Examining the role of the 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 multivariable (MV) Mendelian randomization (MR) to examine the role of the circulating proteome in the relationship between adiposity and CRC. We estimated the univariable (UV) associations between (I) adiposity measures and CRC, (II) adiposity measures and proteins, and (III) adiposity-associated proteins and CRC. Using MVMR we investigated the intermediate status of adiposity and CRC associated proteins. Colocalization and cis-SNP UVMR was performed for all protein-CRC pairs included in the MVMR analyses. BMI and WHR were associated with CRC and site-specific CRC in sex-combined and sex-specific analyses. A total of 285 adiposity-protein-CRC associations were identified and included in MVMR analysis (154 unique proteins). There was suggestive evidence of the effect of BMI on overall CRC in females attenuating after adjusting for 17 proteins, with confidence intervals overlapping the null. Of these proteins, evidence from cis-SNP UVMR and colocalization supported an effect of GREM1 on all CRC outcomes tested. There was evidence of weak instrument bias for a majority of MVMR analyses. Results suggest adiposity and adiposity-associated proteins influence CRC risk. Specifically, evidence was strongest for an effect of the adiposity-associated protein GREM1 with overall, colon, distal, proximal, and rectal CRC. Sex-specific effects, such as with GREM1, may highlight the heterogeneous nature of adiposity and CRC risk among the sexes