The Causal Relationship between Telomere Length and Cancer Risk: A Two-Sample Mendelian Randomization

Abstract

Background: Telomere length (TL) shortens with age and is associated with an increased risk of numerous chronic diseases. However, the causal direction of the association between TL and cancer risk remains uncertain. This study aimed to assess the causal impact of TL on cancer risk using Mendelian randomization (MR) analysis.

Methods: Genome-wide association studies from Singapore and China data, the Korean Cancer Prevention Study II (KCPS-II), the Korean Genome Epidemiologic Study, and the Biobank of Japan were utilized. A two-sample MR study was performed using summary-level genome-wide association study data from individuals of East Asian ancestry. SNPs associated with TL were used as instrumental variables.

Results: Longer TL per 1-SD increase due to germline genetic variants was associated with a higher risk of site-specific cancer. In the KCPS-II and Korean Genome Epidemiologic Study, the strongest association was observed with thyroid cancer {OR, 2.49 [95% confidence interval (CI), 1.79-3.47] and 2.27 (1.49-3.46)}, followed by lung cancer [OR, 2.19 (95% CI, 1.60-3.08) and 1.45 (1.12-1.87)]. Similar results were observed in the Biobank of Japan, with OR, 2.92 (95% CI, 1.75-4.88) for thyroid cancer and 2.04 (1.41-2.94) for lung cancer. In histologic subgroup analysis of KCPS-II, a significant relationship was found with lung adenocarcinoma [OR, 2.26 (95% CI, 1.55-3.31)] but not with lung squamous cell carcinoma (1.21, 0.47-3.06). After removing outlier SNPs in the radial MR analysis, significant associations were identified for both lung adenocarcinoma [OR, 1.88 (95% CI, 1.25-2.82)] and lung squamous cell carcinoma (2.29, 1.05-4.98).

Conclusions: Our findings suggest that longer TL increases the risk of various cancers in East Asian populations.