CYP2A6 genetic score, nicotine metabolism and lung cancer

CYP2A6遗传评分、尼古丁代谢与肺癌

• 批准号: 10411514
• 负责人: SHARON E MURPHY
• 金额: $ 24.87万
• 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/10411514
• 关键词: African American population; Alleles; Base Sequence; Biological Markers; CYP2A7 gene; CYP2D6 gene; Carcinogens; Case-Control Studies; Cigarette; Conversion disorder; Cotinine; Data; Diagnosis; Dose; Ethnic group; 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; base; cancer risk; catalyst; cigarette smoke; cigarette smoking; cohort; disorder risk; environmental tobacco smoke exposure; enzyme activity; former smoker; genetic predictors; genetic variant; genome wide association study; hydroxycotinine; improved; multi-ethnic; racial and ethnic; racial and ethnic disparities; racial difference; sequencing platform; targeted sequencing; tobacco smokers

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.

抽象的 美国今年估计将诊断出 235,760 例新肺癌病例。广阔的 其中大部分归因于吸烟。然而，只有 11-24% 的吸烟者会患上肺癌 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 通过影响吸烟强度来降低风险。尼古丁代谢的主要催化剂是CYP2A6，我们 已证明 CYP2A6 活性与肺癌风险相关。这些数据来自于 多种族队列 (MEC) 中约 2200 名吸烟者的亚队列，具有尼古丁代谢生物标志物数据。这 肺癌的风险因种族/族裔群体的不同而不同，CYP2A6 活性对该风险的影响也不同。 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 以确定该分数与 MEC 中曾经吸烟者患肺癌风险的关联。基因 众所周知，编码 CYP2A6 的基因具有多态性。 CYP2A6与假基因高度同源 CYP2A7、每个等位基因的许多变异等位基因以及它们按种族/族裔群体的独特分布使情况变得复杂 功能变异的准确基因分型。然而，正确表征个体的 CYP2A6 等位基因 是尼古丁代谢基因型指导预测以及完整表征的组成部分 CYP2A6 在多种族人群中的变异。相关基因 CYP2D6 具有相似的遗传复杂性，并且 对基因分型同样具有挑战性。然而，最近的进展已经导致长期的成功应用 范围测序方法可实现准确的 CYP2D6 变异识别。我们建议使用类似的目标 测序方法来表征跨种族/民族群体的 CYP2A6 遗传多样性。改进后的 CYP2A6 的表征将允许全面研究 CYP2A6 变体在烟草中的作用 相关肺癌，最终更好地识别那些肺癌风险最大的人，并针对他们进行治疗 预防策略。我们研究的总体假设是 CYP2A6 活性的变化有助于 观察到的肺癌风险的种族/民族差异，以及 CYP2A6 的相对贡献 根据代谢重要的 CYP2A6 的患病率，不同种族/族裔群体的活动风险有所不同 变种。提出以下具体目标： 目标 1：表征 CYP2A6 的遗传多样性 夏威夷原住民相对于日裔美国人和白人。 CYP2A6（和 CYP2A7）将被测序 使用 PacBio SMRTbellTM 测序平台。目标 2：开发 CYP2A6 遗传评分来预测 MEC 中的 CYP2A6 尼古丁代谢。目标 3：研究 CYP2A6 遗传评分的关联 通过 GWAS 数据，在 MEC 曾经吸烟者的 Aim 2 中开发肺癌。