Introduction: Certain sequences present in the hypervariable region of HLA-DRB1 known as the shared epitope (SE) are hypothesized to increase the risk of rheumatoid arthritis (RA), while alleles encoding aspartic acid at position 70 (D70 alleles) may have a protective effect.
Methods: We assessed patient HLA-DRB1 serotypes and identified which genotypes encoded the SE motif or the putatively protective D70 motif in a large RA cohort. We used logistic regression to analyze associations of genotype with presence of disease, comorbidities and disease severity, as well as association between genotype and change in disease activity over time.
Results: 689 patients had a mean age of 57.9 years (SD±13.7 years) and mean disease duration of 15.3 years (SD±12.7). In a comparison with 482 ethnicity matched population-based controls, the D70 sequence exerted a strong protective effect (OR=0.52, p<0.0001) that remained significant when the SE at the same locus was accounted for (OR=0.72, 95% CI 0.60-0.86, p=0.0003). The SE assessed on all HLA-DRB1 serotypic backgrounds except DR1 was associated with RA susceptibility (additive OR=2.43, p<10-6). We observed associations between SE and serum levels of rheumatoid factor (p=0.0001, with correlation of 0.18) and anti-CCP antibodies (p<0.0001, with correlation of 0.25) but not with serum C-reactive protein.
Conclusion: The D70 allele has a significant protective effect that is mitigated but still significant when the risk effect of the SE at the same locus is accounted for. The presence of the SE on DR4 is associated with greater RA susceptibility and certain disease activity measures.
- Rheumatoid arthritis,
- patient registry
- shared epitope