Background The antinuclear antibody (ANA)-positive asymptomatic individuals are at higher risk of developing systemic lupus erythematosus (SLE). However, the genetic burden for SLE in preclinical ANA-positive phase remains largely unknown. In this study, we analyzed SLE-specific polygenic risk scores (PRSs) from a prospective cohort comprising Korean individuals with preclinical autoantibodies, SLE, or none of these conditions to understand the effect of SLE-risk genetic variants on the development of ANA.
Methods The PRS for SLE was calculated from genome-wide variants data obtained from 349 individuals with preclinical autoimmunity, 2,057 patients with SLE, and 33,596 healthy controls based on the known risk effects of 180 SLE-risk variants. Preclinical autoantibodies-positive individuals who were diagnosed by rheumatologists, tested positive for at least one among ANA, rheumatoid factor (RF), or anti-cyclic citrullinated peptide autoantibody (anti-CCP). Differences in PRSs among phenotypic groups were assessed using ANOVA with adjustment for genotypic principal components and sex while controlling for the family-wise error rate.
Results There was a significant increase in the SLE PRS in the preclinical ANA-positive group (ANA titers ≥ 1:160) compared to healthy controls (p=2.69x10−5) and the preclinical ANA-negative group with preclinical autoimmunity (positive for RF or anti-CCP) (p=2.42x10−²), although their SLE genetic burden was significantly weaker than patients with SLE (p=7.48x10−²5). In addition, SLE PRSs were gradually increased according to the level of ANA titers in a stratified analysis (p=2.38x10−³, figure 1). In contrast, the presence of anti-CCP autoantibodies (irrelevant to SLE) in the preclinical stage was not associated with high SLE PRSs.
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