Mendelian Randomization and Mediation Analysis of Leukocyte Telomere Length and Risk of Lung and Head and Neck Cancers

Citation

Kachuri, Linda; Saarela, Olli; Bojesen, Stig Egil; Davey Smith, George; Liu, Geoffrey; Landi, Maria Teresa; Caporaso, Neil E.; Christiani, David C.; Johansson, Mattias; & Panico, Salvatore, et al. (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. PMCID: PMC6659464

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.

URL

http://dx.doi.org/10.1093/ije/dyy140

Reference Type

Journal Article

Year Published

2019

Journal Title

International Journal of Epidemiology

Author(s)

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

PMCID

PMC6659464

ORCiD

Olshan - 0000-0001-9115-5128