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

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

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January 20, 2022



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.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 two-sample MR, we examined these variants in relation to colorectal cancer risk (48,214 cases and 64,159 controls).In inverse-variance models, higher fasting insulin levels increased colorectal cancer risk (odds ratio [OR] per 1-standard deviation [SD]=1.65, 95% CI = 1.15–2.36). We found no evidence of any effect of 2-hour glucose (OR per 1-SD = 1.02, 95% CI = 0.86–1.21) or fasting glucose (OR per 1-SD = 1.04, 95% CI = 0.88–1.23) concentrations on colorectal cancer risk. Genetic liability to type-2 diabetes (OR per 1-unit increase in log odds = 1.04, 95% CI = 1.01–1.07) and higher HbA1c levels (OR per 1-SD = 1.09, 95% CI = 1.00–1.19) 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 = 1.05–1.40), but not in women.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.

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