Aspirin pharmacogenetics in the Aspirin/Folate Polyp Prevention Trial

阿司匹林/叶酸息肉预防试验中的阿司匹林药物遗传学

• 批准号: 7545365
• 负责人: CORNELIA M ULRICH
• 金额: $ 10.33万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7545365
• 关键词: Address; Affect; Arachidonate 5-Lipoxygenase; Aspirin; CYP2C9 gene; Chemoprevention; Chemopreventive Agent; Clinical Services; Clinical Trials; Collaborations; Colon Carcinoma; Colorectal Adenoma; Colorectal Cancer; Colorectal Neoplasms; Confidence Intervals; Daily; Data; Diagnosis; Enzymes; Epidemiology; Folate; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Hemorrhage; Individual; Inherited; Institution; Intervention; Investigation; Letters; Malignant Neoplasms; Metabolism; P-Glycoproteins; Participant; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacogenetics; Polyp Prevention Trial; Polyps; Prevention; Prostacyclin synthase; Prostaglandin Production; Prostaglandins; Randomized; Randomized Controlled Trials; Recording of previous events; Recruitment Activity; Recurrence; Relative Risks; Research; Research Design; Risk; Site; Stomach; Toxic effect; Transmembrane Transport; United Kingdom; Universities; Upper arm; Work; adenoma; arachidonate; cost; cyclooxygenase 1; day; gastrointestinal; insight; prevent; research study; response

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.

描述（申请人提供）：阿司匹林对结直肠腺瘤和癌症的化学预防有效。然而，长期服用阿司匹林通常与胃毒性有关。针对最有可能从阿司匹林中获益的结直肠癌高危人群量身定制阿司匹林化学预防可以通过药物遗传学来实现。阿司匹林的已知靶标是环氧合酶-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系。具体来说，我们将重点关注与1)前列腺素合成有关的基因：COX-1、前列腺环素合成酶（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)；3)阿司匹林代谢：CYP2C9和UGT1A6。我们建议参加一项随机对照试验（阿司匹林/叶酸息肉预防研究）的1121名受试者进行基因分型。参与者从1994年6月到1998年4月通过九个参与机构的临床服务和相关实践招募，平均随访2.7年。我们的研究目的是：1)研究这些基因的多态性是否与腺瘤复发风险相关；2)在随机服用阿司匹林的个体中分别检查这些关联。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影响的候选多态性，最大限度地利用这些关键途径中遗传变异性的可用信息。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进行汇总分析。本研究采用一种经济有效的方法来解决阿司匹林相关途径和腺瘤复发风险的遗传变异研究问题。这项工作将建立新的合作关系，为阿司匹林化学预防的机制提供见解，并允许在结直肠腺瘤或癌症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15万人被诊断为结直肠癌。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兆。然而，阿司匹林并不能预防所有人的息肉。在一组参加阿司匹林临床试验的人群中——阿司匹林/叶酸息肉预防研究，我们计划探索遗传因素，以解释谁更容易患第二腺瘤，以及为什么有些人从阿司匹林的使用中受益，而另一些人却没有。由于长期服用阿司匹林会导致胃肠道出血，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。