**4. Asthma pathophysiology**

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

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

Parallel to genetic factors, environmental factors are also involved in the development and progression of asthma (**Figure 1**). The exposure to some environmental factors was shown to contribute not only to asthma but also to other related respiratory disorders, for example, emphysema development. By contrast, there are also some other environmental factors that seem to be solely linked to the development of asthma but not to other inflammatory or/and respiratory disorders [30]. Various studies assessed the risk factors of asthma and found evidence that allergen exposure, respiratory tract infections, gastroesophageal reflux disease (GERD), and physical and psychosocial stress might represent individual risk factors. It is important to keep in mind that some other environmental factors are protective, such as

Allergen exposure is the major factor impacting sensitization and constitutes the most common cause of asthmatic exacerbations in adults and children. A wide variety of inhaled allergens may trigger asthma symptoms, for example, house dust mite [32], pollens [33], cockroaches [34], and animal fur [35]. Respiratory tract infections have been implicated in asthma occur‐ rence and exacerbation as well. Examples include infection with viruses [36,37], *Mycoplasma* [38], and *Chlamydia species* [39]. Based on the conclusions from the Japanese study, which

populations.

with total serum IgE levels [29].

140 Asthma - From Childhood Asthma to ACOS Phenotypes

**3. Environmental factors contributing to asthma**

maternal diet, breastfeeding, and farming conditions [31].

Scientists tried to uncover alterations related to asthma since a long time ago. One of the oldest publications that discussed asthma pathophysiology was in 1873 [51]. Later on, in 1886, F.H. Bosworth concluded a possible relation between asthma and hay fever [52]. Clearly, it is well known that asthmatic patients suffer from reversible airway obstruction resulting from an allergen exposure, consequently releasing multiple broncoconstricting mediators that stimu‐ late airway muscles to contract. Furthermore, airways narrow results from past and current mucus and edema occlusion [53]. The chronic inflammation and associated repair of lung airways leads to structural changes, referred to as "*airway remodeling*." Airway remodeling (**Figure 2**) usually involves lung epithelial layer injury and includes features such as subepi‐ thelial thickening, airway smooth muscle hyperplasia, and angiogenesis [6].

**Figure 2.** Schematic representation of the major events underlying asthma pathophysiology.

Asthma and COPD (chronic obstructive pulmonary disease) are now considered to be discrete respiratory disorders. Although both share several similar underlying mechanisms, driving airway obstruction in COPD, and hyperresponsiveness in asthma, core molecular pathology remains to be mostly different for both [54]. Pauwels et al. [55] defined COPD as "a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of lungs to noxious particles and gases." One important reason of asthma and COPD overlap is the effect of aging. Asthma-COPD overlap syndrome (ACOS) is a medically recognized coexisting syndrome of both asthma and COPD [56]. Some other health conditions may occur more frequently in asthmatic patients. Rhinosinusitis [57], obstructive sleep apnea [58], or GERD [59] are the most common documented comorbidities. Substantially, they can contribute to the same pathophysiological process, which is already triggered by allergic response or alter asthma phenotype detrimentally. The impact of these diseases on asthma is variable and still not fully clear [60].
