King's College London

TY - JOUR

T1 - Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in Systemic Lupus Erythematosus

AU - Odhams, Christopher A

AU - Roberts, Amy L

AU - Vester, Susan K

AU - S T Duarte, Carolina

AU - Beales, Charlie T

AU - Clarke, Alexander J

AU - Lindinger, Sonja

AU - Daffern, Samuel J

AU - Zito, Antonino

AU - Chen, Lingyan

AU - Jones, Leonardo L

AU - Boteva, Lora

AU - Morris, David L

AU - Small, Kerrin S

AU - Fernando, Michelle M A

AU - Cunninghame Graham, Deborah S

AU - Vyse, Timothy J

PY - 2019/5/31

Y1 - 2019/5/31

N2 - 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 IFNresponse 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.

AB - 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 IFNresponse 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.

KW - X chromosome

KW - LUPUS-ERYTHEMATOSUS

KW - Autoimmune diseases

KW - gene

U2 - 10.1038/s41467-019-10106-2

DO - 10.1038/s41467-019-10106-2

M3 - Article

VL - 10

SP - 1

EP - 15

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 2164

ER -