期刊
PLOS GENETICS
卷 12, 期 5, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1006034
关键词
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资金
- National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694]
- National Human Genome Research Institute [U01HG004402]
- National Institutes of Health [HHSN268200625226C, HHSN268200782096C]
- National Institutes of Health and NIH Roadmap for Medical Research [UL1RR025005]
- NIH, National Institutes of Environmental Health Sciences
- NHLBI [HHSN268 201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, N01-HC-25195, NIH R01HL105993]
- National Institute of Neurological Disorders and Stroke (NINDS)
- National Institute on Aging (NIA) [R01AG023629]
- National Center for Advancing Translational Sciences
- CTSI [UL1TR000124]
- National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]
- Affymetrix, Inc [N02-HL-6-4278]
- National Heart Lung Blood Institute [2K24HL04334, R01HL077477, R01HL093328]
- NIA [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]
- Intramural Research Program of the NIH, National Institute on Aging
- Bristol-Myers Squibb
- Netherlands Heart Foundation [2001 D 032]
- European commission [223004]
- Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging) [050-060-810]
- Netherlands Organisation of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]
- Research Institute for Diseases in the Elderly [014-93-015, RIDE2]
- Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) [050-060-810]
- Erasmus Medical Center and Erasmus University, Rotterdam
- Netherlands Organization for the Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly (RIDE)
- Ministry of Education, Culture and Science
- Ministry for Health, Welfare and Sports
- European Commission
- Municipality of Rotterdam
- Nestl
- Nutrition (Nestec Ltd.)
- Metagenics Inc.
- AXA
- Swedish Cancer Society
- Swedish Medical Research Council
- Swedish Dairy Association
- Albert Pahlsson and Gunnar Nilsson Foundations
- Malm city council
- Swedish National Health Service
- Marta Winkler Foundation
- Swedish Heart Association
- Swedish Heart-Lung Foundation
- Swedish Research Council
- European Research Council
- Skane University Hospital in Lund
- Crafoord Foundation
- National Cancer Institute [CA-34944, CA-40360, CA-097193]
- National Heart, Lung, and Blood Institute, Bethesda, MD [HL-26490, HL-34595]
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.
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