Journal Article

A gene network regulated by the transcription factor VGLL3 as a promoter of sex-biased autoimmune diseases

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

2017

Overview

Various autoimmune diseases have sex-linked biases. Gudjonsson and colleagues find that the transcription factor VGLL3 is associated with a female-biased molecular signature linked to susceptibility to autoimmune disease. Autoimmune diseases affect 7.5% of the US population, and they are among the leading causes of death and disability. A notable feature of many autoimmune diseases is their greater prevalence in females than in males, but the underlying mechanisms of this have remained unclear. Through the use of high-resolution global transcriptome analyses, we demonstrated a female-biased molecular signature associated with susceptibility to autoimmune disease and linked this to extensive sex-dependent co-expression networks. This signature was independent of biological age and sex-hormone regulation and was 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 identified a VGLL3-regulated network as a previously unknown inflammatory pathway that promotes female-biased autoimmunity. They demonstrate the importance of studying immunological processes in females and males separately and suggest new avenues for therapeutic development.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/337 / 692/699/249/1313 / Adult / Aged / Aged, 80 and over / Autoimmune diseases / Biomedicine / Cells, Cultured / Development and progression / Disease sex factors / Female / Gene Expression Profiling / Gene Regulatory Networks / Genetic aspects / Genetic Association Studies / Genetic regulation / Genome-Wide Association Study / Health aspects / Humans / Immunology / Infectious Diseases / Keratinocytes - physiology / Lupus Erythematosus, Cutaneous - genetics / Male / Middle Aged / Quantitative Trait Loci / Scleroderma, Systemic - genetics / Sex Factors / Sjogren's Syndrome - genetics / Skin - pathology / Transcription factors / Transcription Factors - genetics / Transcription Factors - metabolism / Transcriptome / Young Adult