Associations Between Glycemic Traits and Colorectal Cancer: A Mendelian Randomization Analysis

Neil Murphy*, Mingyang Song, Nikos Papadimitriou, Robert Carreras-Torres, Claudia Langenberg, Richard M. Martin, Konstantinos K. Tsilidis, Inês Barroso, Ji Chen, Timothy M. Frayling, Caroline J. Bull, Emma E. Vincent, Michelle Cotterchio, Stephen B. Gruber, Rish K. Pai, Polly A. Newcomb, Aurora Perez-Cornago, Franzel J.B. van Duijnhoven, Bethany Van Guelpen, Pavel VodickaAlicja Wolk, Anna H. Wu, Ulrike Peters, Andrew T. Chan, Marc J. Gunter

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

30 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)740-752
Number of pages13
JournalJournal of the National Cancer Institute
Issue number5
Publication statusPublished - 9 May 2022


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