Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers
Authors: 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 , Tardón Adonina , Rennert Gad , Olshan Andrew F , Weissler Mark C , Chen Chu , Goodman Gary E , Doherty Jennifer A , Ness Andrew R , Bickeböller 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 , Wünsch-Filho Victor , Tajara Eloiza H , Ayoub Moysés Raquel , Daumas Nunes Fabio , Lam Stephen , Eluf-Neto Jose , Lacko Martin , Peters Wilbert H M , Le Marchand Loïc , Duell Eric J , Andrew Angeline S , Franceschi Silvia , Schabath Matthew B , Manjer Jonas , Arnold Susanne , 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 
Published: June 2018

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 × 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.