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

Abstract

Objectives: 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.

Methods: 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.

Results: 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).

Conclusions: 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.