Abstract
BACKGROUND: Severe coronavirus disease 2019 (COVID-19) and systemic lupus erythematosus (SLE) have been reported to share common gene loci, but the causal relationship between them remains controversial. METHODS: We conducted a linkage disequilibrium score regression analysis to assess the genetic correlations between SLE and the two traits (infection and severity) of COVID-19 in European populations. Mendelian randomisation analysis was then performed to explore the causal effect of SLE on susceptibility to these traits in both European and East Asian data sets. Lastly, enrichment analysis and Protein-Protein Interactions analysis were used to identify key pathways and genes involved, providing insights into the possible mechanism underlying the complex relationship between SLE and COVID-19. RESULTS: A significant genetic correlation was observed between SLE and COVID-19 severity (genetic correlation (rg) = 0.340, P = 0.001). However, no significant genetic correlation was found with COVID-19 infection. Mendelian randomisation analysis revealed a negative causal effect of SLE on both COVID-19 infection (odds ratio (OR) = 0.986; 95% confidence interval (CI) = 0.975-0.997, P = 0.009) and severity (OR = 0.955; 95% CI = 0.921-0.990, P = 0.012) in European populations, with similar findings replicated in East Asians. Notably, interleukin-6 (IL-6) and tumour necrosis factor were identified as hub cytokines connecting SLE to COVID-19 infection, while IL-6 and interleukin-10 (IL-10) were pivotal in connecting SLE to COVID-19 severity. CONCLUSIONS: This study reveals a potentially protective effect of SLE against COVID-19 infection and severity, with IL-6, tumour necrosis factor, and IL-10 playing key roles. Despite immunosuppressant use, SLE patients showed no increased risk of severe outcomes, likely due to their heightened caution in avoiding infection. These findings challenge common assumptions and highlight the need for further research.