Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.

Authors:
Philip C Haycock, Stephen Burgess, Aayah Nounu, Jie Zheng, George N Okoli, Jack Bowden, Kaitlin Hazel Wade, Nicholas J Timpson, David M Evans, Peter Willeit, Abraham Aviv, Tom R Gaunt, Gibran Hemani, Massimo Mangino, Hayley Patricia Ellis, Kathreena M Kurian, Karen A Pooley, Rosalind A Eeles, Jeffrey E Lee, Shenying Fang, Wei V Chen, Matthew H Law, Lisa M Bowdler, Mark M Iles, Qiong Yang, Bradford B Worrall, Hugh Stephen Markus, Rayjean J Hung, Chris I Amos, Amanda B Spurdle, Deborah J Thompson, Tracy A O'Mara, Brian Wolpin, Laufey Amundadottir, Rachael Stolzenberg-Solomon, Antonia Trichopoulou, N Charlotte Onland-Moret, Eiliv Lund, Eric J Duell, Federico Canzian, Gianluca Severi, Kim Overvad, Marc J Gunter, Rosario Tumino, Ulrika Svenson, Andre van Rij, Annette F Baas, Matthew J Bown, Nilesh J Samani, Femke N G van t'Hof, Gerard Tromp, Gregory T Jones, Helena Kuivaniemi, James R Elmore, Mattias Johansson, James Mckay, Ghislaine Scelo, Robert Carreras-Torres, Valerie Gaborieau, Paul Brennan, Paige M Bracci, Rachel E Neale, Sara H Olson, Steven Gallinger, Donghui Li, Gloria M Petersen, Harvey A Risch, Alison P Klein, Jiali Han, Christian C Abnet, Neal D Freedman, Philip R Taylor, John M Maris, Katja K Aben, Lambertus A Kiemeney, Sita H Vermeulen, John K Wiencke, Kyle M Walsh, Margaret Wrensch, Terri Rice, Clare Turnbull, Kevin Litchfield, Lavinia Paternoster, Marie Standl, Gonçalo R Abecasis, John Paul SanGiovanni, Yong Li, Vladan Mijatovic, Yadav Sapkota, Siew-Kee Low, Krina T Zondervan, Grant W Montgomery, Dale R Nyholt, David A van Heel, Karen Hunt, Dan E Arking, Foram N Ashar, Nona Sotoodehnia, Daniel Woo, Jonathan Rosand, Mary E Comeau, W Mark Brown, Edwin K Silverman, John E Hokanson, Michael H Cho, Jennie Hui, Manuel A Ferreira, Philip J Thompson, Alanna C Morrison, Janine F Felix, Nicholas L Smith, Angela M Christiano, Lynn Petukhova, Regina C Betz, Xing Fan, Xuejun Zhang, Caihong Zhu, Carl D Langefeld, Susan D Thompson, Feijie Wang, Xu Lin, David A Schwartz, Tasha Fingerlin, Jerome I Rotter, Mary Frances Cotch, Richard A Jensen, Matthias Munz, Henrik Dommisch, Arne S Schaefer, Fang Han, Hanna M Ollila, Ryan P Hillary, Omar Albagha, Stuart H Ralston, Chenjie Zeng, Wei Zheng, Xiao-Ou Shu, Andre Reis, Steffen Uebe, Ulrike Hüffmeier, Yoshiya Kawamura, Takeshi Otowa, Tsukasa Sasaki, Martin Lloyd Hibberd, Sonia Davila, Gang Xie, Katherine Siminovitch, Jin-Xin Bei, Yi-Xin Zeng, Asta Försti, Bowang Chen, Stefano Landi, Andre Franke, Annegret Fischer, David Ellinghaus, Carlos Flores, Imre Noth, Shwu-Fan Ma, Jia Nee Foo, Jianjun Liu, Jong-Won Kim, David G Cox, Olivier Delattre, Olivier Mirabeau, Christine F Skibola, Clara S Tang, Merce Garcia-Barcelo, Kai-Ping Chang, Wen-Hui Su, Yu-Sun Chang, Nicholas G Martin, Scott Gordon, Tracey D Wade, Chaeyoung Lee, Michiaki Kubo, Pei-Chieng Cha, Yusuke Nakamura, Daniel Levy, Masayuki Kimura, Shih-Jen Hwang, Steven Hunt, Tim Spector, Nicole Soranzo, Ani W Manichaikul, R Graham Barr, Bratati Kahali, Elizabeth Speliotes, Laura M Yerges-Armstrong, Ching-Yu Cheng, Jost B Jonas, Tien Yin Wong, Isabella Fogh, Kuang Lin, John F Powell, Kenneth Rice, Caroline L Relton, Richard M Martin, George Davey Smith
Year of publication:
2017
Volume:
-
Issue:
-
Issn:
2374-2437
Journal title abbreviated:
JAMA Oncol
Journal title long:
JAMA oncology
Abstract:
The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.Genomewide association studies (GWAS) published up to January 15, 2015.GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.