Major histocompatility complex haplotypic associations in Felty's syndrome and large granular lymphocyte syndrome are secondary to allelic association with HLA-DRB1 *0401

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Abstract
Objective. To investigate the role of HLA class I in susceptibility to Felty's syndrome (FS) and large granular lymphocyte (LGL) syndrome. Methods. Fifty caucasoid FS patients, and 55 patients with LGL syndrome, of whom 26 had arthritis and 29 did not, were studied. Complete HLA class I and HLA‐DR typing including, where relevant, DRB1*04 subtyping was carried out by molecular methods. Comparison was made with 78 unselected healthy caucasoid controls and a further 29 DRB1*0401+ individuals. Results. A significant association was found between HLA‐A*02 and FS [odds ratio (OR) 3.9, 95% confidence interval (95% CI) 1.8–8.4, P = 0.0004]. At the B locus, there was an association between B*44 and LGL with arthritis [OR 3.5 (1.3–9.2), P = 0.01]. For HLA‐Cw*0501, there was an association with FS [OR 4 (1.7–9.2) P = 0.0008]. For both FS and LGL with arthritis, the extended haplotype HLA‐A*02;B*44;Cw*0501;DRB1*0401 was significantly associated [OR 9.5 (2.6–35), P = 0.0001; OR 4.6 (1–22.4), P = 0.05, respectively]. There was no association between HLA class I or II and LGL without arthritis. All the allelic and haplotypic associations were lost on comparison with HLA‐DRB1*0401+ controls. The strongest HLA association was with HLA‐DRB1*0401 for FS [OR 27.9 (10.3–75.5), P = 10−13], and LGL with arthritis [OR 35.4 (9.6–131.3), P = 10−10]. Conclusions. The major histocompatibility locus (MHC) associations with FS reported here are due to linkage disequilibrium with HLA‐DRB1*0401. LGL syndrome with arthritis shows identical class II associations with FS, although there may be subtle immunogenetic differences between the two in the class I region. One of the extended haplotypes reported in a number of studies for FS and rheumatoid arthritis (summarized as HLA‐A*02;Cw*0501; B*44;TNFb5;TNFa6;TNFd4;C4A*3;C4BQ*0;DRB1*0401;DQB1*0301) is likely to be attributable to strong primary association with HLA‐DRB1*0401, rather than to epistatic interaction between these loci.

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