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PMID: 28303888 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

DNA methylation signatures in peripheral blood strongly predict all-cause mortality.

Nature communications ·Vol. 8 ·2017-00-17 ·Pages 14617

Zhang Y, Wilson R, Heiss J, Breitling LP, Saum KU, Schöttker B, Holleczek B, Waldenberger M, Peters A, Brenner H

Abstract

DNA methylation (DNAm) has been revealed to play a role in various diseases. Here we performed epigenome-wide screening and validation to identify mortality-related DNAm signatures in a general population-based cohort with up to 14 years follow-up. In the discovery panel in a case-cohort approach, 11,063 CpGs reach genome-wide significance (FDR<0.05). 58 CpGs, mapping to 38 well-known disease-related genes and 14 intergenic regions, are confirmed in a validation panel. A mortality risk score based on ten selected CpGs exhibits strong association with all-cause mortality, showing hazard ratios (95% CI) of 2.16 (1.10-4.24), 3.42 (1.81-6.46) and 7.36 (3.69-14.68), respectively, for participants with scores of 1, 2-5 and 5+ compared with a score of 0. These associations are confirmed in an independent cohort and are independent from the 'epigenetic clock'. In conclusion, DNAm of multiple disease-related genes are strongly linked to mortality outcomes. The DNAm-based risk score might be informative for risk assessment and stratification.

MeSH Terms
Aged Cardiovascular Diseases/epidemiology Cause of Death Cohort Studies CpG Islands DNA Methylation/genetics Diabetes Mellitus/epidemiology Epigenesis, Genetic Female Follow-Up Studies Humans Hypertension/epidemiology Male Middle Aged Mortality Neoplasms/epidemiology Obesity/epidemiology Overweight/epidemiology Proportional Hazards Models Smoking/epidemiology Thinness/epidemiology
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Zhang Yan ORCID
Division of Clinical Epidemiology and Aging Research, German Research Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Wilson Rory
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Center for Environmental Health, D-85764 Neuherberg, Germany. | Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764 Neuherberg, Germany.
Heiss Jonathan
Division of Clinical Epidemiology and Aging Research, German Research Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Breitling Lutz P
Division of Clinical Epidemiology and Aging Research, German Research Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Saum Kai-Uwe
Division of Clinical Epidemiology and Aging Research, German Research Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Schöttker Ben
Division of Clinical Epidemiology and Aging Research, German Research Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. | Network Ageing Research, University of Heidelberg, Bergheimer Strasse 20, D-69115 Heidelberg, Germany.
Holleczek Bernd
Saarland Cancer Registry, Präsident Baltz Strasse 5, D-66119 Saarbrücken, Germany.
Waldenberger Melanie
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Center for Environmental Health, D-85764 Neuherberg, Germany. | Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764 Neuherberg, Germany.
Peters Annette
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Center for Environmental Health, D-85764 Neuherberg, Germany. | Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764 Neuherberg, Germany.
Brenner Hermann
Division of Clinical Epidemiology and Aging Research, German Research Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. | Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany. | German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
References (60)
60 references, click to expand
  1. GADD34-deficient mice develop obesity, nonalcoholic fatty liver disease, hepatic carcinoma and insulin resistance.
    Sci Rep. 2015 Aug 28;5:13519 PMID: 26316333
  2. Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population.
    PLoS Genet. 2012;8(4):e1002629 PMID: 22532803
  3. Case-cohort design in practice - experiences from the MORGAM Project.
    Epidemiol Perspect Innov. 2007 Dec 04;4:15 PMID: 18053196
  4. Increased GADD34 in oligodendrocytes in Alzheimer's disease.
    Neurosci Lett. 2015 Aug 18;602:50-5 PMID: 26142647
  5. Regularization Paths for Generalized Linear Models via Coordinate Descent.
    J Stat Softw. 2010;33(1):1-22 PMID: 20808728
  6. Genome-scale approaches to the epigenetics of common human disease.
    Virchows Arch. 2010 Jan;456(1):13-21 PMID: 19844740
  7. Self-reported smoking, serum cotinine, and blood DNA methylation.
    Environ Res. 2016 Apr;146:395-403 PMID: 26826776
  8. Robust variance estimation for the case-cohort design.
    Biometrics. 1994 Dec;50(4):1064-72 PMID: 7786988
  9. Strong associations of 25-hydroxyvitamin D concentrations with all-cause, cardiovascular, cancer, and respiratory disease mortality in a large cohort study.
    Am J Clin Nutr. 2013 Apr;97(4):782-93 PMID: 23446902
  10. A coherent approach for analysis of the Illumina HumanMethylation450 BeadChip improves data quality and performance in epigenome-wide association studies.
    Genome Biol. 2015 Feb 15;16:37 PMID: 25853392
  11. Smoking and obesity associated BDNF gene variance predicts total and cardiovascular mortality in smokers.
    Heart. 2013 Jul;99(13):949-53 PMID: 23624487
  12. DNA methylation age of human tissues and cell types.
    Genome Biol. 2013;14(10):R115 PMID: 24138928
  13. Association between DNA Methylation in Whole Blood and Measures of Glucose Metabolism: KORA F4 Study.
    PLoS One. 2016 Mar 28;11(3):e0152314 PMID: 27019061
  14. Epigenetic associations of type 2 diabetes and BMI in an Arab population.
    Clin Epigenetics. 2016 Jan 28;8:13 PMID: 26823690
  15. A genome-wide association study of aging.
    Neurobiol Aging. 2011 Nov;32(11):2109.e15-28 PMID: 21782286
  16. Epigenome-wide association of DNA methylation markers in peripheral blood from Indian Asians and Europeans with incident type 2 diabetes: a nested case-control study.
    Lancet Diabetes Endocrinol. 2015 Jul;3(7):526-34 PMID: 26095709
  17. Identification of the growth arrest and DNA damage protein GADD34 in the normal human heart and demonstration of alterations in expression following myocardial ischaemia.
    Int J Cardiol. 2006 Feb 8;107(1):126-9 PMID: 16337513
  18. Tobacco smoking leads to extensive genome-wide changes in DNA methylation.
    PLoS One. 2013 May 17;8(5):e63812 PMID: 23691101
  19. KORA--a research platform for population based health research.
    Gesundheitswesen. 2005 Aug;67 Suppl 1:S19-25 PMID: 16032513
  20. Regulation of functional KCNQ1OT1 lncRNA by β-catenin.
    Sci Rep. 2016 Feb 12;6:20690 PMID: 26868975
  21. DNA methylation levels at individual age-associated CpG sites can be indicative for life expectancy.
    Aging (Albany NY). 2016 Feb;8(2):394-401 PMID: 26928272
  22. Genome-wide DNA methylation analysis of human pancreatic islets from type 2 diabetic and non-diabetic donors identifies candidate genes that influence insulin secretion.
    PLoS Genet. 2014 Mar 06;10(3):e1004160 PMID: 24603685
  23. Cross-sectional and longitudinal changes in DNA methylation with age: an epigenome-wide analysis revealing over 60 novel age-associated CpG sites.
    Hum Mol Genet. 2014 Mar 1;23(5):1186-201 PMID: 24163245
  24. MCPIP1 Selectively Destabilizes Transcripts Associated with an Antiapoptotic Gene Expression Program in Breast Cancer Cells That Can Elicit Complete Tumor Regression.
    Cancer Res. 2016 Mar 15;76(6):1429-40 PMID: 26833120
  25. Frequent MYC coamplification and DNA hypomethylation of multiple genes on 8q in 8p11-p12-amplified breast carcinomas.
    Oncogenesis. 2014 Mar 24;3:e95 PMID: 24662924
  26. Long noncoding RNAs in patients with acute myocardial infarction.
    Circ Res. 2014 Sep 12;115(7):668-77 PMID: 25035150
  27. Insights into the molecular mechanism for type 2 diabetes susceptibility at the KCNQ1 locus from temporal changes in imprinting status in human islets.
    Diabetes. 2013 Mar;62(3):987-92 PMID: 23139357
  28. Chronic conditions and mortality among the oldest old.
    Am J Public Health. 2008 Jul;98(7):1209-14 PMID: 18511714
  29. The Role of DNA Methylation in Cardiovascular Risk and Disease: Methodological Aspects, Study Design, and Data Analysis for Epidemiological Studies.
    Circ Res. 2016 Jan 8;118(1):119-31 PMID: 26837743
  30. F2RL3 methylation, lung cancer incidence and mortality.
    Int J Cancer. 2015 Oct 1;137(7):1739-48 PMID: 25821117
  31. Correlation of Smoking-Associated DNA Methylation Changes in Buccal Cells With DNA Methylation Changes in Epithelial Cancer.
    JAMA Oncol. 2015 Jul;1(4):476-85 PMID: 26181258
  32. Alterations of a Cellular Cholesterol Metabolism Network Are a Molecular Feature of Obesity-Related Type 2 Diabetes and Cardiovascular Disease.
    Diabetes. 2015 Oct;64(10 ):3464-74 PMID: 26153245
  33. A critical re-assessment of DNA repair gene promoter methylation in non-small cell lung carcinoma.
    Sci Rep. 2014 Feb 26;4:4186 PMID: 24569633
  34. DNA methylation age is associated with mortality in a longitudinal Danish twin study.
    Aging Cell. 2016 Feb;15(1):149-54 PMID: 26594032
  35. The role of DNA methylation in stress-related psychiatric disorders.
    Neuropharmacology. 2014 May;80:115-32 PMID: 24452011
  36. Analysis of DNA methylation and gene expression in radiation-resistant head and neck tumors.
    Epigenetics. 2015;10(6):545-61 PMID: 25961636
  37. DNA methylation and body-mass index: a genome-wide analysis.
    Lancet. 2014 Jun 7;383(9933):1990-8 PMID: 24630777
  38. Altered DNA methylation and differential expression of genes influencing metabolism and inflammation in adipose tissue from subjects with type 2 diabetes.
    Diabetes. 2014 Sep;63(9):2962-76 PMID: 24812430
  39. An integrated genomic-transcriptomic approach supports a role for the proto-oncogene BCL3 in atherosclerosis.
    Thromb Haemost. 2015 Mar;113(3):655-63 PMID: 25374339
  40. Amino Acid transporters in cancer and their relevance to "glutamine addiction": novel targets for the design of a new class of anticancer drugs.
    Cancer Res. 2015 May 1;75(9):1782-8 PMID: 25855379
  41. Epigenetics in autoimmune diseases with focus on type 1 diabetes.
    Diabetes Metab Res Rev. 2013 Jan;29(1):8-18 PMID: 23180441
  42. DNA methylation age of blood predicts all-cause mortality in later life.
    Genome Biol. 2015 Jan 30;16:25 PMID: 25633388
  43. Frailty is associated with the epigenetic clock but not with telomere length in a German cohort.
    Clin Epigenetics. 2016 Feb 26;8:21 PMID: 26925173
  44. Expression of Id proteins is regulated by the Bcl-3 proto-oncogene in prostate cancer.
    Oncogene. 2013 Mar 21;32(12):1601-8 PMID: 22580608
  45. F2RL3 methylation as a biomarker of current and lifetime smoking exposures.
    Environ Health Perspect. 2014 Feb;122(2):131-7 PMID: 24273234
  46. The epigenetic clock and telomere length are independently associated with chronological age and mortality.
    Int J Epidemiol. 2016 Apr 13;:null PMID: 27075770
  47. The lasso method for variable selection in the Cox model.
    Stat Med. 1997 Feb 28;16(4):385-95 PMID: 9044528
  48. Genome-wide methylation profiles reveal quantitative views of human aging rates.
    Mol Cell. 2013 Jan 24;49(2):359-67 PMID: 23177740
  49. Dynamics of smoking-induced genome-wide methylation changes with time since smoking cessation.
    Hum Mol Genet. 2015 Apr 15;24(8):2349-59 PMID: 25556184
  50. Change in Epigenome-Wide DNA Methylation Over 9 Years and Subsequent Mortality: Results From the InCHIANTI Study.
    J Gerontol A Biol Sci Med Sci. 2016 Aug;71(8):1029-35 PMID: 26355017
  51. DNA methylation changes of whole blood cells in response to active smoking exposure in adults: a systematic review of DNA methylation studies.
    Clin Epigenetics. 2015 Oct 16;7:113 PMID: 26478754
  52. Discovery of cross-reactive probes and polymorphic CpGs in the Illumina Infinium HumanMethylation450 microarray.
    Epigenetics. 2013 Feb;8(2):203-9 PMID: 23314698
  53. DNA methylation arrays as surrogate measures of cell mixture distribution.
    BMC Bioinformatics. 2012 May 08;13:86 PMID: 22568884
  54. Aging and DNA methylation.
    BMC Biol. 2015 Jan 31;13:7 PMID: 25637097
  55. Dose-response analyses using restricted cubic spline functions in public health research.
    Stat Med. 2010 Apr 30;29(9):1037-57 PMID: 20087875
  56. F2RL3 methylation in blood DNA is a strong predictor of mortality.
    Int J Epidemiol. 2014 Aug;43(4):1215-25 PMID: 24510982
  57. Ageing-associated changes in the human DNA methylome: genomic locations and effects on gene expression.
    BMC Genomics. 2015 Mar 14;16:179 PMID: 25888029
  58. Smoking-Associated DNA Methylation Biomarkers and Their Predictive Value for All-Cause and Cardiovascular Mortality.
    Environ Health Perspect. 2016 Jan;124(1):67-74 PMID: 26017925
  59. DNA demethylation by 5-aza-2-deoxycytidine treatment abrogates 17 beta-estradiol-induced cell growth and restores expression of DNA repair genes in human breast cancer cells.
    Cancer Lett. 2012 Mar;316(1):62-9 PMID: 22082530
  60. Aging of blood can be tracked by DNA methylation changes at just three CpG sites.
    Genome Biol. 2014 Feb 03;15(2):R24 PMID: 24490752
Article Info
Journal
Nature communications
Abbr.
Nat Commun
ISSN
2041-1723
DOI
10.1038/ncomms14617
Published
2017-00-17
Epub
2017-00-17
Pages
14617
Language
English
Region
England
NLM ID
101528555
PMCID
PMC5357865
Subset
IM
External Links
PubMed source DOI: 10.1038/ncomms14617 PMC Full Text View journal details
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