Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, 40 Ruskin St - H4208, Ottawa, Canada.
Atherogenomics Laboratory, University of Ottawa Heart Institute, 40 Ruskin St - H4203, Ottawa, Canada.
Cardiovasc Res. 2019 Sep 1;115(11):1629-1645. doi: 10.1093/cvr/cvz030.
To identify genetic variants that have a regulatory impact on circulating microRNAs (miRNAs) and to connect genetic risk to blood traits/biomarkers through the circulating miRNAs.
Leveraging miRNA-Seq data and the 1000 Genomes imputed genotypes, we carried out genome-wide association analysis for SNPs that regulate the expression of circulating miRNAs in a sample of 710 unrelated subjects of European ancestry. Wherever possible, we used data from the Framingham and the Geuvadis studies to replicate our findings. We found at least one genome-wide significant (P < 5e-8) miRNA-eQTL (mirQTL) for 143 circulating miRNAs. Overall each mirQTL explained a small portion (<1%) of variation in miRNA levels; however, we identified a few mirQTLs that explained 4% to 20% of variation in miRNA levels in plasma. Unlike trans-mirQTLs (P = 0.7), cis-mirQTLs tend to be also associated with their counterpart mature miRNAs (P < 0.0001), this suggests trans-mirQTLs exert their effect through processes that affect the stability of mature miRNAs; whereas, cis-mirQTLs mainly regulate the expression of primary-miRNAs. Next, we used the identified mirQTLs to investigate the links between circulating miRNAs with blood traits/biomarkers through Mendelian randomization analysis. We found miR-1908-5p plays an important role in regulating low-density lipoprotein (LDL), total cholesterol (TC), fasting glucose, HbA1c, and several lipid-metabolites in blood, whereas, miR-10b-5p mediates the trans-regulatory effect of the ABO locus on several blood proteins, coronary artery disease, and TC. Moreover, we demonstrated that a higher plasma level of miR-199a is causally associated with lower levels of LDL and TC. Finally, we found miR-143-3p and miR-145-5p are functionally related and mediate the effect of ZFPM2 on a number of its protein targets in blood including VEGFA, SERPINE1, and PDGFs.
This study identifies SNPs that have a regulatory impact on circulating miRNAs, and underlines the role of several circulating miRNAs in mediating the effect of a number of GWAS loci on cardiometabolic phenotypes.
鉴定对循环 microRNA（miRNA）具有调控作用的遗传变异，并通过循环 miRNA 将遗传风险与血液特征/生物标志物联系起来。
利用 miRNA-Seq 数据和 1000 基因组 imputed 基因型，我们对 710 名欧洲血统无亲缘关系个体样本中调节循环 miRNA 表达的 SNP 进行了全基因组关联分析。在可能的情况下，我们使用 Framingham 和 Geuvadis 研究的数据来复制我们的发现。我们发现了至少 143 个循环 miRNA 存在与全基因组显著相关（P<5e-8）的 miRNA 表达调控区（mirQTL）。总体而言，每个 mirQTL 仅解释 miRNA 水平变化的一小部分（<1%）；然而，我们发现了一些 mirQTL 可解释血浆中 miRNA 水平 4%至 20%的变化。与跨 mirQTL 不同（P=0.7），顺式 mirQTL 往往也与其对应的成熟 miRNA 相关（P<0.0001），这表明跨 mirQTL 通过影响成熟 miRNA 稳定性的过程发挥作用；而顺式 mirQTL 主要调节初级 miRNA 的表达。接下来，我们使用鉴定出的 mirQTL 通过孟德尔随机化分析研究循环 miRNA 与血液特征/生物标志物之间的联系。我们发现 miR-1908-5p 在调节 LDL、总胆固醇（TC）、空腹血糖、HbA1c 和血液中的几种脂质代谢物方面发挥着重要作用，而 miR-10b-5p 介导 ABO 基因座对血液中几种蛋白质、冠心病和 TC 的转录调控作用。此外，我们证明较高的血浆 miR-199a 水平与 LDL 和 TC 水平降低有关。最后，我们发现 miR-143-3p 和 miR-145-5p 具有功能相关性，并介导 ZFPM2 对其在血液中的许多蛋白质靶标（包括 VEGFA、SERPINE1 和 PDGFs）的影响。
本研究鉴定了对循环 miRNA 具有调控作用的 SNP，并强调了几种循环 miRNA 在介导多个 GWAS 位点对心脏代谢表型的影响方面的作用。
