摘要
[研究背景]
银屑病(PS；MIM#177900)是一类以红斑、鳞屑为主要表现的慢性、炎症性、免疫介导的皮肤疾病。目前认为,银屑病是由遗传、免疫及环境等因素共同引起的多因素、复杂疾病,皮损的基因表达谱分析发现有超过1300个基因的表达水平发生了改变；利用家系谱系分析,共发现了至少9个银屑病易感基因位点,但其确切的发病机制还有待明确。BSG(MIM109480),又称CD147,是一类免疫球蛋白超家族成员的跨膜糖蛋白,在胸腺T细胞发育、外周T细胞活化等免疫途径中发挥重要作用。BSG基因位于人类染色体19p13,这个区域通过全基因组扫描及非参数连锁分析鉴定为银屑病易感位点6(PSOR6)。重要的是,在我们前期的研究中发现,在银屑病皮损及原代T细胞中,CD147的表达水平明显增高。基于以上背景,本研究选择编码CD147蛋白分子的BSG基因作为银屑病基因多态性研究的一个候选基因,从遗传学层面来验证BSG基因与银屑病易感性的相关性,并进一步验证BSG基因功能性SNP位点在银屑病发病机制中发挥的生物学效应。
[研究方法和结果]
1.运用real-time PCR及、Vestern blotting的方法,我们证实银屑病患者的PBMCs中BSG的mRNA和蛋白表达水平均较正常人明显增高(p=0.005andp=0.042)。
2.运用病例-对照的方法,随机选取散发性寻常型银屑病患者668例和正常对照1,143例,采用PCR-RFLP的方法,研究了位于BSG基因3'UTR区的多态性位点rs8259：T>A与银屑病易感性的关联。在基因型频率符合Hardy-Weinberg平衡的基础上,我们发现rs8259T等位基因(TT+AT基因型)在银屑病病例较对照组的频率显著降低(63.0%vs68.2%,p=0.0009),进一步根据年龄、性别、吸烟及饮酒史和家族史等银屑病危险因素校正后,证实rs8259多态位点的T等位基因(OR=0.758,95%CI=0.638-0.901；p=0.002)能减低罹患银屑病的风险。
3.基于生物信息学在线软件预测及数据库比对的方法,发现BSG基因3'UTR区的多态性位点rs8259：T>A位于miR-492结合的“种子”序列上,推测rs8259位点的可变等位基因,可能通过影响miR-492与BSGmRNA的结合能力而改变基因表达水平。
4.运用real-time PCR,检测银屑病患者和正常人PBMCs中miR-492均有表达,其两组间表达量并无统计学差异p=0.557)；构建包含多态位点rs8259不同等位基因片段的荧光素酶报告基因载体,通过荧光素报告基因分析方法,观察rs8259多态位点的不同等位基因是否能影响BSG表达,在外源给予不同浓度'mimic miRNA-492'(1.0nM;2.5nM;5.0nM; and10nM)序列和包含rs8259多态位点的荧光素酶报告基因载体共同转染HEK293T细胞的实验中,证实BSG基因rs8259多态位点存在的T等位基因,可以影响miRNA-492与之结合的能力,并呈剂量依赖性的抑制了荧光素酶报告基因的活性,而携带A等位基因的载体不表现出抑制荧光素酶活性的能力。
5.进一步验证功能性SNP位点rs8259：T>A对BSG表达的影响。分别检测了携带rs8259T、A等位基因的银屑病纯合子患者PBMCs中BSG表达情况,证实TT基因型银屑病患者PBMCs中BSG的蛋白表达水平明显低于AA基因型银屑病患者(p=0.027),但其BSG mRNA的表达水平在两组之间并无统计学差异(p=0.237)。且银屑病患者PBMCs中BSG蛋白表达水平与miR-492的相对表达呈负相关(p=0.034,r=—0.639)。
[结论]
位于BSG基因3'UTR区的多态性位点rs8259：T>A与银屑病易感性相关联；功能性SNP位点rs8259：T>A通过改变miR-492介导的抑制作用,从转录后水平调控BSG的表达。
Background
Psoriasis (PS; MIM177900) is a chronic inflammatory immune-mediated skin disorder characterized by red lesions with silver whitish scales. Although the disease is believed to be caused by a combination of genetic, immunologic and environmental factors, the expression of more than1,300genes is observed to be altered in psoriatic lesions. Family-based studies have also suggested genetic basis of the disease. At least nine chromosomal psoriasis susceptibility loci have been identified presently, but its complete etiology has not been fully understood. BSG (MIM109480), aliase CD147, is a transmembrane glycoprotein belongs to the member of the immunoglobulin superfamily, it plays fundamental roles in thymic T cell development as well as peripheral T cell activation. Interestingly, the BSG gene is located on chromosome19p13, a novel psoriasis-susceptibility locus (PSOR6) identified by a genome-wide scan and nonparametric linkage analysis. Important, we have also observed that CD147is highly expressed in skin lesions and primary T cells of psoriasis patients. Therefore, we focused on the gene BSG coding for CD147protein, to identify whether the gene BSG is a susceptibility gene for psoriasis, and to determine whether the functional SNP in BSG gene associates with the biological effect in the pathogenesis of psoriasis.
Methods and Results
First, using the real-time PCR and Western blotting, we confirmed up-regulation of BSG mRNA and protein expression in psoriasis peripheral blood mononuclear cells (PBMCs) as compared with the controls (p=0.005and p<0.042). Second, we performed a case-control study including668psoriasis patients and1,143healthy controls on random basis, through the PCR-RFLP, and investigated association of the polymorphism rs8259:T>A in BSG gene3'UTR with psoriasis susceptibility. Genotype frequencies fulfilled expectation of Hardy-Weinberg equilibrium, we observed that carriers of the rs8259T allele (TT plus AT genotype) were significantly less frequent in psoriasis cases than controls (63.0%vs68.2%,p=0.0009). When adjusted by psoriasis risk factors including age, sex, smoking history, alcohol drinking history, family history of psoriasis in the first degree of relatives, the rs8259T allele was associated with decreased risk for psoriasis, and OR (95%CI) was0.758(0.638-0.901, p=0.002). Third, based on the bioinformatic prediction (online softwares:miRBase and TargetScan) and database enquiries, the rs8259:T>A polymorphism was located in a miR-492seed region. We hypothesized that variations in this region could influence miRNAs binding to the mRNA of BSG and change BSG expression. To confirm our hypothesis, using the real-time PCR, we first detected that PBMCs from both psoriasis patients and controls expressed mature miR-492, however, no significant difference in mature miR-492expression levels in PBMCs between psoriasis patients and controls was observed (p=0.557), and we determined whether the SNP rs8259could influence BSG expression by luciferase reporter assay. Luciferase reporter constructs containing the SNP were co-transfected into HEK293T cell with the various concentration (1.0nM;2.5nM;5.0nM; and10nM) of mimic miRNA-492or control, the expression activity of BSG was determined through the double-luciferase assay. Our results showed that miR-492decreased luciferase activity in a dose-dependent manner when constructed with the BSG3'UTR bearing the rs8259T allele in the presence of mimic miRNA-492. But no significantly change was found in the expression level of luciferase reporter vector carrying the rs8259A allele. Final, to further explore the effect of rs8259:T>A on BSG expression, we detected BSG protein levels in PBMCs from psoriasis patients homozygous for rs8259T and A alleles, respectively. As compared with patients with rs8259AA genotype, PBMCs BSG protein expression in patients with rs8259TT genotype was significantly decreased (p=0.027), no difference in PBMCs BSG mRNA expression was observed between the two rs8259homozygous genotypes (p=0.237). Further analysis indicated that there had a negative correlation between BSG protein espression and the level of miR-492on the PBMCs of psoriasis patients (p=0.034, r=-0.639).
Conclusion
We suggest that the rs8259:T>A polymorphism in3'UTR of BSG gene is associated with decreased psoriasis susceptibility through altered miR-492-mediated repression of BSG at posttranscriptional level.
引文
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