Inherited genetic risk factors common to COPD and lung cancer.

描述（由申请人提供）：慢性阻塞性肺疾病（COPD）和肺癌是美国和世界范围内发病率和死亡率的主要原因。吸入香烟烟雾是已知和可预防的主要原因，但只有10-15%的重度吸烟者患上这些疾病。这表明吸烟暴露与遗传易感性因素相互作用决定风险。虽然一些易感基因是已知的，但它们对这两种疾病的风险贡献率不到5%。目前迫切需要确定这些疾病的其他遗传易感性因素，以解释大多数COPD和肺癌风险。该项目将使用正常支气管上皮细胞（NBEC）和血液样本，这些样本由CA148572资助，来自600名年龄在50岁以上、吸烟史超过20包年的非肺癌受试者，以及150名肺癌受试者的单独队列。目的是确定抗氧化和DNA修复基因转录调控的个体间变异在COPD和肺癌风险中的作用。核心假设是，遗传DNA变异与COPD和肺癌的风险增加有关，其中许多表现为关键抗氧化、DNA修复和转录因子基因的转录丰度分散增加。为了支持我们的假设，我们最近确定了一种肺癌风险测试（LCRT），该测试包含14个基因的转录丰度值，包括9个抗氧化基因，3个DNA修复基因和2个转录因子基因。对于这些基因中的每一个，与匹配的对照组相比，肺癌受试者的转录丰度值分布在更大的范围内。此外，遗传DNA变异导致LCRT组成基因的转录调控发生变异。我们计划通过追求以下两个具体目标来检验我们的中心假设并实现本应用程序的目标：目标1。确定关键的抗氧化和DNA修复基因是否增加了COPD患者正常支气管上皮细胞中转录物丰度的分散，以及包含这些基因子集的多基因测试是否能准确检测COPD患病率。目标2。确定有助于增加与COPD和/或肺癌患病率相关的基因转录物丰度分散的DNA变异。我们预计Aim 1将提供证据，证明关键抗氧化、DNA修复和转录因子基因的高转录丰度分散与COPD风险相关，就像肺癌一样，并将产生COPD风险增加的候选生物标志物。目的2将鉴定与关键基因转录物丰度分散增加相关的DNA变异，这些基因在COPD和肺癌发病机制中具有很高的先验可能性。这项研究与公共卫生相关，因为它将导致生物标志物的发展，用于筛选和/或化学预防试验，并为化学预防和治疗药物的开发提供药物靶点。预计这些发展将降低死亡率和保健费用。

DESCRIPTION (provided by applicant): Chronic Obstructive Pulmonary Disease (COPD) and lung cancer are leading causes of morbidity and mortality both in the United States and worldwide. Inhalation of cigarette smoke is the primary known and preventable cause but only 10-15% of heavy smokers develop these diseases. This suggests that cigarette smoke exposure interacts with inherited susceptibility factors to determine risk. While some susceptibility genes are known, they account for less than 5% of risk for either disease. There is urgent need to identify additional heritable susceptibility factors for these diseases that explain the majority of COPD and lung cancer risk. This proposed project will use normal bronchial epithelial cell (NBEC) and blood samples collected through funding from CA148572 from a cohort of 600 non-lung cancer subjects over age 50, with more than 20 pack-years smoking history, and a separate cohort of 150 lung cancer subjects. The objective here is to determine the role of inter-individual variation in antioxidant and DNA repair gene transcript regulation in conferring risk for both COPD and lung cancer. The central hypothesis is that inherited DNA variants are associated with increased risk for both COPD and lung cancer and that many of these manifest as increased transcript abundance dispersion in key antioxidant, DNA repair, and transcription factor genes. In support of our hypothesis, we recently identified a lung cancer risk test (LCRT) that comprises transcript abundance values of 14 genes, including nine anti-oxidant, three DNA repair, and two transcription factor genes. For each of these genes, transcript abundance values were dispersed over a greater range in lung cancer subjects compared to matched controls. In addition, inherited DNA variation causes variation in transcript regulation of genes comprised by the LCRT. We plan to test our central hypothesis and accomplish the objective of this application by pursuing the following two specific aims: Aim 1. Determine whether key antioxidant and DNA repair genes have increased dispersion of transcript abundance in Normal Bronchial Epithelial Cells of COPD cases and whether a multi-gene test comprising a subset of these genes is an accurate test for COPD prevalence. Aim 2. Identify DNA variants that contribute to increased transcript abundance dispersion of genes associated with COPD and/or Lung Cancer Prevalence. We expect that Aim 1 will produce evidence that higher transcript abundance dispersion of key antioxidant, DNA repair, and transcription factor genes is associated with risk for COPD, as it is for lung cancer and will produce a candidate biomarker for increased COPD risk. Aim 2 will provide identification of DNA variants associated with increased transcript abundance dispersion in key genes with high prior likelihood of involvement in the pathogenesis of COPD and lung cancer. This research is relevant to public health because it will lead to development of biomarkers for selection into screening and/or chemoprevention trials and provide drug targets for development of chemo-preventative and therapeutic pharmaceuticals. These developments are expected to reduce mortality and health care costs.