**2. Genetic control of airway hyperresponsiveness, atopy, and allergic asthma**

The heritable nature of asthma has been demonstrated through various types of studies over the past decades. Family and twin studies indicate that 60–70% of asthma cases are due to genetic factors. Moreover, it has been proven that the concordance of asthma is greater among monozygotic twins rather than among dizygotic ones. Adoption studies have shown greater disease prevalence within biological relatives of the affected people compared to the adopted family [12].

Higher prevalence of allergic disease phenotypes is observed among relatives of atopic individuals compared to nonatopic individuals. Overall, the heritability estimates remain in between the range of 30–66% for airway hyperresponsiveness, 35–95% for asthma, and 35– 84% for total serum IgE levels [13]. It is clear that both the inter-genetic individual differences and the degree of allergen exposure contribute to these variations in heritability. Heritability of asthma is linked to both disease susceptibility and severity. While the main concern of asthma genetic studies has been on disease susceptibility, increasing evidence shows that many genetic variants are important in asthma progression and severity as well [14]. Lung function tests in asthma showed that genes in the T-helper lymphocyte 1 (Th1) pathway affect asthma severity; meanwhile, T-helper lymphocyte 2 (Th2) pathway genes relate to suscepti‐ bility [14]. Based on these hypotheses, genes associated with asthma susceptibility differ from those related to asthma severity; hence, it is important to define both groups distinctly.

of asthmatic cases has been on the rise over the past 10 years and affecting up to 10% of adults and 20% of children worldwide [2]. Globally, more than 300 million people are asthmatics, and this estimate is predicted to become 400 million by 2025 [3]. The worldwide economic burden caused by asthma is predicted to be more than that of both acquired immunod eficiency syndrome (AIDS) and tuberculosis combined together. For example, in the United States of America, the annual asthma care costs exceed US\$6 billion [4]. Moreover, these numbers are due to the fact that more than 50% of asthmatic cases are poorly controlled by medication, since the response to treatments varies considerably among patients despite having similar clinical features [3, 5]. Asthma is characterized by altered and distinct clinical changes in the lung airways obstructing the flow of air into the lungs. The most prominent airway remodel‐ ing features include epithelial and subepithelial layer thickening, increased airway smooth muscle (ASM) mass, and angiogenesis [6]. Different classes of asthma therapies address one or more of the phenotypes of asthma; however, the heterogeneous nature of the disease prevents homogeneous clinical outcomes in response to the current treatment guidelines [7].

138 Asthma - From Childhood Asthma to ACOS Phenotypes

In the past two decades, the field of human genetics has evolved due to the advancements in the human genome project and high-throughput sequencing technologies [8, 9]. Currently, the advances in genetic, pharmacodynamic, and pharmacokinetic studies, analyzing responsive‐ ness of patients to various therapies, may eventually allow to prescribe personalized treatment and to shift asthma therapies from classical standards, using mostly corticosteroids and βadrenergic agonists, to a highly tailored approach [10]. Future genetic profiles of the popula‐ tion would form the basis of tomorrow's treatments in order to potentiate the required therapeutic benefits, and to diminish any possible adverse effect risks. Overall, there remains a great need for comprehensive drug research, paralleled with high-throughput genetic

profiling, in order to treat asthma in a personalized or stratified manner [11].

**asthma**

family [12].

**2. Genetic control of airway hyperresponsiveness, atopy, and allergic**

The heritable nature of asthma has been demonstrated through various types of studies over the past decades. Family and twin studies indicate that 60–70% of asthma cases are due to genetic factors. Moreover, it has been proven that the concordance of asthma is greater among monozygotic twins rather than among dizygotic ones. Adoption studies have shown greater disease prevalence within biological relatives of the affected people compared to the adopted

Higher prevalence of allergic disease phenotypes is observed among relatives of atopic individuals compared to nonatopic individuals. Overall, the heritability estimates remain in between the range of 30–66% for airway hyperresponsiveness, 35–95% for asthma, and 35– 84% for total serum IgE levels [13]. It is clear that both the inter-genetic individual differences and the degree of allergen exposure contribute to these variations in heritability. Heritability of asthma is linked to both disease susceptibility and severity. While the main concern of asthma genetic studies has been on disease susceptibility, increasing evidence shows that many genetic variants are important in asthma progression and severity as well [14]. Lung

By knowing the genetic signature associated with allergic asthma, geneticists can help to better understand the molecular mechanism of this disease, and the shared and distinct pathways among other allergic diseases. Moreover, the genetic signature of asthma-associated genes with altered expression during the peak of asthmatic episodes may help predict the severity and response to therapy. Unfavorable response might be identified and, consequently, more targeted and personalized treatments can be considered for this complex trait. The human genome project and the ongoing advancements in sequencing technologies, both, resulted in more successful gene discovery over the last years, even in diseases as complexed as asthma. Since then, dozens of susceptibility genes were identified through a large variety of methods and rationales. *ADAM33* is the first asthma susceptibility gene to be discovered through positional cloning [15]. ADAM33 (also known as Disintegrin and metalloproteinase domaincontaining protein 33) is a membrane-bound metalloproteinase enzyme that has been involved in several cellular interactions involving cell-cell and cell-matrix events [16]. Variants in this gene have been correlated to asthma susceptibility and bronchial hyperresponsiveness, but not atopy. Due to its clinical significance, *ADAM33* studies were conducted among 33 different asthmatic population samples all over the world. Additionally, numerous studies have suggested that altered *ADAM33* DNA methylation patterns could result in diversely unbal‐ anced biological effects in the airways [17]. Studies focused on candidate genes have examined a number of genes involved in asthma and highlighted more than 100 interesting genetic spots; however, the role of those loci in asthma susceptibility remains largely unexplored [18].

Genome-wide association studies (GWASs) extensively investigate the unknown genetic bases of many intricate disorders including asthma [19,20]. In the first reported GWAS study for asthma susceptibility, Moffatt et al. [21] identified the 17q21 locus, containing several genes, for example, *ORMDL3* and *GSDMB* as being associated with childhood asthma. Importance of this region was later on replicated in numerous subsequent studies [22–24]. Expression levels of the gene *ORMDL3* are differentially regulated by distinct haplotypes in this region. This gene encodes protein acting as an inhibitor of sphingolipid biosynthesis and in general Orm family proteins were shown to be implicated in the control of sphingolipid homeostasis [25]. Dysregulated sphingolipid formation in the respiratory tract instigates airway hyper‐ reactivity [26] although exact molecular steps are still not known. The results of these studies suggested that the mechanisms of asthma development are linked with genetically determined abnormalities in some patients resulting in their inability to control balance between oxidative and anti-oxidative reactions. The mechanisms of asthma development are linked with genetically determined abnormalities in the functioning of antioxidant defense enzymes. These alterations seem to be accompanied by a systemic imbalance between oxidative and antioxidative reactions with the shift of the redox state toward increased free radical production, oxidation of proteins and phospholipids, and eventually to their selective degradation.

To increase the power of detection of modest alleles due to the large sample size, the results of individual GWAS need to be gathered into a meta-analysis. The scientific literature recognizes two meta-analyses of asthma GWAS. One was done by the GABRIEL Consortium [27] of the European investigators, and the other was conducted by the EVE Consortium of the US investigators [22]. While the EVE meta-analysis included diverse subjects from different ethnic background, US and Mexico population backgrounds, the GABRIEL meta-analysis included only European subjects. Overall, these two thorough meta-analyses present a comprehensive overview of the genetic associations for asthma. Some associations are shared among different populations; by contrast, others are specific to one race. Grouping GWAS in this way increases the power of genetic detection, contrasts different ethnic groups' genotypes, and highlights the worldwide populations' genetic patterns. Overall independent GWASs have identified large number of candidate loci that deserve further testing. Replication studies help to prioritize which genes deserve further study, based on their identification in multiple populations.

Additionally, more loci were identified to be associated with asthma; these include interleukin (IL)-33 (on 9p24), *HLA-DR/DQ* (on 6p21), *IL1RL1/IL18R1* (on 2q12), *TSLP* (on 5q22), and *IL13* (on 5q31) [22,27,28]. Collectively with *ORMDL3*/*GSDMB* (on 17q21), these are the most remarkable and consistent loci, which are identified for asthma. Since Moffatt et al. had published the first GWAS results for asthma, identifying *ORMDL3* as a candidate gene, numerous other studies have been conducted investigating an array of phenotypes which are observed in allergic diseases. In particular, FCER1A, RAD50, and STAT6 have been associated with total serum IgE levels [29].
