Elevated platelet count appears to be causally associated with increased risk of lung cancer: A mendelian randomization analysis

Ying Zhu; Yongyue Wei; Ruyang Zhang; Xuesi Dong; Sipeng Shen; Yang Zhao; Jianling Bai; Demetrius Albanes; Neil E. Caporaso; Maria Teresa Landi; Bin Zhu; Stephen J. Chanock; Fangyi Gu; Stephen Lam; Ming Sound Tsao; Frances A. Shepherd; Adonina Tardon; Ana Fernandez-Somoano; Guillermo Fernandez-Tardon; Chu Chen; Matthew J. Barnett; Jennifer Doherty; Stig E. Bojesen; Mattias Johansson; Paul Brennan; James D. McKay; Robert Carreras-Torres; Thomas Muley; Angela Risch; Heunz Erich Wichmann; Heike Bickeboeller; Albert Rosenberger; Gad Rennert; Walid Saliba; Susanne M. Arnold; John K. Field; Michael P.A. Davies; Michael W. Marcus; Xifeng Wu; Yuanqing Ye; Loic Le Marchand; Lynne R. Wilkens; Olle Melander; Jonas Manjer; Hans Brunnstrom; Rayjean J. Hung; Geoffrey Liu; Yonathan Brhane; Linda Kachuri; Angeline S. Andrew; Eric J. Duell; Lambertus A. Kiemeney; Erik H.F.M. Van der Heijden; Aage Haugen; Shanbeh Zienolddiny; Vidar Skaug; Kjell Grankvist; Mikael Johansson; Penella J. Woll; Angela Cox; Fiona Taylor; Dawn M. Teare; Philip Lazarus; Matthew B. Schabath; Melinda C. Aldrich; Richard S. Houlston; John McLaughlin; Victoria L. Stevens; Hongbing Shen; Zhibin Hu; Juncheng Dai; Christopher I. Amos; Younghun Han; Dakai Zhu; Gary E. Goodman; Feng Chen; David C. Christiani

doi:10.1158/1055-9965.EPI-18-0356

Elevated platelet count appears to be causally associated with increased risk of lung cancer: A mendelian randomization analysis

Ying Zhu, Yongyue Wei, Ruyang Zhang, Xuesi Dong, Sipeng Shen, Yang Zhao, Jianling Bai, Demetrius Albanes, Neil E. Caporaso, Maria Teresa Landi, Bin Zhu, Stephen J. Chanock, Fangyi Gu, Stephen Lam, Ming Sound Tsao, Frances A. Shepherd, Adonina Tardon, Ana Fernandez-Somoano, Guillermo Fernandez-Tardon, Chu ChenMatthew J. Barnett, Jennifer Doherty, Stig E. Bojesen, Mattias Johansson, Paul Brennan, James D. McKay, Robert Carreras-Torres, Thomas Muley, Angela Risch, Heunz Erich Wichmann, Heike Bickeboeller, Albert Rosenberger, Gad Rennert, Walid Saliba, Susanne M. Arnold, John K. Field, Michael P.A. Davies, Michael W. Marcus, Xifeng Wu, Yuanqing Ye, Loic Le Marchand, Lynne R. Wilkens, Olle Melander, Jonas Manjer, Hans Brunnstrom, Rayjean J. Hung, Geoffrey Liu, Yonathan Brhane, Linda Kachuri, Angeline S. Andrew, Eric J. Duell, Lambertus A. Kiemeney, Erik H.F.M. Van der Heijden, Aage Haugen, Shanbeh Zienolddiny, Vidar Skaug, Kjell Grankvist, Mikael Johansson, Penella J. Woll, Angela Cox, Fiona Taylor, Dawn M. Teare, Philip Lazarus, Matthew B. Schabath, Melinda C. Aldrich, Richard S. Houlston, John McLaughlin, Victoria L. Stevens, Hongbing Shen, Zhibin Hu, Juncheng Dai, Christopher I. Amos, Younghun Han, Dakai Zhu, Gary E. Goodman, Feng Chen, David C. Christiani

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

Background: Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear. Methods: We performed single and combined multiple instrumental variable Mendelian randomization analysis by an inverse-weighted method, in addition to a series of sensitivity analyses. Summary data for associations between SNPs and platelet count are from a recent publication that included 48,666 Caucasian Europeans, and the International Lung Cancer Consortium and Transdisciplinary Research in Cancer of the Lung data consisting of 29,266 cases and 56,450 controls to analyze associations between candidate SNPs and lung cancer risk. Results: Multiple instrumental variable analysis incorporating six SNPs showed a 62% increased risk of overall non–small cell lung cancer [NSCLC; OR, 1.62; 95% confidence interval (CI), 1.15–2.27; P ¼ 0.005] and a 200% increased risk for small-cell lung cancer (OR, 3.00; 95% CI, 1.27–7.06; P ¼ 0.01). Results showed only a trending association with NSCLC histologic subtypes, which may be due to insufficient sample size and/or weak effect size. A series of sensitivity analysis retained these findings. Conclusions: Our findings suggest a causal relationship between elevated platelet count and increased risk of lung cancer and provide evidence of possible antiplatelet interventions for lung cancer prevention. Impact: These findings provide a better understanding of lung cancer etiology and potential evidence for antiplatelet interventions for lung cancer prevention.

Original language	English
Pages (from-to)	935-942
Number of pages	8
Journal	Cancer Epidemiology Biomarkers and Prevention
Volume	28
Issue number	5
DOIs	https://doi.org/10.1158/1055-9965.EPI-18-0356
State	Published - May 2019

Bibliographical note

Publisher Copyright:
© 2019 American Association for Cancer Research.

Funding

We thank the participants and staff for their important contributions to this study. This study was supported by the NIH (CA092824 and CA209414, to D.C. Christiani), National Natural Science Foundation of China (81530088 and 81473070, to F. Chen; 81373102, to Y. Zhao), State's Key Project of Research and Development Program (2016YFE0204900, to F. Chen), Key Project of Natural Science Foundation of Jiangsu, China (14JA31002, to F. Chen), A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and Outstanding Young Teachers Training Program of Nanjing Medical University (to Y.Y. Wei). Transdisciplinary Research for Cancer in Lung (TRICL) and Oncoarray funding sources are detailed as follows: Transdisciplinary Research for Cancer in Lung (TRICL) of the International Lung Cancer Consortium (ILCCO) was supported by grants U19-CA148127 and CA148127S1. ILCCO data harmonization was supported by the Cancer Care Ontario Research Chair of Population Studies (to R.J. Hung) and the Lunenfeld-Tanenbaum Research Institute, Sinai Health System. The CAPUA study was supported by FIS-FEDER/Spain grants FIS-01/310, FIS-PI03-0365, and FIS-07-BI060604; FICYT/Asturias grants FICYT PB02-67 and FICYT IB09-133; and the University Institute of Oncology (IUOPA) of the University of Oviedo and the Ciber de Epidemiologiay Salud Pública (CIBERESP), Spain. Work performed in the CARET study was supported by the NIH/NCI UM1 CA167462 (principal investigator: G.E. Goodman), NIH UO1-CA6367307 (principalinvestigators:Omen,G.E.Goodman), NIHR01CA111703(principal investigator: C. Chen), and NIH 5R01 CA151989-01A1 (principal investigator: J. Doherty). The Liverpool Lung project was supported by the Roy Castle Lung Cancer Foundation. The Harvard Lung Cancer Study was supported by the NIH/ NCI grants CA092824, CA090578, and CA074386. The Multiethnic Cohort Study was partially supported by NIH grants CA164973, CA033619, CA63464, and CA148127. Work performed in the MSH–PMH study was supported by the Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award (to R.J. Hung and G. Liu), and Alan Brown Chair and Lusi Wong Programs at Princess Margaret Hospital Foundation. NJLCS was funded by the State Key Program of National Natural Science of China (81230067), National Key Basic Research Program (2011CB503805), and Major Program of the National Natural Science Foundation of China (81390543). The Norway study was supported by the Norwegian Cancer Society, Norwegian Research Council. The Shanghai Cohort Study (SCS) was supported by NIH R01 CA144034 (principal investigator: J.M. Yuan) and UM1 CA182876 (principal investigator: J.M. Yuan). The Singapore Chinese Health Study (SCHS) was supported by NIH R01 CA144034 (principal investigator: J.M. Yuan) and UM1 CA182876 (principal investigator: J.M. Yuan). Work in the TLC study has been supported in part by the James & Esther

Funders	Funder number
Ciber de Epidemiologiay Salud Pública
IUOPA
International Lung Cancer Consortium	CA148127S1, U19-CA148127
James and Esther King Florida Biomedical Research Program
Key Project of Natural Science Foundation of Jiangsu	14JA31002
Lunenfeld-Tanenbaum Research Institute
Sinai Health System (Toronto)	FICYT IB09-133, FIS-PI03-0365, FICYT PB02-67, FIS-01/310, FIS-07-BI060604
State's Key Project of Research and Development Program	2016YFE0204900
University Institute of Oncology
National Childhood Cancer Registry – National Cancer Institute	UM1 CA167462, K07CA172294, UO1-CA6367307, 5R01 CA151989-01A1, NIHR01CA111703
National Childhood Cancer Registry – National Cancer Institute
Kreftforeningen
Roy Castle Lung Cancer Foundation	CA164973, CA148127, CA074386, CA63464, CA090578, CA033619
Roy Castle Lung Cancer Foundation
Canadian Cancer Society Research Institute	020214
Canadian Cancer Society Research Institute
National Natural Science Foundation of P.R. China	81230067, 81373102, 81473070, 81530088
National Natural Science Foundation of P.R. China
Norges Forskningsråd	R01 CA144034, UM1 CA182876
Norges Forskningsråd
Universidad de Oviedo
Nanjing Medical University
National Key Basic Research and Development Program of China	2011CB503805, 81390543
National Key Basic Research and Development Program of China
Priority Academic Program Development of Jiangsu Higher Education Institutions

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/1055-9965.EPI-18-0356

Cite this

Zhu, Y., Wei, Y., Zhang, R., Dong, X., Shen, S., Zhao, Y., Bai, J., Albanes, D., Caporaso, N. E., Landi, M. T., Zhu, B., Chanock, S. J., Gu, F., Lam, S., Tsao, M. S., Shepherd, F. A., Tardon, A., Fernandez-Somoano, A., Fernandez-Tardon, G., ... Christiani, D. C. (2019). Elevated platelet count appears to be causally associated with increased risk of lung cancer: A mendelian randomization analysis. Cancer Epidemiology Biomarkers and Prevention, 28(5), 935-942. https://doi.org/10.1158/1055-9965.EPI-18-0356

@article{f4911d0c4e8b4f15932bf74d66ff4db6,

title = "Elevated platelet count appears to be causally associated with increased risk of lung cancer: A mendelian randomization analysis",

abstract = "Background: Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear. Methods: We performed single and combined multiple instrumental variable Mendelian randomization analysis by an inverse-weighted method, in addition to a series of sensitivity analyses. Summary data for associations between SNPs and platelet count are from a recent publication that included 48,666 Caucasian Europeans, and the International Lung Cancer Consortium and Transdisciplinary Research in Cancer of the Lung data consisting of 29,266 cases and 56,450 controls to analyze associations between candidate SNPs and lung cancer risk. Results: Multiple instrumental variable analysis incorporating six SNPs showed a 62% increased risk of overall non–small cell lung cancer [NSCLC; OR, 1.62; 95% confidence interval (CI), 1.15–2.27; P ¼ 0.005] and a 200% increased risk for small-cell lung cancer (OR, 3.00; 95% CI, 1.27–7.06; P ¼ 0.01). Results showed only a trending association with NSCLC histologic subtypes, which may be due to insufficient sample size and/or weak effect size. A series of sensitivity analysis retained these findings. Conclusions: Our findings suggest a causal relationship between elevated platelet count and increased risk of lung cancer and provide evidence of possible antiplatelet interventions for lung cancer prevention. Impact: These findings provide a better understanding of lung cancer etiology and potential evidence for antiplatelet interventions for lung cancer prevention.",

author = "Ying Zhu and Yongyue Wei and Ruyang Zhang and Xuesi Dong and Sipeng Shen and Yang Zhao and Jianling Bai and Demetrius Albanes and Caporaso, {Neil E.} and Landi, {Maria Teresa} and Bin Zhu and Chanock, {Stephen J.} and Fangyi Gu and Stephen Lam and Tsao, {Ming Sound} and Shepherd, {Frances A.} and Adonina Tardon and Ana Fernandez-Somoano and Guillermo Fernandez-Tardon and Chu Chen and Barnett, {Matthew J.} and Jennifer Doherty and Bojesen, {Stig E.} and Mattias Johansson and Paul Brennan and McKay, {James D.} and Robert Carreras-Torres and Thomas Muley and Angela Risch and Wichmann, {Heunz Erich} and Heike Bickeboeller and Albert Rosenberger and Gad Rennert and Walid Saliba and Arnold, {Susanne M.} and Field, {John K.} and Davies, {Michael P.A.} and Marcus, {Michael W.} and Xifeng Wu and Yuanqing Ye and {Le Marchand}, Loic and Wilkens, {Lynne R.} and Olle Melander and Jonas Manjer and Hans Brunnstrom and Hung, {Rayjean J.} and Geoffrey Liu and Yonathan Brhane and Linda Kachuri and Andrew, {Angeline S.} and Duell, {Eric J.} and Kiemeney, {Lambertus A.} and {Van der Heijden}, {Erik H.F.M.} and Aage Haugen and Shanbeh Zienolddiny and Vidar Skaug and Kjell Grankvist and Mikael Johansson and Woll, {Penella J.} and Angela Cox and Fiona Taylor and Teare, {Dawn M.} and Philip Lazarus and Schabath, {Matthew B.} and Aldrich, {Melinda C.} and Houlston, {Richard S.} and John McLaughlin and Stevens, {Victoria L.} and Hongbing Shen and Zhibin Hu and Juncheng Dai and Amos, {Christopher I.} and Younghun Han and Dakai Zhu and Goodman, {Gary E.} and Feng Chen and Christiani, {David C.}",

note = "Publisher Copyright: {\textcopyright} 2019 American Association for Cancer Research.",

year = "2019",

month = may,

doi = "10.1158/1055-9965.EPI-18-0356",

language = "English",

volume = "28",

pages = "935--942",

number = "5",

}

Zhu, Y, Wei, Y, Zhang, R, Dong, X, Shen, S, Zhao, Y, Bai, J, Albanes, D, Caporaso, NE, Landi, MT, Zhu, B, Chanock, SJ, Gu, F, Lam, S, Tsao, MS, Shepherd, FA, Tardon, A, Fernandez-Somoano, A, Fernandez-Tardon, G, Chen, C, Barnett, MJ, Doherty, J, Bojesen, SE, Johansson, M, Brennan, P, McKay, JD, Carreras-Torres, R, Muley, T, Risch, A, Wichmann, HE, Bickeboeller, H, Rosenberger, A, Rennert, G, Saliba, W, Arnold, SM, Field, JK, Davies, MPA, Marcus, MW, Wu, X, Ye, Y, Le Marchand, L, Wilkens, LR, Melander, O, Manjer, J, Brunnstrom, H, Hung, RJ, Liu, G, Brhane, Y, Kachuri, L, Andrew, AS, Duell, EJ, Kiemeney, LA, Van der Heijden, EHFM, Haugen, A, Zienolddiny, S, Skaug, V, Grankvist, K, Johansson, M, Woll, PJ, Cox, A, Taylor, F, Teare, DM, Lazarus, P, Schabath, MB, Aldrich, MC, Houlston, RS, McLaughlin, J, Stevens, VL, Shen, H, Hu, Z, Dai, J, Amos, CI, Han, Y, Zhu, D, Goodman, GE, Chen, F & Christiani, DC 2019, 'Elevated platelet count appears to be causally associated with increased risk of lung cancer: A mendelian randomization analysis', Cancer Epidemiology Biomarkers and Prevention, vol. 28, no. 5, pp. 935-942. https://doi.org/10.1158/1055-9965.EPI-18-0356

TY - JOUR

T1 - Elevated platelet count appears to be causally associated with increased risk of lung cancer

T2 - A mendelian randomization analysis

AU - Zhu, Ying

AU - Wei, Yongyue

AU - Zhang, Ruyang

AU - Dong, Xuesi

AU - Shen, Sipeng

AU - Zhao, Yang

AU - Bai, Jianling

AU - Albanes, Demetrius

AU - Caporaso, Neil E.

AU - Landi, Maria Teresa

AU - Zhu, Bin

AU - Chanock, Stephen J.

AU - Gu, Fangyi

AU - Lam, Stephen

AU - Tsao, Ming Sound

AU - Shepherd, Frances A.

AU - Tardon, Adonina

AU - Fernandez-Somoano, Ana

AU - Fernandez-Tardon, Guillermo

AU - Chen, Chu

AU - Barnett, Matthew J.

AU - Doherty, Jennifer

AU - Bojesen, Stig E.

AU - Johansson, Mattias

AU - Brennan, Paul

AU - McKay, James D.

AU - Carreras-Torres, Robert

AU - Muley, Thomas

AU - Risch, Angela

AU - Wichmann, Heunz Erich

AU - Bickeboeller, Heike

AU - Rosenberger, Albert

AU - Rennert, Gad

AU - Saliba, Walid

AU - Arnold, Susanne M.

AU - Field, John K.

AU - Davies, Michael P.A.

AU - Marcus, Michael W.

AU - Wu, Xifeng

AU - Ye, Yuanqing

AU - Le Marchand, Loic

AU - Wilkens, Lynne R.

AU - Melander, Olle

AU - Manjer, Jonas

AU - Brunnstrom, Hans

AU - Hung, Rayjean J.

AU - Liu, Geoffrey

AU - Brhane, Yonathan

AU - Kachuri, Linda

AU - Andrew, Angeline S.

AU - Duell, Eric J.

AU - Kiemeney, Lambertus A.

AU - Van der Heijden, Erik H.F.M.

AU - Haugen, Aage

AU - Zienolddiny, Shanbeh

AU - Skaug, Vidar

AU - Grankvist, Kjell

AU - Johansson, Mikael

AU - Woll, Penella J.

AU - Cox, Angela

AU - Taylor, Fiona

AU - Teare, Dawn M.

AU - Lazarus, Philip

AU - Schabath, Matthew B.

AU - Aldrich, Melinda C.

AU - Houlston, Richard S.

AU - McLaughlin, John

AU - Stevens, Victoria L.

AU - Shen, Hongbing

AU - Hu, Zhibin

AU - Dai, Juncheng

AU - Amos, Christopher I.

AU - Han, Younghun

AU - Zhu, Dakai

AU - Goodman, Gary E.

AU - Chen, Feng

AU - Christiani, David C.

PY - 2019/5

Y1 - 2019/5

N2 - Background: Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear. Methods: We performed single and combined multiple instrumental variable Mendelian randomization analysis by an inverse-weighted method, in addition to a series of sensitivity analyses. Summary data for associations between SNPs and platelet count are from a recent publication that included 48,666 Caucasian Europeans, and the International Lung Cancer Consortium and Transdisciplinary Research in Cancer of the Lung data consisting of 29,266 cases and 56,450 controls to analyze associations between candidate SNPs and lung cancer risk. Results: Multiple instrumental variable analysis incorporating six SNPs showed a 62% increased risk of overall non–small cell lung cancer [NSCLC; OR, 1.62; 95% confidence interval (CI), 1.15–2.27; P ¼ 0.005] and a 200% increased risk for small-cell lung cancer (OR, 3.00; 95% CI, 1.27–7.06; P ¼ 0.01). Results showed only a trending association with NSCLC histologic subtypes, which may be due to insufficient sample size and/or weak effect size. A series of sensitivity analysis retained these findings. Conclusions: Our findings suggest a causal relationship between elevated platelet count and increased risk of lung cancer and provide evidence of possible antiplatelet interventions for lung cancer prevention. Impact: These findings provide a better understanding of lung cancer etiology and potential evidence for antiplatelet interventions for lung cancer prevention.

AB - Background: Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear. Methods: We performed single and combined multiple instrumental variable Mendelian randomization analysis by an inverse-weighted method, in addition to a series of sensitivity analyses. Summary data for associations between SNPs and platelet count are from a recent publication that included 48,666 Caucasian Europeans, and the International Lung Cancer Consortium and Transdisciplinary Research in Cancer of the Lung data consisting of 29,266 cases and 56,450 controls to analyze associations between candidate SNPs and lung cancer risk. Results: Multiple instrumental variable analysis incorporating six SNPs showed a 62% increased risk of overall non–small cell lung cancer [NSCLC; OR, 1.62; 95% confidence interval (CI), 1.15–2.27; P ¼ 0.005] and a 200% increased risk for small-cell lung cancer (OR, 3.00; 95% CI, 1.27–7.06; P ¼ 0.01). Results showed only a trending association with NSCLC histologic subtypes, which may be due to insufficient sample size and/or weak effect size. A series of sensitivity analysis retained these findings. Conclusions: Our findings suggest a causal relationship between elevated platelet count and increased risk of lung cancer and provide evidence of possible antiplatelet interventions for lung cancer prevention. Impact: These findings provide a better understanding of lung cancer etiology and potential evidence for antiplatelet interventions for lung cancer prevention.

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UR - http://www.scopus.com/inward/citedby.url?scp=85065599711&partnerID=8YFLogxK

U2 - 10.1158/1055-9965.EPI-18-0356

DO - 10.1158/1055-9965.EPI-18-0356

M3 - Article

C2 - 30700444

AN - SCOPUS:85065599711

SN - 1055-9965

VL - 28

SP - 935

EP - 942

JO - Cancer Epidemiology Biomarkers and Prevention

JF - Cancer Epidemiology Biomarkers and Prevention

IS - 5

ER -

Elevated platelet count appears to be causally associated with increased risk of lung cancer: A mendelian randomization analysis

Abstract

Bibliographical note

Funding

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UN SDGs

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