title: Cluster analysis of obesity and asthma phenotypes.
abstract: BACKGROUND
  Asthma 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.
  
  
  RESULTS
  In 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/m(2)) 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 (F(E)NO) and airway hyperresponsiveness (methacholine PC(20)) but were similar with regard to measures of lung function (FEV(1) (%) and FEV(1)/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 dexamethasone
  
  
  CONCLUSIONS
  Obesity 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.
authors.affiliation: Department of Medicine, National Jewish Health, Denver, Colorado, United States of America. sutherlande@njhealth.org
authors.forename: E Rand
authors.initials: ER
authors.lastname: Sutherland
authors.forename: Elena
authors.initials: E
authors.lastname: Goleva
authors.forename: Tonya S
authors.initials: TS
authors.lastname: King
authors.forename: Erik
authors.initials: E
authors.lastname: Lehman
authors.forename: Allen D
authors.initials: AD
authors.lastname: Stevens
authors.forename: Leisa P
authors.initials: LP
authors.lastname: Jackson
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Stream
authors.forename: John V
authors.initials: JV
authors.lastname: Fahy
authors.forename: Donald Y M
authors.initials: DY
authors.lastname: Leung
mesh_terms: D000328:Adult; D001249:Asthma / Q000145:classification / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism; D015992:Body Mass Index; D016535:Bronchial Hyperreactivity; D016000:Cluster Analysis; D015331:Cohort Studies; D005260:Female; D005541:Forced Expiratory Volume; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D011965:Receptors, Glucocorticoid / Q000378:metabolism
chemical_list: D015415:Biomarkers; D005938:Glucocorticoids; D018836:Inflammation Mediators; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha