Genetic burden of lupus increases the risk of transition from normal to preclinical autoimmune conditions via antinuclear antibody development.

Abstract

This study aimed to investigate the association between the genetic burden of systemic lupus erythematosus (SLE) and the loss of tolerance to self-nuclear antigens in the preclinical stage. We analysed genetic data from 349 Korean individuals who tested positive for autoantibodies in the preclinical stage, along with 33,596 healthy controls and 2057 patients with SLE. Genome-wide and pathway-specific polygenic risk scores (PRSs) of SLE were calculated based on 180 known non-human leukocyte antigen (non-HLA) SLE loci, HLA-DRB1 classical alleles, and predefined immune-related pathways to subsequently correlate with clinical phenotypes, particularly the presence of antinuclear antibodies (ANAs) at various titre thresholds. Individuals with preclinical autoimmune conditions exhibited significantly higher SLE PRSs than healthy controls (P = 2.99 × 10^-5), with a significantly upward trend between ANA titres and PRS (P = 1.12 × 10^-3). Stratification analysis revealed that preclinical-stage individuals with PRSs exceeding the means of age- and sex-matched PRSs among patients with SLE were at a significantly higher risk of ANA development (odds ratio = 2.25; P = 8.12 × 10^-3 at a dilution factor of 1:80). Pathway-specific PRS analysis identified the significant enrichment of SLE-risk effects in nine pathways, such as signalling related to reactive oxygen species production, T cell receptor, B cell receptor, and cytokines, in ANA-positive preclinical individuals (P_adjusted < 0.05). Our findings illustrate that the genetic burden of SLE may lead to a crucial transition from normal to preclinical autoimmune conditions prior to the pathogenic stage by increasing the susceptibility to and levels of ANAs.