Plasma fatty acids, genetic susceptibility, and colorectal cancer risk: results from a large prospective cohort study.

[BACKGROUND] Functional evidence indicates that fatty acids are implicated in carcinogenesis. However, it remains unknown about the impact of different circulating fatty acids on colorectal cancer (CRC) risk.

[OBJECTIVES] This study aimed to investigate the associations of plasma fatty acids with CRC risk.

[METHODS] In this prospective cohort study, we analyzed data from 261,395 cancer-free adults at baseline from the UK Biobank. Incident CRC cases were identified through the National Health Service cancer records. Cox regression models were used to assess CRC risk according to plasma fatty acid quartiles or per one standard deviation (SD) increment. A polygenic risk score for CRC was constructed using 93 CRC-associated single-nucleotide polymorphisms to investigate the potential modifying effect of genetic susceptibility on CRC risk.

[RESULTS] During a median follow-up of 11.1 years, 3217 CRC cases were documented. After multivariable adjustment, higher concentrations of polyunsaturated fatty acids (PUFAs), particularly n-3 PUFAs, n-6 PUFAs, docosahexaenoic acid, and linoleic acid, were associated with a lower risk of CRC, with hazard ratios per 1-SD increment ranging from 0.90 (95% CI: 0.85, 0.96) to 0.96 (95% CI: 0.93, 1.00). Moreover, an additive interaction was observed between plasma PUFAs and genetic risk. Individuals with high genetic risk and the lowest PUFA concentrations had the highest CRC risk (hazards ratio: 2.75; 95% CI: 2.17, 3.47).

[CONCLUSIONS] Plasma PUFAs may have protective effects against CRC, particularly for individuals at high genetic risk. Our study provides novel insights into CRC carcinogenesis and potential preventive strategies.