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

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; Timothy J Vyse

doi:10.1038/s41467-019-10106-2

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

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, Timothy J Vyse

Kennedy Institute of Rheumatology
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, King's College London, Guy's Hospital, London, United Kingdom.

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Abstract

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.

Original language	English
Article number	2164
Pages (from-to)	1-15
Journal	Nature Communications
Volume	10
Early online date	15 May 2019
DOIs	https://doi.org/10.1038/s41467-019-10106-2
Publication status	Published - 31 May 2019

Keywords

X chromosome
LUPUS-ERYTHEMATOSUS
Autoimmune diseases
gene

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Interferon inducible X-linked gene_ODHAMS_Accepted11April2019_GOLD AAMAccepted author manuscript, 590 KBLicence: CC BY
Interferon inducible X-linked gene_ODHAMS_Accepted11April2019_GOLD VORFinal published version, 3.54 MBLicence: CC BY

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Odhams, C. A., Roberts, A. L., Vester, S. K., S T Duarte, C., Beales, C. T., Clarke, A. J., Lindinger, S., Daffern, S. J., Zito, A., Chen, L., Jones, L. L., Boteva, L., Morris, D. L., Small, K. S., Fernando, M. M. A., Cunninghame Graham, D. S., & Vyse, T. J. (2019). Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in Systemic Lupus Erythematosus. Nature Communications, 10, 1-15. Article 2164. https://doi.org/10.1038/s41467-019-10106-2

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

abstract = "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.",

keywords = "X chromosome, LUPUS-ERYTHEMATOSUS, Autoimmune diseases, gene",

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

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Odhams, CA , Roberts, AL , Vester, SK , S T Duarte, C, Beales, CT, Clarke, AJ, Lindinger, S, Daffern, SJ, Zito, A , Chen, L, Jones, LL, Boteva, L, Morris, DL , Small, KS , Fernando, MMA , Cunninghame Graham, DS & Vyse, TJ 2019, 'Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in Systemic Lupus Erythematosus', Nature Communications, vol. 10, 2164, pp. 1-15. https://doi.org/10.1038/s41467-019-10106-2

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

SN - 2041-1723

VL - 10

SP - 1

EP - 15

JO - Nature Communications

JF - Nature Communications

M1 - 2164

ER -

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

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Keywords

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