Asthma—snapshot or motion picture?

Asthma is a complex disease physiologically characterized by shortness of breath, coughing, and wheezing (Holgate, 2011). In response to a variety of stimuli, the airways become more sensitive leading to bronchial hyperresponsiveness (Sterk and Bel, 1989; Scichilone et al., 2006; Kang et al., 2012). Consequently, in a process known as bronchoconstriction, airways become narrower, impeding the normal airflow into and out of the lungs (WHO, 2011), by contraction of the bronchial smooth muscle (EPR-3, 2007). In addition, increased production of mucus occurs, further contributing to airway obstruction (EPR-3, 2007). Asthma is a chronic inflammatory disease, which if untreated can lead to structural changes in the smooth muscle and may result in airway remodeling (EPR-3, 2007). At the molecular level, asthma usually involves a T-helper 2-type cell response (Th2)-(Lloyd and Hessel, 2010; Wenzel, 2012). The antigen-presenting cells (APC), including dendritic cells, present the antigen to the T-cell precursor, through the major histocompatibility complex II (MHCII) molecule coupled to the T-cell receptor (Kim et al., 2010). This leads to the activation of Th2 pathway, with the production of IL4, IL5, and IL13 cytokines and the consequent activation of B-lymphocytes and production of plasma cells, these last responsible for IgE production (Wenzel, 2012). Subsequently, basophils, eosinophils, and mast cells are activated, amplifying the allergic inflammation (Lloyd and Hessel, 2010; Wenzel, 2012). More than 100 genes have been implied in asthma susceptibility across populations (Bijanzadeh et al., 2011; Torgerson et al., 2012; Zhang et al., 2013) while the association of environmental factors ranges from excessive cleanliness, constituting the “hygiene hypothesis” (Graham-Rowe, 2011), to poor socioeconomic development (Neto et al., 2012) and smoke exposure (Burke et al., 2012) to “anything and asthma” (Buchanan et al., 2006). Furthermore, replication studies of asthma candidate genes are often inconsistent (Rogers et al., 2009). Among the main reasons pointed out for this lack of replication are the populations’ heterogeneous genetic backgrounds and their interaction with environmental factors, the different study designs and the lack of statistical power of the studied sample sets (Cardon and Bell, 2001; Nicolae and Ober, 2009; Grant and Hakonarson, 2010). Additionally, it is believed that in complex diseases many factors with weak effect rather than few with strong predictive power are thought to contribute to the disease susceptibility (Buchanan et al., 2006; von Mutius, 2009). However, and despite of our current understanding of the biology and the contribution of environmental and genetic factors (Vercelli, 2008; Mukherjee and Zhang, 2011; Antó, 2012; Kumari and Rana, 2012), asthma is still a puzzling concept. The identification of causal factors and their contribution to complex diseases remain mostly unanswered questions, given the lack of robustness, inadequacy and/or limitations of many of the present-day methodologies (Buchanan et al., 2006). In addition, the broadly used case-control and GWA approaches, designed to unveil genetic variants underlying multifactorial diseases, do not take into consideration the evolutionary history of each biological trait (Buchanan et al., 2009). The increasing incidence of complex diseases in the human populations suggests a high frequency of deleterious genetic variants (Kryukov et al., 2007). One may speculate that these genetic variations could have been beneficial or neutral in the past but have become detrimental as a result of changes in the surrounding environment and lifestyle of contemporary societies (Kryukov et al., 2007). A classical example supporting this idea is the “thrifty genes hypothesis” (Neel, 1962), sustaining that genotypes that once were protective against food scarcity are currently predisposing to obesity and diabetes, due to the current abundance in food resources and sedentary lifestyle (McDermott, 2006; Kryukov et al., 2007; Vardi and Bloch, 2008). Given the interface between genes and environment underlying this premise, it has been proposed that not only genetic but also epigenetic factors might be involved in the heritability of type 2 diabetes (Goh and Sum, 2010; Pijl, 2011). Epigenetics, the study of changes in DNA expression that do not imply changes in the DNA sequence (Miller and Ho, 2008) but can be transgenerationally transmitted (Anway et al., 2005), have been transforming the way complex diseases and their risk are perceived (Miller and Ho, 2008; Feinberg and Irizarry, 2010; Relton and Smith, 2010). There is increasing evidence that epigenetic patterns can be altered by environmental factors since as early as in utero life (Fraga et al., 2005; Relton and Smith, 2010; Thornburg et al., 2010; Durham et al., 2011). Ethnic differences in human DNA methylation have been observed between an African and an European population (Fraser et al., 2012) and methylation-associated SNPs (mSNPs) were also found to exist, in which one of the alleles was associated with higher levels of methylation (Fraser et al., 2012). Furthermore, given a particular environmental exposure, genetic