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

Telomeres Mendelian Randomization Collaboration, Haycock PC1, Burgess S2, Nounu A1, Zheng J1, Okoli GN3, Bowden J1, Wade KH1, Timpson NJ1, Evans DM4, Willeit P5, Aviv A6, Gaunt TR1, Hemani G1, Mangino M7, Ellis HP8, Kurian KM8, Pooley KA9, Eeles RA10, Lee JE11, Fang S11, Chen WV12, Law MH13, Bowdler LM14, Iles MM15, Yang Q16, Worrall BB17, Markus HS18, Hung RJ19, Amos CI20, Spurdle AB21, Thompson DJ9, O'Mara TA21, Wolpin B22, Amundadottir L23, Stolzenberg-Solomon R24, Trichopoulou A25, Onland-Moret NC26, Lund E27, Duell EJ28, Canzian F29, Severi G30, Overvad K31, Gunter MJ32, Tumino R33, Svenson U34, van Rij A35, Baas AF36, Bown MJ37, Samani NJ37, van t'Hof FN38, Tromp G39, Jones GT35, Kuivaniemi H39, Elmore JR40, Johansson M41, Mckay J42, Scelo G41, Carreras-Torres R41, Gaborieau V41, Brennan P41, Bracci PM43, Neale RE14, Olson SH44, Gallinger S45, Li D46, Petersen GM47, Risch HA48, Klein AP49, Han J50, Abnet CC51, Freedman ND51, Taylor PR51, Maris JM52, Aben KK53, Kiemeney LA54, Vermeulen SH54, Wiencke JK55, Walsh KM55, Wrensch M55, Rice T56, Turnbull C57, Litchfield K58, Paternoster L1, Standl M59, Abecasis GR60, SanGiovanni JP61, Li Y62, Mijatovic V63, Sapkota Y14, Low SK64, Zondervan KT65, Montgomery GW14, Nyholt DR66, van Heel DA67, Hunt K67, Arking DE68, Ashar FN68, Sotoodehnia N69, Woo D70, Rosand J71, Comeau ME72, Brown WM72, Silverman EK73, Hokanson JE74, Cho MH73, Hui J75, Ferreira MA14, Thompson PJ76, Morrison AC77, Felix JF78, Smith NL79, Christiano AM80, Petukhova L81, Betz RC82, Fan X83, Zhang X83, Zhu C83, Langefeld CD72, Thompson SD84, Wang F85, Lin X85, Schwartz DA86, Fingerlin T87, Rotter JI88, Cotch MF89, Jensen RA90, Munz M91, Dommisch H92, Schaefer AS92, Han F93, Ollila HM94, Hillary RP94, Albagha O95, Ralston SH96, Zeng C97, Zheng W97, Shu XO97, Reis A98, Uebe S98, Hüffmeier U98, Kawamura Y99, Otowa T100, Sasaki T101, Hibberd ML102, Davila S103, Xie G104, Siminovitch K104, Bei JX105, Zeng YX106, Försti A107, Chen B108, Landi S109, Franke A110, Fischer A111, Ellinghaus D112, Flores C113, Noth I114, Ma SF114, Foo JN115, Liu J115, Kim JW116, Cox DG117, Delattre O118, Mirabeau O118, Skibola CF119, Tang CS120, Garcia-Barcelo M120, Chang KP121, Su WH122, Chang YS123, Martin NG14, Gordon S14, Wade TD124, Lee C125, Kubo M126, Cha PC127, Nakamura Y128, Levy D129, Kimura M6, Hwang SJ129, Hunt S130, Spector T131, Soranzo N132, Manichaikul AW133, Barr RG134, Kahali B135, Speliotes E135, Yerges-Armstrong LM136, Cheng CY137, Jonas JB138, Wong TY137, Fogh I139, Lin K139, Powell JF139, Rice K140, Relton CL1, Martin RM141, Davey Smith G1.

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Abstract

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.