with RA risk, rejected this hypothesis. In this report, we propose that a different classification of HLA-DRB1 alleles be considered, based on the amino acid sequence at position 70-74.
  
  
  METHODS
  The fit of both HLA-DRB1 classifications was tested in 2 groups of RA patients. All subjects were recruited through the European Consortium on Rheumatoid Arthritis Families, and included 100 patients with isolated RA and 132 patients with at least 1 affected sibling.
  
  
  RESULTS
  The new classification produced risk estimates that fit all of the observed data, i.e., the distribution of the HLA-DRB1 genotype in the 2 patient groups, and the distribution of parental alleles shared by affected sibpairs. The risk of developing RA under this new classification depends on whether the RAA sequence occupies position 72-74 but is modulated by the amino acid at position 71 (K confers the highest risk, R an intermediate risk, A and E a lower risk) and by the amino acid at position 70 (Q or R confers a higher risk than D).
  
  
  CONCLUSIONS
  A new classification based on amino acid sequence allows us to show that the shared epitope RAA sequence at position 72-74 explains the data, with the risk of developing RA modulated by the amino acids at positions 70 and 71.
authors.affiliation: INSERM U535, Hôpital Paul Brousse, Villejuif, France. sophie.tezenas@psl.ap-hop-paris.fr
authors.forename: Sophie Tezenas
authors.initials: ST
authors.lastname: du Montcel
authors.forename: Laetitia
authors.initials: L
authors.lastname: Michou
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Petit-Teixeira
authors.forename: José
authors.initials: J
authors.lastname: Osorio
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lemaire
authors.forename: Sandra
authors.initials: S
authors.lastname: Lasbleiz
authors.forename: Céline
authors.initials: C
authors.lastname: Pierlot
authors.forename: Patrick
authors.initials: P
authors.lastname: Quillet
authors.forename: Thomas
authors.initials: T
authors.lastname: Bardin
authors.forename: Bernard
authors.initials: B
authors.lastname: Prum
authors.forename: François
authors.initials: F
authors.lastname: Cornelis
authors.forename: Françoise
authors.initials: F
authors.lastname: Clerget-Darpoux
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D000939:Epitopes / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000145:classification* / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D008969:Molecular Sequence Data
chemical_list: D000939:Epitopes; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains