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

<h4>Introduction</h4>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.<h4>Methods</h4>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 sex and disease ([Male SLE - Male HC] - [Female SLE - Female HC]). Benjamini & Hochberg false discovery rate (FDR) was used for multiple test correction.<h4>Results</h4>The strongest signal differentiating males and females with SLE was the aberrant expression of the long non-coding RNA, <i>XIST</i>, in males. This <i>XIST</i> expression in males with SLE was bimodal, with 54% of males having elevated <i>XIST</i> 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.<h4>Conclusion</h4>These results suggest that X-chromosome silencing by <i>XIST</i> may contribute to SLE disease in males.