Telomere Length and Risk of Cancer and Non-Neoplastic Diseases—Reply

In Reply We thank Dr Mormile for her letter, which proposes that survivin, encoded by BIRC5 and a regulator of apoptosis and cellular lifespan, may display conflicting directions of association with risk of cancer and some non-neoplastic diseases, similar to the findings reported for telomere length by the Telomeres Mendelian Randomization Collaboration (TMRC). Mormile further proposes that upregulation of hTERT, the reverse transcriptase that lengthens telomeres, may mediate associations between survivin and disease. We tested the former hypothesis using MR-Base (http://www.mrbase.org, which includes summary data from the GTEx, CARDIoGRAMplusC4D, and ILCCO consortia). Although we found some evidence to suggest that each unit increase in survivin gene expression in lung tissue is associated with higher risk of lung adenocarcinoma (odds ratio, 1.35; 95% CI, 1.13-1.61), there was little evidence in MR-Base to support associations with other cancers or cardiovascular disease (false-discovery rate, ≥0.20; further details available at http://ift.tt/2wM33Rh). Notably, the TMRC used leukocyte telomere length as an index of telomere length in other normal somatic tissues, whose telomerase activity is typically repressed during extrauterine life. In contrast, the proposal by Mormile is based on studies conducted in cells or tissues that display telomerase activity (eg, cancer cells, human placenta, and mouse somatic tissues). What's more, atherosclerotic cardiovascular disease principally affects arteries and is not strictly a process related to cardiomyocyte proliferation. Although the role of survivin may be in doubt, we agree that more research is required to resolve the role of apoptosis and cellular lifespan in the cancer–vascular disease trade-off reported by the TMRC.

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