SNPMiner Trials by Shray Alag


SNPMiner Trials: Clinical Trial Report


Report for Clinical Trial NCT01661764

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

Fatty Acid Desaturase Activity, Fish Oil and Colorectal Cancer Prevention

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

NCT01661764 Colorectal Adenomatous Polyps
MeSH: Colorectal Neoplasms Adenomatous Polyps
HPO: Neoplasm of the large intestine

2 Interventions

Name: Eicosapentanoic acid and docosahexanoic acid

Description: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks

Type: Drug

rs174535 (GG), fish oil supplements rs174535 (GT), fish oil supplements rs174535 (TT), fish oil supplement

Name: Oleic Acid

Description: Placebo

Type: Drug

rs174535 (GG), placebo rs174535 (GT), placebo rs174535 (TT), placebo


Primary Outcomes

Description: The primary outcome of interest is rectal epithelial cell proliferation, as measured by Ki67 (mib-1) labeling. Expression of Ki-67 in colon epithelial cells will be detected following the standard IHC protocol of EnVision™+ System, HRP (DAKO).

Measure: Rectal Epithelial Cell Proliferation

Time: 6 month

Description: The primary outcome of interest is rectal epithelial cell apoptosis as measured by TUNEL (TdT-mediated dUTP Nick-End Labeling). The TUNEL assay is conducted to measure apoptosis of colon epithelium using DeadEnd Colorimetric TUNEL System (Promega). After all fields of each sample are measured, the final immunoreaction indices are generated automatically by setting algorithms as ''total positive area / total nuclear area. Apoptotic activity is also scored using standard morphologic criteria applied to H&E stained sections.

Measure: Rectal Epithelial Cell Apoptosis

Time: 6 months

Secondary Outcomes

Description: Expression of COX-2 in rectal epithelial cells will be detected following the standard IHC protocol of EnVision™+ System, HRP (DAKO).

Measure: Rectal Epithelial Cell COX-2 Expression

Time: 6 months

Description: Expression of 15-PGDH in rectal epithelial cells will be detected following the standard IHC protocol of EnVision™+ System, HRP (DAKO).

Measure: Rectal Epithelial Cell 15-PGDH Expression

Time: 6 months

Description: Lipids will be extracted using the method of Folch-Lees

Measure: Rectal Epithelial Cell Phospholipid Fatty Acid Content

Time: 6 months

Description: liquid chromatography/tandem mass spectrometric on rectal biopsy samples

Measure: Rectal Epithelial Cell Production of PGE2 and PGE3

Time: 6 months

Other Outcomes

Measure: C-reactive Protein

Time: 6 months

Description: leptin and adiponectin

Measure: Adipokines

Time: 6 months

Description: homeostasis model assessment-insulin resistance (HOMA-IR) HOMA-IR. Fasting insulin and glucose were be used to determine HOMA-IR: [fasting glucose (mmol/l) x fasting insulin (µU/ml)]/22.5]", Optimal insulin sensitivity: < 1, Early insulin resistance: > 1.9, Significant insulin resistance: > 2.9

Measure: Insulin Sensitivity

Time: 6 months

Purpose: Prevention

Allocation: Randomized

Factorial Assignment


There are 2 SNPs

SNPs


1 rs174535

Inclusion Criteria: - ≥ 40 and < 80 years of age - History of 1 or more adenomatous polyps - Consent to be contacted for future studies - Participants with known genotype for rs174535 in FADS1 - Prior participation in the Tennessee Colorectal Polyp Study or the Personalized Prevention of Colorectal Cancer Trial Exclusion Criteria: - Previously resected colorectal cancer - Coronary artery disease or congestive heart failure - Current metabolic or life-threatening disease - Currently taking fish oil supplements - Inability or unwillingness to stop NSAIDs or ASA during the study - Allergic to fish products - Diagnosis of inflammatory bowel disease - Diagnosis of any cancer (except non-melanoma skin cancer) - Diagnosis of liver or kidney disease - Pregnant or breast feeding Inclusion Criteria: - ≥ 40 and < 80 years of age - History of 1 or more adenomatous polyps - Consent to be contacted for future studies - Participants with known genotype for rs174535 in FADS1 - Prior participation in the Tennessee Colorectal Polyp Study or the Personalized Prevention of Colorectal Cancer Trial Exclusion Criteria: - Previously resected colorectal cancer - Coronary artery disease or congestive heart failure - Current metabolic or life-threatening disease - Currently taking fish oil supplements - Inability or unwillingness to stop NSAIDs or ASA during the study - Allergic to fish products - Diagnosis of inflammatory bowel disease - Diagnosis of any cancer (except non-melanoma skin cancer) - Diagnosis of liver or kidney disease - Pregnant or breast feeding Colorectal Adenomatous Polyps Colorectal Neoplasms Adenomatous Polyps 1.Rationale and Specific Aims Colorectal cancer (CRC) is the third most common cancer and the second most frequent cause of cancer related mortality in the United States.

At the baseline visit, the investigators will re-genotype rs174535 to confirm the accuracy of the imputation process.


2 rs174537

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.

FADS1 is the rate-limiting enzyme in the conversion of linoleic acid (LA), the most commonly consumed PUFA, to ARA, and homozygotes for the T allele (population frequency of 13%, HapMap -CEU) in rs174537 have lower fatty acid desaturase activity and subsequently lower tissue levels of ARA.

The first factor will be the rs174537 genotype (GG, GT, and TT) in the FADS1 gene and the second factor will be fish oil supplementation (fish oil versus placebo).



HPO Nodes


HPO:
Neoplasm of the large intestine
Genes 71
FOXE1 PMS1 CDKN2A KRAS MST1 TGFBR2 STK11 MSH6 TCF4 BMPR1A PMS2 KLLN MLH3 DLC1 NRAS BRCA1 BRCA2 PDGFRA DOCK8 PIK3CA GPR35 POLD1 NTHL1 POLE SRC BUB1 SH3KBP1 BUB1B CHEK2 APC MLH1 PRKAR1A FLCN COL14A1 AKT1 RPS19 RPS20 HABP2 MSH2 FGFR3 MSH3 KEAP1 GREM1 MINPP1 SEMA4A CTNNB1 DCC BUB3 PTEN MDM2 CEP57 ENG AAGAB TRIP13 KIT EPCAM DICER1 RNF43 PALLD EP300 PALB2 SEC23B MUTYH SDHA TP53 SDHB SDHC SDHD AXIN2 SMAD4 FAN1