VGLL3-regulated gene network as a promoter of sex biased autoimmune diseases

Autoimmune diseases affect 7.5% of the U.S. population, and are among the leading causes of death and disability. A striking feature of many autoimmune diseases is their increased prevalence in females, but the underlying mechanisms have remained unclear. Using high-resolution global transcriptome analyses we demonstrate a female-biased molecular signature associated with autoimmune disease susceptibility, and linked to extensive sex-dependent, co-expression networks. This signature was independent of biological age and sex-hormone regulation, and regulated by the transcription factor VGLL3, which also had a strong female biased expression. On a genome-wide level, VGLL3-regulated genes had a strong association with multiple autoimmune diseases including lupus, scleroderma and Sjögren’s syndrome and had a prominent transcriptomic overlap with inflammatory processes in cutaneous lupus. These results identify VGLL3-regulated gene network as a novel inflammatory pathway promoting female-biased autoimmunity, they demonstrate the importance of studying immunological processes in females and males separately, and open up new avenues for therapeutic development.