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