Fatty acid desaturase activity, fish oil and colorectal cancer chemoprevention

描述（由申请人提供）：结直肠癌是美国癌症相关死亡的第二大原因。动物模型和观察性研究表明，海洋来源的n-3多不饱和脂肪酸[PUFA]，如二十碳五烯酸[EPA]和二十二碳己酸[DHA]可能降低结直肠癌的风险。此外，可能是n-3和n-6 PUFAs的相对比例最好地决定了鱼油的化学预防作用。这个比例很重要，因为n-6 PUFA，花生四烯酸（ARA），通过环加氧酶途径转化为前列腺素E2 (PGE2)，这是一种在结直肠肿瘤中异常产生的炎症类二十烷，而EPA转化为抗炎前列腺素E3 （PGE3）。虽然n-6与n-3 PUFAs的比例可以通过饮食措施来控制，但遗传因素也可能影响这一比例。最近的全基因组关联和单倍型研究表明，ARA组织水平中高达28%的加性变异可由单一基因脂肪酸去饱和酶1 （FADS1）的变异来解释。FADS1是将亚油酸（最常消耗的PUFA）转化为ARA的限速酶，而rs174537中T等位基因（种群频率为13%，HapMap -CEU）的纯合子具有较低的脂肪酸去饱和酶活性，因此ARA的组织水平较低。我们的假设是，基因决定的FADS1活性较低的个体将比FADS1活性较高的个体从鱼油补充中获得更大的益处，因为组织中ARA水平较低，随后有更有利的n-6与n-3 PUFA比率。为了验证这一假设，我们将招募150名最近确诊的腺瘤性息肉患者，进行为期6个月的双盲3 × 2随机对照试验。我们的第一个因素是FADS1基因型（GG， GT和TT），第二个因素是鱼油补充剂（鱼油与安慰剂）。我们的主要结果将是直肠上皮细胞增殖的变化（通过Ki-67标记测量）和直肠隐窝细胞凋亡（通过TUNEL测量）。次要终点将包括直肠上皮细胞COX-2和15-PGDH的表达、直肠细胞PGE2和PGE3的产生、直肠粘膜组织脂肪酸水平、炎症生物标志物（c反应蛋白）、脂肪因子（瘦素、脂联素）和胰岛素敏感性标志物的变化。我们的具体目的包括：1)确定鱼油补充剂对直肠上皮细胞增殖指标和直肠隐窝凋亡标志物的影响；2)确定基因决定的脂肪酸去饱和酶1活性对鱼油补充剂对结直肠癌化学预防的影响。我们的长期目标是确定可能影响鱼油补充剂功效的遗传因素，以便使用海洋来源的n-3 PUFAs进行更明确的腺瘤复发试验。我们预计鱼油将具有抗肿瘤作用，与FADS1活性高的个体相比，FADS1活性低的个体会有更大的反应。

DESCRIPTION (provided by applicant): Colorectal cancer is the second leading cause of cancer-related mortality 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 pathway to prostaglandin E2 (PGE2), an inflammatory eicosanoid aberrantly produced 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 manipulated through dietary measures, genetic factors may also influence this ratio. Recent genome-wide association and haplotype studies have demonstrated that up to 28% of the additive variance in tissue levels of ARA is explained by variants in a single gene, fatty acid desaturase 1 (FADS1). FADS1 is the rate-limiting enzyme in the conversion of linoleic acid, 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. Our 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 we will recruit 150 participants with recently identified adenomatous polyps and conduct a 6-month double blind 3 X 2 factorial randomized controlled trial. Our first factor will be FADS1 genotype (GG, GT, and TT) and our second factor will be fish oil supplementation (fish oil versus placebo). Our primary outcome will be the change in rectal epithelial cell proliferation as measured by Ki-67 labeling and rectal crypt apoptosis as measured by TUNEL. Secondary endpoints will include rectal epithelial cell expression of COX-2 and 15-PGDH, 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. Our 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. Our 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. We 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.