title: HLA heterozygosity contributes to susceptibility to rheumatoid arthritis.
abstract: We have investigated the role of HLA-DR genotypes in 184 patients with severe rheumatoid arthritis (RA) and in 46 patients with Felty syndrome, to establish the relative contribution of the RA-associated subtypes of DR4 (Dw4, Dw14, and Dw15). There was an excess of DR4 homozygotes, particularly Dw4/Dw14 compound heterozygotes (relative risk [RR] 49). The risk associated with Dw4 depended on the other allele present--Dw4/DR1 (RR 21), Dw4/Dw4 (RR 15), and Dw4/DRX (RR 6). There was a significant risk from Dw4/Dw14 compared with Dw4/Dw4, both in those with severe RA (RR 2.9; P less than .02) and in those with Felty syndrome (RR 4.2; P less than .02). In contrast, in a further 63 known DR4 homozygotes with RA, not selected for severe disease, the excess of Dw4/Dw14 was much less striking (RR 1.4; not significant), suggesting that this genotype may be particularly associated with more severe disease. We also found four cases with the rare Dw4/Dw15 genotype (expected less than or equal to 0.5; P less than or equal to .02). Since the Dw4, Dw14, Dw15, and DR1 molecules have similar antigen-binding sites and since combinations of these alleles particularly predispose to severe RA, we suggest that synergistic mechanisms are involved. These could include an effect on T-cell repertoire selection.
authors.affiliation: Institute of Molecular Medicine, Oxford, England.
authors.forename: P
authors.initials: P
authors.lastname: Wordsworth
authors.forename: K D
authors.initials: KD
authors.lastname: Pile
authors.forename: J D
authors.initials: JD
authors.lastname: Buckely
authors.forename: J S
authors.initials: JS
authors.lastname: Lanchbury
authors.forename: B
authors.initials: B
authors.lastname: Ollier
authors.forename: M
authors.initials: M
authors.lastname: Lathrop
authors.forename: J I
authors.initials: JI
authors.lastname: Bell
mesh_terms: D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D004198:Disease Susceptibility; D005787:Gene Frequency / Q000235:genetics; D005802:Genes, MHC Class II; D015798:HLA-DR1 Antigen / Q000235:genetics*; D015804:HLA-DR4 Antigen / Q000235:genetics*; D006579:Heterozygote; D006801:Humans
chemical_list: D015798:HLA-DR1 Antigen; D015804:HLA-DR4 Antigen