Dissecting the roles of microRNAs in coronary heart disease via integrative genomic analyses.
Dissecting the roles of microRNAs in coronary heart disease via integrative genomic analyses.
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DOI：
10.1161/atvbaha.114.305176
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发表时间：
2015-04
期刊：
影响因子：
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通讯作者：
Yang X
中科院分区：
文献类型：
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作者：
Huan T;Rong J;Tanriverdi K;Meng Q;Bhattacharya A;McManus DD;Joehanes R;Assimes TL;McPherson R;Samani NJ;Erdmann J;Schunkert H;Courchesne P;Munson PJ;Johnson AD;O'Donnell CJ;Zhang B;Larson MG;Freedman JE;Levy D;Yang X
microRNAs（miRNAs）在冠心病中的作用尚未得到很好的表征。本研究旨在通过整合186例CHD病例和186例对照的全血miRNA和mRNA表达与遗传变异来系统地表征CHD复杂的基因组结构。FDR<0.2时，CHD组与对照组之间有15个miRNAs差异表达。为了探索调控机制，我们将miRNA和mRNA表达与全基因组的基因型数据相结合，以研究miRNA和mRNA的相关性以及遗传变异与miRNA的关系。我们鉴定了大量相关的miRNA-mRNA对和似乎调节miRNA水平的遗传位点。随后，我们探讨了这些复杂的分子协会冠心病的地位。我们发现CHD病例和对照组之间的miRNA-mRNA相关性存在很大差异，病例组与对照组中负相关的miRNA-mRNA对比例显著较高（80% vs. 30%; p<1 e-16），表明CHD转录组调控结构的全基因组变化。差异共表达的miRNA-mRNA对显示CHD风险遗传变异的富集，影响miRNA和mRNA表达水平，暗示CHD中的puronecular因果作用。此外，三种miRNA（miR-1275、miR-365 a-3 p和miR-150- 5 p）与mRNA共表达模块相关，该mRNA共表达模块与CHD有因果关系，并反映了以B细胞为中心的免疫功能失调。我们的研究结果提供了新的证据表明，miRNA是重要的生物过程中参与冠心病通过遗传控制和通过其紧密的共同表达与mRNA的调节。
The roles of microRNAs (miRNAs) in coronary heart disease (CHD) have not been well characterized. This study sought to systematically characterize the complex genomic architecture of CHD by integrating whole blood miRNA and mRNA expression with genetic variation in 186 CHD cases and 186 controls. At FDR<0.2, 15 miRNAs were differentially expressed between CHD cases and controls. To explore regulatory mechanisms, we integrated miRNA and mRNA expression with genotype data genome-wide to investigate miRNA and mRNA associations and relations of genetic variation to miRNAs. We identified a large number of correlated miRNA-mRNA pairs and genetic loci that appear to regulate miRNA levels. Subsequently, we explored the relations of these complex molecular associations to CHD status. We identified a large difference in miRNA-mRNA associations between CHD cases and controls, as demonstrated by a significantly higher proportion of inversely correlated miRNA-mRNA pairs in cases vs. controls (80% vs. 30%; p<1e-16), suggesting a genome-wide shift in the regulatory structure of the transcriptome in CHD. The differentially co-expressed miRNA-mRNA pairs showed enrichment for CHD risk genetic variants affecting both miRNA and mRNA expression levels, implicating a putatively causal role in CHD. Furthermore, three miRNAs (miR-1275, miR-365a-3p, and miR-150-5p) were associated with an mRNA co-expression module that was causally linked to CHD and reflected dysregulation of B-cell centered immune function. Our results provide novel evidence that miRNAs are important regulators of biological processes involved in CHD via genetic control and via their tight co-expression with mRNAs.