Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure
Autor: | Jemma B. Wilk, Xiaoyin Shan, Christine S. Moravec, Christopher Newton-Cheh, Stella Trompet, Eric Boerwinkle, Javed Butler, Julius S. Ngwa, Laurie A. Boyer, Michael Morley, Nona Sotoodehnia, Nicholas L. Smith, Howard D. Sesso, David J. Stott, David Aguilar, Ying A. Wang, Ian Ford, Kenneth B. Margulies, Kent D. Taylor, André G. Uitterlinden, Jeffrey Brandimarto, Xinchen Wang, Joshua C. Bis, J. Michael Gaziano, Manolis Kellis, Janine F. Felix, Chunyu Liu, Symen Ligthart, Björn Olde, Luc Djoussé, Abbas Dehghan, Serkalem Demissie, Michael M. Mendelson, Roby Joehanes, J. Wouter Jukema, Bruce M. Psaty, Brendan M. Buckley, Marketa Sjögren, Ramachandran S. Vasan, J. Gustav Smith, Stephen B. Kritchevsky, Bruno H. Stricker, Daniel Levy, Andreas P. Kalogeropoulos, Olof Gidlöf, Alanna C. Morrison, Albert Hofman, Kenneth Rice, Oscar H. Franco, Yongmei Liu, L. Adrienne Cupples, Pim van der Harst, Chen Yao, Joyce B. J. van Meurs, Thomas P. Cappola |
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Přispěvatelé: | Cardiovascular Centre (CVC), Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Wang, Xinchen, Kellis, Manolis, Boyer, Laurie Ann, Epidemiology, Internal Medicine, Medical Informatics |
Jazyk: | angličtina |
Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Male Cancer Research Physiology Genome-wide association study 030204 cardiovascular system & hematology VARIANTS Bioinformatics Biochemistry Genome-wide association studies 0302 clinical medicine AFRICAN ANCESTRY HUMAN-POPULATIONS Basic Helix-Loop-Helix Transcription Factors Medicine and Health Sciences Genetics (clinical) AGING RESEARCH RISK Hematology DNA methylation Death rates Genomics Middle Aged Chromatin 3. Good health Body Fluids Nucleic acids Blood PRESERVED EJECTION FRACTION Gene Knockdown Techniques SURVIVAL Chromosomes Human Pair 5 Female Epigenetics Anatomy DNA modification Chromatin modification Research Article Chromosome biology medicine.medical_specialty Cell biology Genotype lcsh:QH426-470 Death Rates Genetic loci Cardiology Heart failure Biology Polymorphism Single Nucleotide Chromosomes 03 medical and health sciences Population Metrics Molecular genetics Internal medicine Genetic variation medicine Genetics Genome-Wide Association Studies Humans Genetic Predisposition to Disease Receptors Cytokine GENOME-WIDE ASSOCIATION Enhancer Molecular Biology Genotyping Ecology Evolution Behavior and Systematics Alleles METAANALYSIS Genetic association Demography Heart Failure Biology and life sciences Population Biology Genetic Variation Computational Biology Human Genetics DNA medicine.disease Genome Analysis Black or African American lcsh:Genetics 030104 developmental biology HEK293 Cells Gene Expression Regulation Genetic Loci People and Places Gene expression Genome-Wide Association Study EPIDEMIOLOGY CHARGE CONSORTIUM |
Zdroj: | PLoS Genetics, Vol 12, Iss 5, p e1006034 (2016) PLoS genetics, 12(5):1006034. PUBLIC LIBRARY SCIENCE PLoS Genetics, 12(5) PLoS Genetics PLOS Genetics PLOS PLoS Genet. 12:e1006034 (2016) PLoS Genetics (online), 12(5):e1006034. Public Library of Science |
ISSN: | 1553-7404 1553-7390 2682-0110 2682-0080 |
Popis: | 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. National Heart, Lung, and Blood Institute (HHSN268201100005C) National Heart, Lung, and Blood Institute (HHSN268201100006C) National Heart, Lung, and Blood Institute (HHSN268201100007C) National Heart, Lung, and Blood Institute (HHSN268201100008C) National Heart, Lung, and Blood Institute (HHSN268201100009C) National Heart, Lung, and Blood Institute (HHSN268201100010C) National Heart, Lung, and Blood Institute (HHSN268201100011C) National Heart, Lung, and Blood Institute (HHSN268201100012C) National Heart, Lung, and Blood Institute (N01-HC-55015) National Heart, Lung, and Blood Institute (N01-HC-55016) National Heart, Lung, and Blood Institute (N01-HC-55018) National Heart, Lung, and Blood Institute (N01-HC-55019) National Heart, Lung, and Blood Institute (N01-HC-55020) National Heart, Lung, and Blood Institute (N01-HC-55021) National Heart, Lung, and Blood Institute (N01-HC-55022) National Heart, Lung, and Blood Institute (R01HL087641) National Heart, Lung, and Blood Institute (R01HL59367) National Heart, Lung, and Blood Institute (R01HL086694) National Human Genome Research Institute (U.S.) (U01HG004402) United States. National Institutes of Health (HHSN268200625226C) United States. National Institutes of Health (UL1RR025005) National Heart, Lung, and Blood Institute (HHSN268201200036C) National Heart, Lung, and Blood Institute (N01HC55222) National Heart, Lung, and Blood Institute (HHSN268200800007C) National Heart, Lung, and Blood Institute (N01HC85079) National Heart, Lung, and Blood Institute (N01HC85080) National Heart, Lung, and Blood Institute (N01HC85081) National Heart, Lung, and Blood Institute (N01HC85082) National Heart, Lung, and Blood Institute (N01HC85083) National Heart, Lung, and Blood Institute (N01HC85086) National Heart, Lung, and Blood Institute (U01HL080295) National Science Foundation (U.S.) (R01HL087652) National Heart, Lung, and Blood Institute (R01HL105756) National Heart, Lung, and Blood Institute (R01HL103612) National Heart, Lung, and Blood Institute (R01HL120393) National Institute on Aging (R01AG023629) National Center for Advancing Translational Sciences (U.S.) (UL1TR000124) National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (DK063491) National Heart, Lung, and Blood Institute (N01-HC-25195) National Heart, Lung, and Blood Institute (2K24HL04334) National Heart, Lung, and Blood Institute (R01HL077477) National Heart, Lung, and Blood Institute (R01HL093328) National Heart, Lung, and Blood Institute (NIH R01HL105993) National Institute on Aging (N01AG62101) National Heart, Lung, and Blood Institute (N01AG62103) National Heart, Lung, and Blood Institute (N01AG62106) National Institute on Aging (1R01AG032098-01A1) United States. National Institutes of Health (HHSN268200782096C) National Cancer Institute (U.S.) (CA-34944) National Cancer Institute (U.S.) (CA-40360) National Cancer Institute (U.S.) (CA-097193) National Heart, Lung, and Blood Institute (HL-26490) National Heart, Lung, and Blood Institute (HL-34595) |
Databáze: | OpenAIRE |
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