BACKGROUND: The relationship between omega-3 polyunsaturated fatty acid (n-3 PUFA) intake and colorectal cancer risk is unclear. Blood n-3 PUFA concentration is a biomarker of dietary n-3 PUFA intake. We examined the relationship between plasma n-3 PUFA concentrations and colorectal cancer risk in UK Biobank (UKBB) participants. METHODS: We analyzed the relationship between tertiles (T) of plasma total n-3 PUFAs and n-3 PUFA docosahexaenoic acid (DHA) levels, and overall colorectal cancer (also stratified by tumor location and sex) risk. Cox proportional hazards regression models were adjusted for clinical covariates. Nonlinearity was tested by restricted cubic splines. RESULTS: There were 2,602 incident colorectal cancer cases in 234,598 UKBB participants with baseline plasma fatty acid data (mean follow-up 13.4 years). There was an inverse association between the plasma total n-3 PUFA level [T2 HR = 0.88 (95% confidence interval, 0.80-0.97) compared with the T1 reference
T3 = 0.91 (0.83-1.00)], as well as the plasma DHA concentration [T2 = 0.89 (0.80-0.98)
T3 = 0.91 (0.82-1.00)], and colorectal cancer risk. The relationship was nonlinear [P for nonlinearity = 0.14 (total n-3 PUFAs) and 0.008 (DHA)], with a plateau effect at the highest n-3 PUFA concentrations. The relationship was more pronounced for proximal colon cancer [T2 = 0.82 (0.69-0.97)
T3 = 0.76 (0.64-0.90) for DHA] and was evident for males [T2 = 0.84 (0.74-0.95)
T3 = 0.89 (0.78-1.00)], but not for females. CONCLUSIONS: Higher plasma n-3 PUFAs are associated with reduced colorectal cancer risk in the UKBB. IMPACT: Nonlinearity, as well as tumor site and sex specificities, of the inverse relationship between plasma n-3 PUFA levels and colorectal cancer risk, if confirmed in other diverse populations, has significant implications for nutritional prevention guidelines.