Abstract
Background: Adiposity is an established risk factor for colorectal cancer (CRC). The pathways underlying this relationship, and specifically the role of circulating proteins, is unclear.
Methods: Utilizing two-sample Mendelian randomization and colocalization, based on summary data from large sex-combined and sex-specific genetic studies, we estimated the univariable (UV) 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 multivariable MR (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 tumour site. 6,591 adiposity-protein (2,628 unique circulating proteins) and 33 protein-CRC (7 unique circulating proteins) associations were identified using UVMR and colocalization. 1 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 cis-SNP UVMR and colocalization analyses, GREM1 was identified as a potential mediator of the BMI-CRC association, particularly in women.
Methods: Utilizing two-sample Mendelian randomization and colocalization, based on summary data from large sex-combined and sex-specific genetic studies, we estimated the univariable (UV) 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 multivariable MR (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 tumour site. 6,591 adiposity-protein (2,628 unique circulating proteins) and 33 protein-CRC (7 unique circulating proteins) associations were identified using UVMR and colocalization. 1 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 cis-SNP UVMR and colocalization analyses, GREM1 was identified as a potential mediator of the BMI-CRC association, particularly in women.
| Original language | English |
|---|---|
| Journal | International Journal of Epidemiology |
| Publication status | Accepted/In press - 8 Nov 2024 |
