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 Tardón, Gad Rennert, Andrew F. Olshan, Mark C. Weissler, Chu Chen, Gary E. Goodman, Jennifer A. Doherty, Andrew R. Ness, Heike Bickeböller, 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 Wünsch-Filho, Eloiza H. Tajara, Raquel Ayoub Moysés, 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

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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 (16396 cases, 13013 controls) and head and neck cancer (4415 cases, 5013 controls) using 8 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 (OR=1.41, 95% 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 etiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.
Original languageEnglish
Pages (from-to)751-766
Number of pages16
JournalInternational Journal of Epidemiology
Volume48
Issue number3
Early online date28 Jul 2018
DOIs
Publication statusPublished - 2019

Keywords

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

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    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