title: Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure.
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.
authors.affiliation: Department of Cardiology, Department of Clinical Sciences, Lund University, Lund, Sweden.|Department of Heart Failure and Valvular Disease, Skåne University Hospital, Lund, Sweden.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.|Center for Human Genetic Research and Cardiovascular Research Center, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, United States of America.|Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: J Gustav
authors.initials: JG
authors.lastname: Smith
authors.affiliation: Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.|Netherlands Consortium for Healthy Aging (NGI-NCHA), The Netherlands Genomics Initiative, Leiden, the Netherlands.
authors.forename: Janine F
authors.initials: JF
authors.lastname: Felix
authors.affiliation: Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
authors.forename: Alanna C
authors.initials: AC
authors.lastname: Morrison
authors.affiliation: Emory Clinical Cardiovascular Research Institute, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Andreas
authors.identifier: 0000-0002-1284-429X
authors.initials: A
authors.lastname: Kalogeropoulos
authors.affiliation: Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.|Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Stella
authors.initials: S
authors.lastname: Trompet
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jemma B
authors.initials: JB
authors.lastname: Wilk
authors.affiliation: Department of Cardiology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Olof
authors.initials: O
authors.lastname: Gidlöf
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Xinchen
authors.identifier: 0000-0002-5198-6581
authors.initials: X
authors.lastname: Wang
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Morley
authors.affiliation: The Framingham Heart Study, Framingham, Massachusetts, United States of America.|The Population Sciences Branch, National Heart, Lund and Blood Institute, Bethesda, Maryland, United States of America.|Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Michael
authors.identifier: 0000-0001-7590-3958
authors.initials: M
authors.lastname: Mendelson
authors.affiliation: The Framingham Heart Study, Framingham, Massachusetts, United States of America.|The Population Sciences Branch, National Heart, Lund and Blood Institute, Bethesda, Maryland, United States of America.
authors.forename: Roby
authors.initials: R
authors.lastname: Joehanes
authors.affiliation: Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Symen
authors.initials: S
authors.lastname: Ligthart
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Xiaoyin
authors.initials: X
authors.lastname: Shan
authors.affiliation: Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Bis
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States of America.
authors.forename: Ying A
authors.identifier: 0000-0001-8863-2376
authors.initials: YA
authors.lastname: Wang
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Marketa
authors.initials: M
authors.lastname: Sjögren
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Julius
authors.initials: J
authors.lastname: Ngwa
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Jeffrey
authors.identifier: 0000-0002-9348-2349
authors.initials: J
authors.lastname: Brandimarto
authors.affiliation: Academic Section of Geriatric Medicine, Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Stott
authors.affiliation: Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Aguilar
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Rice
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Howard D
authors.initials: HD
authors.lastname: Sesso
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Serkalem
authors.initials: S
authors.lastname: Demissie
authors.affiliation: Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland.
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Buckley
authors.affiliation: Institute 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.
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.affiliation: Robertson Center for Biostatistics, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Ford
authors.affiliation: The Framingham Heart Study, Framingham, Massachusetts, United States of America.|The Population Sciences Branch, National Heart, Lund and Blood Institute, Bethesda, Maryland, United States of America.
authors.forename: Chen
authors.initials: C
authors.lastname: Yao
authors.affiliation: The Framingham Heart Study, Framingham, Massachusetts, United States of America.|The Population Sciences Branch, National Heart, Lund and Blood Institute, Bethesda, Maryland, United States of America.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Liu
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Nona
authors.initials: N
authors.lastname: Sotoodehnia
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Pim
authors.initials: P
authors.lastname: van der Harst
authors.affiliation: Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.|Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.|Inspectorate for Health Care, The Hague, the Netherlands.|Department of Medical Informatics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Bruno H Ch
authors.initials: BH
authors.lastname: Stricker
authors.affiliation: Department of Internal Medicine, Section on Geronotology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Kritchevsky
authors.affiliation: Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, North Carolina, United States of America.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: J Michael
authors.initials: JM
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authors.affiliation: Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, United States of America.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Moravec
authors.affiliation: Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.|Netherlands Consortium for Healthy Aging (NGI-NCHA), The Netherlands Genomics Initiative, Leiden, the Netherlands.|Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Manolis
authors.initials: M
authors.lastname: Kellis
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Joyce B
authors.initials: JB
authors.lastname: van Meurs
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Kenneth B
authors.initials: KB
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authors.affiliation: Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehghan
authors.affiliation: The Framingham Heart Study, Framingham, Massachusetts, United States of America.|The Population Sciences Branch, National Heart, Lund and Blood Institute, Bethesda, Maryland, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.affiliation: Department of Cardiology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Björn
authors.initials: B
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authors.affiliation: Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.|Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.|Department of Health Services, University of Washington, Seattle, Washington, United States of America.|Group Health Research Institute, Group Health Cooperative, Seattle, Washington, United States of America.
authors.forename: Bruce M
authors.initials: BM
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authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: L Adrienne
authors.initials: LA
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authors.affiliation: Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.|Durrer Center for Cardiogenetic Research, Amsterdam, the Netherlands.|Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands.
authors.forename: J Wouter
authors.initials: JW
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authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
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authors.initials: L
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authors.affiliation: Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.|Netherlands Consortium for Healthy Aging (NGI-NCHA), The Netherlands Genomics Initiative, Leiden, the Netherlands.
authors.forename: Oscar H
authors.initials: OH
authors.lastname: Franco
authors.affiliation: Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
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authors.initials: LA
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authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.|Center for Human Genetic Research and Cardiovascular Research Center, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, United States of America.
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authors.initials: C
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authors.affiliation: Emory Clinical Cardiovascular Research Institute, Emory University, Atlanta, Georgia, United States of America.
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authors.affiliation: Departments of Medicine and Preventive Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Ramachandran S
authors.initials: RS
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authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Cappola
authors.affiliation: Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.|Department of Health Services, University of Washington, Seattle, Washington, United States of America.|Seattle Epidemiologic Research and Information Center, Department of Veteran Affairs Office of Research and Development, Seattle, Washington, United States of America.
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Smith
mesh_terms: D001741:Black or African American / Q000235:genetics; D000483:Alleles; D051792:Basic Helix-Loop-Helix Proteins / Q000097:blood / Q000235:genetics*; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D057809:HEK293 Cells; D006333:Heart Failure / Q000097:blood / Q000235:genetics* / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D018121:Receptors, Cytokine / Q000097:blood / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018121:Receptors, Cytokine; C498762:CRLF2 protein, human; C076746:NHLH1 protein, human