**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, and other conditions such as age and gender of a patient, nutrition and hygiene, and intestinal microflora, which all highly influence the drug response in addition to the genetic factors. The collective impact of all combination of these factors requires the application of complicated algorithm that could take into consideration each of these factors and their interplay. The prospective genetic profile of an asthmatic should compromise a set of common and rare variants, on ancestral basis, which will be predictive of the pattern of his/her therapeutic responsiveness to different treatment options. The current human variant catalog continues to grow in an exponential manner because of the lower costs associated with whole genomic sequencing. Despite the steep decline in sequencing costs, the technology of sequencing, in terms of speed and quality, enormously increases. The future pharmacogenetic profile would also predict any possible adverse response associated with the chosen line of treatment. Genetic biomarkers are needed to warn the physician about any potential adverse side effects which can be life threatening. It is very important for typical genetic profiling to also consider genegene and gene-environment interactions. Gene-gene interactions are predominately crucial in the framework of combination therapies, for example, ICS and β-adrenergic agonists. Inter‐ actions between the surrounding environment and the patients' genes are assumed to be an additional element, because environmental stress, apart from the genetic makeup, contributes to the development of asthma exacerbations. Future pharmacogenetic directions need to cover also the pharmacokinetic side of the patient profile. Altered drug absorption, metabolism, distribution, or excretion extensively influence drug dosing and even drug selection. All in all, the complete asthma pharmacogenetic catalog has many aspects to cover, before being introduced into the clinical practice.
