Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers

Linda Kachuri; Olli Saarela; Stig Egil Bojesen; George Davey Smith; Geoffrey Liu; Maria Teresa Landi; Neil E. Caporaso; David C. Christiani; Mattias Johansson; Salvatore Panico; Kim Overvad; Antonia Trichopoulou; Paolo Vineis; Ghislaine Scelo; David Zaridze; Xifeng Wu; Demetrius Albanes; Brenda Diergaarde; Pagona Lagiou; Gary J. Macfarlane; Melinda C. Aldrich; Adonina Tardon; Gad Rennert; Andrew F. Olshan; Mark C. Weissler; Chu Chen; Gary E. Goodman; Jennifer A. Doherty; Andrew R. Ness; Heike Bickeboeller; H-Erich Wichmann; Angela Risch; John K. Field; M. Dawn Teare; Lambertus A. Kiemeney; Erik H. F. M. van der Heijden; June C. Carroll; Aage Haugen; Shanbeh Zienolddiny; Vidar Skaug; Victor Wunsch-Filho; Eloiza H. Tajara; Raquel Ayoub Moyses; Fabio Daumas Nunes; Stephen Lam; Jose Eluf-Neto; Martin Lacko; Wilbert H. M. Peters; Loic Le Marchand; Eric J. Duell; Angeline S. Andrew; Silvia Franceschi; Matthew B. Schabath; Jonas Manjer; Susanne Arnold; Philip Lazarus; Anush Mukeriya; Beata Swiatkowska; Vladimir Janout; Ivana Holcatova; Jelena Stojsic; Dana Mates; Jolanta Lissowska; Stefania Boccia; Corina Lesseur; Xuchen Zong; James D. McKay; Paul Brennan; Christopher I. Amos; Rayjean J. Hung

doi:10.1093/ije/dyy140

Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers

Linda Kachuri, Olli Saarela, Stig Egil Bojesen, George Davey Smith, Geoffrey Liu, Maria Teresa Landi, Neil E. Caporaso, David C. Christiani, Mattias Johansson, Salvatore Panico, Kim Overvad, Antonia Trichopoulou, Paolo Vineis, Ghislaine Scelo, David Zaridze, Xifeng Wu, Demetrius Albanes, Brenda Diergaarde, Pagona Lagiou, Gary J. MacfarlaneMelinda C. Aldrich, Adonina Tardon, Gad Rennert, Andrew F. Olshan, Mark C. Weissler, Chu Chen, Gary E. Goodman, Jennifer A. Doherty, Andrew R. Ness, Heike Bickeboeller, H-Erich Wichmann, Angela Risch, John K. Field, M. Dawn Teare, Lambertus A. Kiemeney, Erik H. F. M. van der Heijden, June C. Carroll, Aage Haugen, Shanbeh Zienolddiny, Vidar Skaug, Victor Wunsch-Filho, Eloiza H. Tajara, Raquel Ayoub Moyses, Fabio Daumas Nunes, Stephen Lam, Jose Eluf-Neto, Martin Lacko, Wilbert H. M. Peters, Loic Le Marchand, Eric J. Duell, Angeline S. Andrew, Silvia Franceschi, Matthew B. Schabath, Jonas Manjer, Susanne Arnold, Philip Lazarus, Anush Mukeriya, Beata Swiatkowska, Vladimir Janout, Ivana Holcatova, Jelena Stojsic, Dana Mates, Jolanta Lissowska, Stefania Boccia, Corina Lesseur, Xuchen Zong, James D. McKay, Paul Brennan, Christopher I. Amos, Rayjean J. Hung^*

^*Corresponding author for this work

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

11 Citations (Web of Science)

Abstract

Background: Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses.

Methods: We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects.

Results: The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 x 10(-9)). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk.

Conclusions: Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.

Original language	English
Pages (from-to)	751-766
Number of pages	16
Journal	International Journal of Epidemiology
Volume	48
Issue number	3
DOIs	https://doi.org/10.1093/ije/dyy140
Publication status	Published - Jun 2019

Keywords

lung cancer
telomere length
chromosome 5p15.33
Mendelian Randomization
mediation analysis
TERT
GENOME-WIDE ASSOCIATION
SUSCEPTIBILITY LOCI
GENETIC-VARIANTS
NEVER SMOKERS
DYSFUNCTION
IDENTIFICATION
EPIDEMIOLOGY
METAANALYSIS
CHALLENGES
EXTENSION

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10.1093/ije/dyy140

Cite this

Kachuri, L., Saarela, O., Bojesen, S. E., Smith, G. D., Liu, G., Landi, M. T., Caporaso, N. E., Christiani, D. C., Johansson, M., Panico, S., Overvad, K., Trichopoulou, A., Vineis, P., Scelo, G., Zaridze, D., Wu, X., Albanes, D., Diergaarde, B., Lagiou, P., ... Hung, R. J. (2019). Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers. International Journal of Epidemiology, 48(3), 751-766. https://doi.org/10.1093/ije/dyy140

@article{1ae6eebd85184bf4801de072e6bae64e,

title = "Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers",

abstract = "Background: Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses.Methods: We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects.Results: The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 x 10(-9)). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk.Conclusions: Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.",

keywords = "lung cancer, telomere length, chromosome 5p15.33, Mendelian Randomization, mediation analysis, TERT, GENOME-WIDE ASSOCIATION, SUSCEPTIBILITY LOCI, GENETIC-VARIANTS, NEVER SMOKERS, DYSFUNCTION, IDENTIFICATION, EPIDEMIOLOGY, METAANALYSIS, CHALLENGES, EXTENSION",

author = "Linda Kachuri and Olli Saarela and Bojesen, {Stig Egil} and Smith, {George Davey} and Geoffrey Liu and Landi, {Maria Teresa} and Caporaso, {Neil E.} and Christiani, {David C.} and Mattias Johansson and Salvatore Panico and Kim Overvad and Antonia Trichopoulou and Paolo Vineis and Ghislaine Scelo and David Zaridze and Xifeng Wu and Demetrius Albanes and Brenda Diergaarde and Pagona Lagiou and Macfarlane, {Gary J.} and Aldrich, {Melinda C.} and Adonina Tardon and Gad Rennert and Olshan, {Andrew F.} and Weissler, {Mark C.} and Chu Chen and Goodman, {Gary E.} and Doherty, {Jennifer A.} and Ness, {Andrew R.} and Heike Bickeboeller and H-Erich Wichmann and Angela Risch and Field, {John K.} and Teare, {M. Dawn} and Kiemeney, {Lambertus A.} and {van der Heijden}, {Erik H. F. M.} and Carroll, {June C.} and Aage Haugen and Shanbeh Zienolddiny and Vidar Skaug and Victor Wunsch-Filho and Tajara, {Eloiza H.} and Moyses, {Raquel Ayoub} and Nunes, {Fabio Daumas} and Stephen Lam and Jose Eluf-Neto and Martin Lacko and Peters, {Wilbert H. M.} and {Le Marchand}, Loic and Duell, {Eric J.} and Andrew, {Angeline S.} and Silvia Franceschi and Schabath, {Matthew B.} and Jonas Manjer and Susanne Arnold and Philip Lazarus and Anush Mukeriya and Beata Swiatkowska and Vladimir Janout and Ivana Holcatova and Jelena Stojsic and Dana Mates and Jolanta Lissowska and Stefania Boccia and Corina Lesseur and Xuchen Zong and McKay, {James D.} and Paul Brennan and Amos, {Christopher I.} and Hung, {Rayjean J.}",

year = "2019",

month = jun,

doi = "10.1093/ije/dyy140",

language = "English",

volume = "48",

pages = "751--766",

journal = "International Journal of Epidemiology",

issn = "0300-5771",

publisher = "Oxford University Press",

number = "3",

}

Kachuri, L, Saarela, O, Bojesen, SE, Smith, GD, Liu, G, Landi, MT, Caporaso, NE, Christiani, DC, Johansson, M, Panico, S, Overvad, K, Trichopoulou, A, Vineis, P, Scelo, G, Zaridze, D, Wu, X, Albanes, D, Diergaarde, B, Lagiou, P, Macfarlane, GJ, Aldrich, MC, Tardon, A, Rennert, G, Olshan, AF, Weissler, MC, Chen, C, Goodman, GE, Doherty, JA, Ness, AR, Bickeboeller, H, Wichmann, H-E, Risch, A, Field, JK, Teare, MD, Kiemeney, LA, van der Heijden, EHFM, Carroll, JC, Haugen, A, Zienolddiny, S, Skaug, V, Wunsch-Filho, V, Tajara, EH, Moyses, RA, Nunes, FD, Lam, S, Eluf-Neto, J, Lacko, M, Peters, WHM, Le Marchand, L, Duell, EJ, Andrew, AS, Franceschi, S, Schabath, MB, Manjer, J, Arnold, S, Lazarus, P, Mukeriya, A, Swiatkowska, B, Janout, V, Holcatova, I, Stojsic, J, Mates, D, Lissowska, J, Boccia, S, Lesseur, C, Zong, X, McKay, JD, Brennan, P, Amos, CI & Hung, RJ 2019, 'Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers', International Journal of Epidemiology, vol. 48, no. 3, pp. 751-766. https://doi.org/10.1093/ije/dyy140

TY - JOUR

T1 - Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers

AU - Kachuri, Linda

AU - Saarela, Olli

AU - Bojesen, Stig Egil

AU - Smith, George Davey

AU - Liu, Geoffrey

AU - Landi, Maria Teresa

AU - Caporaso, Neil E.

AU - Christiani, David C.

AU - Johansson, Mattias

AU - Panico, Salvatore

AU - Overvad, Kim

AU - Trichopoulou, Antonia

AU - Vineis, Paolo

AU - Scelo, Ghislaine

AU - Zaridze, David

AU - Wu, Xifeng

AU - Albanes, Demetrius

AU - Diergaarde, Brenda

AU - Lagiou, Pagona

AU - Macfarlane, Gary J.

AU - Aldrich, Melinda C.

AU - Tardon, Adonina

AU - Rennert, Gad

AU - Olshan, Andrew F.

AU - Weissler, Mark C.

AU - Chen, Chu

AU - Goodman, Gary E.

AU - Doherty, Jennifer A.

AU - Ness, Andrew R.

AU - Bickeboeller, Heike

AU - Wichmann, H-Erich

AU - Risch, Angela

AU - Field, John K.

AU - Teare, M. Dawn

AU - Kiemeney, Lambertus A.

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

AU - Carroll, June C.

AU - Haugen, Aage

AU - Zienolddiny, Shanbeh

AU - Skaug, Vidar

AU - Wunsch-Filho, Victor

AU - Tajara, Eloiza H.

AU - Moyses, Raquel Ayoub

AU - Nunes, Fabio Daumas

AU - Lam, Stephen

AU - Eluf-Neto, Jose

AU - Lacko, Martin

AU - Peters, Wilbert H. M.

AU - Le Marchand, Loic

AU - Duell, Eric J.

AU - Andrew, Angeline S.

AU - Franceschi, Silvia

AU - Schabath, Matthew B.

AU - Manjer, Jonas

AU - Arnold, Susanne

AU - Lazarus, Philip

AU - Mukeriya, Anush

AU - Swiatkowska, Beata

AU - Janout, Vladimir

AU - Holcatova, Ivana

AU - Stojsic, Jelena

AU - Mates, Dana

AU - Lissowska, Jolanta

AU - Boccia, Stefania

AU - Lesseur, Corina

AU - Zong, Xuchen

AU - McKay, James D.

AU - Brennan, Paul

AU - Amos, Christopher I.

AU - Hung, Rayjean J.

PY - 2019/6

Y1 - 2019/6

N2 - Background: Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses.Methods: We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects.Results: The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 x 10(-9)). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk.Conclusions: Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.

AB - Background: Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses.Methods: We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects.Results: The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 x 10(-9)). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk.Conclusions: Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.

KW - lung cancer

KW - telomere length

KW - chromosome 5p15.33

KW - Mendelian Randomization

KW - mediation analysis

KW - TERT

KW - GENOME-WIDE ASSOCIATION

KW - SUSCEPTIBILITY LOCI

KW - GENETIC-VARIANTS

KW - NEVER SMOKERS

KW - DYSFUNCTION

KW - IDENTIFICATION

KW - EPIDEMIOLOGY

KW - METAANALYSIS

KW - CHALLENGES

KW - EXTENSION

U2 - 10.1093/ije/dyy140

DO - 10.1093/ije/dyy140

M3 - Article

C2 - 30059977

VL - 48

SP - 751

EP - 766

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

SN - 0300-5771

IS - 3

ER -