Pharmacogenomic Approaches to Asthma Treatment

Abstract

Major classes of medication in asthma management include bronchodilating β2-agonists, anti-inflammatory inhaled corticosteroids, leukotriene modifiers and theophyllines. However, all asthmatics do not respond to the same extent to a given medication. Available data suggest that a substantial range of individual variability, as much as 70%, may be due to genetic characteristics of each patient. Pharmacogenomics offers the potential to optimize medications for individual asthmatics by using genetic information to improve efficacy or avoid adverse effects. The best-studied case of the potential contribution of pharmacogenomics to treatment response in asthma comes from studies on human β2 adrenergic receptors. In addition, genetic variation in β2-adrenergic receptor (Arg16Gly) may predict response to anticholinergics for the treatment of asthma. In case of inhaled corticosteroids, a recent investigation using a traditional SNP-based approach identified a gene for corticotropin releasing hormone receptor 1 as a potential marker of response. Another major pathway that has been investigated is the pathway underlying response to cysteinyl leukotriene receptor antagonist. It is likely that in the near future, pharmacogenomic approaches based on individual genetic information will be introduced into an asthma treatment guideline and this guideline will allow us to identify those who have the best chance to respond to a specific medication.

Leukotriene C4 prevents the complete maturation of murine dendritic cells and modifies interleukin-12/interleukin-23 balance

“…67 Ours results open the way to further studies on the potential role of LTC 4 in inflammatory disorders such as gastritis, cystic fibrosis, 68,69 inflammatory pathologies associated with a greater recruitment of neutrophils in which the levels of LTC 4 and its receptors are excessively increased. [19][20][21][22] In conclusion, here we provide evidence that 'maturity' of DCs and the stimulus that causes it, is critical for the balance of the effector profile induced by LTC 4 . Therefore, LTC 4 prevents the complete maturation of DCs but induces the production of IL-23, resulting in the preferential development of Th17 cells.…”

“…19 In many diseases affecting lung and intestinal mucosa, such as asthma and interstitial cystitis, the use of montelukast, a selective antagonist of CysLTR1, minimizes the effects of these pathologies, probably through the inhibition of cytosolic Ca 2+ . [20][21][22] It is known that LTC 4 induces the chemotaxis of DCs from the skin. 23 Zymosan, a Toll-like receptor 2 agonist, but not lipopolysaccharide (LPS), a classic Toll-like receptor 4 agonist, stimulates the production of CysLT by DCs.…”

Functional analysis of the impact of ORMDL3 expression on inflammation and activation of the unfolded protein response in human airway epithelial cells

“…Current asthma therapy treats symptoms of the disease, however it is ineffective in up to 25% of patients [1]. Asthma and allergic diseases are complex disorders caused by the interaction of various genetic and environmental factors [2-4].…”

Novel Therapies in Asthma

“…116 Future directions for asthma therapy include not only improvements on existing classes, as with the newer ultralong-acting beta agonists and inhaled versions of oral drugs such as LTRAs and PDE4 inhibitors but also into the new frontiers of medicine such as biologic agents and pharmacogenomics. 238 The current view of asthma is one of different phenotypes, rather than a homogeneous disorder of generalized airway hyperresponsiveness. 239 At least 6 different phenotypes have been identified, 3 and unfortunately, in the vast majority of cases, identifying the phenotype of a specific patient, either in terms of symptoms or clinical response to medications, is primarily a process of (therapeutic) trial and error.…”