Background/Purpose: Rheumatoid arthritis (RA) is an autoimmune disease characterized by the presence of RA-related autoantibodies prior to the development of clinical disease. While HLA-shared epitope (SE) is the strongest genetic factor for RA, genome-wide association scans (GWAS) have identified additional single nucleotide polymorphisms (SNPs) associated with RA. We investigated whether these SNPs were associated with the presence of anti-cyclic citrullinated peptide autoantibodies (CCP) in RA-free At-Risk individuals, and/or with progression to classified RA in CCP positive (CCP+) individuals.

Methods: We tested 1066 RA-free first degree relatives (FDRs) of RA patients for CCP2 and CCP3.1 as part of the Studies of the Etiology of RA (SERA); 124 ever tested CCP+ at baseline or during follow-up. We examined associations between 41 GWAS-identified SNPs and ever CCP+ using logistic regression in additive models. We also assessed SE, age, and sex as effect modifiers. When a significant interaction was found, results were stratified. Of the CCP+ FDRs, 84 were followed over time and 10 developed classified RA. We examined whether the SNPs were associated with development of RA in CCP+ FDRs using Cox proportional hazards; effect modification was not tested due to small numbers. As each SNP was of interest due to the known association with RA, we did not adjust for multiple comparisons in this exploratory analysis.

Results: FDRs who were ever CCP+ were less likely to be ≥50 years old than CCP- FDRs (Table 1). Significant SNP and CCP+ associations and their interactions are presented in table 2. For some SNPs, associations differed by SE, age, and sex. In longitudinal analyses, CCP+ FDRs who developed RA were less likely to be non-Hispanic White (NHW) and more likely to be SE+ than CCP+ FDRs that did not develop RA (Table 1). In CCP+ FDRs, progression to RA was associated with different SNPs than those associated with CCP+ (Table 2).

Conclusion: These findings indicate that some RA-associated SNPs may play a role in the early development of serum CCP+ in absence of RA, and others may play a role in the progression from CCP+ without RA to classifiable disease. Moreover, associations between SNPs and autoimmunity differ by SE, age, and sex, suggesting disease heterogeneity. The effect modification by SE that we observed may suggest that GWAS SNPs may have a more influential effect when the individual does not have SE to promote disease. These findings need further exploration to inform disease mechanisms, prediction and therapeutic/prevention studies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/association-between-genetic-variants-and-the-presence-of-rheumatoid-arthritis-related-autoimmunity-and-progression-to-classified-rheumatoid-arthritis-in-an-at-risk-population/