INFLUENCE OF THE HLA-DR-BETA SHARED EPITOPE ON SUSCEPTIBILITY TO AND CLINICAL EXPRESSION OF RHEUMATOID-ARTHRITIS IN CHILEAN PATIENTS

Objective - To analyse the influence of shared epitope positive HLA-DR B1 alleles (QKRAA or QRRAA)) on rheumatoid arthritis (RA) susceptibili ty and severity in Chileans, a population that exhibits a weak associa tion with HLA-DR4. Methods - Prevalence of alleles DRB101 and DRB1*04 alleles was determined by polymerase chain reaction amplification and sequence specific oligonucleotide hybridisation in 129 RA patients wi th defined clinical features and in 97 healthy controls. Results - The shared epitope was found in 70 (54%) of the RA patients and in 29 (30 %) of controls (odds ratio (OR) = 3; 95% confidence intervals (CI) = 1 .5, 5.1; p = 0.0004), and was present in a double dose in 20% of patie nts versus 4% of controls (OR = 6; 95% CI = 2, 21; p = 0.0009). HLA-DR B10403 was the most prevalent DR4 subtype in controls (19%). HLA-DRB1 0404 or *0408 were the alleles most prominently associated with RA, 1 9% versus 6% in controls (OR = 3; 95% CI = 1.3, 10; p = 0.01). The ris k of RA in those carrying a double dose of the shared epitope was 7.5 times that seen in patients lacking the epitope. Disease severity was moderate: 33% had extra-articular manifestations. The double dose was associated with an increased risk of vasculitis or extra-articular man ifestations. However, 59 patients (46%) did not carry the shared epito pe and 18 of them (31%) had extra-articular manifestations. Conclusion s - The weak association of RA with DR4 in Chileans seems to relate to a relatively high frequency of the DRB10403 allele among DR4 subtype s. As in other populations, the shared epitope in double dose is assoc iated with RA development, especially in its more severe forms. Howeve r, both development and expression of severe forms of the disease were independent of the shared epitope in a high proportion of patients, t hus emphasising the genetic heterogeneity of the disease and the possi ble involvement of other genetic elements.