Albuminuria and incident chronic lung disease exacerbations in five population-based cohorts

 描述(申请人提供)：急性加重是慢性肺病(CLD)发病率和死亡率的主要原因，现在是美国第三大死亡原因。慢性阻塞性肺疾病(COPD)、慢性支气管炎、肺气肿和哮喘的CLD表型经常重叠，以呼吸道症状增加为定义的加重是常见的临床表现。病情恶化的危险因素几乎只在患有慢性阻塞性肺病的吸烟者中进行了检查；然而，多达三分之一的慢性阻塞性肺病恶化住院患者事先没有CLD的诊断。因此，研究慢性阻塞性肺疾病恶化的“突发事件”住院治疗可能是寻找适合于一级预防研究的高危患者标志物的有效策略。蛋白尿可能是全身性神经酰胺相关微血管病变的生物标志物，因此也是发生CLD和加重的生物学相关预测因子。动脉粥样硬化多种族研究(MESA)是一项基于人群的老年人队列研究，其初步分析显示，12年来，微量白蛋白尿者发生CLD恶化的风险几乎翻了一番，尿白蛋白/肌酐比率(UACR)&GT；300 mg/g的人增加了5倍。因此，我们建议测试白蛋白尿预测CLD事件恶化的可能性，这是一个创新的终点，将通过一项新的裁决方案在来自5个高度表型的NHLBI队列的37,600名参与者中得到验证。此外，为了建立这一生物标记物的生物学基础，我们建议对CERS2单核苷酸变异(SNV)进行遗传分析，该变异与蛋白尿有关，并编码神经酰胺合成酶2的氨基酸变化，以及探索与最先进的肺血流灌注放射学指标的相关性。如果我们的假设在这一独特的基于人群的队列中得到证实，它们将允许在 使用廉价、临床可用的生物标记物将CLD事件的高风险纳入预防试验；提供一种新的生物标记物，并潜在地提供一种探索性放射学测量方法，以表征症状前CLD的特征，以设计未来的初级预防试验；以及，建议CERS2途径上的药物开发目标，以预防CLD和普通人群的恶化。

 DESCRIPTION (provided by applicant): Acute exacerbations are the major cause of morbidity and mortality in chronic lung disease (CLD), now the third leading cause of death in the US. Exacerbations, defined by an increase in respiratory symptoms, are a common clinical presentation of the frequently overlapping "obstructive" CLD phenotypes of chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, and asthma. Risk factors for exacerbations have been examined almost exclusively among smokers with prevalent CLD; however, up to one third of patients admitted for CLD exacerbations have no prior CLD diagnosis. Studying "incident" hospitalizations for CLD exacerbations may therefore be an effective strategy for finding markers of high-risk patients suitable for primary prevention studie. Albuminuria may be a biomarker for systemic ceramide-related microangiopathy and hence a biologically relevant predictor of incident CLD and exacerbations. Preliminary analyses in the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based cohort of older adults, showed that over 12 years the risk of incident CLD exacerbation was almost doubled among persons with microalbuminuria and five-fold increased among those with urine albumin-to-creatinine ratio (uACR) > 300 mg/g. We therefore propose to test the potential for albuminuria to predict incident CLD exacerbations an innovative endpoint that will be validated via a novel adjudication protocol in 37,600 participants from five highly phenotyped NHLBI cohorts. In addition, in order to establish the biological underpinning for this biomarker, we propose genetic analyses focusing on a CERS2 single nucleotide variant (SNV) that is implicated in albuminuria and that encodes an amino acid change in Ceramide Synthase 2, as well as exploration of associations with state-of-the-art radiological indices of pulmonary perfusion. If our hypotheses are confirmed in this unique population-based cohort, they will allow identification of patients at high risk of incident CLD for inclusion in prevention trials using an inexpensive, clinically available biomarker; provide a novel biomarker and, potentially, an exploratory radiologic measure to characterize pre- symptomatic CLD for designing future primary prevention trials; and, suggest targets for drug development on the CERS2 pathway to prevent CLD and exacerbations in the general population.