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Associations Between Glycemic Traits and Colorectal Cancer: A Mendelian Randomization Analysis.
Pubmed ID
35048991 (View this publication on the PubMed website)
Digital Object Identifier
J Natl Cancer Inst. 2022 Jan 20
Murphy N, Song M, Papadimitriou N, Carreras-Torres R, Langenberg C, Martin RM, Tsilidis KK, Barroso I, Chen J, Frayling TM, Bull CJ, Vincent EE, Cotterchio M, Gruber SB, Pai RK, Newcomb PA, Perez-Cornago A, van Duijnhoven FJB, Van Guelpen B, Vodicka P, more Wolk A, Wu AH, Peters U, Chan AT, Gunter MJ
  • 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. more
  • 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.

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