Abstract

Nonsyndromic mitral valve prolapse (MVP) is a common degenerative cardiac valvulopathy of unknown etiology that predisposes to mitral regurgitation, heart failure and sudden death1. Previous family and pathophysiological studies suggest a complex pattern of inheritance2,3,4,5. We performed a meta-analysis of 2 genome-wide association studies in 1,412 MVP cases and 2,439 controls. We identified 6 loci, which we replicated in 1,422 cases and 6,779 controls, and provide functional evidence for candidate genes. We highlight LMCD1 (LIM and cysteine-rich domains 1), which encodes a transcription factor6 and for which morpholino knockdown of the ortholog in zebrafish resulted in atrioventricular valve regurgitation. A similar zebrafish phenotype was obtained with knockdown of the ortholog of TNS1, which encodes tensin 1, a focal adhesion protein involved in cytoskeleton organization. We also showed expression of tensin 1 during valve morphogenesis and describe enlarged posterior mitral leaflets in Tns1−/− mice. This study identifies the first risk loci for MVP and suggests new mechanisms involved in mitral valve regurgitation, the most common indication for mitral valve repair7.

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Acknowledgements

We acknowledge the major contribution of the Leducq Foundation, Paris for supporting a transatlantic consortium investigating the physiopathology of mitral valve disease, for which this genome-wide association study was a major project (coordinators: R.A.L. and A.A.H.). We thank J. Leyton-Mange, X.-X. Nguyen and M. McLellan for help with the zebrafish experiments and P. Mathieu as one of the main investigators of the PROGRAM (Determinants of the Progression and Outcomes of Organic Mitral Regurgitation) study, from which was ascertained the Canadian MVP case control study. C.D., T.L.T. and J.-J.S. acknowledge a translational research grant on genetics of mitral valve funded by the Nantes Hospital (CHU Nantes). R.A.L. acknowledges grant support from the US National Institutes of Health (NIH; grants K24 HL67434, R01 HL72265 and HL109506). N.B.-N. is recipient of a French young investigator fund (ANR-13-ISV1-0006-0). D.J.M. acknowledges the support of the Hassenfeld Scholar Program and a gift from Michael Zak. P.T.E. is supported by grants from the NIH (HL092577, HL104156, K24HL105780, HL065962), an Established Investigator Award from the American Heart Association (13EIA14220013) and support from the Fondation Leducq (14CVD01). P.P. holds the Canada Research Chair in Valvular Heart Diseases and is supported by grants from the Canadian Institutes of Health Research (CIHR; grants MOP-102737, MOP-114997 and MOP-126072). Y.B. is the recipient of a Junior 2 Research Scholar award from the Fonds de recherche Québec–Santé (FRQS) and is supported by the CIHR (MOP-102481 and MOP-137058). L.F.-F. and J.S. received financial support from the Spanish Society of Cardiology. R.D. was supported by fellowships from the fund for medical discovery of the Massachusetts General Hospital and by a Marie Curie reintegration award from the European Commission R.R.M. and R.A.N. performed their work in a facility constructed with support from the US National Institutes of Health, grant C06 RR018823, from the Extramural Research Facilities Program of the Heart, Lung, and Blood Institute: R01-HL33756 (R.R.M.), COBRE 1P30 GM103342 (R.R.M. and R.A.N.), 8P20 GM103444-07 (R.R.M. and R.A.N.), R01-HL127692 (D.J.M., S.A.S. and R.A.N.) and American Heart Association 15GRNT25080052 (R.A.N.). A.A.H., N.B.-N. and X.J. acknowledge funds from INSERM and the French Society of Cardiology.

Author information

Author notes

    • Christian Dina
    • , Nabila Bouatia-Naji
    •  & Nathan Tucker

    These authors contributed equally to this work.

    • Russell A Norris
    • , David J Milan
    • , Susan A Slaugenhaupt
    • , Robert A Levine
    • , Jean-Jacques Schott
    • , Albert A Hagege
    •  & Xavier Jeunemaitre

    These authors jointly supervised this work.

Affiliations

  1. INSERM Unité Mixte de Recherche (UMR) 1087, Centre National de la Recherche Scientifique (CNRS) UMR 6291, Institut du Thorax, Nantes, France.

    • Christian Dina
    • , Thierry Le Tourneau
    • , Vincent Probst
    • , Floriane Simonet
    • , Simon Lecointe
    • , Florence Kyndt
    • , Richard Redon
    • , Hervé Le Marec
    •  & Jean-Jacques Schott
  2. Centre Hospitalier Universitaire (CHU) Nantes, Université de Nantes, Nantes, France.

    • Christian Dina
    • , Thierry Le Tourneau
    • , Vincent Probst
    • , Simon Lecointe
    • , Florence Kyndt
    • , Richard Redon
    • , Hervé Le Marec
    •  & Jean-Jacques Schott
  3. INSERM UMR 970, Paris Cardiovascular Research Center, Paris, France.

    • Nabila Bouatia-Naji
    • , Maelle Perrocheau
    • , Patrick Bruneval
    • , Albert A Hagege
    •  & Xavier Jeunemaitre
  4. Paris Descartes University, Paris Sorbonne Cité, Paris, France.

    • Nabila Bouatia-Naji
    • , Maelle Perrocheau
    • , Serge Hercberg
    • , Patrick Bruneval
    •  & Xavier Jeunemaitre
  5. Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA.

    • Nathan Tucker
    • , Elena Dolmatova
    • , Patrick T Ellinor
    •  & David J Milan
  6. Framingham Heart Study, Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, US National Institutes of Health, Framingham, Massachusetts, USA.

    • Francesca N Delling
    • , Ming-Huei Chen
    • , Emelia J Benjamin
    •  & Ramachandran S Vasan
  7. Department of Medicine (Cardiovascular Division), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

    • Francesca N Delling
    •  & Emelia J Benjamin
  8. Department of Regenerative Medicine and Cell Biology, Cardiovascular Developmental Biology Center, Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina, USA.

    • Katelynn Toomer
    • , Roger R Markwald
    •  & Russell A Norris
  9. Department of Cardiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

    • Ronen Durst
  10. Hospital Universitario Montepríncipe, Universidad Centro de Estudios Universitarios (CEU) San Pablo, Madrid, Spain.

    • Leticia Fernandez-Friera
    •  & Jorge Solis
  11. Centro Nacional de Investigaciones Cardiovasculares, Carlos III (CNIC), Madrid, Spain.

    • Leticia Fernandez-Friera
    •  & Jorge Solis
  12. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Ming-Huei Chen
  13. Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Quebec City, Quebec, Canada.

    • Yohan Bosse
    •  & Philippe Pibarot
  14. Centre National de Génotypage, Evry, France.

    • Diana Zelenika
    •  & Mark Lathrop
  15. Génome Québec, Montreal, Quebec, Canada.

    • Mark Lathrop
  16. Paris 13 University, Sorbonne Paris Cité, Bobigny, France.

    • Serge Hercberg
  17. INSERM U1153, Institut National de Recherche en Agronomie (INRA) U1125, Nutritional Epidemiology Research Unit, Epidemiology and Biostatistics Center, Bobigny, France.

    • Serge Hercberg
  18. Assistance Publique–Hôpitaux de Paris (AP-HP), Department of Public Health, Avicenne Hospital, Bobigny, France.

    • Serge Hercberg
  19. Paris Diderot University, Paris, France.

    • Serge Hercberg
    •  & Ronan Roussel
  20. INSERM UMRS 1138, Centre de Recherche des Cordeliers, Paris, France.

    • Ronan Roussel
  21. AP-HP, Department of Endocrinology, Diabetes and Nutrition, Fibrosis, Inflammation, Remodeling in Cardiovascular, Respiratory and Renal Diseases (FIRE) Department Hospital University, Bichat Hospital, Paris, France.

    • Ronan Roussel
  22. INSERM, Clinical Investigation Centre (CIC) 0203, University Hospital of Pontchaillou, Rennes, France.

    • Fabrice Bonnet
  23. Department of Endocrinology, University Hospital, Rennes, France.

    • Fabrice Bonnet
  24. Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, California, USA.

    • Su Hao Lo
  25. CNRS UMR 8199, Lille Pasteur Institute, Lille 2 University, European Genomic Institute for Diabetes (EGID), Lille, France.

    • Philippe Froguel
  26. Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK.

    • Philippe Froguel
  27. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

    • Patrick T Ellinor
  28. AP-HP, Department of Pathology, Hôpital Européen Georges Pompidou, Paris, France.

    • Patrick Bruneval
  29. Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Susan A Slaugenhaupt
  30. Cardiac Ultrasound Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Robert A Levine
  31. AP-HP, Department of Cardiology, Hôpital Européen Georges Pompidou, Paris, France.

    • Albert A Hagege
  32. AP-HP, Department of Genetics, Hôpital Européen Georges Pompidou, Paris, France.

    • Xavier Jeunemaitre

Consortia

  1. PROMESA investigators

    A full list of members is provided in the Supplementary Note.

  2. MVP-France

    A full list of members is provided in the Supplementary Note.

  3. Leducq Transatlantic MITRAL Network

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Contributions

C.D., N.B.-N. and X.J. organized and designed the genome-wide association study and the manuscript preparation. A.A.H., R.A.L., S.A.S., H.L.M., P.P., J.S. and L.F.-F. organized and coordinated the network efforts and recruitment of patients. R.D., V.P., T.L.T., F.K., P.P. and Y.B. participated in the recruitment of patients and the interpretation of the echocardiographs. J.-J.S. and X.J. coordinated the collection of patient samples. M.P. and S.L. managed the collection of patient samples and performed DNA extraction and genotyping. C.D. and N.B.-N. conceptualized the statistical analyses. C.D. supervised the statistical analyses. C.D., M.-H.C. and F.S. performed the statistical analyses. D.J.M. conceptualized and supervised the zebrafish experiments. N.T. performed zebrafish experiments, interpreted the data and wrote parts of the manuscript. P.T.E. and E.D. participated in zebrafish experiments and interpretation of data. R.R.M. and R.A.N. conceptualized and supervised the mouse studies and interpreted the data. K.T. performed immunohistochemistry staining of mouse organs. S.H.L. generated the mice. F.N.D., E.J.B., D.Z., M.L., S.H., R. Roussel, F.B., R. Redon, P.F. and R.S.V. conducted the epidemiological studies in control cohorts and/or contributed samples to the GWAS and/or follow-up genotyping. P.B. supervised valve tissues DNA extraction. S.A.S. contributed patient samples and organized follow-up genotyping and interpreted the GWAS and follow-up data. C.D., N.B.-N. and X.J. wrote the manuscript. F.N.D., R.A.N., D.J.M. S.A.S., R.A.L., J.-J.S. and A.A.H. edited the manuscript, and all authors approved its content.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Christian Dina or Nabila Bouatia-Naji or Xavier Jeunemaitre.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–9, Supplementary Tables 1–6 and Supplementary Note.

Videos

  1. 1.

    Control zebrafish heart.

  2. 2.

    Tns1 knockdown zebrafish heart.

  3. 3.

    Lmcd1 knockdown zebrafish heart.

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DOI

https://doi.org/10.1038/ng.3383

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