• International Agency for Research on Cancer (IARC/WHO), Nutrition and Metabolism Branch, Lyon, France.
• Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
• Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
• Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom.
• Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
• Department of Epidemiology and Biostatistics, University of California-San Francisco, San Francisco, CA, United States.
• Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Korea.
• University of Hawaii Cancer Center, Honolulu, HI, United States.
• Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States.
• Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, United States.

BACKGROUND: Adiposity is an established risk factor for colorectal cancer (CRC). The pathways underlying this relationship, and specifically the role of circulating proteins, are unclear.

METHODS: Utilizing two-sample univariable Mendelian randomization (UVMR), multivariable Mendelian randomization (MVMR), and colocalization, based on summary data from large sex-combined and sex-specific genetic studies, we estimated the univariable associations between: (i) body mass index (BMI) and waist-hip ratio (WHR) and overall and site-specific (colon, proximal colon, distal colon, and rectal) CRC risk, (ii) BMI and WHR and circulating proteins, and (iii) adiposity-associated circulating proteins and CRC risk. We used MVMR to investigate the potential mediating role of adiposity- and CRC-related circulating proteins in the adiposity-CRC association.

RESULTS: BMI and WHR were positively associated with CRC risk, with similar associations by anatomical tumor site. In total, 6591 adiposity-protein (2628 unique circulating proteins) and 33 protein-CRC (7 unique circulating proteins) associations were identified using UVMR and colocalization. One circulating protein, GREM1, was associated with BMI (only) and CRC outcomes in a manner that was consistent with a potential mediating role in sex-combined and female-specific analyses. In MVMR, adjusting the BMI-CRC association for GREM1, effect estimates were attenuated-suggestive of a potential mediating role-most strongly for the BMI-overall CRC association in women.

CONCLUSION: Results highlight the impact of adiposity on the plasma proteome and of adiposity-associated circulating proteins on the risk of CRC. Supported by evidence from UVMR and colocalization analyses using cis-single-nucleotide polymorphisms, GREM1 was identified as a potential mediator of the BMI-CRC association, particularly in women.