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

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 two-sample MR, we examined these variants in relation to colorectal cancer risk (48,214 cases and 64,159 controls).

Results
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
6 concentrations increased rectal cancer risk in men (OR per 1-SD=1.21, 95% CI = 1.05-1.40), 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.