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

Lookup NU author(s): Professor Dawn Teare

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by Oxford University Press, 2019.

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Abstract

© 2018 The Author(s) 2018; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association. 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 × 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.


Publication metadata

Author(s): Kachuri L, Saarela O, Bojesen SE, Davey Smith G, 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, Bickeboller 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, Ayoub Moyses R, Daumas Nunes F, 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

Publication type: Article

Publication status: Published

Journal: International Journal of Epidemiology

Year: 2019

Volume: 48

Issue: 3

Pages: 751-766

Print publication date: 01/06/2019

Online publication date: 28/07/2018

Acceptance date: 14/06/2018

Date deposited: 12/11/2019

ISSN (print): 0300-5771

ISSN (electronic): 1464-3685

Publisher: Oxford University Press

URL: https://doi.org/10.1093/ije/dyy140

DOI: 10.1093/ije/dyy140

PubMed id: 30059977


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