系统性红斑狼疮是一种具有极强遗传倾向的系统性自身免疫病，I型干扰素通路过度活化是其重要的分子表型。microRNA（miRNA）在维持免疫系统稳态中发挥重要作用。中科院上海生命科学研究院/上海交大医学院健康所分子风湿病学研究组的前期研究发现，miRNA表达或者功能的异常与自身免疫性疾病的发生和发展有关，系统性红斑狼疮（Systemic lupus erythematosus，SLE）患者存在miR-146a表达缺陷，引起I型干扰素通路过度活化，进而参与红斑狼疮疾病的发生发展。
最近，该课题组罗晓兵博士在沈南教授的指导下，找到了miR-146a参与狼疮发病的分子遗传学证据，这一研究成果A Functional Variant in MicroRNA-146a Promoter Modulates Its Expression and Confers Disease Risk for Systemic Lupus Erythematosus近日发表在PloS GENETICS志上。
该项研究采用候选基因测序的策略，选择大样本的病例-对照研究方法，在多个人群中发现miR-146a启动子区域存在一个重要的SNP与SLE显著相关。携带疾病相关等位基因的个体，其miR-146a基因表达水平显著低于对照组。体外功能研究亦证实，此疾病相关SNP不同的基因型与已被报道的狼疮易感基因ETS1编码表达的蛋白转录因子结合能力不同，增加或者降低ETS-1表达水平可导致miR-146a启动子活性的改变。遗传学分析也证实，ETS1与miR-146a可相互影响，在狼疮发病中发挥叠加效应。
该项研究首次鉴定出miRNA分子启动子区域与狼疮疾病发生中发挥重要作用的SNP，同时也例证了复杂性疾病中多个易感基因通过相互作用从而共同参与疾病的发生。
该项研究工作得到了国家科技部973计划、863计划、国家自然科学基金委和上海市科委项目的支持。
生物探索推荐英文原文：
A Functional Variant in MicroRNA-146a Promoter Modulates Its Expression and Confers Disease Risk for Systemic Lupus Erythematosus
Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a strong genetic predisposition, characterized by an upregulated type I interferon pathway. MicroRNAs are important regulators of immune homeostasis, and aberrant microRNA expression has been demonstrated in patients with autoimmune diseases. We recently identified miR-146a as a negative regulator of the interferon pathway and linked the abnormal activation of this pathway to the underexpression of miR-146a in SLE patients. To explore why the expression of miR-146a is reduced in SLE patients, we conducted short parallel sequencing of potentially regulatory regions of miR-146a and identified a novel genetic variant (rs57095329) in the promoter region exhibiting evidence for association with SLE that was replicated independently in 7,182 Asians (Pmeta = 2.74×10−8, odds ratio = 1.29 [1.18–1.40]). The risk-associated G allele was linked to reduced expression of miR-146a in the peripheral blood leukocytes of the controls. Combined functional assays showed that the risk-associated G allele reduced the protein-binding affinity and activity of the promoter compared with those of the promoter containing the protective A allele. Transcription factor Ets-1, encoded by the lupus-susceptibility gene ETS1, identified in recent genome-wide association studies, binds near this variant. The manipulation of Ets-1 levels strongly affected miR-146a promoter activity in vitro; and the knockdown of Ets-1, mimicking its reduced expression in SLE, directly impaired the induction of miR-146a. We also observed additive effects of the risk alleles of miR-146a and ETS1. Our data identified and confirmed an association between a functional promoter variant of miR-146a and SLE. This risk allele had decreased binding to transcription factor Ets-1, contributing to reduced levels of miR-146a in SLE patients.
