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）和二十二碳六烯酸（DHA），可以降低结直肠癌的风险。此外，可能是n-3与n-6 PUFA的相对比例最能确定鱼油的化学预防效果。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（PGE 2），一种在结直肠肿瘤中异常产生的炎性类二十烷酸，而EPA转化为抗炎性前列腺素E3（PGE 3）。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，高达28%的ARA组织水平的加性方差是由单个基因，脂肪酸去饱和酶1（FADS 1）的变体解释的。FADS 1是亚油酸（最常消耗的PUFA）转化为ARA的限速酶，rs 174537中T等位基因的纯合子（群体频率为13%，HapMap-CEU）具有较低的脂肪酸去饱和酶活性，随后具有较低的ARA组织水平。我们的假设是，具有遗传决定的FADS 1活性较低的个体将从鱼油补充中获得比具有较高FADS 1活性的个体更大的益处，因为ARA的组织水平较低，随后n-6与n-3 PUFA的比例更有利。为了验证这一假设，我们将招募150名最近发现患有腺瘤性息肉的参与者，并进行为期6个月的双盲3 × 2析因随机对照试验。我们的第一个因素将是FADS 1基因型（GG，GT和TT），我们的第二个因素将是鱼油补充剂（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标记和直肠隐窝凋亡，通过TUNEL测定。次要终点将包括直肠上皮细胞考克斯-2和15-PGDH的表达、直肠细胞PGE 2和PGE 3的产生、直肠粘膜组织脂肪酸水平以及炎症生物标志物（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。我们的具体目标包括：1）确定鱼油补充剂对直肠上皮细胞增殖指数和直肠隐窝细胞凋亡标志物的功效，和2）确定遗传确定的脂肪酸去饱和酶1活性对鱼油补充剂用于结肠直肠癌化学预防的作用。我们的长期目标是确定可能影响鱼油补充剂疗效的遗传因素，以便使用海洋来源的n-3 PUFA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，与具有高FADS 1活性的个体相比，具有低FADS 1活性的个体将具有更大的反应。 公共卫生相关性：结直肠癌是美国癌症相关死亡的第二大原因。然而，鱼油可能通过其抗炎特性有益于癌症化学预防;与多不饱和脂肪酸生物合成相关的基因变异可能会减弱这些作用。这项研究将研究鱼油补充剂在结直肠癌化学预防中的营养基因组学，并可能具有癌症预防以外的意义，因为鱼油正在积极研究心血管，精神和代谢疾病。

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. PUBLIC HEALTH RELEVANCE: Colorectal cancer is the second leading cause of cancer-related mortality within the United States. Fish oils may be beneficial for cancer chemoprevention through their anti-inflammatory properties, however; variations in genes related to polyunsaturated fatty acid biosynthesis may attenuate these effects. This study will investigate the nutrigenomics of fish oil supplementation in colorectal cancer chemoprevention and may have implications beyond cancer prevention as fish oil is being actively investigated for cardiovascular, psychiatric and metabolic diseases.