Chronic obstructive pulmonary disease in non-smokers

项目摘要：慢性阻塞性肺疾病(COPD)是导致死亡的第三大原因 在全球和美国，四分之一的慢性阻塞性肺病发生在不吸烟的人身上。非吸烟者占50% 美国50岁以上的人口，但已被排除在主要的COPD研究之外。在多民族中 动脉粥样硬化的研究(MESA)肺研究，我们最近证明了不同的呼吸道解剖是 常见，并与较高的COPD患病率相关。在吸烟者和非吸烟者中的发现是一致的 吸烟者，但在后一组中动力不足。目前的应用将定义其临床意义 非吸烟者中COPD和呼吸道症状的不同呼吸道解剖，以及COPD和 肺功能在10年内下降。假设1：不同的呼吸道解剖结构独立地与 2,635名非吸烟者中COPD和呼吸道症状的横断面研究 2000名不吸烟者的肺功能下降跟踪调查的中位数为10年。 初步的计算流体动力学(CFD)模拟表明，不同的呼吸道解剖结构可能会改变 呼吸道阻力和颗粒物向远端呼吸道转移。额外的试点工作表明，这些 近端气道变异可能是通过肺分支的气道改变的标志，提示 该变种适用于非吸烟者，增加了呼吸道阻力。当前应用程序将测试是否 这些机制不同地适用于非吸烟者和吸烟者，以促进风险和护理的个性化 用于慢性阻塞性肺病。假设2：非吸烟者的共同呼吸道变异导致慢性阻塞性肺疾病风险机制不同 和吸烟者：2A是副呼吸道节段变异，与非吸烟者风险增加有关 吸烟者，在参与者特定几何的CFD模型中减少区域气流，而没有吸烟者 节段性呼吸道变异与吸烟者风险增加有关，增加了颗粒物向 远端肺。2b辅助段气道变体与整体改变的气道分支相关联， 而缺失的节段性气道变异代表肺叶特异性改变的气道分支。 呼吸道解剖学有发育起源，可能提供一种精细的表型(与肺功能相比)。 进行基因研究。经PI鉴定成纤维细胞生长因子10基因变异的初步分析， 一种与呼吸道发育有关的基因，与不同的呼吸道解剖结构有关。建议进行的研究 将样本量增加5倍，以执行变种的第一个全基因组关联研究(GWAS) 人体呼吸道解剖学，在独立样本中复制。假设3：GWAS将发现基因 常见呼吸道变异的基础，并在独立样本中复制。 目前的应用是在非吸烟者中对慢性阻塞性肺疾病进行的最大结构-功能评估；以及 将测试发育和生物学假说，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群体。

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.