The application of an hypothesis-free cluster analytical approach to a well-characterized cohort of adults with mild-to-moderate persistent asthma demonstrates that obesity is a determinant of clinical phenotype in asthma, playing a more significant role than other commonly-assessed clinical, physiologic or inflammatory variables. Of the four distinct clusters of asthma revealed, two had BMI in the obese range and two did not. There was heterogeneity of airway inflammation, symptoms and control in the obese clusters, suggesting that asthma phenotype is not uniform in obese individuals. In the two non-obese clusters, sex emerged as an important determinant of cluster membership; one cluster had a predominance of males the other a predominance of females, with comparatively earlier age of onset and lower lung function (as reflected by FEV1%
predicted) in the male-predominant cluster. Additionally, we have demonstrated that in vitro
GC insensitivity in obese asthmatics (as represented by a reduced ability of dexamethasone to induce the expression of MKP-1, an anti-inflammatory marker of GC-induced transactivation 
) appears to be mediated by reduced expression of GCRα, the dominant isoform of the receptor and a ligand-dependent transcription factor necessary for glucocorticoid-induced transactivation 
. Exploratory analysis also suggests an important role for 25(OH)D concentrations in mediating this relationship.
Our findings also suggest that the mechanisms which underlie clinical response to GC in obese asthmatics are complex and likely involve an interaction between alterations in GC-mediated anti-inflammatory processes and both systemic and airway inflammation. This conclusion is based on our observation that while evidence of in vitro
GC insensitivity was observed across both obese clusters, persistently poor asthma control and increased symptoms were observed in the cluster of asthmatics with the earliest onset of asthma, a greater degree of airway hyperresponsiveness and increased concentration of nitric oxide in exhaled breath. The GC insensitivity observed in obese asthmatics was also directly associated with the degree of systemic inflammation, as indicated by the inverse association between hsCRP and GCRα expression, and also is enhanced in the presence of reduced serum 25(OH) vitamin D concentrations. It is also interesting to note that our findings appear to minimize the role of comparative differences in sputum eosinophils as a reason for GC insensitivity in obese asthmatics. Independent of BMI, sputum eosinophils averaged less than 1% in the study population, suggesting that the GC insensitivity observed in obese patients with asthma is likely attributable to the defects in molecular GC response or increased inflammation that we have demonstrated, rather than to a pauci-eosinophilic airway inflammatory phenotype specific to obese asthmatics, as has been suggested in other reports 
Potential limitations of our must be considered: first, our analytical approach is hypothesis-independent. While this provides the opportunity to identify new associations that one might not be able (on the basis of current knowledge) to prespecify, it runs the risk of returning results that are counterintuitive or which differ from current hypothetical constructs of disease. Second, as with any meta-analytical technique, the results are entirely dependent on the data available for entry into the analysis. Thus, while we have attempted to include all clinically-relevant data, the derivation of our data from a clinical trial dataset limits the availability of certain data (e.g. socioeconomic or environmental status) and may introduce issues of generalizability given the highly-selected nature of clinical trial participants. Next, as with any cross-sectional data, we are unable to comment on causation, per se, and thus can only conclude that there are specific aspects of the obesity-asthma relationship that are clinically relevant. In fact, a number of questions regarding causal aspects of the relationship between obesity and asthma remain unanswered. Although many epidemiologic studies suggest that antecedent obesity increases subsequent asthma risk, asthma could also increase the risk of becoming overweight or obese. Factors that may play a role in this regard include chronic glucocorticoid use leading to weight gain, as well as respiratory impairment leading to sedentariness, reduced participation in physical, educational or occupational activities, as well as overall reductions in quality of life, all of which may lead to or be associated with increases in body mass.
Our analytical approach and validation of clinical phenotypes with studies of the molecular mechanisms of GC insensitivity in asthma strengthen the assertion that patients with asthma, both adult and pediatric 
, who are overweight or obese bear a disproportionate burden of illness when compared with non-obese asthmatics. Notwithstanding, the mechanisms of GC insensitivity are complex 
, and the mechanisms by which obesity reduces molecular response to GC require further study. In this light, recent studies have shown that monokines secreted by adipose tissue activate blood monocytes and recruit activated macrophages to adipose tissue, significantly amplifying pro-inflammatory cytokine generation 
. This phenomenon can be associated with classical activation 
which has been documented in both blood monocytes and alveolar macrophages in glucocorticoid-insensitive asthma 
, and may be relevant in obese patients with asthma as well. Additionally, these data provide additional support to the importance of recent observations 
, that low serum vitamin D concentrations are associated with impaired glucocorticoid response in asthma.
Clinicians frequently encounter obese asthmatics who do not respond optimally to therapy, but no specific guidance currently exists in national and international guidelines as to the optimal therapeutic approach to the obese asthmatic 
. Many obese asthmatics receive complicated asthma treatment regimens to which they do not respond 
and which may subject them to increased risk of treatment-related adverse effects. Given this, and given the prevalence of both obesity and asthma, additional information on which to base therapeutic decision making is critical. This study used unbiased analytical approaches to further validate reports that asthma phenotype differs between obese and non-obese asthmatics, while also demonstrating that asthma phenotype is not homogenous in all obese individuals, particularly with regard to the degree of control achieved with ICS treatment. Thus, clinical GC response may not be uniformly attenuated in obese asthmatics, and more work is needed to identify the pathways by which GC signaling mechanisms, systemic inflammation and airway inflammation interact to lead to clinical insensitivity to GC in some, but not all, obese asthmatics.