Journal Article

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

Elder, James T., Nair, Rajan P., Xing, Xianying, Swindell, William R, Beamer, Maria A, Kahlenberg, J. Michelle, Stuart, Philip E, Voorhees, John J., Tsoi, Lam C, Liang, Yun, Sarkar, Mrinal K, Berthier, Celine C, Harms, Paul W., Gudjonsson, Johann E.

2016

Overview

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.