Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure
Year: 2016
Type: article
Study design: Observational Study
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.
Source: PLoS Genetics
Authors: J. Gustav Smith, Janine F. Felix, Alanna C. Morrison, Andreas Kalogeropoulos, Stella Trompet, Jemma B. Wilk, Olof Gidlöf, Xinchen Wang, Michael Morley, Michael Mendelson, Roby Joehanes, Symen Ligthart, Xiaoyin Shan, Joshua C. Bis, Ying A. Wang, Marketa Sjögren, Julius Ngwa, Jeffrey Brandimarto, David J. Stott, David Aguilar, Kenneth M. Rice, Howard D. Sesso, Serkalem Demissie, Brendan M. Buckley, Kent D. Taylor, Ian Ford, Chen Yao, Chunyu Liu, Nona Sotoodehnia, Pim van der Harst, Bruno H. Ch. Stricker, Stephen B. Kritchevsky, Yongmei Liu, J. Michael Gaziano, Albert Hofman, Christine S. Moravec, André G. Uitterlinden, Manolis Kellis, Joyce B. van Meurs, Kenneth B. Margulies, Abbas Dehghan, Daniel Levy, Björn Olde, Bruce M. Psaty, L. Adrienne Cupples, J. Wouter Jukema, Luc Djousse, Oscar H. Franco, Eric Boerwinkle, Laurie A. Boyer, Christopher Newton-Cheh, Javed Butler, Ramachandran S. Vasan, Thomas P. Cappola, Nicholas L. Smith
Institutions: Broad Institute, Harvard University, Lund University, Massachusetts General Hospital, Skåne University Hospital, Massachusetts Institute of Technology, Erasmus MC, Netherlands Consortium for Healthy Ageing, The University of Texas Health Science Center at Houston, Emory University, Leiden University Medical Center, Brigham and Women's Hospital, University of Pennsylvania, Boston Children's Hospital, National Heart, Lung, and Blood Institute, Framingham Heart Study, University of Washington, Boston University, University of Glasgow, Baylor College of Medicine, University College Cork, University of California, Los Angeles, The Lundquist Institute, Harbor–UCLA Medical Center, University Medical Center Groningen, University of Groningen, Wake Forest University Health Sciences, Wake Forest University, Cleveland Clinic, Group Health Cooperative, Kaiser Permanente Washington Health Research Institute, Netherlands Heart Institute, VA Office of Research and Development, Seattle Epidemiologic Information and Research Center
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,043
Funders: Wake Forest University, Johns Hopkins University, National Institutes of Health, National Institute on Aging, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Eye Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: G100949702, G1023702118, G1028935811, G1083180012, G1083489883, G1097528416, G1168185457, G118440752, G1220223050, G125972088, Genetic Determinants of Visceral Adiposity, CORONARY HEART DISEASE AND STROKE, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, G1325221871, G1332411685, G1346894162, G1401438683, G1407109571, G1438302022, DYNAMICS OF HEALTH,AGING, AND BODY COMPOSITION, G1466586219, G1490530680, CORONARY HEART DISEASE AND STROKE, G1691174148, G1696540499, G1726490033, G2070131968, Atherosclerosis Risk in Communities Study (ARIC), G2145550945, G2146332128, G215333750, DYNAMICS OF HEALTH, AGING, AND BODY COMPOSITION, Rare variants and NHLBI traits in deeply phenotyped cohorts, G2189639697, G2194386449, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, G232264632, G234459253, G2391884931, G2404385439, G247538147, G250621538, G2513955590, CCSP FIELD CENTER, G25881238, CORONARY HEART DISEASE &STROKE IN THE ELDERLY, COMMUNITY AND COHORT SURVEILLANCE PROGRAM, G270907595, G2800149121, CENTRAL HEMOSTATIS LABORATORY FOR CCSP, G2815873878, G2818913090, G2899267414, G2918387404, G297113894, G29933701, G3045517347, WGA Study to Identify Genetic Variants Associated with CV Events in CHS, G3087775723, G3114902838, G3137375862, G3152385821, HEALTH ABC--COORDINATING UNIT, Prospective meta-analyses of drug-gene interactions: CHARGE GWAS consortium, G3200378041, G3205625555, G3216861457, G3220743633, G322252321, G3236609591, UCLA Clinical and Translational Science Institute, G3307733961, G3322037220, G34347772, G343705321, G3648845612, G3667269547, G3692229207, G36937976, G3860090032, G390162502, CENTRAL BLOOD ANALYSIS LABORATORY FOR CHS, G4167445418, G4219624527, G423252844, G4429312988, G445457422, Atherosclerosis Risk in Communities Study (ARIC), G4522543292, G4582778782, G4622379297, G4824283243, G4864106686, G4942589162, G5026578359, G5125936451, G5145575165, G5164707915, G5251985303, G5281659474, G536099884, G537455924, G5386252567, Genome-Wide Association for Loci Influencing CHD and Other Heart, Lung and Blood, G5439707361, G544148272, Physicians' Health Study II: Prevention Trial of Vitamins, G5451084504, Epidemiology of Venous Thrombosis and Pulmonary Embolism, G5713454673, Atherosclerosis Risk in Communities Study (ARIC), G581554933, G581887176, G5909482378, CHS Events Follow-up Study, G6177097893, G6203107232, G6226795708, G6279754272, G6401035755, The Framingham Heart Study, TRIAL OF ASPIRIN AND BETA-CAROTENE IN U S MD'S, G670738241, G6902273418, G7007046788, G7093047072, G716312657, G7176672723, G7217924807, G7415749889, G7505613430, G764651519, G766700449, G766843672, G7693351332, G77250574, G772876839, Eye and Vision Genomics Training Program, G793702358, Integrative genomics of human heart failure, G806768229, G812579647, G820615960, G824087253, G8486527673, G8541424066, G8554986239, G861947890, CHS-Transition Phase -268055222, G870807107, G8937114048, G9000018826, G9000026278, G9000027259, G9000028264, G9000046001, G9000069887, G9000071222, G9000096660, G9000108254, G9000124008, G9000124674, G9000139054, G9000140433, G9000155215, G9000254626, Diabetes Research Center (DRC), From GWAS loci to blood pressure genes, variants & mechanisms - Renewal, UCLA Clinical and Translational Science Institute, G905887895, G931818222, G939971039, G945304896, G947029668, Atherosclerosis Risk in Communities Study (ARIC)
OpenAlex ID: W2346985355