Biochemistry and Molecular Biology, School of Chemistry and Biochemistry, The University of Western Australia, Perth, Western Australia, Australia.
Mol Immunol. 2012 Oct;52(3-4):165-73. doi: 10.1016/j.molimm.2012.04.013. Epub 2012 Jun 4.
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.
系统性红斑狼疮（SLE）是一种复杂的自身免疫性疾病，具有强烈的遗传成分，决定了风险。补体受体 2（CR2）基因的常见三个单核苷酸多态性（SNP）单倍型与 SLE 风险增加相关（Wu 等人，2007 年；Douglas 等人，2009 年），而较少见的单倍型由 SNP1 的主要等位基因和 SNP2 和 3 的次要等位基因组成，可提供保护（Douglas 等人，2009 年）。SNP1（rs3813946）位于 CR2 基因的 5'非翻译区（UTR），改变了瞬时转染到 B 细胞系中的 CR2 启动子-荧光素酶报告基因构建体的转录活性（Wu 等人，2007 年），并且在保护性单倍型中具有独立作用（Douglas 等人，2009 年）。在这项研究中，我们表明该 SNP 改变了瞬时转染的非 B 细胞系以及稳定转染细胞系中的转录活性，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 基因的一个新的调节元件，其中变异可能改变基因功能并改变狼疮的发展。
