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.
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. We propose to test the potential for albuminuria to predict incident CLD exacerbations an endpoint that will be validated via a novel adjudication protocol in 37,600 participants from five highly phenotyped NHLBI cohorts, as well as establishing the biological underpinning for this biomarker via genetic analyses focusing on ceramide pathways and exploratory analyses with respect to radiologic indices of pulmonary perfusion. The results have the potential to risk stratify persons in the general population for inclusion in prevention trials; to provide a novel biomarker and, potentially, a radiologic measure to characterize pre-symptomatic CLD; and, to suggest targets for drug development on the CERS2 pathway to prevent CLD and exacerbations in the general population.
