Transcriptional effects of a lupus-associated polymorphism in the 5′ untranslated region (UTR) of human complement receptor 2 (CR2/CD21)
Transcriptional effects of a lupus-associated polymorphism in the 5′ untranslated region (UTR) of human complement receptor 2 (CR2/CD21)
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DOI：
10.1016/j.molimm.2012.04.013
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发表时间：
2012-10-01
影响因子：
3.6
通讯作者：
Ulgiati, Daniela
中科院分区：
文献类型：
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作者：
Cruickshank, Mark N.;Karimi, Mahdad;Ulgiati, Daniela
系统性红斑狼疮（SLE）是一种复杂的自身免疫性疾病，具有很强的遗传成分决定风险。补体受体2 （CR2）基因常见的三个单核苷酸多态性（SNP）单倍型与SLE风险增加有关（Wu等人，2007；Douglas等人，2009），而由SNP1的主要等位基因和SNP2和3的次要等位基因组成的较不常见的单倍型具有保护作用（Douglas等人，2009）。SNP1 （rs3813946）位于CR2基因的5'非翻译区（UTR），瞬时转染到B细胞系后改变了CR2启动子-荧光素酶报告基因结构的转录活性（Wu et al., 2007），并在保护性单倍型中具有独立作用（Douglas et al., 2009）。在这项研究中，我们发现该SNP改变了瞬时转染的非b细胞系以及稳定转染的细胞系的转录活性，支持其在体内的相关性。此外，该SNP的等位基因影响周围序列的染色质可及性和转录因子的结合。这些数据证实了rs3813946对CR2转录的影响，确定了5' UTR是CR2基因的一个新的调控元件，其变异可能改变基因功能并改变狼疮的发展。(C) 2012 Elsevier Ltd.版权所有。
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a strong genetic component that determines risk A common three single-nucleotide polymorphism (SNP) haplotype of the complement receptor 2 (CR2) gene has been associated with increased risk of SLE (Wu et al., 2007; Douglas et al., 2009), and a less common haplotype consisting of the major allele at SNP1 and minor alleles at SNP2 and 3 confers protection (Douglas et al., 2009). SNP1 (rs3813946), which is located in the 5' untranslated region (UTR) of the CR2 gene, altered transcriptional activity of a CR2 promoter-luciferase reporter gene construct transiently transfected into a B cell line (Wu et al., 2007) and had an independent effect in the protective haplotype (Douglas et al., 2009). In this study, we show that this SNP alters transcriptional activity in a transiently transfected non B-cell line as well as in stably transfected cell lines, supporting its relevance in vivo. Furthermore, the allele at this SNP affects chromatin accessibility of the surrounding sequence and transcription factor binding. These data confirm the effects of rs3813946 on CR2 transcription, identifying the 5' UTR to be a novel regulatory element for the CR2 gene in which variation may alter gene function and modify the development of lupus. (C) 2012 Elsevier Ltd. All rights reserved.