Autoantibody-defined subsets of patients with systemic lupus erythematosus associate with clinical manifestations, NCF2, and HLA DR3-DQ2 genotypes

Introduction: Understanding the associations between genetic markers, serological subsets and clinical manifestations in patients with Systemic lupus erythematosus (SLE) may elucidate disease mechanisms and inform personalised treatment strategies. This study aimed to classify SLE patients into distinct subsets based on autoantibody profiles and to examine associations with clinical and genetic characteristics, focusing on key risk loci. Methods: A cohort of 846 SLE patients from the Danish SLE Gene-Environment Interaction study (SLE-GEIST) was analysed. Patients were grouped by cluster analysis of cumulative history of autoantibody positivity, and genotyped for known risk alleles, including HLA and non-HLA variants. Multinomial, multivariable logistic regression models were employed to identify associations between autoantibody subsets, clinical manifestations, and genetic markers. Results: Six serological subsets with distinct characteristics were identified. The NCF2 variant was significantly associated with the subset characterised by antiphospholipid antibodies, showing an odds ratio (OR) of 2.42 (95% confidence interval [CI] 1.24–4.74) for co-positivity of anti-cardiolipin IgG and anti-beta2-glycoprotein IgG. This subset also demonstrated a higher prevalence of thrombocytopenia (OR 2.16, 95% CI 1.41–3.29). The DRB3-DQB2 haplotype exhibited a strong association with anti-SSB positivity (OR 4.85, 95% CI 2.57–9.5) and was inversely related to lupus nephritis (OR 0.57, 95% CI 0.34–0.95). Conclusions: This study shows how the clinical and serological complexity of SLE is associated with the genetic diversity of HLA and non-HLA regions. We thus suggest further investigation of mechanistic correlates to variations in the NCF2 gene as well as the tight association between DRB3-DQB2 haplotype and anti-SSB production.