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

Importance A 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. Objective We 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. Design Secondary analysis of the randomized, placebo-controlled, 2×2 factorial seAFOod polyp prevention trial of EPA 2g daily and aspirin 300mg daily, stratified for FADS2 Indel genotype. Setting Colonoscopy surveillance 12 months after clearance screening colonoscopy, in the English Bowel Cancer Screening Programme (BCSP). Participants A 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. Results EPA 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 Relevance The 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 Registration The seAFOod polyp prevention trial and STOP-ADENOMA project - [ISRCTN05926847][1]. Question Does a functional fatty acid desaturase 2 (FADS2) insertion-deletion (Indel) polymorphism (rs66698963) predict colorectal polyp prevention efficacy of eicosapentaenoic acid (EPA)? Findings In 528 participants of the 2 × 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). Meaning Further 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. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial ISRCTN05926847 ### Funding Statement This study was funded by the Efficacy and Mechanism Evaluation (EME) Programme (NIHR128210), an MRC and NIHR partnership. The views expressed in this publication are those of the authors and not necessarily those of the MRC, NIHR or the Department of Health and Social Care. MAH is a NIHR Senior Investigator. MAH is supported by Cancer Research UK grant C23434/A24939. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: London and Surrey Borders Research Ethics Committee gave ethical approval for this work (19/LO/1655) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN05926847