Aspirin pharmacogenetics in the Aspirin/Folate Polyp Prevention Trial

点击翻译按钮获取中文摘要

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.