IMMUNOPRINTING - VARIOUS GENES ARE ASSOCIATED WITH INCREASED RISK TO DEVELOP RHEUMATOID-ARTHRITIS IN DIFFERENT GROUPS OF ADULT PATIENTS

To identify genes that contribute to the manifestation of rheumatoid a rthritis we performed association studies via microsatellite analyses of immunorelevant loci (HLA-DRB, 5 T cell receptor loci, TNFa, IL1, IL 2, IL5R and CD40L), A total of 183 patients and 275 healthy controls w ere typed in terms of HLA and grouped according to the known predispos ing HLA-DRB1 genes (DRB104; relative risk approx. 5; DRB1*01, relativ e risk approx. 2; a third group carried neither allele). Microsatellit e polymorphisms characterizing the TCRBV6S3, CD3D, IL1A, IL2, and IL5R genes did not show significant associations with rheumatoid arthritis ,whereas TCRBV6S1, TCRBV6S7, TNFa, and CD40L genes may influence relat ive protection or risk in certain groups of patients. Analysis of a mi crosatellite marker adjacent to the transcription element alpha (TEA) in the T cell receptor alpha delta complex indicates that in the cohor t carrying neither the DRB104 nor the DRB1*01 allele the relative ris k to acquire rheumatoid arthritis is increased (>13) or decreased (<0. 07), depending on the inherited microsatellite allele adjacent to the TEA locus. Sequence analysis of the closely linked TEA region from pat ients and controls revealed a novel dimorphism. Only the newly identif ied TEA allele leads to binding of a nuclear protein that may be invol ved in the regulated expression of the TCRDA genes. Subsequent typing of rheumatoid arthritis patients and controls revealed, however, that the association of the microsatellite marker is largely independent of the TEA allele, confirming incomplete linkage in the 2 kb region of t he TCRDA locus. These results are discussed in the context of hot spot s of recombination in this genomic region and other linked candidate s equences that predispose to develop rheumatoid arthritis.