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  • Bouras, EmmanouilDepartment of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece (author)

Identification of potential mediators of the relationship between body mass index and colorectal cancer : a Mendelian randomization analysis

  • Article/chapterEnglish2024

Publisher, publication year, extent ...

  • Oxford University Press,2024
  • electronicrdacarrier

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  • LIBRIS-ID:oai:DiVA.org:umu-225322
  • https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-225322URI
  • https://doi.org/10.1093/ije/dyae067DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:238725300URI

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  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

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  • 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) ¼ 1.17, 95% CI: 1.08–1.24, P-value ¼ 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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  • Gill, DipenderChief Scientific Advisor Office, Research and Early Development, Novo Nordisk, Copenhagen, Denmark; Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, United Kingdom (author)
  • Zuber, VerenaDepartment of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, United Kingdom (author)
  • Murphy, NeilNutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France (author)
  • Dimou, NikiNutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France (author)
  • Aleksandrova, KrasimiraFaculty of Human and Health Sciences, University of Bremen, Bremen, Germany; Department Epidemiological Methods and Etiological Research, Leibniz Institute for Prevention Research and Epidemiology, Bremen, Germany (author)
  • Lewis, Sarah J.Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom (author)
  • Martin, Richard M.Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; NIHR Bristol Biomedical Research Centre, University Hospitals Bristol, Weston NHS Foundation Trust, the University of Bristol, United Kingdom (author)
  • Yarmolinsky, JamesDepartment of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom (author)
  • Albanes, DemetriusDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States (author)
  • Brenner, HermannDivision of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany (author)
  • Castellví-Bel, SergiDepartment 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 (author)
  • Chan, Andrew T.Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, MA, Boston, United States; Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, MA, Boston, United States; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Harvard Medical School, MA, Boston, United States; Broad Institute of Harvard and MIT, MA, Cambridge, United States; Department of Epidemiology, Harvard TH Chan School of Public Health, Harvard University, MA, Boston, United States; Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Harvard University, MA, Boston, United States (author)
  • Cheng, IonaDepartment of Epidemiology and Biostatistics, University of California-San Francisco, CA, San Francisco, United States (author)
  • Gruber, StephenDepartment of Medical Oncology & Therapeutics Research, Center for Precision Medicine, City of Hope National Medical Center, CA, Duarte, United States (author)
  • van Guelpen, BethanyUmeå universitet,Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM),Onkologi(Swepub:umu)beyvan99 (author)
  • Li, Christopher I.Public Health Sciences Division, Fred Hutchinson Cancer Center, WA, Seattle, United States (author)
  • Le Marchand, LoicUniversity of Hawaii Cancer Center, HI, Honolulu, United States (author)
  • Newcomb, Polly A.Public Health Sciences Division, Fred Hutchinson Cancer Center, WA, Seattle, United States; Department of Epidemiology, University of Washington, WA, Seattle, United States (author)
  • Ogino, ShujiBroad Institute of Harvard and MIT, MA, Cambridge, United States; Department of Epidemiology, Harvard TH Chan School of Public Health, Harvard University, MA, Boston, United States; Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, MA, Boston, United States; Department of Oncologic Pathology, Dana-Farber Cancer Institute, MA, Boston, United States (author)
  • Pellatt, AndrewDepartment of Medicine, University of Utah, UT, Salt Lake City, United States (author)
  • Schmit, Stephanie L.Genomic Medicine Institute, Cleveland Clinic, OH, Cleveland, United States; Population and Cancer Prevention Program, Case Comprehensive Cancer Center, OH, Cleveland, United States (author)
  • Wolk, AlicjaKarolinska Institutet,Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (author)
  • Wu, Anna H.University of Southern California, Preventative Medicine, CA, Los Angeles, United States (author)
  • Peters, UlrikePublic Health Sciences Division, Fred Hutchinson Cancer Center, WA, Seattle, United States; Department of Epidemiology, University of Washington, WA, Seattle, United States (author)
  • Gunter, Marc J.Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, United Kingdom; Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France (author)
  • Tsilidis, Konstantinos K.Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece; Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, United Kingdom (author)
  • Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, GreeceChief Scientific Advisor Office, Research and Early Development, Novo Nordisk, Copenhagen, Denmark; Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, United Kingdom (creator_code:org_t)

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  • In:International Journal of Epidemiology: Oxford University Press53:30300-57711464-3685

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