XIST expression and hypermethylation of the X chromosome in males with systemic lupus erythematosus

Introduction Systemic Lupus Erythematosus (SLE) exhibits a pronounced sex bias, affecting females approximately nine times more frequently than males; however, males tend to experience a more severe clinical course yet the molecular basis for these differences remains unclear. Methods Leveraging epigenomic, transcriptomic, and proteomic data from the whole blood of 720 SLE patients (679 females, 41males) and 84 healthy controls (77 females, 7 males), we conducted comprehensive multi-omic analyses to identify sex-specific molecular features of this disease. Specifically, differential expression analysis for each modality was conducted using a factorial design to identify differences between disease and healthy controls (SLE–HC) for each sex, as well as the interaction effects between send and disease (Male SLE – Male HC – Female SLE – Female HC). Benjamini Hochberg false discovery rate (FDR) was used for multiple test correction. Results The strongest signal differentiating males and females with SLE was the aberrant expression of the long non-coding RNA, XIST , in males. This XIST expression in males with SLE was bimodal, with 54% of males having elevated XIST expression, and correlated with disease severity. Males with SLE also exhibited significant hypermethylation of the X chromosome and transcriptional silencing of X-linked genes – hallmarks of X-chromosome inactivation (XCI), a process typically restricted to females. Conclusion These results suggest that X-chromosome silencing by XIST may contribute to SLE disease in males.