Longitudinal Lung Function Changes--Aging/Genetics/Risk

描述（由申请人提供）：肺功能低下是慢性阻塞性肺疾病（COPD）的核心特征，是美国发病率和死亡率的重要原因。此外，肺功能低下与各种疾病有关，如糖尿病和心血管疾病，并与全因死亡率有关。虽然吸烟仍然是肺功能低下和慢性阻塞性肺病的最大危险因素，但只有少数吸烟者发展为临床认可的肺功能低下和慢性阻塞性肺病。此外，约有6- 10%的普通人群有未被识别的肺功能低下。因此，更好地了解与肺功能低下相关的危险因素是必要的。由于炎症标志物即使在健康衰老中也会升高，我们假设炎症机制与衰老和肺功能下降是共同的。针对这一RFA，我们打算在一个随访约30年的队列中对肺功能变化进行纵向分析。我们将研究全身炎症标志物对衰老过程中肺功能下降的影响。由于对吸烟的反应有很大的差异，我们也假设对吸烟和其他炎症刺激的反应是由遗传变异改变的。我们将研究参与这些炎症途径的基因（如白细胞介素[IL]-6、IL-10、IL-2和肿瘤坏死因子[TNF]- α）对肺功能下降率的影响。这一建议的结果将揭示影响肺功能衰退的潜在机制。

DESCRIPTION (provided by applicant): Low lung function is a central characteristic of chronic obstructive pulmonary disease (COPD), an important cause of morbidity and mortality in the United States. Furthermore, low lung function has been associated with various diseases such as diabetes and cardiovascular disorders, and is associated with all-cause mortality. Although smoking remains the strongest risk factor for low lung function and COPD, only a minority of smokers develop clinically recognized low lung function and COPD. Furthermore, about 6- 10% of the general population have unrecognized low lung function. Thus, a better understanding of the risk factors associated with low lung function is necessary. Since inflammatory markers are seen to be elevated even in healthy aging, we hypothesize that inflammatory mechanisms are common to both aging and lung function decline. In response to this RFA, we intend to perform longitudinal analyses of lung function change, in a cohort that has been followed for about 30 years. We will investigate systemic markers of inflammation for their effect on lung function decline in aging. Because there is great variation in the response to smoking, we also hypothesize that response to smoking and other inflammatory stimuli are modified by genetic variation. We will study genes that participate in these inflammatory pathways (e.g. interleukin[IL]-6, IL-10, IL-2, and tumor necrosis factor[TNF]-alpha) for their effect on rates of lung function decline. The results of this proposal will shed light on potential mechanisms that affect lung function decline in aging.