Journal Article

Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in Systemic Lupus Erythematosus

Chen, Lingyan, Small, Kerrin S., Cunninghame Graham, Deborah S., Beales, Charlie T., Zito, Antonino, Daffern, Samuel J., Morris, David L., Fernando, Michelle M. A., Boteva, Lora, Duarte, Carolina S. T., Roberts, Amy L., Jones, Leonardo L., Vyse, Timothy J., Lindinger, Sonja, Vester, Susan K., Odhams, Christopher A., Clarke, Alexander J.

2019

Overview

Systemic lupus erythematosus (SLE) is an autoimmune disease, characterised by increased expression of type I interferon (IFN)-regulated genes and a striking sex imbalance towards females. Through combined genetic, in silico, in vitro, and ex vivo approaches, we define CXorf21 , a gene of hitherto unknown function, which escapes X-chromosome inactivation, as a candidate underlying the Xp21.2 SLE association. We demonstrate that CXorf21 is an IFN-response gene and that the sexual dimorphism in expression is magnified by immunological challenge. Fine-mapping reveals a single haplotype as a potential causal cis-eQTL for CXorf21 . We propose that expression is amplified through modification of promoter and 3′-UTR chromatin interactions. Finally, we show that the CXORF21 protein colocalises with TLR7, a pathway implicated in SLE pathogenesis. Our study reveals modulation in gene expression affected by the combination of two hallmarks of SLE: CXorf21 expression increases in a both an IFN-inducible and sex-specific manner. Systemic lupus erythematosus (SLE) shows a striking bias towards higher prevalence in females. Here, the authors perform fine-mapping of an SLE-associated locus at Xp21.2 and characterise a candidate gene, CXorf21 , as IFN-responsive in immune cells that shows sexually dimorphic expression.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14/63 / 3' Untranslated regions / 3' Untranslated Regions - genetics / 38/1 / 38/43 / 38/61 / 38/91 / 49/31 / 631/208/191 / 631/208/199 / 631/250/248 / 692/699/249/1313/1613 / Adult / Age Factors / Autoimmune diseases / Case-Control Studies / Chromatin / Chromosomes, Human, X - genetics / Chronic conditions / Deactivation / Female / Gene expression / Gene mapping / Genes, X-Linked - genetics / Genes, X-Linked - immunology / Genetic Predisposition to Disease / Humanities and Social Sciences / Humans / Immunology / Inactivation / Interferon / Interferon Type I - immunology / Interferon Type I - metabolism / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / Lupus / Lupus Erythematosus, Systemic - genetics / Lupus Erythematosus, Systemic - immunology / Male / Mapping / multidisciplinary / Pathogenesis / Promoter Regions, Genetic - genetics / Science / Science (multidisciplinary) / Sex / Sex Factors / Sexual dimorphism / Systemic lupus erythematosus / TLR7 protein / Toll-Like Receptor 7 - genetics / Toll-like receptors / X-chromosome inactivation