Department for Biochemistry, Pharmacology and Genetics, Odense University Hospital, Odense, Denmark.
Am J Hypertens. 2011 Sep;24(9):999-1006. doi: 10.1038/ajh.2011.92. Epub 2011 Jun 16.
We hypothesized that single nucleotide polymorphisms (SNPs) located in microRNA (miR) binding sites in genes of the renin angiotensin aldosterone system (RAAS) can influence blood pressure and risk of myocardial infarction.
Using online databases dbSNP and TargetScan, we identified 10 SNPs in potential miR binding sites in eight RAAS-related genes, common in Caucasians. We genotyped a large case-control study on myocardial infarctions, the Study of Myocardial Infarctions LEiden (SMILE) for these 10 SNPs and found nine SNPs, in seven genes, to be prevalent. Functionality of each SNP in interfering with mRNA/miR binding was tested using a dual luciferase reporter gene system.
Of these nine SNPs, four SNPs, located in the arginine vasopressin 1A receptor (AVPR1A), bradykinin 2 receptor (BDKRB2), and thromboxane A2 receptor (TBXA2R) genes were associated with blood pressure. The rare allele of the AVPR1A SNP rs11174811, was associated with increased blood pressure whereas the rare alleles of the two linked BDKRB2 SNPs rs5225 and rs2069591 and of the TBXA2R SNP rs13306046 were associated with decreased blood pressure. Although not associated with blood pressure, the rare allele of the mineralocorticoid receptor (NR3C2) SNP rs5534, was associated with a twofold increased risk of myocardial infarction in men younger than 50 years. For all of these five SNPs, except rs2069591, we could demonstrate a reduction in miR-induced repression of gene expression.
Common SNPs in miR binding sites of RAAS-related genes can influence both blood pressure and risk of myocardial infarction. These results may imply an important role for SNPs in miR target sites in human disease.
我们假设位于肾素-血管紧张素-醛固酮系统（RAAS）基因的 miRNA（miR）结合位点的单核苷酸多态性（SNP）可以影响血压和心肌梗死的风险。
使用在线数据库 dbSNP 和 TargetScan，我们在 8 个 RAAS 相关基因中确定了 10 个位于潜在 miR 结合位点的 SNP，这些 SNP 在白种人中很常见。我们对心肌梗死进行了一项大型病例对照研究，即莱顿心肌梗死研究（SMILE），对这 10 个 SNP 进行了基因分型，发现其中 9 个 SNP 在 7 个基因中很常见。使用双荧光素酶报告基因系统测试了每个 SNP 对 mRNA/miR 结合的干扰功能。
在这 9 个 SNP 中，有 4 个 SNP 位于血管加压素 1A 受体（AVPR1A）、缓激肽 2 受体（BDKRB2）和血栓素 A2 受体（TBXA2R）基因中，与血压有关。AVPR1A 基因 rs11174811 的罕见等位基因与血压升高有关，而两个连锁的 BDKRB2 基因 rs5225 和 rs2069591 以及 TBXA2R 基因 rs13306046 的罕见等位基因与血压降低有关。尽管与血压无关，但 NR3C2 基因 rs5534 的罕见等位基因与 50 岁以下男性心肌梗死的风险增加两倍有关。除了 rs2069591 之外，对于所有这五个 SNP，我们都可以证明 miR 诱导的基因表达抑制减少。
RAAS 相关基因的 miR 结合位点的常见 SNP 可以影响血压和心肌梗死的风险。这些结果可能暗示了 SNP 在 miR 靶位点在人类疾病中的重要作用。
