A disease-associated gene desert orchestrates macrophage inflammatory responses via ETS2

Abstract

AbstractIncreasing global rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1and high failure rates during drug development2– underscoring an urgent need to better understand disease mechanisms. Here we show how genetics could address this challenge. By investigating an intergenic haplotype on chr21q22, independently linked to inflammatory bowel disease (IBD), ankylosing spondylitis, primary sclerosing cholangitis and Takayasu’s arteritis3–6, we discover that the causal gene,ETS2, is a master regulator of inflammatory responses in human macrophages and delineate how the risk haplotype increasesETS2expression. Genes regulated by ETS2 were prominently expressed in affected tissues from chr21q22-associated diseases and more enriched for IBD GWAS hits than almost all previously described pathways. OverexpressingETS2in resting macrophages produced an activated effector state that phenocopied intestinal macrophages from IBD7, with upregulation of multiple drug targets including TNFα and IL-23. Using a database of cellular signatures8, we identify drugs that could modulate this pathway and validate the potent anti-inflammatory activity of one class of small moleculesin vitroandex vivo. Together, this highlights the potential for common genetic associations to improve both the understanding and treatment of human disease.