Background/Purpose: Investigators have long speculated that the two subtypes of rheumatoid arthritis (RA), anti-citrullinated protein autoantibody positive (ACPA+) and negative (ACPA-), have distinct underlying genetic factors. The MHC region is the strongest genetic risk factor to ACPA+ RA, but plays a much more modest role in ACPA- RA. To understand the similarities and differences between these two disease subtypes, we fine-mapped and compared MHC associations. 

Methods: Using densely genotyped SNP data consisting of 7,222 ACPA+ RA cases, 3,339 ACPA- RA cases, and 15,870 controls from six different cohorts (Eyre et al., Nat Gen, 2012), we imputed and tested HLA alleles in the two RA subtypes separately. 

Results: We mapped associations to ACPA+ RA using forward search conditional analysis and confirmed previously published associations at amino acid sites at positions 13 (P < 10^-705), 71, and 74 in HLA-DRB1, position 9 in HLA-B, and position 9 in HLA-DPB1. In addition, we identified a novel association at position 77 in HLA-A (P=1.7×10^‑8) located in the peptide binding groove implicating antigen presentation as the major mechanism by which MHC variation confers risk. Then in parallel we mapped associations to ACPA- RA. We recognized that ACPA- RA associations to the MHC might be confounded due to the inclusion of misclassified samples that are actually ACPA+ RA (false negative testing) or ankylosing spondylitis. We developed a novel statistical approach that estimates the proportion of misclassified samples and regresses out their effects. Using this approach we observed that each cohort consistently contained 3-9% of cases that likely had ankylosing spondylitis, and a variable number of cases that likely had ACPA+ RA. Controlling for misclassification effects, we identified the amino acid residues at position 13 in HLA-DRB1 as strongly associated with risk (Omnibus test P=1.2×10^‑16). Serine conferred the highest risk (OR=1.28, P=5.7×10^-13); in stark contrast serine conferred protection to ACPA+ disease (OR=0.4). We also observed a shared association to the presence of an aspartate in position 9 in HLA-B (P=1.3×10^-15, OR=1.38) with a more modest effect size than for ACPA+ disease (OR=2.1).

Conclusion: Our analysis is the first to define specific amino acid sites for ACPA- RA, and demonstrates a distinct genetic basis for ACPA+ and ACPA- RA in the MHC region. Our analysis also underscores the importance of phenotypic classification for accurate fine-mapping.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mapping-the-shared-and-distinct-hla-alleles-for-seropositive-and-seronegative-rheumatoid-arthritis/