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.

Bristol Medical School Department of Population Health Sciences University of Bristol Bristol UK

Cancer Epidemiology Unit Nuffield Department of Population Health University of Oxford Oxford UK

Channing Division of Network Medicine Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA USA

Clinical and Translational Epidemiology Unit Massachusetts General Hospital and Harvard Medical School Boston MA USA

Colorectal Cancer Group ONCOBELL Program Bellvitge Biomedical Research Institute L'Hospitalet de Llobregat Barcelona Spain

Computational Medicine Berlin Institute of Health Charité University Medicine Berlin Germany

Department of Epidemiology and Biostatistics School of Public Health Imperial College London London UK

Department of Epidemiology Harvard T H Chan School of Public Health Harvard University Boston MA USA

Department of Epidemiology University of Washington Seattle WA USA

Department of Human Genetics University of Exeter Research Innovation Learning and Development Building Royal Devon and Exeter Hospital Exeter UK

Department of Hygiene and Epidemiology University of Ioannina School of Medicine Ioannina Greece

Department of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences Prague Czech Republic

Department of Nutrition Harvard T H Chan School of Public Health Boston MA USA

Department of Pathology and Laboratory Medicine Mayo Clinic Arizona Scottsdale AZ USA

Department of Preventive Medicine USC Norris Comprehensive Cancer Center CA USA

Department of Radiation Sciences Oncology Umeå University Umeå Sweden

Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston MA USA

Division of Human Nutrition and Health Wageningen University and Research Wageningen the Netherlands

Exeter Centre of Excellence in Diabetes Exeter Medical School University of Exeter Exeter UK

Faculty of Medicine and Biomedical Center in Pilsen Charles University Pilsen Czech Republic

Health Data Research UK Wellcome Genome Campus and University of Cambridge Cambridge UK

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

Keck School of Medicine University of Southern California Los Angeles CA USA

MRC Epidemiology Unit University of Cambridge Cambridge UK

MRC Integrative Epidemiology Unit Population Health Sciences Bristol Medical School University of Bristol Bristol UK

National Institute for Health Research Bristol Biomedical Research Centre University Hospitals Bristol NHS Foundation Trust and the University of Bristol Bristol UK

Nutrition and Metabolism Branch International Agency for Research on Cancer Lyon France

Prevention and Cancer Control Clinical Institutes and Quality Programs Ontario Health Ontario Canada

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle WA USA

School of Cellular and Molecular Medicine University of Bristol Bristol UK

University of Southern California Preventative Medicine Los Angeles CA USA

Wallenberg Centre for Molecular Medicine Umeå University Umeå Sweden

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Genetic Predictors for Fecal Propionate and Butyrate-Producing Microbiome Pathway Are Not Associated with Colorectal Cancer Risk: A Mendelian Randomization Analysis