Anti-citrullinated peptide antibody-negative RA is a genetically distinct subset: a definitive study using only bone-erosive ACPA-negative rheumatoid arthritis

Abstract

Objectives. ACPA is a highly specific marker for RA. It was recently reported that ACPA can be used to classify RA into two disease subsets, ACPA-positive and ACPA-negative RA. ACPA-positive RA was found to be associated with the HLA-DR shared epitope (SE), but ACPA negative was not. However, the suspicion remained that this result was caused by the ACPA-negative RA subset containing patients with non-RA diseases. We examined whether this is the case even when possible non-RA ACPA-negative RA patients were excluded by selecting only patients with bone erosion.Methods. We genotyped HLA-DRB1 alleles for 574 ACPA-positive RA, 185 ACPA-negative RA (including 97 erosive RA) and 1508 healthy donors. We also tested whether HLA-DR SE is associated with RF-negative or ANA-negative RA.Results. ACPA-negative RA with apparent bone erosion was not associated with SE, supporting the idea that ACPA-negative RA is genetically distinct from ACPA-positive RA. We also tested whether these subsets are based on autoantibody-producing activity. In accordance with the ACPA-negative RA subset, the RF-negative RA subset showed a clearly distinct pattern of association with SE from the RF-positive RA. In contrast, ANA-negative as well as ANA-positive RA was similarly associated with SE, suggesting that the subsets distinguished by ACPA are not based simply on differences in autoantibody production.Conclusions. ACPA-negative erosive RA is genetically distinct from ACPA-positive RA.

The Association Between Schizophrenia and Rheumatoid Arthritis: A Nationwide Population-Based Swedish Study on Intraindividual and Familial Risks

“…11 The MHC is most strongly associated with ACPA-positive RA. [12][13][14] Most, but not all, ACPApositive patients are also RF-positive, and it is estimated that 50%-80% of all individuals with RA have RF, ACPA, or both. 15 Hence, a comprehensive assessment of the association between RA and schizophrenia needs to take RA subtype into account.…”

Homogeneous case subgroups increase power in genetic association studies

“…Examples of diseases with genetically distinct subgroups include ischaemic stroke, where at least three distinct pathologies (cardioembolic, small vessel and large vessel) lead to stroke events; 13,14 migraine, where cases with or without aura have distinct genetic susceptibility factors; 15 and rheumatoid arthritis, where anti-citrullinated peptide antibody-negative individuals show distinct genetic associations, particularly in the HLA region. 16,17 Third, heterogeneity in genetic susceptibility to disease may exist. For example, cases with later disease onset have more exposure to environmental risk factors, and therefore under a liability threshold model will have a weaker genetic susceptibility.…”

A genome-wide screen of gene–gene interactions for rheumatoid arthritis susceptibility

“…Some RA patients have antibodies to citrullinated protein antigens (ACPA), and the clinical characteristics for ACPApositive RA are different from that for ACPA-negative RA (Furuya et al 2007;Huizinga et al 2005;van der Helm-van Mil et al 2005). Genetic variation in the HLA locus, including HLA-SE, is associated only with ACPA-positive (i.e., anti-CCP positive) RA (Ding et al 2009;Huizinga et al 2005;Ohmura et al 2010).…”