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Original Investigation
May 2017

Association Between Telomere Length and Risk of Cancer and Non-Neoplastic DiseasesA Mendelian Randomization Study

The Telomeres Mendelian Randomization Collaboration
JAMA Oncol. 2017;3(5):636-651. doi:10.1001/jamaoncol.2016.5945
Key Points

Question  What is the causal relevance of telomere length for risk of cancer and non-neoplastic diseases?

Findings  In this Mendelian randomization study, genetically longer telomeres were associated with higher odds of disease for 9 of 22 primary cancers tested but with reduced odds of disease for 6 of 32 primary non-neoplastic diseases, including cardiovascular diseases.

Meaning  It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases. This trade-off in risk should be carefully considered in any diagnostic, prognostic, or therapeutic applications based on telomere length.

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.

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