Lupus susceptibility region containing CTLA4 rs17268364 functionally reduces CTLA4 expression by binding EWSR1 and correlates IFN-α signature
Abstract Background Dysregulation of T cells mediated immune responses is a hallmark in the development of systemic lupus erythematosus (SLE). Recent genome wide association study (GWAS) revealed the genetic contribution of variants located in the cytotoxic T lymphocyte-associated protein-4 (CTLA4)-...
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oai:doaj.org-article:0ab8d93c84ba44f4954179dd230001522021-11-07T12:05:49ZLupus susceptibility region containing CTLA4 rs17268364 functionally reduces CTLA4 expression by binding EWSR1 and correlates IFN-α signature10.1186/s13075-021-02664-y1478-6362https://doaj.org/article/0ab8d93c84ba44f4954179dd230001522021-11-01T00:00:00Zhttps://doi.org/10.1186/s13075-021-02664-yhttps://doaj.org/toc/1478-6362Abstract Background Dysregulation of T cells mediated immune responses is a hallmark in the development of systemic lupus erythematosus (SLE). Recent genome wide association study (GWAS) revealed the genetic contribution of variants located in the cytotoxic T lymphocyte-associated protein-4 (CTLA4)-inducible T cell co-stimulator (ICOS) intergenic region to SLE susceptibility. Our aim is to find a functional variant in this region. Methods The genetic association results in the CTLA4-ICOS region from previous GWAS were adopted to select the potential variant which was further replicated in two independent cohorts (Henan cohort 2053 SLE patients and 1845 healthy controls, Beijing cohort 2303 SLE patients and 19,262 healthy). In order to explore the functional significance in SLE, bioinformatics with validation experiments (including electrophoretic mobility shift assay and luciferase reporter assay) and mRNA expression analysis were also performed. Results A variant located in the CTLA4-ICOS intergenic region, rs17268364, was associated with susceptibility to SLE patients in Chinese populations (risk allele, p meta = 7.02×10−11, OR 1.19, 95%CI 1.13–1.26). The bioinformatics suggested that rs17268364 might affect the expression of CTLA4, not ICOS. The rs17268364 risk G allele containing sequence reduced the expression of the reporter gene by binding transcriptional repressor Ewing sarcoma breakpoint region 1 (EWSR1). Following genotype-mRNA expression, the analysis also showed the risk allele of rs17268364 was associated with low CTLA4 expression in lupus nephritis (LN) patients. Healthy individuals carrying rs17268364 risk G allele was significantly correlated with higher levels of IFN-α signature including increased lymphocyte antigen 6E (LY6E) (p=0.031), interferon-stimulated gene 15 (ISG15) (p=0.038), interferon regulatory factor 9 (IRF9) (p=0.028), and interferon regulatory factor 5 (IRF5) (p=0.040) mRNA expression. Conclusions The present study confirmed the functional role of rs17268364 in the CTLA4-ICOS intergenic region that increased SLE susceptibility in the Chinese population.Yuan-yuan QiXin-yu ZhaoXin-ran LiuYan-na WangYa-ling ZhaiXiao-xue ZhangXiao-yang WangLi-jie ZhangYa-fei ZhaoYan CuiXiang-hui NingXu-jie ZhouBMCarticleSystemic lupus erythematosusSingle nucleotide polymorphismsImmune checkpointCTLA4-ICOSrs17268364Diseases of the musculoskeletal systemRC925-935ENArthritis Research & Therapy, Vol 23, Iss 1, Pp 1-9 (2021) |
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DOAJ |
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EN |
| topic |
Systemic lupus erythematosus Single nucleotide polymorphisms Immune checkpoint CTLA4-ICOS rs17268364 Diseases of the musculoskeletal system RC925-935 |
| spellingShingle |
Systemic lupus erythematosus Single nucleotide polymorphisms Immune checkpoint CTLA4-ICOS rs17268364 Diseases of the musculoskeletal system RC925-935 Yuan-yuan Qi Xin-yu Zhao Xin-ran Liu Yan-na Wang Ya-ling Zhai Xiao-xue Zhang Xiao-yang Wang Li-jie Zhang Ya-fei Zhao Yan Cui Xiang-hui Ning Xu-jie Zhou Lupus susceptibility region containing CTLA4 rs17268364 functionally reduces CTLA4 expression by binding EWSR1 and correlates IFN-α signature |
| description |
Abstract Background Dysregulation of T cells mediated immune responses is a hallmark in the development of systemic lupus erythematosus (SLE). Recent genome wide association study (GWAS) revealed the genetic contribution of variants located in the cytotoxic T lymphocyte-associated protein-4 (CTLA4)-inducible T cell co-stimulator (ICOS) intergenic region to SLE susceptibility. Our aim is to find a functional variant in this region. Methods The genetic association results in the CTLA4-ICOS region from previous GWAS were adopted to select the potential variant which was further replicated in two independent cohorts (Henan cohort 2053 SLE patients and 1845 healthy controls, Beijing cohort 2303 SLE patients and 19,262 healthy). In order to explore the functional significance in SLE, bioinformatics with validation experiments (including electrophoretic mobility shift assay and luciferase reporter assay) and mRNA expression analysis were also performed. Results A variant located in the CTLA4-ICOS intergenic region, rs17268364, was associated with susceptibility to SLE patients in Chinese populations (risk allele, p meta = 7.02×10−11, OR 1.19, 95%CI 1.13–1.26). The bioinformatics suggested that rs17268364 might affect the expression of CTLA4, not ICOS. The rs17268364 risk G allele containing sequence reduced the expression of the reporter gene by binding transcriptional repressor Ewing sarcoma breakpoint region 1 (EWSR1). Following genotype-mRNA expression, the analysis also showed the risk allele of rs17268364 was associated with low CTLA4 expression in lupus nephritis (LN) patients. Healthy individuals carrying rs17268364 risk G allele was significantly correlated with higher levels of IFN-α signature including increased lymphocyte antigen 6E (LY6E) (p=0.031), interferon-stimulated gene 15 (ISG15) (p=0.038), interferon regulatory factor 9 (IRF9) (p=0.028), and interferon regulatory factor 5 (IRF5) (p=0.040) mRNA expression. Conclusions The present study confirmed the functional role of rs17268364 in the CTLA4-ICOS intergenic region that increased SLE susceptibility in the Chinese population. |
| format |
article |
| author |
Yuan-yuan Qi Xin-yu Zhao Xin-ran Liu Yan-na Wang Ya-ling Zhai Xiao-xue Zhang Xiao-yang Wang Li-jie Zhang Ya-fei Zhao Yan Cui Xiang-hui Ning Xu-jie Zhou |
| author_facet |
Yuan-yuan Qi Xin-yu Zhao Xin-ran Liu Yan-na Wang Ya-ling Zhai Xiao-xue Zhang Xiao-yang Wang Li-jie Zhang Ya-fei Zhao Yan Cui Xiang-hui Ning Xu-jie Zhou |
| author_sort |
Yuan-yuan Qi |
| title |
Lupus susceptibility region containing CTLA4 rs17268364 functionally reduces CTLA4 expression by binding EWSR1 and correlates IFN-α signature |
| title_short |
Lupus susceptibility region containing CTLA4 rs17268364 functionally reduces CTLA4 expression by binding EWSR1 and correlates IFN-α signature |
| title_full |
Lupus susceptibility region containing CTLA4 rs17268364 functionally reduces CTLA4 expression by binding EWSR1 and correlates IFN-α signature |
| title_fullStr |
Lupus susceptibility region containing CTLA4 rs17268364 functionally reduces CTLA4 expression by binding EWSR1 and correlates IFN-α signature |
| title_full_unstemmed |
Lupus susceptibility region containing CTLA4 rs17268364 functionally reduces CTLA4 expression by binding EWSR1 and correlates IFN-α signature |
| title_sort |
lupus susceptibility region containing ctla4 rs17268364 functionally reduces ctla4 expression by binding ewsr1 and correlates ifn-α signature |
| publisher |
BMC |
| publishDate |
2021 |
| url |
https://doaj.org/article/0ab8d93c84ba44f4954179dd23000152 |
| work_keys_str_mv |
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| _version_ |
1718443527644381184 |