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 - Davey Smith, George

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 - Tardón, 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 - Bickeböller, 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 - Wünsch-Filho, Victor

AU - Tajara, Eloiza H

AU - Ayoub Moysés, Raquel

AU - Daumas Nunes, Fabio

AU - Lam, Stephen

AU - Eluf-Neto, Jose

AU - Lacko, Martin

AU - Peters, Wilbert H M

AU - Le Marchand, Loïc

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

Y1 - 2019

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 × 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 × 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.

U2 - 10.1093/ije/dyy140

DO - 10.1093/ije/dyy140

M3 - Journal 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 -