Genome-wide association study reveals novel genetic loci: a new polygenic risk score for mitral valve prolapse.

Adult Genetic Loci / genetics Genome-Wide Association Study Humans Latent TGF-beta Binding Proteins / genetics Mitral Valve Prolapse / genetics Proteomics Risk Factors
Genetic correlation Genome-wide association study Mitral valve prolapse Polygenic risk score Proteomics RNA-sequencing

Journal

European heart journal
ISSN: 1522-9645
Titre abrégé: Eur Heart J
Pays: England
ID NLM: 8006263

Informations de publication

Date de publication:
01 05 2022
Historique:
received: 02 02 2021
revised: 18 08 2021
accepted: 01 02 2022
pubmed: 5 3 2022
medline: 4 5 2022
entrez: 4 3 2022
Statut: ppublish

Résumé

Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder. We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors. We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-β signalling molecules and spectrin β. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention.

Identifiants

DOI: 10.1093/eurheartj/ehac049 PMID: 35245370 PMC: PMC9649914
pubmed: 35245370
pii: 6542554
doi: 10.1093/eurheartj/ehac049
pmc: PMC9649914
doi:

Substances chimiques

LTBP2 protein, human 0
Latent TGF-beta Binding Proteins 0

Types de publication

Journal Article Meta-Analysis Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

1668-1680

Subventions

Organisme : NHLBI NIH HHS
ID : R01 HL149696
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM103444
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL131546
Pays : United States
Organisme : NHLBI NIH HHS
ID : K23 HL116652
Pays : United States
Organisme : NHLBI NIH HHS
ID : R03 HL145238
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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Auteurs

Carolina Roselli (C)

Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
ORCID: 0000-0001-5267-6756

Mengyao Yu (M)

Université de Paris, PARCC, Inserm, F-75015 Paris, France.

Victor Nauffal (V)

Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA.
ORCID: 0000-0001-7199-299X

Adrien Georges (A)

Université de Paris, PARCC, Inserm, F-75015 Paris, France.
ORCID: 0000-0003-4208-2393

Qiong Yang (Q)

School of Public Health, Boston University, Boston, MA, USA.
ORCID: 0000-0002-3658-1375

Katie Love (K)

Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
ORCID: 0000-0002-4541-1087

Lu-Chen Weng (LC)

Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
ORCID: 0000-0003-1475-4930

Francesca N Delling (FN)

Division of Cardiology, University of California San Francisco, San Francisco, CA, USA.
ORCID: 0000-0002-5224-4096

Svetlana R Maurya (SR)

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, København 2200, Denmark.
ORCID: 0000-0002-4700-2711

Maren Schrölkamp (M)

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, København 2200, Denmark.
ORCID: 0000-0003-3522-6379

Jacob Tfelt-Hansen (J)

Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Department of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
ORCID: 0000-0003-3895-9316

Albert Hagège (A)

Université de Paris, PARCC, Inserm, F-75015 Paris, France.
Assistance Publique-Hôpitaux de Paris, Departments of Cardiology and Genetics, Hôpital Européen Georges Pompidou, 75015 Paris, France.

Xavier Jeunemaitre (X)

Université de Paris, PARCC, Inserm, F-75015 Paris, France.
Assistance Publique-Hôpitaux de Paris, Departments of Cardiology and Genetics, Hôpital Européen Georges Pompidou, 75015 Paris, France.

Stéphanie Debette (S)

Bordeaux Population Health Research Center, Inserm Center U1219, University of Bordeaux, Bordeaux, France.
Department of Neurology, Bordeaux University Hospital, Inserm U1219, Bordeaux, France.
ORCID: 0000-0001-8675-7968

Philippe Amouyel (P)

Univ. Lille, Inserm, Centre Hosp. Univ Lille, Institut Pasteur de Lille, UMR1167 - RID-AGE- Risk factors and molecular determinants of aging-related diseases, F-59000 Lille, France.
ORCID: 0000-0001-9088-234X

Wyliena Guan (W)

Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
Demoulas Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, MA, USA.
ORCID: 0000-0002-7493-7985

Jochen D Muehlschlegel (JD)

Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA.
ORCID: 0000-0002-6209-7253

Simon C Body (SC)

Department of Anesthesiology, Boston University School of Medicine, Boston, MA, USA.
ORCID: 0000-0001-6721-7050

Svati Shah (S)

Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
ORCID: 0000-0002-3495-2830

Zainab Samad (Z)

Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
Department of Medicine, Aga Khan University, Karachi, Pakistan.

Sergiy Kyryachenko (S)

Université de Paris, PARCC, Inserm, F-75015 Paris, France.
ORCID: 0000-0002-1249-2351

Carol Haynes (C)

Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
ORCID: 0000-0001-6769-3292

Michiel Rienstra (M)

Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
ORCID: 0000-0002-2581-070X

Thierry Le Tourneau (T)

l'institut du thorax, INSERM, CNRS, Univ Nantes, CHU Nantes, Nantes, France.
l'institut du thorax, CHU Nantes, Nantes, France.
ORCID: 0000-0002-0110-9054

Vincent Probst (V)

l'institut du thorax, INSERM, CNRS, Univ Nantes, CHU Nantes, Nantes, France.

Ronan Roussel (R)

Cordeliers Research Centre, ImMeDiab Team, INSERM, Université de Paris, Paris, France.
Hôpital Bichat-Claude-Bernard, APHP, Department of Diabetology, Paris, France.

Inez J Wijdh-Den Hamer (IJ)

Department of Cardiothoracic Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
ORCID: 0000-0001-9466-274X

Joylene E Siland (JE)

Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
ORCID: 0000-0003-4404-1245

Kirk U Knowlton (KU)

Intermountain Medical Center Heart Institute, Salt Lake City, UT, USA.
Division of Cardiovascular Medicine, Department of Medicine, University of California San Diego, San Diego, CA, USA.

Jean Jacques Schott (J)

l'institut du thorax, INSERM, CNRS, Univ Nantes, CHU Nantes, Nantes, France.
ORCID: 0000-0002-9578-9475

Robert A Levine (RA)

Cardiac Ultrasound Laboratory, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
ORCID: 0000-0002-9484-8218

Emelia J Benjamin (EJ)

National Heart, Lung, and Blood Institute's and Boston University's, The Framingham Heart Study, Framingham, MA, USA.
Section of Cardiovascular Medicine, Boston University School of Medicine, Boston, MA, USA.
Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
ORCID: 0000-0003-4076-2336

Ramachandran S Vasan (RS)

School of Public Health, Boston University, Boston, MA, USA.
National Heart, Lung, and Blood Institute's and Boston University's, The Framingham Heart Study, Framingham, MA, USA.
School of Medicine, Boston University, Boston, MA, USA.
ORCID: 0000-0001-7357-5970

Benjamin D Horne (BD)

Intermountain Medical Center Heart Institute, Salt Lake City, UT, USA.
Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
ORCID: 0000-0002-2656-0263

Joseph B Muhlestein (JB)

Intermountain Medical Center Heart Institute, Salt Lake City, UT, USA.
Cardiology Division, Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
ORCID: 0000-0002-3366-9857

Giovanni Benfari (G)

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
ORCID: 0000-0002-5660-6162

Maurice Enriquez-Sarano (M)

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
ORCID: 0000-0003-0910-5450

Andrea Natale (A)

Texas Cardiac Arrhythmia Institute, St David's Medical Center, Austin, TX, USA.

Sanghamitra Mohanty (S)

Texas Cardiac Arrhythmia Institute, St David's Medical Center, Austin, TX, USA.

Chintan Trivedi (C)

Texas Cardiac Arrhythmia Institute, St David's Medical Center, Austin, TX, USA.

Moore B Shoemaker (MB)

Department of Medicine, Division of Cardiovascular Diseases, Vanderbilt University Medical Center, Nashville, TN, USA.

Zachary T Yoneda (ZT)

Department of Medicine, Division of Cardiovascular Diseases, Vanderbilt University Medical Center, Nashville, TN, USA.
ORCID: 0000-0002-2055-732X

Quinn S Wells (QS)

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.

Michael T Baker (MT)

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
ORCID: 0000-0002-7803-939X

Eric Farber-Eger (E)

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
ORCID: 0000-0003-0281-3796

Hector I Michelena (HI)

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.

Alicia Lundby (A)

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, København 2200, Denmark.
The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, København 2200, Denmark.

Russell A Norris (RA)

Cardiovascular Developmental Biology Center, Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA.
ORCID: 0000-0001-8462-5726

Susan A Slaugenhaupt (SA)

Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.

Christian Dina (C)

l'institut du thorax, INSERM, CNRS, Univ Nantes, CHU Nantes, Nantes, France.
ORCID: 0000-0002-7722-7348

Steven A Lubitz (SA)

Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
Demoulas Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, MA, USA.
ORCID: 0000-0002-9599-4866

Nabila Bouatia-Naji (N)

Université de Paris, PARCC, Inserm, F-75015 Paris, France.
ORCID: 0000-0001-5424-2134

Patrick T Ellinor (PT)

Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
Demoulas Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, MA, USA.
ORCID: 0000-0002-2067-0533

David J Milan (DJ)

Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
Leducq Foundation, Boston, MA 02110, USA.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Genome-wide association study reveals novel...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Locus génétiques › Genome-wide association study reveals novel...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Genome-wide association study reveals novel...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Genome-wide association study reveals novel...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Scléroprotéines › Protéines de la matrice extracellulaire › Protéines de liaison au TGF-bêta latent › Genome-wide association study reveals novel...
questionsmedicales.fr › Maladies cardiovasculaires › Cardiopathies › Valvulopathies › Prolapsus des valves cardiaques › Prolapsus de la valve mitrale › Genome-wide association study reveals novel...
questionsmedicales.fr › Disciplines des sciences naturelles › Chimie › Biochimie › Protéomique › Genome-wide association study reveals novel...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Probabilité › Risque › Facteurs de risque › Genome-wide association study reveals novel...