Aspirin pharmacogenetics in the Aspirin/Folate Polyp Prevention Trial

描述(申请人提供)：阿司匹林在结直肠腺瘤和癌症的化学预防中有效。然而，长期使用阿司匹林通常与胃毒性有关。针对最有可能受益于阿司匹林的结直肠癌高危人群定制阿司匹林化学预防可能通过药物遗传学实现。阿司匹林公认的靶标是环氧合酶-1(COX-1)，它是花生四烯酸转化为前列腺素的关键酶。我们将评估与阿司匹林靶点和代谢相关的候选基因多态与结直肠腺瘤复发之间的关系。具体地说，我们将关注与1)前列腺素合成有关的基因：COX-1、前列环素合成酶(PGIs)和花生四烯酸脂氧合酶-5(ALOX5)；2)前列腺素转运：多药耐药蛋白4(MRP4)；以及3)阿司匹林代谢：CYP2C9和UGT1A6。我们建议对参与随机对照试验(阿司匹林/叶酸息肉预防研究)的1121名受试者进行基因分型。参与者是从1994年6月至1998年4月通过9个参与机构的临床服务和相关实践招募的，平均跟踪时间为2.7年。我们研究的目的是：1)调查这些基因的多态是否与腺瘤复发的风险有关；2)在随机服用阿司匹林的个体中分别检查这些相关性。我们建议使用一种研究设计，通过检查具有已知或可能功能效应的候选多态来最大化关于这些关键途径中的遗传可变性的可用信息。如果我们的结果是有希望的，那么我们计划进行更全面的调查，包括与其他试验合作者的联合分析。这项研究使用了一种经济有效的方法来解决阿司匹林相关途径中的遗传变异性和腺瘤复发风险的研究问题。这项工作将建立新的合作，提供对阿司匹林化学预防机制的洞察，并允许在结直肠腺瘤或癌症的高风险人群中更好地定制阿司匹林治疗。2007年，美国将有超过15万人被诊断出患有结直肠癌。阿司匹林已被证明可以预防结直肠腺瘤--结直肠癌的已知先兆。然而，阿司匹林并不能预防所有个体的息肉。在一组参与了阿司匹林临床试验-阿司匹林/叶酸息肉预防研究的小组中，我们计划探索遗传因素，以解释谁更有可能患有第二腺瘤，以及为什么一些人从使用阿司匹林中受益，而另一些人则不受益。由于长期使用阿司匹林可能会导致胃肠道出血，因此确定哪些人最有可能在减少癌症方面受益是很重要的。

DESCRIPTION (provided by applicant): Aspirin is effective in the chemoprevention of colorectal adenoma and cancer. However, long-term use of aspirin is commonly associated with gastric toxicities. Tailoring aspirin chemoprevention to target individuals at high risk of colorectal cancer who are most likely to benefit from aspirin may be achieved with pharmacogenetics. The recognized target of aspirin is cyclooxygenase-1 (COX-1), a key enzyme in the conversion of arachidonate to prostaglandins. We will evaluate the association between colorectal adenoma recurrence and candidate polymorphisms related to aspirin targets and metabolism. Specifically, we will focus on genes involved in 1) prostaglandin synthesis: COX-1, prostacyclin synthase (PGIS), and arachidonate lipoxygenase-5 (ALOX5); 2) prostaglandin transport: multidrug resistance protein 4 (MRP4); and 3) aspirin metabolism: CYP2C9 and UGT1A6. We propose to genotype 1121 subjects who participated in a randomized controlled trial (the Aspirin/Folate Polyp Prevention Study). Participants were recruited from June 1994 through April 1998 through clinical services and associated practices of the nine participating institutions and were followed for an average of 2.7 years. The aims of our study are: 1) to investigate whether polymorphisms in these genes are associated with risk of adenoma recurrence; and 2) to examine these associations separately among those individuals randomized to aspirin. We propose to use a study design that maximizes available information regarding genetic variability in these key pathways by examining candidate polymorphisms with known or likely functional effects. If our results are promising, then we plan more comprehensive investigations, including pooled analyses with other trial collaborators. This study uses a cost-effective approach to address the research question of genetic variability in aspirin- related pathways and adenoma recurrence risk. This work will establish new collaborations, provide insight into the mechanisms of aspirin chemoprevention and allow better tailoring of aspirin therapy among those at high risk of colorectal adenoma or cancer. More than 150,000 people in the U.S. will be diagnosed with colorectal cancer in 2007. Aspirin has been shown to prevent colorectal adenoma - a known precursor to colorectal cancer. However, aspirin does not prevent polyps in all individuals. Within a group who participated in a clinical trial of aspirin - the Aspirin/Folate Polyp Prevention Study, we plan to explore genetic factors that may explain who is more likely to have a second adenoma and why some people benefit from aspirin use and others do not. Because aspirin can cause gastrointestinal bleeding with long-term use, it is important to identify those who are most likely to benefit in terms of cancer reduction.