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. 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.
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.
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.
Authors: K Bidzhekov; L Gan; B Denecke; A Rostalsky; M Hristov; T A Koeppel; A Zernecke; C Weber Journal: Thromb Haemost Date: 2012-02-28 Impact factor: 5.249
Authors: Eric R Gamazon; Dana Ziliak; Hae Kyung Im; Bonnie LaCroix; Danny S Park; Nancy J Cox; R Stephanie Huang Journal: Am J Hum Genet Date: 2012-05-31 Impact factor: 11.025
Authors: Heribert Schunkert; Inke R König; Sekar Kathiresan; Muredach P Reilly; Themistocles L Assimes; Hilma Holm; Michael Preuss; Alexandre F R Stewart; Maja Barbalic; Christian Gieger; Devin Absher; Zouhair Aherrahrou; Hooman Allayee; David Altshuler; Sonia S Anand; Karl Andersen; Jeffrey L Anderson; Diego Ardissino; Stephen G Ball; Anthony J Balmforth; Timothy A Barnes; Diane M Becker; Lewis C Becker; Klaus Berger; Joshua C Bis; S Matthijs Boekholdt; Eric Boerwinkle; Peter S Braund; Morris J Brown; Mary Susan Burnett; Ian Buysschaert; John F Carlquist; Li Chen; Sven Cichon; Veryan Codd; Robert W Davies; George Dedoussis; Abbas Dehghan; Serkalem Demissie; Joseph M Devaney; Patrick Diemert; Ron Do; Angela Doering; Sandra Eifert; Nour Eddine El Mokhtari; Stephen G Ellis; Roberto Elosua; James C Engert; Stephen E Epstein; Ulf de Faire; Marcus Fischer; Aaron R Folsom; Jennifer Freyer; Bruna Gigante; Domenico Girelli; Solveig Gretarsdottir; Vilmundur Gudnason; Jeffrey R Gulcher; Eran Halperin; Naomi Hammond; Stanley L Hazen; Albert Hofman; Benjamin D Horne; Thomas Illig; Carlos Iribarren; Gregory T Jones; J Wouter Jukema; Michael A Kaiser; Lee M Kaplan; John J P Kastelein; Kay-Tee Khaw; Joshua W Knowles; Genovefa Kolovou; Augustine Kong; Reijo Laaksonen; Diether Lambrechts; Karin Leander; Guillaume Lettre; Mingyao Li; Wolfgang Lieb; Christina Loley; Andrew J Lotery; Pier M Mannucci; Seraya Maouche; Nicola Martinelli; Pascal P McKeown; Christa Meisinger; Thomas Meitinger; Olle Melander; Pier Angelica Merlini; Vincent Mooser; Thomas Morgan; Thomas W Mühleisen; Joseph B Muhlestein; Thomas Münzel; Kiran Musunuru; Janja Nahrstaedt; Christopher P Nelson; Markus M Nöthen; Oliviero Olivieri; Riyaz S Patel; Chris C Patterson; Annette Peters; Flora Peyvandi; Liming Qu; Arshed A Quyyumi; Daniel J Rader; Loukianos S Rallidis; Catherine Rice; Frits R Rosendaal; Diana Rubin; Veikko Salomaa; M Lourdes Sampietro; Manj S Sandhu; Eric Schadt; Arne Schäfer; Arne Schillert; Stefan Schreiber; Jürgen Schrezenmeir; Stephen M Schwartz; David S Siscovick; Mohan Sivananthan; Suthesh Sivapalaratnam; Albert Smith; Tamara B Smith; Jaapjan D Snoep; Nicole Soranzo; John A Spertus; Klaus Stark; Kathy Stirrups; Monika Stoll; W H Wilson Tang; Stephanie Tennstedt; Gudmundur Thorgeirsson; Gudmar Thorleifsson; Maciej Tomaszewski; Andre G Uitterlinden; Andre M van Rij; Benjamin F Voight; Nick J Wareham; George A Wells; H-Erich Wichmann; Philipp S Wild; Christina Willenborg; Jaqueline C M Witteman; Benjamin J Wright; Shu Ye; Tanja Zeller; Andreas Ziegler; Francois Cambien; Alison H Goodall; L Adrienne Cupples; Thomas Quertermous; Winfried März; Christian Hengstenberg; Stefan Blankenberg; Willem H Ouwehand; Alistair S Hall; Panos Deloukas; John R Thompson; Kari Stefansson; Robert Roberts; Unnur Thorsteinsdottir; Christopher J O'Donnell; Ruth McPherson; Jeanette Erdmann; Nilesh J Samani Journal: Nat Genet Date: 2011-03-06 Impact factor: 38.330
Authors: Brigitte M Sondermeijer; Annemieke Bakker; Amalia Halliani; Maurice W J de Ronde; Arnoud A Marquart; Anke J Tijsen; Ties A Mulders; Maayke G M Kok; Suzanne Battjes; Steffi Maiwald; Suthesh Sivapalaratnam; Mieke D Trip; Perry D Moerland; Joost C M Meijers; Esther E Creemers; Sara-Joan Pinto-Sietsma Journal: PLoS One Date: 2011-10-13 Impact factor: 3.240
Authors: Tianxiao Huan; Michael Mendelson; Roby Joehanes; Chen Yao; Chunyu Liu; Ci Song; Anindya Bhattacharya; Jian Rong; Kahraman Tanriverdi; Joshua Keefe; Joanne M Murabito; Paul Courchesne; Martin G Larson; Jane E Freedman; Daniel Levy Journal: Epigenetics Date: 2019-07-17 Impact factor: 4.528
Authors: Charlotte Andersson; Andrew D Johnson; Emelia J Benjamin; Daniel Levy; Ramachandran S Vasan Journal: Nat Rev Cardiol Date: 2019-11 Impact factor: 32.419