FADS2 Indel polymorphism rs66698963 predicts colorectal polyp prevention by the n-3 fatty acid EPA

ImportanceA precision medicine approach to identify who would benefit from supplementation with the n-3 highly unsaturated fatty acid (HUFA) eicosapentaenoic acid (EPA) for colorectal cancer prevention has not been reported. A fatty acid desaturase 2 (FADS2) insertion-deletion (Indel) polymorphism (rs66698963) controls levels of the n-6 HUFA arachidonic acid (AA), which drives intestinal tumorigenesis and which is antagonized by EPA. ObjectiveWe tested the hypothesis that the FADS2 Insertion (I) allele, which is associated with elevated AA levels, predicts those individuals who display colorectal polyp risk reduction by EPA. DesignSecondary analysis of the randomized, placebo-controlled, 2x2 factorial seAFOod polyp prevention trial of EPA 2g daily and aspirin 300mg daily, stratified for FADS2 Indel genotype. SettingColonoscopy surveillance 12 months after clearance screening colonoscopy, in the English Bowel Cancer Screening Programme (BCSP). ParticipantsA predominantly White European, male cohort (mirroring the BCSP colonoscopy demographic). 528 trial participants with colonoscopy data and a FADS2 Indel genotype from the original randomized trial population of n=707. Main Outcome(s) and Measure(s)Total (adenomatous and serrated) colorectal polyp risk associated with EPA or aspirin compared with its respective placebo. Presence of at least one I allele and an interaction term (at least one I allele x active intervention) were co-variates in negative binomial regression models. ResultsEPA use, irrespective of FADS2 Indel genotype, was not associated with reduced total colorectal polyp number (incidence rate ratio [IRR] 0.92, 95% confidence interval 0.74,1.16), mirroring the original seAFOod trial analysis. However, the presence of at least one I allele identified EPA users with a significant reduction in colorectal polyp number (IRR 0.50 [0.28, 0.90]), unlike aspirin for which there was no evidence of an interaction. Similar findings were obtained for analysis of the polyp detection rate (% of individuals with at least one polyp). Conclusions and RelevanceThe FADS2 Indel I allele identifies individuals who display colorectal polyp prevention efficacy of EPA, with a similar effect size to aspirin. Assessment of rs66698963 as a therapeutic response biomarker in other populations and healthcare settings is warranted. Trial RegistrationThe seAFOod polyp prevention trial and STOP-ADENOMA project - ISRCTN05926847. Key pointsO_ST_ABSQuestionC_ST_ABSDoes a functional fatty acid desaturase 2 (FADS2) insertion-deletion (Indel) polymorphism (rs66698963) predict colorectal polyp prevention efficacy of eicosapentaenoic acid (EPA)? FindingsIn 528 participants of the 2 x 2 factorial seAFOod polyp prevention trial of the n-3 highly unsaturated fatty acid (HUFA) EPA and aspirin, who had both colonoscopy outcome and Indel genotype data, a gene (I allele carrier) x treatment interaction identified individuals for whom EPA significantly reduced colorectal polyp number by approximately 50% (a similar effect size to aspirin). MeaningFurther evaluation of a precision medicine approach using the FADS2 Indel polymorphism rs66698963 as a therapeutic response biomarker for cancer and cardiovascular disease prevention by n-3 HUFAs is warranted.