Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.
Level 3 - non-randomized controlled study
Mendelian randomization study using summary statistics from published genome-wide association studies.
PubMed 28241208 · doi:10.1001/jamaoncol.2016.5945
What was done
The authors performed a two-sample Mendelian randomization study using summary association statistics from 103 genome-wide association studies (GWAS) published up to January 15, 2015. Single nucleotide polymorphisms (SNPs) strongly associated with telomere length in the general population were used as instrumental variables to assess causal relationships with 35 site-specific cancers and 48 non-neoplastic diseases across 420,081 cases and 1,093,105 controls. Odds ratios (ORs) were calculated per 1-standard deviation (SD) increase in genetically predicted telomere length.
What was found
Genetically increased telomere length was associated with higher risk across multiple site-specific cancers, with the largest effects per 1-SD increase observed for glioma (OR 5.27, 95% CI 3.15 to 8.81), serous low-malignant-potential ovarian cancer (OR 4.35, 95% CI 2.39 to 7.94), lung adenocarcinoma (OR 3.19, 95% CI 2.40 to 4.22), neuroblastoma (OR 2.98, 95% CI 1.92 to 4.62), bladder cancer (OR 2.19, 95% CI 1.32 to 3.66), melanoma (OR 1.87, 95% CI 1.55 to 2.26), testicular cancer (OR 1.76, 95% CI 1.02 to 3.04), kidney cancer (OR 1.55, 95% CI 1.08 to 2.23), and endometrial cancer (OR 1.31, 95% CI 1.07 to 1.61). Conversely, genetically longer telomeres were protective against coronary heart disease (OR 0.78, 95% CI 0.67 to 0.90), abdominal aortic aneurysm (OR 0.63, 95% CI 0.49 to 0.81), celiac disease (OR 0.42, 95% CI 0.28 to 0.61), and interstitial lung disease (OR 0.09, 95% CI 0.05 to 0.15), with little evidence of association found for most other non-neoplastic conditions.
Why it matters
This study demonstrates a biological trade-off: genetically longer telomeres appear to increase susceptibility to various malignancies while protecting against specific cardiovascular and fibrotic disorders, clarifying conflicting observational findings prone to reverse causation.
Limits
The analysis depends on the validity of Mendelian randomization assumptions, including the absence of horizontal pleiotropy where instruments affect disease risk through pathways unrelated to telomere length. Summary data were available for only 103 of 163 identified GWAS, and individual-level exposures, non-linear effects, tissue-specific telomere dynamics, and detailed population demographics were not evaluated in the abstract.
Cited by
- supports Longer telomeres measured in the blood predict an increased risk of certain cancers, including glioma and melanoma.