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

• Published in: JNCI : Journal of the National Cancer Institute 2022-05, Vol.114 (5), p.740-752
• Main Authors: Murphy, Neil, Song, Mingyang, Papadimitriou, Nikos, Carreras-Torres, Robert, Langenberg, Claudia, Martin, Richard M, Tsilidis, Konstantinos K, Barroso, Inês, Chen, Ji, Frayling, Timothy M, 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
• Format: Article
• Language: English
• Subjects: Blood Glucose - analysis; Blood Glucose - genetics; Cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - complications; Colorectal Neoplasms - epidemiology; Colorectal Neoplasms - genetics; Confidence intervals; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - epidemiology; Diabetes Mellitus, Type 2 - genetics; Fasting; Female; Genetic diversity; Genetic variance; Genome-wide association studies; Genome-Wide Association Study; Genomes; Glucose; Glycated Hemoglobin - analysis; Health risks; Hemoglobin; Humans; Hyperglycemia; Hyperinsulinemia; Hyperinsulinism - complications; Hyperinsulinism - genetics; Insulin; Laboratory testing; Liability; Male; Medicin och hälsovetenskap; Mendelian Randomization Analysis; Pleiotropy; Polymorphism, Single Nucleotide; Randomization; Risk; Risk Factors; Tumorigenesis
• ISSN: 0027-8874; 1460-2105; 1460-2105
• DOI: 10.1093/jnci/djac011

Abstract 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.