Integrating omics data unravels potential mechanisms linking diet-related inflammation and colorectal cancer risk

Although diet-related inflammation has been linked to colorectal cancer (CRC) risk, the biological mechanisms underlying this association remain unclear. We conducted integrative analyses of diet, clinical, and multi-omics data in a prospective cohort to investigate potential molecular pathways linking diet-related inflammation to CRC risk. We used the Energy-adjusted Dietary Inflammatory Index (EDII) to proxy diet-related inflammation in 203,770 UK Biobank participants with at least one 24-hour dietary recall. The index has been extensively validated in previous studies, and we further examined its associations with inflammatory proteins interleukin-6 (IL6), interleukin-18 (IL18), TNF receptor superfamily member 1B (TNFRSF1B), and adiponectin in our study, adjusting for age, sex, BMI, smoking, and non-steroidal anti-inflammatory drug use. We derived metabolic (mEDII) and proteomic (pEDII) signatures of the EDII using stability selection and cross-validated elastic net modelling, and examined their associations with CRC risk using regression models, adjusting for the aforementioned confounders. Genetic determinants of the signatures were identified through multi-trait GWAS analyses, and signals were prioritized via Ensembl's Variant Effect Predictor. We explored potentially shared variants using colocalization analyses, integrating GWAS data for mEDII and pEDII, gene expression in colon and visceral fat tissue (GTEx v8), and CRC risk (185,616 participants, including 78,473 CRC cases). The EDII showed positive associations with plasma IL-6 (beta per SD increase = 0.039; 95%CI: 0.025, 0.052), IL-18 (0.060; 0.046, 0.075), and TNFRSF1B (0.057; 0.043, 0.072), and an inverse association with adiponectin (-0.025; -0.037, -0.013). The mEDII comprised 26 metabolites and the pEDII comprised 21 proteins, each explaining approximately 11.5% of EDII variance. Over a median follow-up of 9.8 years, 1,427 CRC cases occurred (42.9% in women), of which 934 (65.4%) in the colon. There was a suggestive positive association between EDII and colon cancer risk in men (OR per SD increase = 1.11; 95%CI: 1.01, 1.22). The mEDII was positively associated with colon cancer risk across both sexes, independently of EDII (OR per SD increase = 1.14; 95%CI: 1.01, 1.29). GWAS identified 19 loci for mEDII and pEDII, with potential functional consequences for 102 genes. We found evidence for a shared genetic basis across both signatures, CRC risk, and gene expression in colon tissue [in the Fatty Acid Desaturase 1 ( FADS1 ), Ras Interacting Protein 1 ( RASIP1 ), and MEF2 Activating Motif and SAP Domain Containing Transcriptional Regulator ( MAMSTR ) regions], and in visceral fat [in the FADS1 and Transmembrane Protein 258 ( TMEM258 ) regions]. Diet-related inflammation may contribute to CRC risk through mechanisms involving lipid metabolism, endothelial function, and intestinal inflammation.