Associations Between Glycemic Traits and Colorectal Cancer: A Mendelian Randomization Analysis.
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
- MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
- MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
- Exeter Centre of Excellence in Diabetes (ExCEeD), Exeter Medical School, University of Exeter, Exeter, UK.
- Prevention and Cancer Control, Clinical Institutes and Quality Programs, Ontario Health (Cancer Care Ontario), Ontario, Canada.
- Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, CA, USA.
- Department of Pathology and Laboratory Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA.
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
- Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, the Netherlands.
- Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic.
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
- University of Southern California, Preventative Medicine, Los Angeles, CA, USA.
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 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.
- 2014-0244: Colorectal Tumor Risk Prediction in the PLCO Trial (ULRIKE PETERS)