ArticlePLoS genetics2016
Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure.
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In one paragraph
Article in PLoS genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 3 of them syntheses that pooled it.
0numbers the graph read from it
0cells of the map it votes in
25citing papers in PubMed, 3 pooled it
6.6field-weighted citation impact, top 3% of its field
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
25 citing papers in PubMed, 3 syntheses or guidelines pooled it, 42 citations in OpenAlex.
- Association between tricuspid regurgitation and heart failure outcomes: A meta-analysis.ESC heart failure · 2025Pooled it
- Common Variants onCirculation. Heart failure · 2023Pooled it
- The landscape of GWAS validation; systematic review identifying 309 validated non-coding variants across 130 human diseases.BMC medical genomics · 2022Pooled it
- Plasma Proteomic Profile Predicts Survival in Heart Failure With Reduced Ejection Fraction.Circulation. Genomic and precision medicine · 2021Trial
- Connecting intermediate phenotypes to disease using multi-omics in heart failure.Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing · 2025Article
- Connecting intermediate phenotypes to disease using multi-omics in heart failure.medRxiv : the preprint server for health sciences · 2024Article
- Risk Assessment and Personalized Treatment Options in Inherited Dilated Cardiomyopathies: A Narrative Review.Biomedicines · 2024Review
- Using Omics to Identify Novel Therapeutic Targets in Heart Failure.Circulation. Genomic and precision medicine · 2024Review
- Arrhythmic Sudden Cardiac Death in Heart Failure With Preserved Ejection Fraction: Mechanisms, Genetics, and Future Directions.CJC open · 2022Review
- The genomics of heart failure: design and rationale of the HERMES consortium.ESC heart failure · 2021Article
- Clinical impact of echocardiography parameters and molecular biomarkers in heart failure: Correlation ofExperimental and therapeutic medicine · 2021Article
- Advances in the Genetics and Genomics of Heart Failure.Current cardiology reports · 2020Review
- Epigenomes of Human Hearts Reveal New Genetic Variants Relevant for Cardiac Disease and Phenotype.Circulation research · 2020Article
- DNA Methylation Is Predictive of Mortality in Current and Former Smokers.American journal of respiratory and critical care medicine · 2020Article
- Genetics of dilated cardiomyopathy: practical implications for heart failure management.Nature reviews. Cardiology · 2020Review
- Profiling of the plasma proteome across different stages of human heart failure.Nature communications · 2019Article
- A common variant of RIP3 promoter region is associated with poor prognosis in heart failure patients by influencing SOX17 binding.Journal of cellular and molecular medicine · 2019Article
- Familial Mortality Risks in Patients With Heart Failure-A Swedish Sibling Study.Journal of the American Heart Association · 2018Article
- Epigenomes in Cardiovascular Disease.Circulation research · 2018Review
- Genome-Wide Associations of Global Electrical Heterogeneity ECG Phenotype: The ARIC (Atherosclerosis Risk in Communities) Study and CHS (Cardiovascular Health Study).Journal of the American Heart Association · 2018Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
59 authors at 20 institutions in 5 countries.
J Gustav SmithDepartment of Cardiology, Department of Clinical Sciences, Lund University, Lund, Sweden.
Janine F FelixDepartment of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
Alanna C MorrisonHuman Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
Andreas KalogeropoulosEmory Clinical Cardiovascular Research Institute, Emory University, Atlanta, Georgia, United States of America.ORCID 0000-0002-1284-429X
Stella TrompetDepartment of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
Jemma B WilkBrigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
Olof GidlöfDepartment of Cardiology, Department of Clinical Sciences, Lund University, Lund, Sweden.
Xinchen WangProgram in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.ORCID 0000-0002-5198-6581
Michael MorleyPerelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Michael MendelsonThe Framingham Heart Study, Framingham, Massachusetts, United States of America.ORCID 0000-0001-7590-3958
Roby JoehanesThe Framingham Heart Study, Framingham, Massachusetts, United States of America.
Symen LigthartDepartment of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
Xiaoyin ShanPerelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Joshua C BisDepartment of Epidemiology, University of Washington, Seattle, Washington, United States of America.
Ying A WangNovartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States of America.ORCID 0000-0001-8863-2376
Marketa SjögrenDepartment of Clinical Sciences, Lund University, Malmö, Sweden.
Julius NgwaDepartment of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
Jeffrey BrandimartoPerelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.ORCID 0000-0002-9348-2349
David J StottAcademic Section of Geriatric Medicine, Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom.
David AguilarBaylor College of Medicine, Houston, Texas, United States of America.
Kenneth M RiceDepartment of Biostatistics, University of Washington, Seattle, Washington, United States of America.
Howard D SessoBrigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
Serkalem DemissieDepartment of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
Brendan M BuckleyDepartment of Pharmacology and Therapeutics, University College Cork, Cork, Ireland.
Kent D TaylorInstitute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, United States of America.
Ian FordRobertson Center for Biostatistics, University of Glasgow, Glasgow, United Kingdom.
Chen YaoThe Framingham Heart Study, Framingham, Massachusetts, United States of America.
Chunyu LiuThe Framingham Heart Study, Framingham, Massachusetts, United States of America.
CHARGE-SCD consortium
EchoGen consortium
QT-IGC consortium
CHARGE-QRS consortium
Nona SotoodehniaCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
Pim van der HarstDepartment of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Bruno H Ch StrickerDepartment of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
Stephen B KritchevskyDepartment of Internal Medicine, Section on Geronotology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
Yongmei LiuDepartment of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, North Carolina, United States of America.
J Michael GazianoBrigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
Albert HofmanDepartment of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
Christine S MoravecDepartment of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, United States of America.
André G UitterlindenDepartment of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
Manolis KellisProgram in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
Joyce B van MeursDepartment of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
Kenneth B MarguliesPerelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Abbas DehghanDepartment of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
Daniel LevyThe Framingham Heart Study, Framingham, Massachusetts, United States of America.
Björn OldeDepartment of Cardiology, Department of Clinical Sciences, Lund University, Lund, Sweden.
Bruce M PsatyDepartment of Epidemiology, University of Washington, Seattle, Washington, United States of America.
L Adrienne CupplesDepartment of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
J Wouter JukemaDepartment of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
Luc DjousseBrigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
Oscar H FrancoDepartment of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
Eric BoerwinkleHuman Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
Laurie A BoyerDepartment of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
Christopher Newton-ChehProgram in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
Javed ButlerEmory Clinical Cardiovascular Research Institute, Emory University, Atlanta, Georgia, United States of America.
Ramachandran S VasanDepartments of Medicine and Preventive Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
Thomas P CappolaPerelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Nicholas L SmithDepartment of Epidemiology, University of Washington, Seattle, Washington, United States of America.
Erasmus MC · NLUniversity of Pennsylvania · USBoston University · USBrigham and Women's Hospital · USBroad Institute · USNational Heart Lung and Blood Institute · USUniversity of Washington · USLund University · SEBaylor College of Medicine · USEmory University · USLeiden University Medical Center · NLUniversity of Glasgow · GBWake Forest University · USBoston Children's Hospital · USCleveland Clinic · USDutch Health Care Inspectorate · NLGroup Health Cooperative · USMassachusetts Institute of Technology · USNovartis (United States) · USThe Lundquist Institute · US
Funding
UCLA Clinical Translational Science InstituteUL1TR001881 · NCATS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ARLEEN F. BROWN, ARASH NAEIM · 2016 to 2026
$118.1MInstitute for Clinical and Translational Research (UL1)UL1RR025005 · NCRR · JOHNS HOPKINS UNIVERSITY · PI FORD, DANIEL ERNEST · 2007 to 2011
$75.8MUCLA Clinical and Translational Science InstituteUL1TR000124 · NCATS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI DUBINETT, STEVEN M. · 2012 to 2015
$57.0MTransgenic & Knock-out MouseP30DK063491 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI ALAN R. SALTIEL · 2003 to 2026
$40.4MGenome-Wide Association Analysis in Essential Hypertension (FEHGAS study)R01HL086694 · NHLBI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI ARAVINDA CHAKRAVARTI · 2007 to 2026
$21.2MPhysicians' Health Study II: Prevention Trial of VitaminsR01CA097193 · NCI · BRIGHAM AND WOMEN'S HOSPITAL · PI GAZIANO, J. MICHAEL · 2002 to 2011
$15.7MEpidemiology of Venous Thrombosis & Pulmonary EmbolismR01HL059367 · NHLBI · UNIVERSITY OF MINNESOTA TWIN CITIES · PI TANG, WEIHONG · 1998 to 2024
$11.8MExceptional Survival: Trajectories to Functional Aging (CHS All Stars)R01AG023629 · NIA · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI NEWMAN, ANNE B. · 2004 to 2016
$9.5MCHARGE Consortium: Omics Discovery for CVD and Aging PhenotypesR01HL105756 · NHLBI · UNIVERSITY OF WASHINGTON · PI Bruce M Psaty, NICHOLAS L SMITH · 2011 to 2026
$9.5MRare variants and NHLBI traits in deeply phenotyped cohortsR01HL120393 · NHLBI · UNIVERSITY OF WASHINGTON · PI PSATY, BRUCE M, RICE, KENNETH M. · 2014 to 2016
$8.9MIntegrative genomics of human heart failureR01HL105993 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI ASHLEY, EUAN A, CAPPOLA, THOMAS P. · 2011 to 2014
$8.9MProspective meta-analyses of drug-gene interactions: CHARGE GWAS consortiumR01HL103612 · NHLBI · UNIVERSITY OF WASHINGTON · PI PSATY, BRUCE M · 2011 to 2014
$5.4MNCATS NIH HHS UL1 TR000124NCATS NIH HHS UL1 TR001881NCI NIH HHS R01 CA034944NCI NIH HHS R01 CA040360NCI NIH HHS R01 CA097193NCRR NIH HHS UL1 RR025005NEI NIH HHS T32 EY022303NHGRI NIH HHS R01 HG008155NHGRI NIH HHS U01 HG004402NHLBI NIH HHS K24 HL004334NHLBI NIH HHS N01 HC025195NHLBI NIH HHS N01 HC055015NHLBI NIH HHS N01 HC055016NHLBI NIH HHS N01 HC055018NHLBI NIH HHS N01 HC055019NHLBI NIH HHS N01 HC055020NHLBI NIH HHS N01 HC055021NHLBI NIH HHS N01 HC055022NHLBI NIH HHS N01 HC055222NHLBI NIH HHS N01 HC085079NHLBI NIH HHS N01 HC085080NHLBI NIH HHS N01 HC085081NHLBI NIH HHS N01 HC085082NHLBI NIH HHS N01 HC085083NHLBI NIH HHS N01 HC085086NHLBI NIH HHS R01 HL026490NHLBI NIH HHS R01 HL034595NHLBI NIH HHS R01 HL059367NHLBI NIH HHS R01 HL077477NHLBI NIH HHS R01 HL086694NHLBI NIH HHS R01 HL087641NHLBI NIH HHS R01 HL087652NHLBI NIH HHS R01 HL093328NHLBI NIH HHS R01 HL103612NHLBI NIH HHS R01 HL105756NHLBI NIH HHS R01 HL105993NHLBI NIH HHS R01 HL120393NHLBI NIH HHS U01 HL080295NIA NIH HHS N01 AG062101NIA NIH HHS N01 AG062103NIA NIH HHS N01 AG062106NIA NIH HHS R01 AG023629NIA NIH HHS R01 AG032098NIDDK NIH HHS P30 DK063491
Abstract
Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.
Indexed as
AllelesBasic Helix-Loop-Helix ProteinsBlack or African AmericanChromosomes, Human, Pair 5DNA MethylationFemaleGene Expression RegulationGene Knockdown TechniquesGenetic Predisposition to DiseaseGenetic VariationGenome-Wide Association StudyGenotypeHeart FailureHEK293 CellsHumansMaleBasic Helix-Loop-Helix ProteinsCRLF2 protein, humanNHLH1 protein, humanReceptors, Cytokine
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