Strong Primary Selection for the Dw4 Subtype of DR4 Accounts for the HLA-DQw7 Association with Felty's Syndrome Jerry S. S. Lanchbury, Emma E. M. Jaeger, David M. Sansom, Margaret A. Hall, Paul Wordsworth, Judith Stedeford, John I. Bell, and Gabriel S. Panayi ABSTRACT: Felty's syndrome (FS) is a rare complica- tion of rheumatoid arthritis (RA) previously shown to be strongly associated with HLA.DR4 and less significantly with HLA-DQw7. To map more precisely the HLA locus responsible for suzceptibility to FS, we have examined HLA-DR4 and DQ fl-chain polymorphisms in FS pa- tients and controls using restriction fragment length poly- mnrphism analysis and polymerase chain reaction amplifi- cation in conjunction with oligonuclemide probing. The increased frequency of DR4 in FS (93% vs. 32% con- trols) was due almost entirely to enrichment for the Dw4 subtlrpe (88% vs. 20% controls) with a secondary in- crease of the Dw14 subtype. Dwl0 and Dwl 3 subtypes ABBREVIATIONS FS Felty's syndrome MHC major histocompatibility complex PCR polymerase chain reaction INTRODUCTION Approximately I% of patients with rheumatoid arthritis (RA) develop Felty's syndrome (FS). There is strong evidence for the importance of a genetic component in the development of FS since the disease is associated From the Molecular lmmunogenetics and Rheumatologv Unit~, Divi- sion of Medicine, UMDS, Gay's Hospital (LS.S.L.; E.E.Md.; M.A.H.; G.S.P.h London, Bath lmtitate for Rheumatic DiJeam fD.M.$.), Trim Bridge, Bath, and Institute of Moluular Medicine, Univenity of Oxford, John Radcliffe Hospital (P.W.;J.S.; J.I.BJ, Oxford, United Kingdom. Addressreprint requestJto Dr.Jerry$.S. Lanehbury, Division of Medi- cine, UMDS, 4th Floor Hunt's House, Guy's Hospital, London. SEl 9RT. United Kingdom. Ruei~d Februar~ 12, 1991; accepted April 17. 1991. 56 0198-8859191153.50 of DR4 were absent from the patient group. Increase in DQw7 frequency among DRZi FS patients could be ac- counted for by linkage disequilibrium between Dw4 and DQw7 alleles. Whereas susceptibility to RA is strongly associated with a conserved HLA-DR~ epimpe associ- ated with several DRBI alleles, it is primarily the Dw4 allele which is associated with progression to Felty's syn- drome. The finding that amino acid sequence variation at the DR4B1 locus rather than DQBI is associated with development of FS will have important implications for the development of novel immunotherapies which are major histocompadbility complex allele-dependent. Hu- man Immunology 32, 56-64 (1991) KFLP restriction fragment length polymocphism RA rheumatoid arthritis HVR3 third hypervariahle region with polymorphic markers of the HLA complex. HLA- DR4 is strongly associated with Pelty's syndrome, being present in 92% to 95% of patients compared to approx- imately 30% of healthy controls [1-3]. This contrasts with the moderate DR4 association found with RA [4]. Identification of primary disease associations in the ma- jor histocompatibilitT complex (MHC) is complicated by strong linkage disequilibrium but the step is essential in defining precise susceptibility loci and therefore in developing specific immunotherapeutic strategies. Ap- plication of molectflar techniques to the dissection of DR4 haplotypes has revealed considerable complexity. HLA-DR4 is a serological determinant encoded by a Humen Immunology 32, 56-64 (L991) © American Society for Hismcompatibility and lmmuaogenetics, L99!