Abstract
BackgroundAsthma is a heterogeneous disease with variability among patients in characteristics such as lung function, symptoms and control, body weight, markers of inflammation, and responsiveness to glucocorticoids (GC). Cluster analysis of well-characterized cohorts can advance understanding of disease subgroups in asthma and point to unsuspected disease mechanisms. We utilized an hypothesis-free cluster analytical approach to define the contribution of obesity and related variables to asthma phenotype.Methodology and Principal FindingsIn a cohort of clinical trial participants (n = 250), minimum-variance hierarchical clustering was used to identify clinical and inflammatory biomarkers important in determining disease cluster membership in mild and moderate persistent asthmatics. In a subset of participants, GC sensitivity was assessed via expression of GC receptor alpha (GCRα) and induction of MAP kinase phosphatase-1 (MKP-1) expression by dexamethasone. Four asthma clusters were identified, with body mass index (BMI, kg/m2) and severity of asthma symptoms (AEQ score) the most significant determinants of cluster membership (F = 57.1, p<0.0001 and F = 44.8, p<0.0001, respectively). Two clusters were composed of predominantly obese individuals; these two obese asthma clusters differed from one another with regard to age of asthma onset, measures of asthma symptoms (AEQ) and control (ACQ), exhaled nitric oxide concentration (FENO) and airway hyperresponsiveness (methacholine PC20) but were similar with regard to measures of lung function (FEV1 (%) and FEV1/FVC), airway eosinophilia, IgE, leptin, adiponectin and C-reactive protein (hsCRP). Members of obese clusters demonstrated evidence of reduced expression of GCRα, a finding which was correlated with a reduced induction of MKP-1 expression by dexamethasoneConclusions and SignificanceObesity is an important determinant of asthma phenotype in adults. There is heterogeneity in expression of clinical and inflammatory biomarkers of asthma across obese individuals. Reduced expression of the dominant functional isoform of the GCR may mediate GC insensitivity in obese asthmatics.
Highlights
Cluster analyses of cross-sectional data from clinical populations have identified phenotypic subsets of patients with asthma, and the assessment of body mass index (BMI) in recent asthma cluster analyses has allowed assessment of the relationship of BMI to clinical features of asthma
These reports notwithstanding, other analyses using standard comparative analytical approaches between asthmatics categorized by BMI have suggested that there is phenotypic heterogeneity among obese asthmatics, with some studies suggesting that asthma is more severe in obese asthmatics [7,8], possibly due to increased airway or systemic inflammation [9], and others suggesting that obesity has a more modest effect, independent of inflammation or altered lung mechanics [10,11]
Race, age at asthma onset, asthma duration, body mass index (BMI), % predicted forced expiratory volume in one second (FEV1%), forced vital capacity (FVC), airway hyperresponsiveness (PC20 FEV1 to methacholine), Juniper Asthma Control Questionnaire score (ACQ) [18], Asthma Evaluation Questionnaire score (AEQ, a composite of asthma symptoms over the prior two weeks [13]), exhaled nitric oxide (FENO, ppb), percent eosinophils in induced sputum, serum IgE (IU/mL), hsCRP, serum interleukin 6 (IL-6), serum tumor necrosis factor-alpha (TNFa), serum adiponectin, serum leptin, prior controller use, and change in AEQ and ACQ scores
Summary
Cluster analyses of cross-sectional data from clinical populations have identified phenotypic subsets of patients with asthma, and the assessment of BMI in recent asthma cluster analyses has allowed assessment of the relationship of BMI to clinical features of asthma. A separate cluster analysis of patients participating in the NIH Severe Asthma Research Program indicated that elevated body mass index (BMI) was associated with specific clinical features in severe asthma, with the identification of a cluster of patients in whom elevated BMI was associated with female sex, adult onset asthma, a greater likelihood of complicated asthma treatment regimens, and more frequent health care utilization and need for systemic glucocorticoids (GC) [2] These two studies have supported the conclusion that asthma phenotype is relatively homogenous in obese patients, with high symptom expression, low atopy and airway eosinophilia, and relative insensitivity to GC, a phenomenon that has been reported by others in both clinical [3,4,5] and in vitro [6] settings. We utilized an hypothesis-free cluster analytical approach to define the contribution of obesity and related variables to asthma phenotype
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call