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Zhang, C.* ; Doherty, J.A.* ; Burgess, S.L.* ; Hung, R.J.* ; Lindström, S.* ; Kraft, P.* ; Gong, J.* ; Amos, C.I.* ; Sellers, T.A.* ; Monteiro, A.N.* ; Chenevix-Trench, G.* ; Bickeböller, H.* ; Risch, A.* ; Brennan, P.* ; Mckay, J.* ; Houlston, R.* ; Landi, M.T.* ; Timofeeva, M.* ; Wang, Y.* ; Heinrich, J. ; Kote-Jarai, Z.* ; Eeles, R.A.* ; Muir, K.* ; Wiklund, F.* ; Grönberg, H.* ; Berndt, S.I.* ; Chanock, S.J.* ; Schumacher, F.* ; Haiman, C.A.* ; Henderson, B.E.* ; Amin Al Olama, A.* ; Andrulis, I.L.* ; Hopper, J.L.* ; Chang-Claude, J.* ; John, E.M.* ; Malone, K.E.* ; Gammon, M.D.* ; Ursin, G.* ; Whittemore, A.S.* ; Hunter, D.J.* ; Gruber, S.B.* ; Knight, J.A.* ; Hou, L.* ; Le Marchand, L.* ; Newcomb, P.A.* ; Hudson, T.J.* ; Chan, A.T.* ; Li, L.* ; Woods, M.O.* ; Ahsan, H.* ; Pierce, B.L.*

Genetic determinants of telomere length and risk of common cancers: A Mendelian randomization study.

Hum. Mol. Genet. 24, 5356-5366 (2015)
Verlagsversion DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51,725 cases and 62,035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P=6.3x10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P=6.6x10(-6)). Under Mendelian randomization assumptions, the association estimate (odds ratio (OR)=2.78) is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 base pair increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Sprache englisch
Veröffentlichungsjahr 2015
HGF-Berichtsjahr 2015
ISSN (print) / ISBN 0964-6906
e-ISSN 1460-2083
Zeitschrift Human Molecular Genetics
Quellenangaben Band: 24, Heft: 18, Seiten: 5356-5366 Artikelnummer: , Supplement: ,
Verlag Oxford University Press
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Epidemiology (EPI)
POF Topic(s) 30503 - Chronic Diseases of the Lung and Allergies
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-503900-001
PubMed ID 26138067
DOI 10.1093/hmg/ddv252
WOS ID WOS:000361317200024
Scopus ID 84940656427
Erfassungsdatum 2015-07-05
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