Lupus susceptibility region containing CTLA4 rs17268364 functionally reduces CTLA4 expression by binding EWSR1 and correlates IFN-α signature,Arthritis Research & Therapy

当前位置： X-MOL 学术 › Arthritis Res. Ther. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Lupus susceptibility region containing CTLA4 rs17268364 functionally reduces CTLA4 expression by binding EWSR1 and correlates IFN-α signature
Arthritis Research & Therapy ( IF 4.9 ) Pub Date : 2021-11-04 , DOI: 10.1186/s13075-021-02664-y
Yuan-Yuan Qi _{1,

2} , Xin-Yu Zhao _{1,

2} , Xin-Ran Liu _{1,

2} , Yan-Na Wang ₃ , Ya-Ling Zhai _{1,

2} , Xiao-Xue Zhang _{1,

2} , Xiao-Yang Wang _{1,

2} , Li-Jie Zhang _{1,

2} , Ya-Fei Zhao _{1,

2} , Yan Cui _{1,

2} , Xiang-Hui Ning ₄ , Xu-Jie Zhou _{3,

5,

6}

Affiliation

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. 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. A variant located in the CTLA4-ICOS intergenic region, rs17268364, was associated with susceptibility to SLE patients in Chinese populations (risk allele, pmeta = 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. The present study confirmed the functional role of rs17268364 in the CTLA4-ICOS intergenic region that increased SLE susceptibility in the Chinese population.

更新日期：2021-11-04

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南

全部期刊列表>>