Association between telomere length and risk of cancer and non-neoplastic diseases a mendelian randomization study

Telomeres Mendelian Randomization Collaboration

Research output: Contribution to journalArticle

119 Citations (Scopus)

Abstract

IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

Original languageEnglish
Pages (from-to)636-651
Number of pages16
JournalJAMA Oncology
Volume3
Issue number5
DOIs
Publication statusPublished - 1 Jan 2017

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Telomere
Random Allocation
Odds Ratio
Confidence Intervals
Neoplasms
Preexisting Condition Coverage
Kidney Neoplasms
Interstitial Lung Diseases
Abdominal Aortic Aneurysm
Testicular Neoplasms
Celiac Disease
Endometrial Neoplasms
Neuroblastoma
Urinary Bladder Neoplasms
Glioma
Causality
Cell Division
Ovarian Neoplasms
Observational Studies
Single Nucleotide Polymorphism

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Telomeres Mendelian Randomization Collaboration. / Association between telomere length and risk of cancer and non-neoplastic diseases a mendelian randomization study. In: JAMA Oncology. 2017 ; Vol. 3, No. 5. pp. 636-651.
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title = "Association between telomere length and risk of cancer and non-neoplastic diseases a mendelian randomization study",
abstract = "IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95{\%} confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95{\%} CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95{\%} CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95{\%} CI, 0.49-0.81]), celiac disease (OR, 0.42 [95{\%} CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95{\%} CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.",
author = "{Telomeres Mendelian Randomization Collaboration} and Haycock, {Philip C.} and Stephen Burgess and Aayah Nounu and Jie Zheng and Okoli, {George N.} and Jack Bowden and Wade, {Kaitlin Hazel} and Timpson, {Nicholas J.} and Evans, {David M.} and Peter Willeit and Abraham Aviv and Gaunt, {Tom R.} and Gibran Hemani and Massimo Mangino and Ellis, {Hayley Patricia} and Kurian, {Kathreena M.} and Pooley, {Karen A.} and Eeles, {Rosalind A.} and Lee, {Jeffrey E.} and Shenying Fang and Chen, {Wei V.} and Law, {Matthew H.} and Bowdler, {Lisa M.} and Iles, {Mark M.} and Qiong Yang and Worrall, {Bradford B.} and Markus, {Hugh Stephen} and Hung, {Rayjean J.} and Amos, {Chris I.} and Spurdle, {Amanda B.} and Thompson, {Deborah J.} and O'Mara, {Tracy A.} and Brian Wolpin and Laufey Amundadottir and Rachael Stolzenberg-Solomon and Antonia Trichopoulou and Onland-Moret, {N. Charlotte} and Eiliv Lund and Duell, {Eric J.} and Federico Canzian and Gianluca Severi and Kim Overvad and Gunter, {Marc J.} and Rosario Tumino and Ulrika Svenson and {Van Rij}, Andre and Baas, {Annette F.} and Bown, {Matthew J.} and Samani, {Nilesh J.} and {Van t'Hof}, {Femke N.G.} and Gerard Tromp and Jones, {Gregory T.} and Helena Kuivaniemi and Elmore, {James R.} and Mattias Johansson and James Mckay and Ghislaine Scelo and Robert Carreras-Torres and Valerie Gaborieau and Paul Brennan and Bracci, {Paige M.} and Neale, {Rachel E.} and Olson, {Sara H.} and Steven Gallinger and Donghui Li and Petersen, {Gloria M.} and Risch, {Harvey A.} and Klein, {Alison P.} and Jiali Han and Abnet, {Christian C.} and Freedman, {Neal D.} and Taylor, {Philip R.} and Maris, {John M.} and Aben, {Katja K.} and Kiemeney, {Lambertus A.} and Vermeulen, {Sita H.} and Wiencke, {John K.} and Walsh, {Kyle M.} and Margaret Wrensch and Terri Rice and Clare Turnbull and Kevin Litchfield and Lavinia Paternoster and Marie Standl and Abecasis, {Gon{\cc}alo R.} and SanGiovanni, {John Paul} and Yong Li and Vladan Mijatovic and Yadav Sapkota and Low, {Siew Kee} and Zondervan, {Krina T.} and Montgomery, {Grant W.} and Nyholt, {Dale R.} and {Van Heel}, {David A.} and Karen Hunt and Arking, {Dan E.} and Ashar, {Foram N.} and Nona Sotoodehnia and Daniel Woo and Jonathan Rosand and Comeau, {Mary E.} and Brown, {W. Mark} and Silverman, {Edwin K.} and Hokanson, {John E.} and Cho, {Michael H.} and Jennie Hui and Ferreira, {Manuel A.} and Thompson, {Philip J.} and Morrison, {Alanna C.} and Felix, {Janine F.} and Smith, {Nicholas L.} and Christiano, {Angela M.} and Lynn Petukhova and Betz, {Regina C.} and Xing Fan and Xuejun Zhang and Caihong Zhu and Langefeld, {Carl D.} and Thompson, {Susan D.} and Feijie Wang and Xu Lin and Schwartz, {David A.} and Tasha Fingerlin and Rotter, {Jerome I.} and Cotch, {Mary Frances} and Jensen, {Richard A.} and Matthias Munz and Henrik Dommisch and Schaefer, {Arne S.} and Fang Han and Ollila, {Hanna M.} and Hillary, {Ryan P.} and Omar Albagha and Ralston, {Stuart H.} and Chenjie Zeng and Wei Zheng and Shu, {Xiao Ou} and Andre Reis and Steffen Uebe and Ulrike H{\"u}ffmeier and Yoshiya Kawamura and Takeshi Otowa and Tsukasa Sasaki and Hibberd, {Martin Lloyd} and Sonia Davila and Gang Xie and Katherine Siminovitch and Bei, {Jin Xin} and Zeng, {Yi Xin} and Asta F{\"o}rsti and Bowang Chen and Stefano Landi and Andre Franke and Annegret Fischer and David Ellinghaus and Carlos Flores and Imre Noth and Ma, {Shwu Fan} and Foo, {Jia Nee} and Jianjun Liu and Kim, {Jong Won} and Cox, {David G.} and Olivier Delattre and Olivier Mirabeau and Skibola, {Christine F.} and Tang, {Clara S.} and Merce Garcia-Barcelo and Chang, {Kai Ping} and Su, {Wen Hui} and Chang, {Yu Sun} and Martin, {Nicholas G.} and Scott Gordon and Wade, {Tracey D.} and Chaeyoung Lee and Michiaki Kubo and Cha, {Pei Chieng} and Yusuke Nakamura and Daniel Levy and Masayuki Kimura and Hwang, {Shih Jen} and Steven Hunt and Tim Spector and Nicole Soranzo and Manichaikul, {Ani W.} and Barr, {R. Graham} and Bratati Kahali and Elizabeth Speliotes and Yerges-Armstrong, {Laura M.} and Cheng, {Ching Yu} and Jonas, {Jost B.} and Wong, {Tien Yin} and Isabella Fogh and Kuang Lin and Powell, {John F.} and Kenneth Rice and Relton, {Caroline L.} and Martin, {Richard M.} and {Davey Smith}, George",
year = "2017",
month = "1",
day = "1",
doi = "10.1001/jamaoncol.2016.5945",
language = "English",
volume = "3",
pages = "636--651",
journal = "JAMA Oncology",
issn = "2374-2437",
publisher = "American Medical Association",
number = "5",

}

Association between telomere length and risk of cancer and non-neoplastic diseases a mendelian randomization study. / Telomeres Mendelian Randomization Collaboration.

In: JAMA Oncology, Vol. 3, No. 5, 01.01.2017, p. 636-651.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Association between telomere length and risk of cancer and non-neoplastic diseases a mendelian randomization study

AU - Telomeres Mendelian Randomization Collaboration

AU - Haycock, Philip C.

AU - Burgess, Stephen

AU - Nounu, Aayah

AU - Zheng, Jie

AU - Okoli, George N.

AU - Bowden, Jack

AU - Wade, Kaitlin Hazel

AU - Timpson, Nicholas J.

AU - Evans, David M.

AU - Willeit, Peter

AU - Aviv, Abraham

AU - Gaunt, Tom R.

AU - Hemani, Gibran

AU - Mangino, Massimo

AU - Ellis, Hayley Patricia

AU - Kurian, Kathreena M.

AU - Pooley, Karen A.

AU - Eeles, Rosalind A.

AU - Lee, Jeffrey E.

AU - Fang, Shenying

AU - Chen, Wei V.

AU - Law, Matthew H.

AU - Bowdler, Lisa M.

AU - Iles, Mark M.

AU - Yang, Qiong

AU - Worrall, Bradford B.

AU - Markus, Hugh Stephen

AU - Hung, Rayjean J.

AU - Amos, Chris I.

AU - Spurdle, Amanda B.

AU - Thompson, Deborah J.

AU - O'Mara, Tracy A.

AU - Wolpin, Brian

AU - Amundadottir, Laufey

AU - Stolzenberg-Solomon, Rachael

AU - Trichopoulou, Antonia

AU - Onland-Moret, N. Charlotte

AU - Lund, Eiliv

AU - Duell, Eric J.

AU - Canzian, Federico

AU - Severi, Gianluca

AU - Overvad, Kim

AU - Gunter, Marc J.

AU - Tumino, Rosario

AU - Svenson, Ulrika

AU - Van Rij, Andre

AU - Baas, Annette F.

AU - Bown, Matthew J.

AU - Samani, Nilesh J.

AU - Van t'Hof, Femke N.G.

AU - Tromp, Gerard

AU - Jones, Gregory T.

AU - Kuivaniemi, Helena

AU - Elmore, James R.

AU - Johansson, Mattias

AU - Mckay, James

AU - Scelo, Ghislaine

AU - Carreras-Torres, Robert

AU - Gaborieau, Valerie

AU - Brennan, Paul

AU - Bracci, Paige M.

AU - Neale, Rachel E.

AU - Olson, Sara H.

AU - Gallinger, Steven

AU - Li, Donghui

AU - Petersen, Gloria M.

AU - Risch, Harvey A.

AU - Klein, Alison P.

AU - Han, Jiali

AU - Abnet, Christian C.

AU - Freedman, Neal D.

AU - Taylor, Philip R.

AU - Maris, John M.

AU - Aben, Katja K.

AU - Kiemeney, Lambertus A.

AU - Vermeulen, Sita H.

AU - Wiencke, John K.

AU - Walsh, Kyle M.

AU - Wrensch, Margaret

AU - Rice, Terri

AU - Turnbull, Clare

AU - Litchfield, Kevin

AU - Paternoster, Lavinia

AU - Standl, Marie

AU - Abecasis, Gonçalo R.

AU - SanGiovanni, John Paul

AU - Li, Yong

AU - Mijatovic, Vladan

AU - Sapkota, Yadav

AU - Low, Siew Kee

AU - Zondervan, Krina T.

AU - Montgomery, Grant W.

AU - Nyholt, Dale R.

AU - Van Heel, David A.

AU - Hunt, Karen

AU - Arking, Dan E.

AU - Ashar, Foram N.

AU - Sotoodehnia, Nona

AU - Woo, Daniel

AU - Rosand, Jonathan

AU - Comeau, Mary E.

AU - Brown, W. Mark

AU - Silverman, Edwin K.

AU - Hokanson, John E.

AU - Cho, Michael H.

AU - Hui, Jennie

AU - Ferreira, Manuel A.

AU - Thompson, Philip J.

AU - Morrison, Alanna C.

AU - Felix, Janine F.

AU - Smith, Nicholas L.

AU - Christiano, Angela M.

AU - Petukhova, Lynn

AU - Betz, Regina C.

AU - Fan, Xing

AU - Zhang, Xuejun

AU - Zhu, Caihong

AU - Langefeld, Carl D.

AU - Thompson, Susan D.

AU - Wang, Feijie

AU - Lin, Xu

AU - Schwartz, David A.

AU - Fingerlin, Tasha

AU - Rotter, Jerome I.

AU - Cotch, Mary Frances

AU - Jensen, Richard A.

AU - Munz, Matthias

AU - Dommisch, Henrik

AU - Schaefer, Arne S.

AU - Han, Fang

AU - Ollila, Hanna M.

AU - Hillary, Ryan P.

AU - Albagha, Omar

AU - Ralston, Stuart H.

AU - Zeng, Chenjie

AU - Zheng, Wei

AU - Shu, Xiao Ou

AU - Reis, Andre

AU - Uebe, Steffen

AU - Hüffmeier, Ulrike

AU - Kawamura, Yoshiya

AU - Otowa, Takeshi

AU - Sasaki, Tsukasa

AU - Hibberd, Martin Lloyd

AU - Davila, Sonia

AU - Xie, Gang

AU - Siminovitch, Katherine

AU - Bei, Jin Xin

AU - Zeng, Yi Xin

AU - Försti, Asta

AU - Chen, Bowang

AU - Landi, Stefano

AU - Franke, Andre

AU - Fischer, Annegret

AU - Ellinghaus, David

AU - Flores, Carlos

AU - Noth, Imre

AU - Ma, Shwu Fan

AU - Foo, Jia Nee

AU - Liu, Jianjun

AU - Kim, Jong Won

AU - Cox, David G.

AU - Delattre, Olivier

AU - Mirabeau, Olivier

AU - Skibola, Christine F.

AU - Tang, Clara S.

AU - Garcia-Barcelo, Merce

AU - Chang, Kai Ping

AU - Su, Wen Hui

AU - Chang, Yu Sun

AU - Martin, Nicholas G.

AU - Gordon, Scott

AU - Wade, Tracey D.

AU - Lee, Chaeyoung

AU - Kubo, Michiaki

AU - Cha, Pei Chieng

AU - Nakamura, Yusuke

AU - Levy, Daniel

AU - Kimura, Masayuki

AU - Hwang, Shih Jen

AU - Hunt, Steven

AU - Spector, Tim

AU - Soranzo, Nicole

AU - Manichaikul, Ani W.

AU - Barr, R. Graham

AU - Kahali, Bratati

AU - Speliotes, Elizabeth

AU - Yerges-Armstrong, Laura M.

AU - Cheng, Ching Yu

AU - Jonas, Jost B.

AU - Wong, Tien Yin

AU - Fogh, Isabella

AU - Lin, Kuang

AU - Powell, John F.

AU - Rice, Kenneth

AU - Relton, Caroline L.

AU - Martin, Richard M.

AU - Davey Smith, George

PY - 2017/1/1

Y1 - 2017/1/1

N2 - IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

AB - IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

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U2 - 10.1001/jamaoncol.2016.5945

DO - 10.1001/jamaoncol.2016.5945

M3 - Article

VL - 3

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EP - 651

JO - JAMA Oncology

JF - JAMA Oncology

SN - 2374-2437

IS - 5

ER -