Dissecting the Roles of microRNAs in Coronary Heart Disease via Integrative Genomics Analyses

Objective: 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. Approach and Results: 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. Conclusions: 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. case-control pairs. Using systems biology approaches, we explored the genetic architecture of miRNA regulation and investigated differential miRNA expression, and differential miRNA-mRNA correlation between cases and controls, seeking to delineate gene regulatory networks capturing complex DNA-miRNA-mRNA relationships that may contribute to CHD. To our knowledge, our study is the first comprehensive interrogation of CHD to integrate multidimensional molecular data including genetic variation, mRNA, and miRNA in a large, community-based cohort. Our study yielded important evidence supporting genetic control of miRNAs as well as an important role of miRNAs in CHD development. This study systematically characterized the complex genomic architecture of CHD by integrating whole blood miRNA and mRNA expression with genetic variation in 186 CHD cases and 186 controls. We identified a large number of correlated miRNA-mRNA pairs and genetic loci that appear to regulate miRNA levels. We also detected 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. Further, we found that 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. These findings 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.