Quantifying the exact role of HLA-DRB1 alleles in susceptibility to inflammatory polyarthritis - Results from a large, population-based study

Objective. To accurately determine the contributions of HLA-DRB1 alleles in explaining susceptibility to inflammatory polyarthritis in a large, true p opulation-based cohort of new-onset cases. Methods. A cohort of 680 consecutive patients with inflammatory polyarthrit is, of whom 404 satisfied the American College of Rheumatology (ACR) criter ia for rheumatoid arthritis (RA), was recruited from the population-based N orfolk Arthritis Register. All cases were compared with 286 local populatio n controls. A standardized clinical assessment was performed on all patient s. HLA-DRB1 phenotypes, including DR4 subtypes, were determined using a sem iautomated, reverse dot-blot method. Results were expressed as odds ratios (OR) and 95% confidence intervals (95% CI). Results. There was only a modest association (OR 1.8, 95% CI 1.4-2.4) betwe en inflammatory polyarthritis and the presence of any shared epitope (SE) a llele; the strongest individual risk was with DRB1*0404 (OR 3.5, 95% CI 1.8 -6.8). Comparison of the genotypes demonstrated that the effect of being SE homozygous (OR 2.1, 95% CI 1.5-3.0) was only moderately greater than the e ffect of being SE heterozygous (OR 1.3, 95% CI 1.01-1.6). The exception to this was genotypic combinations that included HLA-DRB1*0404, which exhibite d ORs ranging up to 18.0. There were no differences between either the phen otype or genotype data when the patients were stratified by RA status (defi ned by the ACR criteria). In contrast, the associations were substantially stronger in patients who were positive for rheumatoid factor. Conclusion. Previous studies had not been able to clarify whether the influ ence of HLA-DRB1 on RA was related to disease susceptibility or to disease severity and progression. These data on a unique population-based incident cohort suggest only weak effects on susceptibility, with the exception of t he clearly distinct influence of HLA-DRB1*0404.