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About this Publication
Title
Identification of potential mediators of the relationship between body mass index and colorectal cancer: a Mendelian randomization analysis.
Pubmed ID
38725300 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Int J Epidemiol. 2024 Apr 11; Volume 53 (Issue 3)
Authors
Bouras E, Gill D, Zuber V, Murphy N, Dimou N, Aleksandrova K, Lewis SJ, Martin RM, Yarmolinsky J, Albanes D, Brenner H, Castellví-Bel S, Chan AT, Cheng I, Gruber S, Van Guelpen B, Li CI, Le Marchand L, Newcomb PA, Ogino S, ...show more Pellatt A, Schmit SL, Wolk A, Wu AH, Peters U, Gunter MJ, Tsilidis KK
Affiliations
  • Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
  • Chief Scientific Advisor Office, Research and Early Development, Novo Nordisk, Copenhagen, Denmark.
  • Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, UK.
  • Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.
  • Faculty of Human and Health Sciences, University of Bremen, Bremen, Germany.
  • Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Department of Gastroenterology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínic, Barcelona, Spain.
  • Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
...show more
  • Department of Epidemiology and Biostatistics, University of California-San Francisco, San Francisco, CA, USA.
  • Department of Medical Oncology & Therapeutics Research and Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, USA.
  • Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
  • Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
  • University of Hawaii Cancer Center, Honolulu, HI, USA.
  • Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Department of Medicine, University of Utah, Salt Lake City, UT, USA.
  • Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
  • Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • University of Southern California, Preventative Medicine, Los Angeles, CA, USA.
Abstract

BACKGROUND: Colorectal cancer (CRC) is the third-most-common cancer worldwide and its rates are increasing. Elevated body mass index (BMI) is an established risk factor for CRC, although the molecular mechanisms behind this association remain unclear. Using the Mendelian randomization (MR) framework, we aimed to investigate the mediating effects of putative biomarkers and other CRC risk factors in the association between BMI and CRC.

METHODS: We selected as mediators biomarkers of established cancer-related mechanisms and other CRC risk factors for which a plausible association with obesity exists, such as inflammatory biomarkers, glucose homeostasis traits, lipids, adipokines, insulin-like growth factor 1 (IGF1), sex hormones, 25-hydroxy-vitamin D, smoking, physical activity (PA) and alcohol consumption. We used inverse-variance weighted MR in the main univariable analyses and performed sensitivity analyses (weighted-median, MR-Egger, Contamination Mixture). We used multivariable MR for the mediation analyses.

RESULTS: Genetically predicted BMI was positively associated with CRC risk [odds ratio per SD (5 kg/m2) = 1.17, 95% CI: 1.08-1.24, P-value = 1.4 × 10-5] and robustly associated with nearly all potential mediators. Genetically predicted IGF1, fasting insulin, low-density lipoprotein cholesterol, smoking, PA and alcohol were associated with CRC risk. Evidence for attenuation was found for IGF1 [explained 7% (95% CI: 2-13%) of the association], smoking (31%, 4-57%) and PA (7%, 2-11%). There was little evidence for pleiotropy, although smoking was bidirectionally associated with BMI and instruments were weak for PA.

CONCLUSIONS: The effect of BMI on CRC risk is possibly partly mediated through plasma IGF1, whereas the attenuation of the BMI-CRC association by smoking and PA may reflect confounding and shared underlying mechanisms rather than mediation.

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