• MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.
• Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
• Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
• Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
• University of Hawaii Cancer Center, Honolulu, Hawaii.
• Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, Utah.
• Department of Epidemiology, University of Washington, Seattle, Washington.
• Cancer Screening and Prevention Research Group (CSPRG), Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
• Division of Gastroenterology, Mayo Clinic, Phoenix, Arizona.
• Department of Health Research Methods, Evidence, and Impact, Faculty of Health Sciences, McMaster University, Hamilton, Canada.

BACKGROUND: Epidemiological and laboratory-based studies have provided conflicting evidence for a role of ghrelin in colorectal cancer development. We conducted two-sample Mendelian randomization (MR) analyses to evaluate evidence for an association of circulating ghrelin and colorectal cancer risk overall and by sex, cancer subsite, and age at diagnosis.

METHODS: Genetic instruments proxying plasma total ghrelin levels were obtained from a recent genome-wide association study of 54,219 participants. Summary data for colorectal cancer risk were obtained from a recent meta-analysis of several genetic consortia (up to 73,673 cases and 86,854 controls). A two-sample MR approach and several sensitivity analyses were applied.

RESULTS: We found no evidence for an association of genetically predicted plasma total ghrelin levels and colorectal cancer risk (0.95, 95% confidence interval, 0.81-1.12; R2 of ghrelin genetic instruments: 4.6%), with similarly null results observed when stratified by sex, anatomical subsite, and for early-onset colorectal cancer.

CONCLUSIONS: Our study suggests that plasma ghrelin levels are unlikely to have a causal relationship with overall, early-onset, and sex- and cancer subsite-stratified colorectal cancer risk.

IMPACT: This large-scale analysis adds to the growing body of evidence that plasma total ghrelin levels are not associated with colorectal cancer risk.