Advances in lupus genetics and epigenetics.
Advances in lupus genetics and epigenetics.
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DOI：
10.1097/bor.0000000000000086
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发表时间：
2014-09
影响因子：
5.1
通讯作者：
Tsao BP
中科院分区：
文献类型：
--
作者：
Deng Y;Tsao BP
全基因组关联研究（GWAS）已经确定了50多个与SLE易感性相关的基因座，后续研究有助于揭示候选致病遗传变异及其与SLE发展的生物学相关性。表观遗传调节是理解相关基因如何与环境因素相互作用的重要机制。我们回顾了最近在识别SLE相关位点的致病变异和狼疮的表观遗传影响方面的进展，特别是调节SLE易感基因表达水平的遗传-表观遗传相互作用。一些sled风险基因座已经被改进，以定位可能导致观察到的GWAS信号的致病变异。这些变异中很少破坏编码序列，导致编码蛋白的功能增加或丧失，而大多数变异位于非编码区，具有通过转录活性、剪接、mRNA稳定性和表观遗传修饰的改变来调节基因表达的潜力。已确定的遗传危险因素提示了与SLE发病机制相关的多个关键通路，包括I型干扰素信号通路，该信号通路也可被SLE发生的表观遗传改变所调节。这些发现为该病的发病机制提供了新的见解，并为患者管理提供了更好的诊断准确性和新的治疗靶点。
Genome-wide association studies (GWAS) have identified more than 50 robust loci associated with SLE susceptibility, and follow-up studies help reveal candidate causative genetic variants and their biological relevance contributing to the development of SLE. Epigenetic modulation is emerging as an important mechanism for understanding how the implicated genes interact with environmental factors. We review recent progress towards identifying causative variants of SLE-associated loci and epigenetic impact to lupus, especially genetic-epigenetic interactions that modulate expression levels of SLE susceptibility genes. A few SLE-risk loci have been refined to localize likely causative variants responsible for the observed GWAS signals. Few of such variants disrupt coding sequences resulting in gain or loss of function for the encoded protein, while most fall in noncoding regions with potential to regulate gene expression through alterations in transcriptional activity, splicing, mRNA stability and epigenetic modifications. Multiple key pathways related to the SLE pathogenesis have been indicated by the identified genetic risk factors, including type I interferon signaling pathway that can also be regulated by epigenetic changes occurred in SLE. These findings provide novel insights of the disease pathogenesis, and promise better diagnostic accuracy and new therapeutic targets for patient management.