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- Title
Associations Between Glycemic Traits and Colorectal Cancer: A Mendelian Randomization Analysis.
- 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; Duijnhoven, Franzel J B van; Guelpen, Bethany Van; Vodicka, Pavel
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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).<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
BLOOD sugar analysis; SEQUENCE analysis; HYPERINSULINISM; BLOOD sugar; GENETIC polymorphisms; TYPE 2 diabetes; COLORECTAL cancer; INSULIN; RESEARCH funding; DISEASE complications
- Publication
JNCI: Journal of the National Cancer Institute, 2022, Vol 114, Issue 5, p740
- ISSN
0027-8874
- Publication type
journal article
- DOI
10.1093/jnci/djac011