Humanitas Research Hospital-IRCCS, Rozzano, Italy.
Institute of Genetics and Biomedical Research, National Research Council, Rozzano, Italy.
EMBO Mol Med. 2021 Oct 7;13(10):e14060. doi: 10.15252/emmm.202114060. Epub 2021 Sep 22.
The role of single nucleotide polymorphisms (SNPs) in the etiopathogenesis of cardiovascular diseases is well known. The effect of SNPs on disease predisposition has been established not only for protein coding genes but also for genes encoding microRNAs (miRNAs). The miR-143/145 cluster is smooth muscle cell-specific and implicated in the pathogenesis of atherosclerosis. Whether SNPs within the genomic sequence of the miR-143/145 cluster are involved in cardiovascular disease development is not known. We thus searched annotated sequence databases for possible SNPs associated with miR-143/145. We identified one SNP, rs41291957 (G > A), located -91 bp from the mature miR-143 sequence, as the nearest genetic variation to this miRNA cluster, with a minor allele frequency > 10%. In silico and in vitro approaches determined that rs41291957 (A) upregulates miR-143 and miR-145, modulating phenotypic switching of vascular smooth cells towards a differentiated/contractile phenotype. Finally, we analysed association between rs41291957 and CAD in two cohorts of patients, finding that the SNP was a protective factor. In conclusion, our study links a genetic variation to a pathological outcome through involvement of miRNAs.
单核苷酸多态性（SNPs）在心血管疾病的病因发病机制中的作用是众所周知的。不仅在编码蛋白质的基因中，而且在编码 microRNA（miRNA）的基因中，SNP 对疾病易感性的影响也已经确定。miR-143/145 簇是平滑肌细胞特异性的，与动脉粥样硬化的发病机制有关。miR-143/145 簇基因组序列内的 SNP 是否参与心血管疾病的发展尚不清楚。因此，我们在注释序列数据库中搜索与 miR-143/145 相关的可能 SNP。我们确定了一个 SNP，rs41291957（G>A），位于成熟 miR-143 序列的-91bp 处，是该 miRNA 簇最近的遗传变异，其次要等位基因频率>10%。计算机模拟和体外方法确定 rs41291957（A）上调 miR-143 和 miR-145，调节血管平滑肌细胞向分化/收缩表型的表型转换。最后，我们在两个患者队列中分析了 rs41291957 与 CAD 之间的关联，发现该 SNP 是一个保护因素。总之，我们的研究通过 miRNA 的参与将遗传变异与病理结果联系起来。
