Associations Between Glycemic Traits and Colorectal Cancer: A Mendelian Randomization Analysis.
Newcomb, Polly A
Wu, Anna H
J Natl Cancer Inst
Oxford University Press (OUP)
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Murphy, N., Song, M., Papadimitriou, N., Carreras-Torres, R., Langenberg, C., Martin, R. M., Tsilidis, K. K., et al. (2022). Associations Between Glycemic Traits and Colorectal Cancer: A Mendelian Randomization Analysis.. J Natl Cancer Inst https://doi.org/10.1093/jnci/djac011
BACKGROUND: Glycemic traits-such as hyperinsulinemia, hyperglycemia, and type 2 diabetes-have been associated with higher colorectal cancer risk in observational studies; however, causality of these associations is uncertain. We used Mendelian randomization (MR) to estimate the causal effects of fasting insulin, 2-hour glucose, fasting glucose, glycated hemoglobin (HbA1c), and type 2 diabetes with colorectal cancer. METHODS: Genome-wide association study summary data were used to identify genetic variants associated with circulating levels of fasting insulin (n = 34), 2-hour glucose (n = 13), fasting glucose (n = 70), HbA1c (n = 221), and type 2 diabetes (n = 268). Using 2-sample MR, we examined these variants in relation to colorectal cancer risk (48 214 case patient and 64 159 control patients). RESULTS: In inverse-variance models, higher fasting insulin levels increased colorectal cancer risk (odds ratio [OR] per 1-SD = 1.65, 95% confidence interval [CI] = 1.15 to 2.36). We found no evidence of any effect of 2-hour glucose (OR per 1-SD = 1.02, 95% CI = 0.86 to 1.21) or fasting glucose (OR per 1-SD = 1.04, 95% CI = 0.88 to 1.23) concentrations on colorectal cancer risk. Genetic liability to type 2 diabetes (OR per 1-unit increase in log odds = 1.04, 95% CI = 1.01 to 1.07) and higher HbA1c levels (OR per 1-SD = 1.09, 95% CI = 1.00 to 1.19) increased colorectal cancer risk, although these findings may have been biased by pleiotropy. Higher HbA1c concentrations increased rectal cancer risk in men (OR per 1-SD = 1.21, 95% CI = 1.05 to 1.40), but not in women. CONCLUSIONS: Our results support a causal effect of higher fasting insulin, but not glucose traits or type 2 diabetes, on increased colorectal cancer risk. This suggests that pharmacological or lifestyle interventions that lower circulating insulin levels may be beneficial in preventing colorectal tumorigenesis.
Mendelian randomization, glucose, glycemic traits, insulin, type-2 diabetes colorectal cancer
Medical Research Council (G1000143)
Embargo Lift Date
External DOI: https://doi.org/10.1093/jnci/djac011
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333410
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