Fish Oil Supplementation, Nutrigenomics and Colorectal Cancer Prevention
Status:
Completed
Trial end date:
2018-01-23
Target enrollment:
Participant gender:
Summary
Colorectal cancer is the second leading cause of cancer-related death within the United
States. Animal models and observational studies have suggested that marine-derived n-3
polyunsaturated fatty acids [PUFA] such as eicosapentanoic acid [EPA] and docosahexanoic acid
[DHA] may reduce the risk of colorectal cancer. In addition, it may be the relative
proportion of n-3 to n-6 PUFAs that best determines the chemopreventive effects of fish oils.
This ratio is important because the n-6 PUFA, arachidonic acid (ARA), is converted via the
cyclo-oxygenase (COX) pathway to prostaglandin E2 (PGE2), an inflammatory eicosanoid
overproduced in colorectal neoplasms while EPA is converted to the anti-inflammatory
prostaglandin E3 (PGE3). While the ratio of n-6 to n-3 PUFAs can be altered through dietary
changes, genetic factors may also influence this ratio. Recent genetic studies have
demonstrated that much of the tissue levels of ARA is determined by differences in a gene
called fatty acid desaturase 1 (FADS1). FADS1 is the rate-limiting enzyme in the conversion
of linoleic acid, the most commonly consumed PUFA in the Western diet, to ARA, and one
particular genetic variant caller rs174537 is associated with lower fatty acid desaturase
activity and subsequently lower tissue levels of ARA.
The study hypothesis is that individuals with genetically determined lower activity of FADS1
will derive greater benefit from fish oil supplementation than individuals with higher FADS1
activity because of lower tissue levels of ARA and subsequently a more favorable n-6 to n-3
PUFA ratio. To test this hypothesis the investigators will recruit 150 participants with
recently identified adenomatous polyps and conduct a 6-month double blind 3 X 2 factorial
randomized controlled trial. The first factor will be FADS1 genotype (GG, GT, and TT) and the
second factor will be fish oil supplementation (fish oil versus placebo). The primary outcome
will be the change in rectal epithelial cell growth and cell death. Secondary outcomes will
include rectal epithelial cell expression of genes important in PGE2 production, rectal cell
production of PGE2 and PGE3, rectal mucosal tissue levels of fatty acids, and changes in
biomarkers of inflammation (C-reactive protein), adipokines (leptin, adiponectin), and
markers of insulin sensitivity.
The specific aims include: 1) to determine the efficacy of fish oil supplements on rectal
epithelial cell proliferation indexes and markers of rectal crypt apoptosis, and 2) to
determine the effect of genetically-determined fatty acid desaturase 1 activity on fish oil
supplementation for colorectal cancer chemoprevention. The investigators long-term objectives
are to determine genetic factors that might influence the efficacy of fish oil
supplementation in order to conduct a more definitive adenoma recurrence trial using
marine-derived n-3 PUFAs. The investigators anticipate that fish oil will have
anti-neoplastic effect and individuals with low FADS1 activity will have a greater response
compared to individuals with high FADS1 activity