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

五个基于人群的队列中的蛋白尿和慢性肺病恶化事件

• 批准号: 8997288
• 负责人: Elizabeth Oelsner
• 金额: $ 20万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8997288
• 关键词: Acute; Adult; Age; Albumins; Albuminuria; Amino Acids; Apoptosis; Asthma; Atherosclerosis; Basic Science; Biological; Biological Markers; Blood flow; Cause of Death; Ceramides; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Chronic lung disease; Clinical; Comorbidity; Creatinine; Cross-Sectional Studies; Development; Elderly; Future; Gases; General Population; Hospitalization; Hypoxia; Individual; Investigation; Kidney; Link; Lung; Magnetic Resonance Angiography; Measures; Metabolic; Microalbuminuria; Missense Mutation; Modeling; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Nucleotides; Obstruction; Oxidative Stress; Participant; Pathogenesis; Pathway interactions; Patients; Perfusion; Persons; Phenotype; Prevention trial; Primary Prevention; Prognostic Marker; Protocols documentation; Public Health; Pulmonary Emphysema; Randomized; Respiratory physiology; Risk; Risk Factors; Sampling; Smoke; Smoker; Smoking History; Smoking Status; Sphingolipids; Spirometry; Symptoms; Testing; Urine; Variant; Work; adjudication; clinical risk; cohort; demographics; design; diabetic; dihydroceramide desaturase; disease diagnosis; disease phenotype; disorder subtype; drug development; endothelial dysfunction; follow-up; genetic analysis; high risk; indexing; innovation; mortality; novel; population based; prevent; public health relevance; respiratory

 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.

 描述（由申请方提供）：急性加重是慢性肺病（CLD）发病率和死亡率的主要原因，目前是美国第三大死亡原因。急性加重（定义为呼吸道症状增加）是慢性阻塞性肺疾病（COPD）、慢性支气管炎、肺气肿和哮喘经常重叠的“阻塞性”CLD表型的常见临床表现。急性加重的风险因素几乎仅在吸烟者中进行了检查，但高达三分之一的CLD急性加重患者既往未诊断为CLD。因此，研究CLD急性加重的“事件”住院可能是寻找适合一级预防研究的高危患者标志物的有效策略。白蛋白尿可能是全身性神经酰胺相关微血管病的生物标志物，因此是CLD事件和急性加重的生物学相关预测因子。动脉粥样硬化多种族研究（梅萨）的初步分析（一项基于人群的老年人队列研究）显示，12年后，微量白蛋白尿患者发生CLD加重的风险几乎增加了一倍，尿白蛋白与肌酐比值（uACR）> 300 mg/g的患者增加了5倍。因此，我们建议测试白蛋白尿预测CLD急性加重的可能性，这是一个创新的终点，将通过一个新的裁定方案在来自5个高表型NHLBI队列的37，600名参与者中进行验证。此外，为了建立这种生物标志物的生物学基础，我们提出了集中在CERS 2单核苷酸变异（SNV）的遗传分析，涉及蛋白尿和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灌注放射学指标的关联。如果我们的假设在这个独特的基于人群的队列中得到证实，它们将允许识别患者 使用廉价的临床可用生物标志物纳入预防试验的CLD事件高风险;提供一种新的生物标志物，并可能提供一种探索性放射学测量，以表征症状前CLD，用于设计未来的一级预防试验;并建议CERS 2途径的药物开发目标，以预防一般人群中的CLD和加重。