Genetic Variations in MicroRNA-Binding Sites Affect MicroRNA-Mediated Regulation of Several Genes Associated With Cardio-metabolic Phenotypes
Genetic Variations in MicroRNA-Binding Sites Affect MicroRNA-Mediated Regulation of Several Genes Associated With Cardio-metabolic Phenotypes
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DOI：
10.1161/circgenetics.114.000968
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发表时间：
2015-06-01
影响因子：
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通讯作者：
Dehghan, Abbas
中科院分区：
文献类型：
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作者：
Ghanbari, Mohsen;Franco, Oscar H.;Dehghan, Abbas
全基因组关联研究使我们能够发现大量与心血管和代谢疾病有关的变异和基因组位点。然而，由于绝大多数已确定的变异被认为仅仅是其他功能变异的代理，其因果机制仍有待阐明。我们假设，与心脏代谢基因失调有关的部分功能变异位于microRNA （miRNA）结合位点。方法和结果利用目前最大的关于血糖指数、脂质特征、人体测量、血压、冠状动脉疾病和2型糖尿病的全基因组关联研究，我们确定了11067个与心脏代谢表型相关的变异。其中，230个变异位于155个心脏代谢基因3-非翻译区的mirna结合位点。230个变异中有37个符合我们预先设定的基因座功能标准。随后，根据全基因组关联研究结果、表达数量性状位点（eQTL）分析以及宿主基因和相关组织中调控mirna的共表达，选择10个变异进行实验验证。荧光素酶报告基因分析揭示了microrna对携带这些变异的基因的等位基因特异性调控。这些共转染实验表明，rs174545 （FADS1:miR-181a-2）、rs1059611 （LPL:miR-136）、rs13702 （LPL:miR-410）、rs1046875 （FN3KRP:miR-34a）、rs7956 （MKRN2:miR-154）、rs3217992 （CDKN2B:miR-138-2-3p）和rs11735092 （HSD17B13:miR-375）降低或取消了这些基因的mirna依赖性调控。相反，2个变体rs6857 （PVRL2:miR-320e）和rs907091 （IKZF3:miR-326）被证明可以增强mirna对其宿主基因的活性。结论我们为mirna结合位点的多态性可以积极或消极地影响mirna介导的心脏代谢基因调节的模型提供了证据。
Background Genome-wide association studies enabled us to discover a large number of variants and genomic loci contributing to cardiovascular and metabolic disorders. However, because the vast majority of the identified variants are thought to merely be proxies for other functional variants, the causal mechanisms remain to be elucidated. We hypothesized that the part of the functional variants involved in deregulating cardiometabolic genes is located in microRNA (miRNA)-binding sites.Methods and Results Using the largest genome-wide association studies available on glycemic indices, lipid traits, anthropometric measures, blood pressure, coronary artery diseases, and type 2 diabetes mellitus, we identified 11067 variants that are associated with cardiometabolic phenotypes. Of these, 230 variants are located within miRNA-binding sites in the 3-untranslated region of 155 cardiometabolic genes. Thirty-seven of 230 variants were found to fulfill our predefined criteria for being functional in their genomic loci. Ten variants were subsequently selected for experimental validation based on genome-wide association studies results, expression quantitative trait loci (eQTL) analyses, and coexpression of their host genes and regulatory miRNAs in relevant tissues. Luciferase reporter assays revealed an allele-specific regulation of genes hosting the variants by miRNAs. These cotransfection experiments showed that rs174545 (FADS1:miR-181a-2), rs1059611 (LPL:miR-136), rs13702 (LPL:miR-410), rs1046875 (FN3KRP:miR-34a), rs7956 (MKRN2:miR-154), rs3217992 (CDKN2B:miR-138-2-3p), and rs11735092 (HSD17B13:miR-375) decrease or abrogate miRNA-dependent regulation of the genes. Conversely, 2 variants, rs6857 (PVRL2:miR-320e) and rs907091 (IKZF3:miR-326), were shown to enhance the activity of miRNAs on their host genes.Conclusions We provide evidence for a model in which polymorphisms in miRNA-binding sites can both positively and negatively affect miRNA-mediated regulation of cardiometabolic genes.