Circulating inflammatory proteins mediate the causal relationship between blood alliin and cancer: A two-step, multivariable Mendelian randomization study

An association has been found between alliin and reduced risks of various cancers; however, evidence for these causal relationships remain limited. This study utilized Mendelian randomization (MR) analysis to assess the potential causal relationships between circulating alliin levels and the risks of 22 common cancers. We selected instrumental variables from the latest and largest European genome-wide association study (GWAS) datasets. First, we comprehensively assessed the causal relationships between blood alliin levels and the risks of 22 common cancers through two-sample MR analysis. Subsequently, we repeated the validation of instrumental variables using cancer GWAS statistics from different studies and merged the results by meta-analysis. Two-step MR analysis was used to investigate whether 91 inflammatory proteins mediate the effect of alliin on the risk of cancer. Finally, multivariable MR analysis was conducted to determine the direct effects of alliin on the risk of cancer, with adjustment for potential mediators. Inverse variance weighted results were considered the primary observation outcome, and additional sensitivity analyses were conducted. Increased blood alliin levels were significantly causally associated with decreased risks of prostate cancer, ovarian cancer, breast cancer, cervical cancer, lymphoma, and colorectal cancer, with the corresponding meta-analyses also showing significant associations. In the two-step MR analysis, chemokine ligand 23 (CCL23) and oncostatin M (OSM) as well as interleukin-12B (IL12B) were the key mediators of the inverse causal relationships between blood alliin levels and the risk of prostate cancer as well as the risks of ovarian and colorectal cancers, respectively. STAM-binding protein was a key mediator of the causal relationships between blood alliin levels and the risk of lymphoma. The results of this study support that increased blood alliin levels can reduce the risks of multiple cancers, with circulating inflammatory proteins potentially mediating this association.