DNA methylation-based estimator of telomere length

被引：244

作者：

Lu, Ake T. ^{[1
]}

Seeboth, Anne ^{[2
]}

Tsai, Pei-Chien ^{[3
,4
,5
]}

Sun, Dianjianyi ^{[6
,7
]}

Quach, Austin ^{[1
]}

Reiner, Alex P. ^{[8
]}

Kooperberg, Charles ^{[8
]}

Ferrucci, Luigi ^{[9
]}

Hou, Lifang ^{[10
,11
]}

Baccarelli, Andrea A. ^{[12
]}

Li, Yun ^{[13
,14
,15
]}

Harris, Sarah E. ^{[16
,17
]}

Corley, Janie ^{[16
,17
]}

Taylor, Adele ^{[16
,17
]}

Deary, Ian J. ^{[16
,17
]}

Stewart, James D. ^{[18
]}

Whitsel, Eric A. ^{[18
,19
]}

Assimes, Themistocles L. ^{[20
,21
]}

Chen, Wei ^{[7
]}

Li, Shengxu ^{[22
]}

Mangino, Massimo ^{[3
]}

Bell, Jordana T. ^{[3
]}

Wilson, James G. ^{[23
]}

Aviv, Abraham ^{[24
]}

Marioni, Riccardo E. ^{[2
,16
]}

Raj, Kenneth ^{[25
]}

Horvath, Steve ^{[1
,26
]}

机构：

[1] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA

[2] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Edinburgh EH4 2XU, Midlothian, Scotland

[3] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England

[4] Chang Gung Univ, Dept Biomed Sci, Taoyuan, Taiwan

[5] Chang Gung Mem Hosp, Genom Med Res Core Lab, Linkou, Taiwan

[6] Peking Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Hlth Sci Ctr, Beijing, Peoples R China

[7] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA 70112 USA

[8] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA

[9] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA

[10] Northwestern Univ, Feinberg Sch Med, Ctr Populat Epigenet, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA

[11] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA

[12] Columbia Univ, Mailman Sch Publ Hlth, Lab Environm Epigenet, Dept Environm Hlth Sci Epidemiol, New York, NY 10032 USA

[13] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA

[14] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA

[15] Univ N Carolina, Dept Comp Sci, Chapel Hill, NC 27599 USA

[16] Univ Edinburgh, Dept Psychol, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland

[17] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland

[18] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA

[19] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC 27599 USA

[20] VA Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA

[21] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA

[22] Childrens Hosp & Clin Minnesota, Childrens Minnesota Res Inst, Minneapolis, MN 55404 USA

[23] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA

[24] Rutgers State Univ, New Jersey Med Sch, Ctr Dev & Aging, Newark, NJ 07103 USA

[25] Publ Hlth England, Ctr Radiat Chem & Environm Hazards, Radiat Effects Dept, Didcot OX11 0RQ, Oxon, England

[26] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90095 USA

来源：

AGING-US | 2019年 / 11卷 / 16期

基金：

英国惠康基金; 美国国家卫生研究院; 英国生物技术与生命科学研究理事会; 英国医学研究理事会;

关键词：

telomere length; DNA methylation; molecular biomarker; aging; CARDIOVASCULAR-DISEASE; EPIGENETIC CLOCK; AGE; ASSOCIATION; HEALTH; NORMALIZATION; METAANALYSIS; MENOPAUSE; BIOMARKER; VARIANTS;

D O I：

10.18632/aging.102173

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Telomere length (TL) is associated with several aging-related diseases. Here, we present a DNA methylation estimator of TL (DNAmTL) based on 140 CpGs. Leukocyte DNAmTL is applicable across the entire age spectrum and is more strongly associated with age than measured leukocyte TL (LTL) (r (similar to)-0.75 for DNAmTL versus r (similar to) -0.35 for LTL). Leukocyte DNAmTL outperforms LTL in predicting: i) time-to-death (p=2.5E-20), ii) time-tocoronary heart disease (p=6.6E-5), iii) time-to-congestive heart failure (p=3.5E-6), and iv) association with smoking history (p=1.21E-17). These associations are further validated in large scale methylation data (n=10k samples) from the Framingham Heart Study, Women's Health Initiative, Jackson Heart Study, InChianti, Lothian Birth Cohorts, Twins UK, and Bogalusa Heart Study. Leukocyte DNAmTL is also associated with measures of physical fitness/functioning (p=0.029), age-at-menopause (p=0.039), dietary variables (omega 3, fish, vegetable intake), educational attainment (p=3.3E-8) and income (p=3.1E-5). Experiments in cultured somatic cells show that DNAmTL dynamics reflect in part cell replication rather than TL per se. DNAmTL is not only an epigenetic biomarker of replicative history of cells, but a useful marker of age-related pathologies that are associated with it.

引用

页码：5895 / 5923

页数：29

共 69 条

[1] DNA Methylation Analysis in Nonalcoholic Fatty Liver Disease Suggests Distinct Disease-Specific and Remodeling Signatures after Bariatric Surgery [J].

Ahrens, Markus ;

Ammerpohl, Ole ;

von Schoenfels, Witigo ;

Kolarova, Julia ;

Bens, Susanne ;

Itzel, Timo ;

Teufel, Andreas ;

Herrmann, Alexander ;

Brosch, Mario ;

Hinrichsen, Holger ;

Erhart, Wiebke ;

Egberts, Jan ;

Sipos, Bence ;

Schreiber, Stefan ;

Haesler, Robert ;

Stickel, Felix ;

Becker, Thomas ;

Krawczak, Michael ;

Roecken, Christoph ;

Siebert, Reiner ;

Schafmayer, Clemens ;

Hampe, Jochen .

CELL METABOLISM, 2013, 18 (02) :296-302

[2]

Anderson G, 1998, CONTROL CLIN TRIALS, V19, P61

[3] Implementation of the Women's Health Initiative Study Design [J].

Anderson, GL ;

Manson, J ;

Wallace, R ;

Lund, B ;

Hall, D ;

Davis, S ;

Shumaker, S ;

Wang, CY ;

Stein, E ;

Prentice, RL .

ANNALS OF EPIDEMIOLOGY, 2003, 13 (09) :S5-S17

[4] Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays [J].

Aryee, Martin J. ;

Jaffe, Andrew E. ;

Corrada-Bravo, Hector ;

Ladd-Acosta, Christine ;

Feinberg, Andrew P. ;

Hansen, Kasper D. ;

Irizarry, Rafael A. .

BIOINFORMATICS, 2014, 30 (10) :1363-1369

[5] Reflections on telomere dynamics and ageing-related diseases in humans [J].

Aviv, Abraham ;

Shay, Jerry W. .

PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, 2018, 373 (1741)

[6] Quantitative comparison of DNA methylation assays for biomarker development and clinical applications [J].

Bock, Christoph ;

Halbritter, Florian ;

Carmona, Francisco J. ;

Tierling, Sascha ;

Datlinger, Paul ;

Assenov, Yassen ;

Berdasco, Maria ;

Bergmann, Anke K. ;

Booher, Keith ;

Busato, Florence ;

Campan, Mihaela ;

Dahl, Christina ;

Dahmcke, Christina M. ;

Diep, Dinh ;

Fernandez, Agustin F. ;

Gerhauser, Clarissa ;

Haake, Andrea ;

Heilmann, Katharina ;

Holcomb, Thomas ;

Hussmann, Dianna ;

Ito, Mitsuteru ;

Klaever, Ruth ;

Kreutz, Martin ;

Kulis, Marta ;

Lopez, Virginia ;

Nair, Shalima S. ;

Paul, Dirk S. ;

Plongthongkum, Nongluk ;

Qu, Wenjia ;

Queiros, Ana C. ;

Reinicke, Frank ;

Sauter, Guido ;

Schlomm, Thorsten ;

Statham, Aaron ;

Stirzaker, Clare ;

Strogantsev, Ruslan ;

Urdinguio, Rocio G. ;

Walter, Kimberly ;

Weichenhan, Dieter ;

Weisenberger, Daniel J. ;

Beck, Stephan ;

Clark, Susan J. ;

Esteller, Manel ;

Ferguson-Smith, Anne C. ;

Fraga, Mario F. ;

Guldberg, Per ;

Hansen, Lise Lotte ;

Laird, Peter W. ;

Martin-Subero, Jose I. ;

Nygren, Anders O. H. .

NATURE BIOTECHNOLOGY, 2016, 34 (07) :726-+

[7] Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer [J].

Bojesen, Stig E. ;

Pooley, Karen A. ;

Johnatty, Sharon E. ;

Beesley, Jonathan ;

Michailidou, Kyriaki ;

Tyrer, Jonathan P. ;

Edwards, Stacey L. ;

Pickett, Hilda A. ;

Shen, Howard C. ;

Smart, Chanel E. ;

Hillman, Kristine M. ;

Mai, Phuong L. ;

Lawrenson, Kate ;

Stutz, Michael D. ;

Lu, Yi ;

Karevan, Rod ;

Woods, Nicholas ;

Johnston, Rebecca L. ;

French, Juliet D. ;

Chen, Xiaoqing ;

Weischer, Maren ;

Nielsen, Sune F. ;

Maranian, Melanie J. ;

Ghoussaini, Maya ;

Ahmed, Shahana ;

Baynes, Caroline ;

Bolla, Manjeet K. ;

Wang, Qin ;

Dennis, Joe ;

McGuffog, Lesley ;

Barrowdale, Daniel ;

Lee, Andrew ;

Healey, Sue ;

Lush, Michael ;

Tessier, Daniel C. ;

Vincent, Daniel ;

Bacot, Francis ;

Vergote, Ignace ;

Lambrechts, Sandrina ;

Despierre, Evelyn ;

Risch, Harvey A. ;

Gonzalez-Neira, Anna ;

Rossing, Mary Anne ;

Pita, Guillermo ;

Doherty, Jennifer A. ;

Alvarez, Nuria ;

Larson, Melissa C. ;

Fridley, Brooke L. ;

Schoof, Nils ;

Chang-Claude, Jenny .

NATURE GENETICS, 2013, 45 (04) :371-384

[8] Frailty is associated with the epigenetic clock but not with telomere length in a German cohort [J].

Breitling, Lutz Philipp ;

Saum, Kai-Uwe ;

Perna, Laura ;

Schoettker, Ben ;

Holleczek, Bernd ;

Brenner, Hermann .

CLINICAL EPIGENETICS, 2016, 8 :1-8

[9] Leukocyte telomere length, T cell composition and DNA methylation age [J].

Chen, Brian H. ;

Carty, Cara L. ;

Kimura, Masayuki ;

Kark, Jeremy D. ;

Chen, Wei ;

Li, Shengxu ;

Zhang, Tao ;

Kooperberg, Charles ;

Levy, Daniel ;

Assimes, Themistocles ;

Absher, Devin ;

Horvath, Steve ;

Reiner, Alexander P. ;

Aviv, Abraham .

AGING-US, 2017, 9 (09) :1983-1995

[10] Longitudinal versus Cross-sectional Evaluations of Leukocyte Telomere Length Dynamics: Age-Dependent Telomere Shortening is the Rule [J].

Chen, W. ;

Kimura, M. ;

Kim, S. ;

Cao, X. ;

Srinivasan, S. R. ;

Berenson, G. S. ;

Kark, J. D. ;

Aviv, A. .

JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES, 2011, 66 (03) :312-319

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