Περίληψη:
IMPORTANCE 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.
OBJECTIVE 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.
DATA SOURCES Genomewide association studies (GWAS) published up to
January 15, 2015.
STUDY SELECTION 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.
DATA EXTRACTION AND SYNTHESIS Summary association statistics for single
nucleotide polymorphisms (SNPs) that are strongly associated with
telomere length in the general population.
MAIN OUTCOMES AND MEASURES Odds ratios (ORs) and 95% confidence
intervals (CIs) for disease per standard deviation (SD) higher telomere
length due to germline genetic variation.
RESULTS 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]).
CONCLUSIONS AND RELEVANCE It is likely that longer telomeres increase
risk for several cancers but reduce risk for some non-neoplastic
diseases, including cardiovascular diseases.
Συγγραφείς:
Haycock, Philip C.
Burgess, Stephen
Nounu, Aayah
Zheng, Jie
and Okoli, George N.
Bowden, Jack
Wade, Kaitlin Hazel and
Timpson, Nicholas J.
Evans, David M.
Willeit, Peter
Aviv,
Abraham
Gaunt, Tomr.
Hemani, Gibran
Mangino, Massimo and
Ellis, Hayley Patricia
Kurian, Kathreena M.
Pooley, Karen A. and
Eeles, Rosalind A.
Lee, Jeffrey E.
Fang, Shenying
Chen, Wei
V.
Law, Matthew H.
Bowdler, Lisa M.
Iles, Mark M.
Yang,
Qiong
Worrall, Bradford B.
Markus, Hugh Stephen
Hung,
Rayjean J.
Amos, Chris I.
Spurdle, Amanda B.
Thompson,
Deborah J.
O'Mara, Tracy A.
Wolpin, Brian
Amundadottir,
Laufey
Stolzenberg-Solomon, Rachael
Trichopoulou, Antonia and
Onland-Moret, Charlotte
Lund, Eiliv
Duell, Eric J.
Canzian,
Federico
Severi, Gianluca
Overvad, Kim
Gunter, Marc J. and
Tumino, Rosario
Svenson, Ulrika
van Rij, Andre
Baas, Annette
F.
Bown, Matthew J.
Samani, Nilesh J.
van t'Hof, Femke N. G.
and Tromp, Gerard
Jones, Gregory T.
Kuivaniemi, Helena and
Elmore, James R.
Johansson, Mattias
Mckay, James
Scelo,
Ghislaine
carreras-Torres, Robert
Gaborieau, Valerie and
Brennan, Paul
Bracci, Paige M.
Neale, Rachel E.
Olson, Sara
H.
Gallinger, Steven
Li, Donghui
Petersen, Gloria M. and
Risch, Harvey A.
Klein, Alison P.
Han, Jiali
Abnet,
Christian C.
Freedman, Neal D.
Taylor, Philip R.
Maris, John
M.
Aben, Katja K.
Kiemeney, Lambertus A.
Vermeulen, Sita H.
and Wiencke, John K.
Walsh, Kyle M.
Wrensch, Margaret
Rice,
Terri
Turnbull, Clare
Litchfield, Kevin
Paternoster, Lavinia
and Standl, Marie
Abecasis, Goncalo R.
SanGiovanni, John Paul
and Li, Yong
Mijatovic, Vladan
Sapkota, Yadav
Low, Siew-Kee
and Zondervan, Krina T.
Montgomery, Grant W.
Nyholt, Dale R. and
van Heel, David A.
Hunt, Karen
Arking, Dan E.
Ashar, Foram
N.
Sotoodehnia, Nona
Woo, Daniel
Rosand, Jonathan and
Comeau, Mary E.
Brown, W. Mark
Silverman, Edwin K.
Hokanson,
John E.
Cho, Michael H.
Hui, Jennie
Ferreira, Manuel A. and
Thompson, Philip J.
Morrison, Alanna C.
Felix, Janine F. and
Smith, Nicholas L.
Christiano, Angela M.
Petukhova, Lynn and
Betz, Regina C.
Fan, Xing
Zhang, Xuejun
Zhu, Caihong and
Langefeld, Carl D.
Thompson, Susan D.
Wang, Feijie
Lin, Xu
and Schwartz, David A.
Fingerlin, Tasha
Rotter, Jerome I. and
Cotch, Mary Frances
Jensen, Richard A.
Munz, Matthias and
Dommisch, Henrik
Schaefer, Arne S.
Han, Fang
Ollila, Hanna
M.
Hillary, Ryan P.
Albagha, Omar
Ralston, Stuart H. and
Zeng, Chenjie
Zheng, Wei
Shu, Xiao-Ou
Reis, Andre
Uebe,
Steffen
Hueffmeier, Ulrike
Kawamura, Yoshiya
Otowa, Takeshi
and Sasaki, Tsukasa
Hibberd, Martin Lloyd
Davila, Sonia
Xie,
Gang
Siminovitch, Katherine
Bei, Jin-Xin
Zeng, Yi-Xin and
Foersti, Asta
Chen, Bowang
Landi, Stefano
Franke, Andre and
Fischer, Annegret
Ellinghaus, David
Flores, Carlos
Noth,
Imre
Ma, Shwu-Fan
Foo, Jia Nee
Liu, Jianjun
Kim,
Jong-Won
Cox, David G.
Delattre, Olivier
Mirabeau, Olivier
and Skibola, Christine F.
Tang, Clara S.
Garcia-Barcelo, Merce
and Chang, Kai-Ping
Su, Wen-Hui
Chang, Yu-Sun
Martin,
Nicholas G.
Gordon, Scott
Wade, Tracey D.
Lee, Chaeyoung and
Kubo, Michiaki
Cha, Pei-Chieng
Nakamura, Yusuke
Levy, Daniel
and Kimura, Masayuki
Hwang, Shih-Jen
Hunt, Steven
Spector,
Tim
Soranzo, Nicole
Manichaikul, Aniw.
Barr, Graham and
Kahali, Bratati
Speliotes, Elizabeth
Yerges-Armstrong, LauraM.
and Cheng, Ching-Yu
Jonas, Jost B.
Wong, Tien Yin
Fogh,
Isabella
Lin, Kuang
Powell, John F.
Rice, Kenneth and
Relton, Caroline L.
Martin, Richard M.
Smith, George Davey and
Telomeres Mendelian Randomization
