LINKAGE DISEQUILIBRIUM OF HLA-DR3 AND HLA-DR4 WITH HLA-B ALLELES IN MEXICAN PATIENTS WITH RHEUMATOID-ARTHRITIS

Objective. We studied the gene frequencies of classes I, II and III an tigens of the Major Histocompatibility Complex (MHC) in 32 Mexican mes tizo patients with rheumatoid arthritis (RA) and compared them with th ose obtained from 110 of their first degree relatives and 100 Mexican mestizo controls. Furthermore, we analyzed the observed and expected f requencies of the haplotypes and calculated the delta values in the th ree groups. Methods. The class I and class II MHC antigens were determ ined by the microlymphocytotoxicity test; class III MHC antigens were obtained by high voltage agarose gel electrophoresis and immunofixatio n. The significance of differences among the three groups was tested b y chi-square analysis; linkage disequilibrium among the different alle les in each haplotype was estimated by computing the delta values (obs erved vs expected frequencies). Results. Patients showed a significant ly increased frequency of HLA-A1 (corrected p=10(-5)), DR3 (corrected p=0.04) and DQ2 (corrected p=10(-4)) and a decreased frequency of A31 (corrected p=0.003) as compared to the normal controls. First degree r elatives compared to patients and controls showed a decreased frequenc y of HLA-DR4 (corrected p=0.02 and 0.008 respectively); consequently, DQ3 was also diminished (corrected p=10(-4)). Analysis of MHC haplotyp es within families revealed in the patients seven MHC haplotypes with significant differences between the observed and expected frequencies (statistically significant delta values). These haplotypes were: [HLA- B8; DR3], [HLAB44; FC31], [HLA-B8; SC42], [HLA-DR4; SC31], [HLA-B35; S C32], [HLA-DR7; FC31] and [HLA-DR2; SC31]. On the other hand, the cont rol haplotypes showed significant delta values in only one of these ha plotypes ([HLA-DR4; SC31]), whereas first degree relatives showed none . Analysis of all the class I, II and III alleles, either alone or as part of specific haplotypes, showed two B-DR haplotypes with higher re lative risks than their alleles alone. These haplotypes were: [B44; DR 4] (RR=6.0, p=0.005), and [B8; DR3] (RR=8.3, p=0.010). Conclusion. The results suggest that a specific combination of antigens in the same h aplotype (for instance between HLA-B and HLA-DR) could contribute to i ncreasing the generic susceptibility to develop RA.