Background/Purpose : Numerous genetic susceptibility loci have been identified in RA. The HLA-DRB1 shared epitope (SE) sequence is most strongly associated, though there has been increasing interest in amino acids outside the SE region. Recently, investigators have identified 16 HLA haplotypes defined by amino acids at positions 11, 71, and 74. Valine at position 11, particularly the VKA haplotype, has been associated with radiographic progression, mortality, and poor RA treatment response. In this study we examined HLA haplotypes and associations with mortality, presence of subcutaneous nodules, radiographic damage, and RA-associated autoantibodies.

Methods: The study included 1443 U.S veteran participants. Clinical characteristics were recorded at enrolment. Mortality was ascertained via linkage to the National Death Index. DNA was obtained at enrollment and 4-digit HLA-DRB1 genotyping was completed. Amino acids at positions 11, 71, and 74 were determined, and haplotypes assigned based on three amino acid combinations. RF and aCCP were measured from banked serum. Haplotype associations with mortality were examined using age- and sex-adjusted Cox proportional hazards regression, while associations with other disease characteristics were examined using Chi square or Student’s t-tests comparing subjects with at least one copy of a given haplotype to those with no copies.

Results: The most frequent haplotype was VKA with 34% of subjects possessing at least one copy. Eight haplotypes were present in frequencies >10% (VKA, VRA, LRA, PAA, GRQ, SRA, SKR, SEA). We found an increased risk of all-cause mortality with SKA (HR 1.38 [95% CI 1.13-1.69]) but not with SE status or other haplotypes, including those with valine at position 11. Radiographic damage was more common in patients with VKA (60% vs 51%, p = 0.002) or VRE (70% vs 53%, p = 0.032) but less common with SRA (44% vs 55%, p = 0.005) and SEA (46% vs 57%, p = 0.023). There were no haplotype associations with subcutaneous nodules. We identified associations between several haplotypes and autoantibody concentration (Table). The VKA haplotype was associated with higher RF and aCCP concentrations. SE positivity based on dual autoantibody status was: RF+/aCCP+ = 77%; RF-/aCCP+ = 79%; RF+/aCCP- = 53%; and RF-/aCCP- = 56%. A similar pattern was observed for VKA haplotype positivity: RF+/aCCP+ = 39%; RF-/aCCP+ = 37%; RF+/aCCP- = 18%; and RF-/aCCP- = 18%.

Conclusion: In contrast to recent reports, we observed little association between HLA haplotype and all cause mortality. However, there were associations of both VKA and VRE haplotypes with presence of radiographic damage and robust associations of VKA with higher RF and aCCP values. Our observations also suggest that associations of both SE and VKA status with seropositivity are driven by associations with aCCP status independent of RF.      

*P-values generated from t-test comparing log-transformed values

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/associations-of-hla-drb1-haplotypes-with-disease-characteristics-and-all-cause-mortality-in-rheumatoid-arthritis/