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

Abstract

Objective. To accurately determine the contributions of HLA-DRB1 alleles in explaining susceptibility to inflammatory polyarthritis in a large, true population-based cohort of new-onset cases. Methods. A cohort of 680 consecutive patients with inflammatory polyarthritis, of whom 404 satisfied the American College of Rheumatology (ACR) criteria for rheumatoid arthritis (RA), was recruited from the population-based Norfolk Arthritis Register. All cases were compared with 286 local population controls. A standardized clinical assessment was performed on all patients. HLA-DRB1 phenotypes, including DR4 subtypes, were determined using a semiautomated, 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) between inflammatory polyarthritis and the presence of any shared epitope (SE) allele; 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 effect of being SE heterozygous (OR 1.3, 95% CI 1.11.6). The exception to this was genotypic combinations that included HLA-DRB1*0404, which exhibited ORs ranging up to 18.0. There were no differences between either the phenotype or genotype data when the patients were stratified by RA status (defined 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 influence 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 the clearly distinct influence of HLA-DRB1*0404.