Chronic obstructive pulmonary disease in non-smokers

项目概述：慢性阻塞性肺疾病（COPD）是第三大死亡原因 在全球和美国，四分之一的COPD发生在非吸烟者中。非吸烟者占50% 50岁以上的美国人群，但已被排除在主要COPD研究之外。多民族 动脉粥样硬化研究（梅萨）肺研究，我们最近证明，变异的气道解剖结构， 常见且与较高的COPD患病率相关。结果在吸烟者和非吸烟者中是一致的。 吸烟者，但在后一组动力不足。本申请将定义以下临床意义 非吸烟者COPD和呼吸道症状的气道解剖结构变异，以及COPD和 肺功能下降超过10年。假设1：变异气道解剖结构与 2，635名非吸烟者和COPD患者的COPD和呼吸道症状横断面， 2,000名非吸烟者的肺功能下降，平均随访时间为10年。 初步的计算流体动力学（CFD）模型表明，不同的气道解剖结构可能会改变 气道阻力和颗粒物质转移到远端气道。更多的试点工作表明， 近端气道变异可能是通过肺的气道分支改变的标志，提示了一个全球性的 增加气道阻力的变化适用于非吸烟者。当前应用程序将测试， 这些机制分别适用于非吸烟者和吸烟者，以促进风险和护理的个性化 慢性阻塞性肺病假设2：COPD风险机制因非吸烟者的常见气道变异而异 和吸烟者：2a辅助节段性气道变异，这与非吸烟者的风险增加有关。 吸烟者，减少了参与者特定几何结构的CFD模型中的区域气流，而不存在 与吸烟者风险增加相关的节段性气道变异，增加了颗粒物转移到 远端肺2b副段气道变异与气道分支的整体改变有关， 而缺失的节段性气道变体代表叶特异性改变的气道分支。 气道解剖具有发育起源，并可能提供精细的表型（与肺功能相比） 进行基因研究PI的初步分析确定了成纤维细胞生长因子10的遗传变异， 一种与气道发育有关的基因，与气道解剖结构的变异有关。拟定研究 将样本量增加5倍，以进行第一次全基因组关联研究（GWAS）的变异 人体气道解剖学，并在独立样本中进行复制。假设3：GWAS将发现遗传 常见的气道变异的基础上，在一个独立的样本复制。 目前的应用代表了非吸烟者中COPD的最大结构-功能评价;以及 将测试发育和生物学假设，以确定新的预防和治疗策略， 这个未被充分研究但在美国人口中占多数的亚群。

PROJECT SUMMARY: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally, and in the US, where one-quarter of COPD occurs in non-smokers. Non-smokers represent 50% of the US population over 50 years old, but have been excluded from major COPD studies. In the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study, we recently demonstrated that variant airway anatomy was common and associated with higher COPD prevalence. Findings were consistent among smokers and non- smokers but underpowered in the latter group. The current application would define the clinical significance of variant airway anatomy among non-smokers for COPD and respiratory symptoms, and for incident COPD and lung function decline over 10 years. Hypothesis 1: Variant airway anatomy is independently associated with COPD and respiratory symptoms cross-sectionally among 2,635 non-smokers and with incident COPD and decline in lung function among 2,000 non-smokers followed for a median of 10 years. Preliminary computational fluid dynamic (CFD) modeling suggests that variant airway anatomy may alter airway resistance and particulate matter transit to the distal airways. Additional pilot work suggests that these proximal airway variants may be markers of altered airway branching through the lung, suggesting a global increase in airway resistance with the variant applying to non-smokers. The current application would test if these mechanisms apply differentially to non-smokers and smokers to facilitate personalization of risk and care for COPD. Hypothesis 2: Mechanisms of COPD risk differ by common airway variant among non-smokers and smokers: 2a The accessory segmental airway variant, which is associated with increased risk among non- smokers, reduces regional airflow in a CFD model of participant-specific geometry, whereas the absent segmental airway variant, associated with increased risk among smokers, increases particulate transfer to the distal lung. 2b The accessory segmental airway variant is associated with globally altered airway branching, whereas the absent segmental airway variant represents lobe-specific altered airway branching. Airway anatomy has developmental origins and may provide a refined phenotype (compared to lung function) for genetic investigation. Preliminary analysis by the PI identified genetic variants in fibroblast growth factor 10, a gene implicated in airway development, to be associated with variant airway anatomy. The proposed study will increase the sample size 5-fold to perform the first genome-wide association study (GWAS) of variant human airway anatomy, with replication in an independent sample. Hypothesis 3: GWAS will discover genetic variants underlying the common airway variants, with replication in an independent sample. The current application represents the largest structure-function evaluation of COPD among non-smokers; and will test developmental and biological hypotheses to identify novel preventative and therapeutic strategies for this understudied but majority subgroup of the US population.