Background/Purpose: We previously found that presence of rheumatoid arthritis(RA)-related autoantibodies is associated with systemic inflammation, and that decreased consumption of anti-inflammatory omega-3 fatty acids (n-3 FA) is associated with RA-related autoantibody positivity. We examined whether selected genes in inflammatory pathways in which n-3 FA also play a role are associated with the presence of RA-related autoantibodies in individuals without RA but at future risk for the disease.   

Methods: Participants were enrolled in The Studies of the Etiology of RA (SERA), which is a multisite observational study following a cohort of first-degree relatives of RA probands and a cohort enriched with the HLA-DR4 genetic variant, both of which are RA-free at their baseline visit. Participant DNA was screened at the Benaroya Research Institute for specific shared epitope subtypes of HLA-DR4 and HLA-DR1. Participants were positive for the shared epitope if they were either DR4 or DR1 subtype positive. Serum was measured for the following autoantibodies: anti-cyclic citrullinated peptide version 2 (CCP2), CCP3.1 (in a subset), rheumatoid factor (RF) by nephelometry, and RF isotypes (RF-IgM, RF-IgG, RF-IgA). Participants were considered positive for RA-related autoantibodies if they tested positive for any of these autoantibodies at their baseline visit.

Participants were typed for single nucleotide polymorphisms (SNPs) in Cox-2, TNFA, NF-KB, IkBkB, PPARA, and PPARG at the Broad Institute using the Sequenom platform. The association between RA-related autoantibody positivity and inflammatory genes was assessed using logistic regression, accounting for the correlation within family members, and adjusting for age at visit, sex, and race.

Results: Demographic characteristics were similar between autoantibody positive (n=306) and autoantibody negative (n=1,576) participants (Table 1). We observed a significant association between increasing number of minor alleles for Cox-2 and NF-KB and autoantibody positivity (Table 2).

Conclusion: Our results suggest that Cox-2 and NF-KB could be associated with an increased likelihood of developing RA-related autoantibodies. The association observed with Cox-2 is of interest due to the enzyme’s role in producing inflammatory lipid molecules, while the association observed with NF-KB is of interest given the potential roles that NF-KB has in the RA disease process, including cytokine production and stimulating B cell differentiation to immunoglobulin-producing B cells. These results need to be explored in further detail.