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

Emmanouil Bouras; Dipender Gill; Verena Zuber; Neil Murphy; Niki Dimou; Krasimira Aleksandrova; Sarah J Lewis; Richard M Martin; James Yarmolinsky; Demetrius Albanes; Hermann Brenner; Sergi Castellví-Bel; Andrew T Chan; Iona Cheng; Stephen Gruber; Bethany Van Guelpen; Christopher I Li; Loic Le Marchand; Polly A Newcomb; Shuji Ogino; Andrew Pellatt; Stephanie L Schmit; Alicja Wolk; Anna H Wu; Ulrike Peters; Marc J Gunter; Konstantinos K Tsilidis

doi:10.1093/ije/dyae067

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

Int J Epidemiol. 2024 Apr 11;53(3):dyae067. doi: 10.1093/ije/dyae067.

Authors

Emmanouil Bouras¹, Dipender Gill^{2

3}, Verena Zuber³, Neil Murphy⁴, Niki Dimou⁴, Krasimira Aleksandrova^{5

6}, Sarah J Lewis^{7

8}, Richard M Martin^{7

8

9}, James Yarmolinsky^{7

8}, Demetrius Albanes¹⁰, Hermann Brenner^{11

12

13}, Sergi Castellví-Bel¹⁴, Andrew T Chan^{15

16

17

18

19

20}, Iona Cheng²¹, Stephen Gruber²², Bethany Van Guelpen^{23

24}, Christopher I Li²⁵, Loic Le Marchand²⁶, Polly A Newcomb^{25

27}, Shuji Ogino^{18

19

28

29}, Andrew Pellatt³⁰, Stephanie L Schmit^{31

32}, Alicja Wolk³³, Anna H Wu³⁴, Ulrike Peters^{25

27}, Marc J Gunter^{3

4}, Konstantinos K Tsilidis^{1

3}

Affiliations

¹ Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
² Chief Scientific Advisor Office, Research and Early Development, Novo Nordisk, Copenhagen, Denmark.
³ Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, UK.
⁴ Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.
⁵ Faculty of Human and Health Sciences, University of Bremen, Bremen, Germany.
⁶ Department Epidemiological Methods and Etiological Research, Leibniz Institute for Prevention Research and Epidemiology, Bremen, Germany.
⁷ Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁸ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁹ NIHR Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol.
¹⁰ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
¹¹ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹² Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
¹³ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁴ 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.
¹⁵ Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁶ Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁷ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁸ Broad Institute of Harvard and MIT, Cambridge, MA, USA.
¹⁹ Department of Epidemiology, Harvard TH Chan School of Public Health, Harvard University, Boston, MA, USA.
²⁰ Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Harvard University, Boston, MA, USA.
²¹ Department of Epidemiology and Biostatistics, University of California-San Francisco, San Francisco, CA, USA.
²² Department of Medical Oncology & Therapeutics Research and Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, USA.
²³ Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
²⁴ Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
²⁵ Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
²⁶ University of Hawaii Cancer Center, Honolulu, HI, USA.
²⁷ Department of Epidemiology, University of Washington, Seattle, WA, USA.
²⁸ Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
²⁹ Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
³⁰ Department of Medicine, University of Utah, Salt Lake City, UT, USA.
³¹ Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
³² Population and Cancer Prevention Program, Case Comprehensive Cancer Center, Cleveland, OH, USA.
³³ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
³⁴ 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.

Keywords: BMI; Body mass index; CRC; Mendelian randomization; colorectal cancer; mediation analysis; obesity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alcohol Drinking / epidemiology
Body Mass Index*
Colorectal Neoplasms* / epidemiology
Colorectal Neoplasms* / genetics
Humans
Insulin-Like Growth Factor I / metabolism
Mendelian Randomization Analysis*
Obesity* / epidemiology
Obesity* / genetics
Risk Factors

Substances

Insulin-Like Growth Factor I

Grants and funding

CRUK_/Cancer Research UK/United Kingdom