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
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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