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

Telomeres Mendelian Randomization Collaboration, Haycock PC, Burgess S, Nounu A, Zheng J, Okoli GN, Bowden J, Wade KH, Timpson NJ, Evans DM, Willeit P, Aviv A, Gaunt TR, Hemani G, Mangino M, Ellis HP, Kurian KM, Pooley KA, Eeles RA, Lee JE, Fang S, Chen WV, Law MH, Bowdler LM, Iles MM, Yang Q, Worrall BB, Markus HS, Hung RJ, Amos CI, Spurdle AB, Thompson DJ, O'Mara TA, Wolpin B, Amundadottir L, Stolzenberg-Solomon R, Trichopoulou A, Onland-Moret NC, Lund E, Duell EJ, Canzian F, Severi G, Overvad K, Gunter MJ, Tumino R, Svenson U, van Rij A, Baas AF, Bown MJ, Samani NJ, van t'Hof FN, Tromp G, Jones GT, Kuivaniemi H, Elmore JR, Johansson M, Mckay J, Scelo G, Carreras-Torres R, Gaborieau V, Brennan P, Bracci PM, Neale RE, Olson SH, Gallinger S, Li D, Petersen GM, Risch HA, Klein AP, Han J, Abnet CC, Freedman ND, Taylor PR, Maris JM, Aben KK, Kiemeney LA, Vermeulen SH, Wiencke JK, Walsh KM, Wrensch M, Rice T, Turnbull C, Litchfield K, Paternoster L, Standl M, Abecasis GR, SanGiovanni JP, Li Y, Mijatovic V, Sapkota Y, Low SK, Zondervan KT, Montgomery GW, Nyholt DR, van Heel DA, Hunt K, Arking DE, Ashar FN, Sotoodehnia N, Woo D, Rosand J, Comeau ME, Brown WM, Silverman EK, Hokanson JE, Cho MH, Hui J, Ferreira MA, Thompson PJ, Morrison AC, Felix JF, Smith NL, Christiano AM, Petukhova L, Betz RC, Fan X, Zhang X, Zhu C, Langefeld CD, Thompson SD, Wang F, Lin X, Schwartz DA, Fingerlin T, Rotter JI, Cotch MF, Jensen RA, Munz M, Dommisch H, Schaefer AS, Han F, Ollila HM, Hillary RP, Albagha O, Ralston SH, Zeng C, Zheng W, Shu XO, Reis A, Uebe S, Hüffmeier U, Kawamura Y, Otowa T, Sasaki T, Hibberd ML, Davila S, Xie G, Siminovitch K, Bei JX, Zeng YX, Försti A, Chen B, Landi S, Franke A, Fischer A, Ellinghaus D, Flores C, Noth I, Ma SF, Foo JN, Liu J, Kim JW, Cox DG, Delattre O, Mirabeau O, Skibola CF, Tang CS, Garcia-Barcelo M, Chang KP, Su WH, Chang YS, Martin NG, Gordon S, Wade TD, Lee C, Kubo M, Cha PC, Nakamura Y, Levy D, Kimura M, Hwang SJ, Hunt S, Spector T, Soranzo N, Manichaikul AW, Barr RG, Kahali B, Speliotes E, Yerges-Armstrong LM, Cheng CY, Jonas JB, Wong TY, Fogh I, Lin K, Powell JF, Rice K, Relton CL, Martin RM, Davey Smith G.

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.