**9. Conclusion**

**7.3. Leukotriene pathway pharmacogenetics**

166 Asthma - From Childhood Asthma to ACOS Phenotypes

and Montelukast [189, 190].

triene pathway identified loci, are still needed.

Relative to the corticosteroid and β-adrenergic pathways, the cysteinyl leukotriene pathway pharmacogenetic studies are generally fewer and have smaller sample sizes. The oldest of these studies [185], held in 1999, had investigated the tandem repeat polymorphism in *ALOX5* promoter. Among 114 asthmatics, it has been shown that the *ALOX5* promoter repeat is associated with altered lung functions in response to a 5-LO inhibitor [185]. It has been shown in children that those who had more or less than five repeats (3, 4, and 6) of the *ALOX5* promoter-binding motif experienced increased urinary leukotriene E4 (the terminal cysteinyl leukotriene metabolite) concentrations and reduced FEV1 baseline than the wild-type geno‐ type with five repeats [186]. Further pharmacogenetic studies revealed that the *ALOX5* promoter polymorphism, along with the *ALOX5* SNPs rs892690, rs2029253, and rs2115819, influences leukotriene pathway antagonist therapy [187–190]. Moreover, variants of *LTC4S*, encoding Leukotriene C4 synthase, and *MRP1* (or *ABCC1*), encoding multidrug resistanceassociated protein 1, have been linked to lung function response while treatment with Zileuton

Arg312Gln, rs12422149, which is a coding variant in *SLCO2B1* (solute carrier organic anion transporter family member 2B1 gene), has been related to symptom control during Montelu‐ kast therapy. This fact was due to the interindividual variability of carrier-mediated Monte‐ lukast transport in the intestines, and consequently its plasma levels [191]. By contrast, two other studies, probably due to their small sample sizes, were unable to replicate similar *SLCO2B1* pharmacokinetic effects [192, 193]. Overall, larger replicate cohorts, for the leuko‐

**8. Current and future challenges facing asthma pharmacogenetics**

As demonstrated above, there has been fundamental progress in the field of asthma pharma‐ cogenetics; however, these efforts have not yet been introduced into clinical practice to guide physician. There are several reasons that account for this gap. Most important is the limited number of asthma pharmacogenetics-focused GWAS, which would compare common candidate gene methodology that would allow combining all patients from small cohorts studied. Small sample sizes prevent any expansion of the pharmacogenetic research of asthma, which needs a large number of subjects for statistical significance. Along with limited cohort size, study defects due to poor ancestry structuring and stratification substantially result in replication inconsistencies. Furthermore, genes interact together in networks; therefore, simply attributing phenotypic variation to individual genes is not appropriate. Epigenetics studies investigate the changes in gene activities, which are heritable to the subsequent generations, but are independent of any DNA sequence alterations [194, 195]. Epigenetic tuning of the genes associated with asthma has a significant impact on determining the drug response. Several mechanisms, related to epigenetics, are currently being investigated for both biomarker tagging and therapeutic innovation intervention [196]. Moreover, epigenetic changes have the ability to override the genetic effects of time, environment, tissue specificity,

Asthma is a complex respiratory and immune disease. Inadequate (or exaggerated) ability of genetically predisposed individuals to control inflammation, induced by innate and environ‐ mental factors, results in asthma. Further, studies using allergic asthma and atopy models enable to better understand several interacting gene products and variable responsiveness of asthmatic subjects to current therapies. Eventually, thorough investigation of the complexity of asthma might lead to successful designing of personalized therapies for patients suffering from allergic asthma.
