miR-17-92 簇启动子中的功能性多态性与缺血性脑卒中风险降低相关。
A functional polymorphism in the promoter of miR-17-92 cluster is associated with decreased risk of ischemic stroke.
机构信息
Department of Clinical Laboratory, The Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China.
Department of Clinical Laboratory, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, 533000, Guangxi, China.
出版信息
BMC Med Genomics. 2019 Nov 8;12(1):159. doi: 10.1186/s12920-019-0589-1.
BACKGROUND
The microRNA-17-92 (miR-17-92) cluster is one of the most extensively studied miRNA clusters. Abnormal expression of the cluster has been found to play important role in different kinds of human diseases, including ischemic stroke (IS). The aim of our study was to investigate the association between three polymorphisms (rs1491034, rs9301654 and rs982873) in the promoter of the miR-17-92 cluster and risk of IS.
METHODS
Three hundred and ninety-eight patients with IS and 397 control subjects were included. The genotypes of the three polymorphisms were determined by Snapshot SNP genotyping assay. Relative expression of the cluster in peripheral blood mononuclear cells (PBMCs) of cases and controls were examined by quantitative real-time PCR.
RESULTS
Significant association between rs9301654 polymorphism and risk of IS were observed basing on genotype, model and allele analyses (GA vs. AA: adjusted OR = 0.63, 95% CI: 0.410.97, P = 0.037; GG vs. AA: adjusted OR = 0.23, 95% CI: 0.070.78, P = 0.018; GA + GG vs. AA: adjusted OR = 0.57, 95% CI: 0.380.87, P = 0.009; GA + AA vs. GG: adjusted OR = 0.27, 95% CI: 0.080.89, P = 0.032; G vs. A: adjusted OR = 0.58, 95% CI: 0.400.83). Haplotype analysis showed that TGC and TGT haplotypes were associated with decreased risk of IS (OR = 0.59, 95% CI: 0.400.87, P = 0.007 for TGC haplotype; OR = 0.21, 95% CI: 0.06~0.75, P = 0.009 for TGT haplotype). Importantly, we found the expression of miR-17-5p was significant higher while miR-19a-3p was significant lower in patient with IS compared with the control group (P < 0.01), and patients with rs9301654GG or GA genotype displayed lower level of miR-19a-3p compared with the AA genotype (P < 0.01).
CONCLUSIONS
Our findings indicated that rs9301654 polymorphism in the promoter of miR-17-92 cluster may be associated with susceptibility of IS in the Chinese population. However, we found that rs9301654 polymorphism and its respective gene expression did not demonstrate consistent association with IS in the Chinese population. Further studies such as gene-gene interaction are warranted to reveal the role of miR-19a and its regulatory genes in the etiology of IS.
背景
微小 RNA-17-92（miR-17-92）簇是研究最多的 miRNA 簇之一。研究发现，该簇的异常表达在包括缺血性中风（IS）在内的多种人类疾病中发挥着重要作用。本研究旨在探讨 miR-17-92 簇启动子中的三个多态性（rs1491034、rs9301654 和 rs982873）与 IS 风险之间的关系。
方法
纳入 398 例 IS 患者和 397 例对照。采用 Snapshot SNP 基因分型检测试剂盒检测三个多态性的基因型。采用实时定量 PCR 检测病例和对照组外周血单个核细胞（PBMCs）中簇的相对表达。
结果
基于基因型、模型和等位基因分析，发现 rs9301654 多态性与 IS 风险显著相关（GA 与 AA：调整 OR=0.63，95%CI：0.410.97，P=0.037；GG 与 AA：调整 OR=0.23，95%CI：0.070.78，P=0.018；GA+GG 与 AA：调整 OR=0.57，95%CI：0.380.87，P=0.009；GA+AA 与 GG：调整 OR=0.27，95%CI：0.080.89，P=0.032；G 与 A：调整 OR=0.58，95%CI：0.400.83）。单体型分析表明，TGC 和 TGT 单体型与 IS 风险降低相关（OR=0.59，95%CI：0.400.87，P=0.007 用于 TGC 单体型；OR=0.21，95%CI：0.06~0.75，P=0.009 用于 TGT 单体型）。重要的是，我们发现与对照组相比，IS 患者 miR-17-5p 的表达显著升高，miR-19a-3p 的表达显著降低（P<0.01），并且 rs9301654 GG 或 GA 基因型患者的 miR-19a-3p 水平明显低于 AA 基因型患者（P<0.01）。
结论
我们的研究结果表明，miR-17-92 簇启动子中的 rs9301654 多态性可能与中国人群 IS 的易感性有关。然而，我们发现 rs9301654 多态性及其相应的基因表达与中国人群的 IS 没有一致的关联。需要进一步的基因-基因相互作用研究来揭示 miR-19a 及其调节基因在 IS 发病机制中的作用。
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