Few studies have examined associations between plasma choline metabolites and risk of colorectal cancer (CRC). Therefore, we investigated associations between plasma biomarkers of choline metabolism [choline, betaine, dimethylglycine and trimethylamine N-oxide (TMAO)] and CRC risk among postmenopausal women in a case-control study nested within the Women's Health Initiative Observational Study. We selected 835 matched case-control pairs, and cases were further stratified by tumor site (proximal, distal, or rectal) and stage (local/regional or metastatic). CRC was assessed by self-report and confirmed by medical records over the mean 5.2y of follow-up. Baseline plasma choline metabolites were measured by liquid chromatography-tandem mass spectrometry. In multivariable-adjusted conditional logistic regression models, plasma choline tended to be positively associated with rectal cancer risk [OR (95% CI)highest vs. lowest quartile=2.44 (0.93-6.40);P-trend=0.08], while plasma betaine was inversely associated with CRC overall [0.68 (0.47-0.99);P-trend=0.01] and with local/regional tumors [0.64 (0.42-0.99);P-trend=0.009]. Notably, the plasma betaine:choline ratio was inversely associated with CRC overall [0.56 (0.39-0.82);P-trend=0.004] as well as with proximal [0.66 (0.41-1.06);P-trend=0.049], rectal [0.27 (0.10-0.78);P-trend=0.02] and local/regional [0.50 (0.33-0.76);P-trend=0.001] tumors. Finally, plasma TMAO, an oxidative derivative of choline produced by intestinal bacteria, was positively associated with rectal cancer [3.38 (1.25-9.16);P-trend=0.02] and with overall CRC risk among women with lower (vs. higher) plasma vitamin B12 levels (P-interaction=0.003). Collectively, these data suggest that alterations in choline metabolism, which may arise early in disease development, may be associated with higher risk of CRC. The positive association between plasma TMAO and CRC risk is consistent with an involvement of the gut microbiome in CRC pathogenesis.
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Journal article published