Dissecting the roles of microRNAs in coronary heart disease via integrative genomic analyses

Tianxiao Huan¹, Jian Rong¹, Kahraman Tanriverdi¹, Qingying Meng¹, Anindya Bhattacharya¹, David D McManus¹, Roby Joehanes¹, Themistocles L Assimes¹, Ruth McPherson¹, Nilesh J Samani¹, Jeanette Erdmann¹, Heribert Schunkert¹, Paul Courchesne¹, Peter J Munson¹, Andrew D Johnson¹, Christopher J O'Donnell¹, Bin Zhang¹, Martin G Larson¹, Jane E Freedman², Daniel Levy¹, Xia Yang¹

Affiliations

¹ From the National Heart, Lung, and Blood Institute's Framingham Heart Study, MA (T.H., R.J., P.C., A.D.J., C.J.O., D.L.); The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD (T.H., R.J., P.C., D.L.); Cardiovascular Epidemiology and Human Genomics Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD (A.D.J., C.J.O.); Department of Mathematics and Statistics, Boston University, MA (J.R., M.G.L.); Department of Medicine, University of Massachusetts Medical School, Worcester (K.T., D.D.M., J.E.F.); Department of Integrative Biology and Physiology, University of California, Los Angeles (Q.M., A.B., X.Y.); Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, MD (R.J., P.J.M); Department of Medicine, Harvard Medical School, Harvard University, Boston, MA (R.J.); Department of Medicine, Stanford University School of Medicine, Palo Alto, CA (T.L.A.); Departments of Medicine and Biochemistry, University of Ottawa, Ottawa, Ontario, Canada (R.M.); Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Leicester, United Kingdom; Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Lübeck, Germany (J.E.); DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany (J.E.); Deutsches Herzzentrum München, Technische Universität München, München, Germany (H.S.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (H.S.); and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (B.Z.).
² From the National Heart, Lung, and Blood Institute's Framingham Heart Study, MA (T.H., R.J., P.C., A.D.J., C.J.O., D.L.); The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD (T.H., R.J., P.C., D.L.); Cardiovascular Epidemiology and Human Genomics Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD (A.D.J., C.J.O.); Department of Mathematics and Statistics, Boston University, MA (J.R., M.G.L.); Department of Medicine, University of Massachusetts Medical School, Worcester (K.T., D.D.M., J.E.F.); Department of Integrative Biology and Physiology, University of California, Los Angeles (Q.M., A.B., X.Y.); Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, MD (R.J., P.J.M); Department of Medicine, Harvard Medical School, Harvard University, Boston, MA (R.J.); Department of Medicine, Stanford University School of Medicine, Palo Alto, CA (T.L.A.); Departments of Medicine and Biochemistry, University of Ottawa, Ottawa, Ontario, Canada (R.M.); Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Leicester, United Kingdom; Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Lübeck, Germany (J.E.); DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany (J.E.); Deutsches Herzzentrum München, Technische Universität München, München, Germany (H.S.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (H.S.); and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (B.Z.). jane.freedman@umassmed.edu Levyd@nih.gov xyang123@ucla.edu.

PMID: 25657313
PMCID: PMC4376567
DOI: 10.1161/ATVBAHA.114.305176

Dissecting the roles of microRNAs in coronary heart disease via integrative genomic analyses

Tianxiao Huan et al. Arterioscler Thromb Vasc Biol. 2015 Apr.

. 2015 Apr;35(4):1011-21.

doi: 10.1161/ATVBAHA.114.305176. Epub 2015 Feb 5.

Authors

Affiliations

¹ From the National Heart, Lung, and Blood Institute's Framingham Heart Study, MA (T.H., R.J., P.C., A.D.J., C.J.O., D.L.); The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD (T.H., R.J., P.C., D.L.); Cardiovascular Epidemiology and Human Genomics Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD (A.D.J., C.J.O.); Department of Mathematics and Statistics, Boston University, MA (J.R., M.G.L.); Department of Medicine, University of Massachusetts Medical School, Worcester (K.T., D.D.M., J.E.F.); Department of Integrative Biology and Physiology, University of California, Los Angeles (Q.M., A.B., X.Y.); Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, MD (R.J., P.J.M); Department of Medicine, Harvard Medical School, Harvard University, Boston, MA (R.J.); Department of Medicine, Stanford University School of Medicine, Palo Alto, CA (T.L.A.); Departments of Medicine and Biochemistry, University of Ottawa, Ottawa, Ontario, Canada (R.M.); Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Leicester, United Kingdom; Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Lübeck, Germany (J.E.); DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany (J.E.); Deutsches Herzzentrum München, Technische Universität München, München, Germany (H.S.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (H.S.); and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (B.Z.).
² From the National Heart, Lung, and Blood Institute's Framingham Heart Study, MA (T.H., R.J., P.C., A.D.J., C.J.O., D.L.); The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD (T.H., R.J., P.C., D.L.); Cardiovascular Epidemiology and Human Genomics Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD (A.D.J., C.J.O.); Department of Mathematics and Statistics, Boston University, MA (J.R., M.G.L.); Department of Medicine, University of Massachusetts Medical School, Worcester (K.T., D.D.M., J.E.F.); Department of Integrative Biology and Physiology, University of California, Los Angeles (Q.M., A.B., X.Y.); Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, MD (R.J., P.J.M); Department of Medicine, Harvard Medical School, Harvard University, Boston, MA (R.J.); Department of Medicine, Stanford University School of Medicine, Palo Alto, CA (T.L.A.); Departments of Medicine and Biochemistry, University of Ottawa, Ottawa, Ontario, Canada (R.M.); Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Leicester, United Kingdom; Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Lübeck, Germany (J.E.); DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany (J.E.); Deutsches Herzzentrum München, Technische Universität München, München, Germany (H.S.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (H.S.); and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (B.Z.). jane.freedman@umassmed.edu Levyd@nih.gov xyang123@ucla.edu.

PMID: 25657313
PMCID: PMC4376567
DOI: 10.1161/ATVBAHA.114.305176

Abstract

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 false discovery rate <0.2, 15 miRNAs were differentially expressed between CHD cases and controls. To explore regulatory mechanisms, we integrated miRNA and mRNA expression with genome-wide genotype data to investigate miRNA and mRNA associations and relationships of genetic variation with miRNAs. We identified a large number of correlated miRNA-mRNA pairs and genetic loci that seem to regulate miRNA levels. Subsequently, we explored the relationships of these complex molecular associations with 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 versus controls (80% versus 30%; P<1×10(-16)), suggesting a genome-wide shift in the regulatory structure of the transcriptome in CHD. The differentially coexpressed 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, 3 miRNAs (miR-1275, miR-365a-3p, and miR-150-5p) were associated with an mRNA coexpression module that was causally linked to CHD and reflected the 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 coexpression with mRNAs.

Keywords: coronary disease; genetics; systems biology.

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Figures

**Figure 1. Integrative Genomics Analysis Framework Depicting the Genome-wide Evaluation of the Relations between SNPs, miRNAs, and mRNAs, and the Identification of CHD-related Signals**
A) Genome-wide evaluation of SNP-miRNA-mRNA associations. The genome-wide evaluation includes the identification of mRNA/miRNA eSNPs, and miRNA-mRNA expression pairs. B) Identification of CHD-related molecular relationships in CHD case-control samples. The overall analysis includes five steps. First, identify CHD differential mRNA signatures and mRNA co-expression module (this step and results were reported in our previous paper). Second, identify differentially expressed miRNA signatures in CHD vs. controls. Third, identify miRNA-mRNA co-expression patterns in CHD cases and controls, and then identify differential miRNA-mRNA co-expression pairs between the two groups. Fourth, identify miRNAs correlated with CHD differential mRNA co-expression module. Fifth, integrate the CHD miRNA and mRNA sets identified in Step 1 to 4 with CHD GWAS as well as miRNA and mRNA eSNPs by the SNP set enrichment method, in order to assess the directionality of causality.

**Figure 2. Distinct Patterns of miRNA-mRNA Correlation in CHD Cases and Controls**
A) Venn diagram of the overlap in the correlated miRNA-mRNA pairs between cases and controls; B) Comparison of the correlation coefficients of correlated miRNA-mRNA pairs between cases (Y-axis) and controls (X-axis). Each dot indicates a miRNA-mRNA pair. The blue and green dots indicate the miRNA-mRNA correlation pairs at FDR<5% in CHD cases and controls respectively, and the red dots indicate the miRNA-mRNA correlation pairs at FDR<5% in both CHD cases and controls. C) Distribution of the Pearson correlation coefficients in CHD cases shows a dominance of negative correlations. D) Distribution of the Pearson correlation coefficients in controls shows a dominance of positive correlations.

**Figure 3. Comparison of the proportion of inversely correlated miRNA-mRNA co-expression pairs between CHD cases and controls**
A) A re-sampling replication strategy confirmed the predominance of inversely correlated miRNA-mRNA pairs is in CHD cases, with the average proportion of negatively correlated pairs being 0.76 in CHD cases and 0.25 in controls (p=2.2e-16 by T-test). B) In an independent validation set of 63 CHD cases, 101 (30%) positively and 238 (70%) negatively correlated miRNA-mRNA pairs were observed at p<0.05.

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References

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Dissecting the roles of microRNAs in coronary heart disease via integrative genomic analyses

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Dissecting the roles of microRNAs in coronary heart disease via integrative genomic analyses

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