Aspirin pharmacogenetics in the Aspirin/Folate Polyp Prevention Trial

描述（由申请人提供）：阿司匹林在结肠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。调整阿司匹林的化学预防，以针对那些最有可能从阿司匹林中获益的结直肠癌高危人群，可以通过药物遗传学来实现。阿司匹林公认的作用靶点是环氧合酶-1（考克斯-1），它是花生四烯酸转化为异丙肾上腺素的关键酶。我们将评估结直肠腺瘤复发与阿司匹林靶点和代谢相关的候选多态性之间的关联。具体而言，我们将重点关注参与1）前列腺素合成的基因：考克斯-1、前列环素合酶（PGIS）和花生四烯酸脂氧合酶-5（ALOX 5）; 2）前列腺素转运：多药耐药蛋白4（MRP 4）; 3）阿司匹林代谢：CYP 2C 9和UGT 1A 6。我们建议对1121名参加随机对照试验（阿司匹林/叶酸息肉预防研究）的受试者进行基因分型。从1994年6月到1998年4月，通过9个参与机构的临床服务和相关实践招募了参与者，并平均随访2.7年。我们研究的目的是：1）研究这些基因的多态性是否与腺瘤复发的风险相关; 2）在随机分配服用阿司匹林的个体中分别检查这些相关性。我们建议使用的研究设计，最大限度地利用现有的信息，在这些关键途径的遗传变异性，通过检查候选多态性与已知的或可能的功能性的影响。如果我们的结果是有希望的，那么我们计划更全面的研究，包括与其他试验合作者的汇总分析。本研究采用成本效益的方法来解决阿司匹林相关途径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，深入了解阿司匹林化学预防的机制，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肠直肠癌。阿司匹林已被证明可以预防结直肠腺瘤-一种已知的结直肠癌的前体。然而，阿司匹林并不能预防所有人的息肉。在一个参与阿司匹林临床试验的小组中-阿司匹林/叶酸息肉预防研究，我们计划探索遗传因素，这些遗传因素可能解释谁更有可能患有第二个腺瘤，以及为什么有些人受益于阿司匹林的使用，而其他人则没有。由于阿司匹林长期使用会导致胃肠道出血，因此确定那些最有可能在癌症减少方面受益的人非常重要。

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.