CYP2A6 genetic score, nicotine metabolism and lung cancer

摘要 在美国，今年估计将诊断出235，760例新的肺癌病例。绝 其中大部分是由于吸烟。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这一点 通过影响吸烟的强度来降低风险。尼古丁代谢的主要催化剂是CYP 2A 6，我们 已经证明CYP 2A 6活性与肺癌风险相关。这些数据来自A 多种族队列（MEC）中约2200名具有尼古丁代谢生物标志物数据的吸烟者亚队列。的 肺癌的风险因种族/民族而异，CYP 2A 6活性对该风险的贡献也是如此。 在这个项目中，我们建议开发一种遗传评分来预测α 2A 6催化的尼古丁代谢， 以确定该评分与MEC中曾经吸烟者患肺癌风险的相关性。基因 编码CYP 2A 6的基因是众所周知的多态性。CYP 2A 6与假基因高度同源 CYP 2A 7，每种基因的许多变体等位基因，以及它们在种族/民族群体中的独特分布， 功能变体的准确基因分型。然而，正确表征个体的CYP 2A 6等位基因 是尼古丁代谢的基因型指导预测和尼古丁代谢的完整表征不可或缺的。 多种族人群中的CYP 2A 6变异。相关基因CYP 2D 6具有相似的遗传复杂性， 对基因分型同样具有挑战性。然而，最近的进展导致了长- 范围测序方法，以准确的CYP 2D 6变异调用。我们建议使用类似的目标 测序方法来表征不同种族/民族的CYP 2A 6遗传多样性。改进的 CYP 2A 6的表征将允许全面研究CYP 2A 6变体在烟草中的作用， 相关的肺癌，并最终更好地识别那些患肺癌的风险最大的人， 预防战略。我们研究的总体假设是，CYP 2A 6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CYP 2A 6的相对贡献 基于代谢重要性CYP 2A 6的患病率，不同种族/民族的活性风险比不同 变体。目的1：研究中国汉族人群CYP 2A 6基因的遗传多样性，为进一步研究中国汉族人群CYP 2A 6基因的遗传多样性奠定基础。 夏威夷原住民相对于日裔美国人和白人。将对CYP 2A 6（和CYP 2A 7）进行测序 使用PacBio SMRTbellTM测序平台。目的2：开发CYP 2A 6遗传评分来预测 MEC中的CYP 2A 6尼古丁代谢。目的3：探讨CYP 2A 6基因分型与糖尿病的相关性 在具有GWAS数据的MEC吸烟者中，Aim 2发生肺癌。

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.