Examining the role of the circulating proteome as an intermediate in the relationship between adiposity and colorectal cancer: Mendelian randomization analyses

Adiposity is an established risk factor for colorectal cancer (CRC). However, the pathways underlying this relationship, and the role of the circulating proteome, is unclear. We used Mendelian randomization (MR) to examine the role of the circulating proteome in the relationship between adiposity and CRC. Utilizing two-sample summary level MR, we estimated the univariable (UV) associations between (I) adiposity measures (body mass index, BMI; waist hip ratio, WHR) and CRC risk, (II) adiposity measures and circulating plasma proteins, and (III) adiposity-associated proteins and CRC risk. We used multivariable MR (MVMR) to investigate the potential mediating role of adiposity-related proteins in the association between adiposity and CRC. Colocalization and cis-SNP UVMR was performed for all protein-CRC pairs included in the MVMR analyses. BMI and WHR were associated with CRC risk overall, by tumour site and in men and women. A total of 426 adiposity-protein-CRC associations (including 238 unique proteins) were identified and included in the MVMR analyses, many of these associations were observed for female-specific analyses of proximal colon cancer. MVMR revealed attenuation of odds ratios and confidence intervals which overlapped the null for 17 proteins in the association between BMI and overall CRC risk in women and for 2 proteins in the association between WHR and distal colon cancer in sex-combined analysis. Of these 19 proteins, evidence from cis-SNP UVMR and colocalization supported an effect of the protein GREM1 on all CRC risk outcomes tested. Results suggest adiposity and adiposity-associated proteins influence CRC risk. Specifically, evidence was strongest for an effect of GREM1 with all CRC risk outcomes, with evidence of a mediating role in the association between BMI and overall CRC in female-specific analysis. Identified sex-specific effects, such as the GREM1 results, highlight the heterogeneous nature of adiposity and CRC risk by sex