CYP2A6 genetic score, nicotine metabolism and lung cancer

CYP2A6遗传评分、尼古丁代谢与肺癌

• 批准号: 10705683
• 负责人: SHARON E MURPHY
• 金额: $ 22.61万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705683
• 关键词: 7alpha hydroxylase; African American population; Alleles; Base Sequence; Biological Markers; CYP2A7 gene; CYP2D6 gene; Calibration; Carcinogens; Case/Control Studies; Cigarette; Conversion disorder; Cotinine; Data; Diagnosis; Dose; Ethnic Population; Funding; Gene Conversion; Genes; Genetic; Genetic Variation; Genotype; Goals; Grant; Hybrids; Individual; Individual Differences; Japanese American; Low Prevalence; Malignant neoplasm of lung; Measures; Mediating; Metabolic; Metabolism; Native Hawaiian; Nicotine; Phenotype; Population; Prevalence; Prevention strategy; Pseudogenes; Race; Relative Risks; Research; Risk; Role; Smoke; Smoker; Smoking; Tobacco; United States; Variant; cancer risk; catalyst; cigarette smoking; cohort; disorder risk; environmental tobacco smoke exposure; enzyme activity; ethnic difference; ethnic disparity; former smoker; genetic predictors; genetic variant; genome wide association study; hydroxycotinine; improved; multi-ethnic; racial difference; racial disparity; racial population; sequencing platform; targeted sequencing

ABSTRACT In the United States this year, an estimated 235,760 new lung cancer cases will be diagnosed. The vast majority of those are attributable to smoking. However, only 11-24% of smokers will develop lung cancer and the risk among smokers varies significantly. Individual differences in nicotine metabolism can influence that risk by influencing the intensity of smoking. The primary catalyst of nicotine metabolism is CYP2A6, and we have demonstrated an association of CYP2A6 activity with the risk of lung cancer. These data are from a subcohort of ~2200 smokers with nicotine metabolism biomarker data in the Multiethnic Cohort (MEC). The risk of lung cancer varies across racial/ethnic group as does the contribution of CYP2A6 activity to that risk. In this project, we propose to develop a genetic score to predict CYP 2A6-catalyzed nicotine metabolism and to determine the association of that score with the lung cancer risk of ever smokers in the MEC. The gene that encodes CYP2A6 is notoriously polymorphic. The high homology between CYP2A6 and the pseudogene CYP2A7, the many variant alleles of each, and their unique distribution by racial/ethnic group complicates the accurate genotyping of functional variants. However, correctly characterizing an individual's CYP2A6 alleles is integral to the genotype-guided prediction of nicotine metabolism, and to the complete characterization of CYP2A6 variation in multiethnic populations. The related gene CYP2D6 has similar genetic complexities and is equally challenging to genotype. However, recent advances have led to the successful application of long- range sequencing approaches to accurate CYP2D6 variant calling. We propose to use a similar targeted sequencing approach to characterize CYP2A6 genetic diversity across racial/ethnic groups. The improved characterization of CYP2A6 will allow the comprehensive study of the role of CYP2A6 variants in tobacco- related lung cancer and ultimately better identify those at greatest risk for lung cancer and target them for prevention strategies. The overall hypothesis of our research is that variation in CYP2A6 activity contributes to the observed racial/ethnic disparities in lung cancer risk, and that the relative contribution of CYP2A6 activity to risk varies by racial/ethnic group based on the prevalence of metabolically important CYP2A6 variants. The following specific aims are proposed: Aim 1: To characterize the genetic diversity of CYP2A6 in Native Hawaiians relative to Japanese Americans and Whites. CYP2A6 (and CYP2A7) will be sequenced using the PacBio SMRTbellTM Sequencing platform. Aim 2: To develop a CYP2A6 genetic score to predict CYP2A6 nicotine metabolism in the MEC. Aim 3: To investigate the association of the CYP2A6 genetic score developed in Aim 2 with lung cancer in MEC ever smokers with GWAS data.

摘要 在美国，今年估计将有235760例新的肺癌病例被诊断出来。浩瀚无边 其中大部分可归因于吸烟。然而，只有11-24%的吸烟者会患上肺癌和 吸烟者之间的风险差异很大。尼古丁代谢的个体差异会影响这一点 通过影响吸烟强度来增加风险。尼古丁代谢的主要催化剂是CYP2A6，我们 已经证明了CYP2A6活性与肺癌风险之间的关系。这些数据来自 多种族队列(MEC)中有尼古丁代谢生物标记物数据的约2200名吸烟者的亚队列。这个 不同种族/民族患肺癌的风险不同，CYP2A6活性对该风险的贡献也不同。 在这个项目中，我们建议开发一个遗传评分来预测CyP2A6催化的尼古丁代谢和 以确定该得分与MEC中吸烟者患肺癌风险的相关性。基因 编码CYP2A6的基因是出了名的多态。CYP2A6基因与假基因的高度同源性 CYP2A7，每个基因的许多变异等位基因，以及它们在种族/民族群体中的独特分布，使 对功能变异进行准确的基因分型。然而，正确地描述一个人的CYP2A6等位基因 对于尼古丁代谢的基因导向性预测，以及对 多民族人群中的细胞色素P450 2A6基因变异相关基因CYP2D6具有相似的遗传复杂性和 对基因分型也同样具有挑战性。然而，最近的进展导致了Long-Long-Long的成功应用 范围排序的方法，以准确的CYP2D6变种叫声。我们建议使用类似的定向 用测序方法表征不同种族/民族群体的细胞色素P450 2A6基因多样性。改进后的 通过对细胞色素P450 2 A6的鉴定，可以全面研究细胞色素P4 2 6变异在烟草中的作用。 与肺癌相关，最终更好地识别肺癌风险最高的人，并针对他们 预防策略。我们研究的总体假设是，CYP2A6活性的变化对 对于观察到的肺癌风险的种族/民族差异，以及CYP2A6的相对贡献 根据代谢性重要的CYP2A6的流行情况，对风险的活动因种族/民族而异 变种。本研究的具体目标如下：目的1：研究黄瓜细胞色素P450 2A6基因的遗传多样性。 夏威夷原住民相对于日裔、美国人和白人。将对CYP2A6(和CYP2A7)进行测序 使用PacBio SMRTbelTM测序平台。目的2：开发一种预测细胞色素P450 2A6基因分值的方法 CYP2A6在MEC中的尼古丁代谢目的3：探讨细胞色素P4502A6基因评分与基因分值的关系 在AIM 2中开发的MEC曾经吸烟者的肺癌与Gwas数据。