Genetic Basis for Personalized Medicine in Asthma

Phosphodiesterase Inhibitors

There has been intense interest in PDE4 inhibition as an asthma and COPD treatment. Phosphodiesterase enzymes catalyze the breakdown of cAMP and cGMP to 5' monophosphates. PDE4 inhibition is thought to lead to elevated levels of intracellular cAMP, which has many physiological implications; for example, suppression of inflammatory cell influx and function, inhibition of mucin production from airway epithelial cells and alterations in airway smooth muscle tone. The two main PDE4 inhibitors that have reached Phase III development are roflumilast (Altana) and cilomilast (GlaxoSmithKline), and both compounds have shown some clinical efficacy in asthma, with primary end points being; baseline FEV₁, early and late response to allegen (FEV₁), morning peak expiratory flow and asthma symptom scores. These compounds are second-generation PDE inhibitors, and have greater PDE4D selectivity and fewer side effects – for example, nausea.

The identification of PDE4D as an asthma susceptibility gene in 2009 further confirmed the importance of this enzyme in underlying mechanisms of relevance to asthma. The top SNPs identified involve predominantly intronic SNPs – that is, rs1588265 and rs1544791. However, these SNPs are in linkage disequilibrium with SNPs in the promoter region, therefore it is tempting to speculate that these SNPs may tag polymorphisms that influence mRNA expression and/or protein structure. These findings are extremely pertinent to the recent report that suggested both PDE4D expression and PDE activity are increased (approximately twofold) in airway smooth muscle cells isolated from asthma patients compared with control subjects. Importantly, this elevated PDE4D expression in the asthma airway smooth muscle was associated with approximately 50% lower cAMP production in response to β₂-adrenergic receptor agonists, including salbutamol and formoterol (in the presence of IBMX, a pan PDE inhibitor). Overall, these data suggest that SNPs within PDE4D are risk factors for the development of asthma and that alterations in PDE4D expression and activity are a feature of asthma patients airway smooth muscle influencing responses to β₂-adrenergic receptor agonists. PDE4D SNPs may at least, in part, determine the clinical efficacy of PDE4D inhibitors, that is, these individuals have a subphenotype of asthma driven more by PDE4D dysregulation. Interestingly this class of drugs has several reported adverse effects including nausea, headache and diarrhea and thus, pharmacogenetics has the potential to avoid these effects in patients unlikely to respond to this specific therapy. We have identified SNPs spanning PDE4D as potential genetic determinants of FEV₁ in a general population of 20,288 individuals, again suggesting a role for this enzyme beyond asthma.

To date, no Phase II or III trials of PDE inhibitors have been reported or retrospectively analyzed to include pharmacogenetics; however, based on the PDE4D GWA study data this would appear to be an opportunity. Similarly, an investigation of the role of PDE4D genotypes influencing β₂-adrenergic receptor agonists is warranted.