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Epigenetics, hypersensibility and asthma: what do we know so far?
Douglas da Silva Limaa,b, Rahuany Velleda de Moraisb,c, Ciliana Rechenmachera,b, Mariana Bohns Michalowskia,b,d,
Corresponding author
mmichalowski@hcpa.edu.br

Corresponding author.
, Marcelo Zubaran Goldania,b,e
a Programa de Pós-Graduação em Saúde da Criança e do Adolescente, Departamento de Pediatria, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
b Laboratório de Pediatria Translacional, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
c Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil
d Serviço de Oncologia Pediátrica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
e Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0001" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0005">Introduction</span><p id="para0007" class="elsevierStylePara elsevierViewall">According to Cavalli and Heard &#40;2019&#41;&#44; epigenetic means &#8220;The study of molecules and mechanisms that can perpetuate alternative states of gene activity in the context of the same DNA sequence&#8221;&#46; This perspective aims to cover transgenerational inheritance&#44; mitotic inheritance&#44; and the persistence of genetic activity or chromatin states for periods of time&#44; even without cell division&#46; It can also be related to environmental exposures leading to structural damage or functional changes in cells&#44; tissues&#44; and organs&#46;<a class="elsevierStyleCrossRefs" href="#bib0001"><span class="elsevierStyleSup">1-3</span></a> In this context&#44; the epigenome represents the interface between genes and the environment and provides a particular opportunity to recognize this intersection of causal components&#46;<a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a></p><p id="para0008" class="elsevierStylePara elsevierViewall">The relationship between epigenetic changes and their results was first described by Conrad Waddington&#44; in the&#160;1940s&#44; introducing the theory of &#8220;Epigenetic Landscape&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a> From there&#44; numerous studies were developed and recent researchers were able to design how a single-cell unit would become a complex of differentiated cells&#44; with specific functions&#44; expressing specific sets of genes as a result of cellular identity mechanisms&#46; Further&#44; the authors are able to understand how phenotype becomes an aftermath of genotype and its interplay with the environment&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a></p><p id="para0009" class="elsevierStylePara elsevierViewall">The trajectory of Developmental Origins of Health and Disease &#40;DOHaD&#41; studies suggests a mesh with those causal components and epigenetic variants&#44; considering that in-utero and post-natal life can induce biological changes leading to distinct outcomes&#46;<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0006">Epigenetics and DNA methylation</span><p id="para0010" class="elsevierStylePara elsevierViewall">The importance of epigenetic events is based on their long-lasting effects&#44; starting from early life &#40;gestation&#41; until adulthood&#46;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a> Besides&#44; epigenetic regulation is highly specific&#44; may induce short and long-term changes in gene expression&#44; and may be passed on from one generation to another&#46;<a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a> For this reason&#44; they provide a baseline of the environmental influence on gene expression and disease hazard&#46;<a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a></p><p id="para0011" class="elsevierStylePara elsevierViewall">Among possible epigenetic biomarkers&#44; DNA methylation &#40;DNAm&#41; is likely the most prominent and frequent approach&#46;<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a> DNAm consists of the addition of a methyl group onto the C5&#160;position of the cytosine to form&#160;5-methylcytosine&#44; and is predominantly found at Cytosine-Phosphateguanine &#40;CpG&#41; dinucleotide sites&#46;<a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a> Initially&#44; DNAm was proposed as the only carrier of epigenetic information&#44; but later it was accepted that chromatin&#44; proteins&#44; and non-coding RNAs also act in this process&#46; Likewise&#44; variations in histones can influence the local structure of chromatin&#44; directly or indirectly&#46; Those variations can be inheritable&#44; but reversible and may vary in different parts of the genome at different stages of the life cycle&#46; Recent studies of cell reprogramming have shown that DNAm and chromatin can also behave as epigenetic barriers&#44; preventing alterations in gene expression and cell identity&#46; Nevertheless&#44; chromatin states may impact transcriptional factor binding and DNA sequence polymorphism&#44; targeting the balance of genomic mutability and stability&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a> Altogether&#44; those mechanisms compound epigenetic regulation that controls several processes&#44; like cellular response to endogenous and exogenous stimuli&#44; leading to healthy conditions or diseases &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a> As an example&#44; cell differentiation in embryogenesis is triggered by DNAm&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a></p><elsevierMultimedia ident="fig0001"></elsevierMultimedia><p id="para0012" class="elsevierStylePara elsevierViewall">Human health is influenced by the exposure to the environment&#46; In this perspective&#44; the in-utero life must be imperatively considered&#44; once exposures through this period may disturb the immune system&#44; lung growth&#44; and respiratory performance later in life&#46;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a> It has been shown that extrinsic factors during the perinatal period&#44; such as adverse environment and maternal depression may impact the DNAm of the offspring and future outcomes inducing physical and psychiatric diseases&#46; Otherwise&#44; a good standard of nurturing may lead to healthier outcomes&#44; inducing a &#8220;reshape&#8221; effect of DNAm during a lifetime&#46;<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a> It is also important to highlight that genetic variants can explain how environmental factors impact epigenetic modifications&#46;<a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a> In this scenario&#44; environmental exposures are likely to contribute to the increase in allergic diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0007">Epigenetic paths for hipersensibilization</span><p id="para0013" class="elsevierStylePara elsevierViewall">Allergic diseases are increasing on a global scale&#46; In the United States&#44; US&#36;&#160;18&#160;billion is spent annually on their treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0012"><span class="elsevierStyleSup">12</span></a> As previously mentioned&#44; the early years of life play a decisive role in atopic diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a></p><p id="para0014" class="elsevierStylePara elsevierViewall">Methylation patterns and gene expression changes are well connected to persistent atopic asthma in respiratory epithelia of American children and some genes are significantly correlated to immune response&#46;<a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a> In a recent trial by Popovic et al&#46;&#44; 2019&#44; a case-control study nested in a birth cohort&#44; with&#160;136&#160;children between&#160;6 and 18&#160;months old&#44; to figure the association of early childhood wheezing and DNAm&#44; has observed a longitudinal temporal tendency towards allergic sensitization&#44; reinforcing the idea that the methylation profile at birth can be a marker of allergic vulnerability during childhood&#46;<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a> DNAm is known to be associated with asthma&#44; which can be triggered by smoking&#44; air pollution&#44; indoor contaminants&#44; and allergens&#46; Passive tobacco exposure decreases lung function and increases the risk of respiratory diseases&#46; Also&#44; prenatal tobacco smoking exposure increases the risk for the development of asthma in the neonate&#46;<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a> In a similar manner&#44; air pollutants or allergens can go through the airway epithelial barriers and reshape immune responses&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a> Likewise&#44; air pollution as well as viral infections and intestinal and pulmonary dysbiosis can induce sensitization&#44; exacerbations&#44; or trigger the onset of asthma&#46;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a></p><p id="para0015" class="elsevierStylePara elsevierViewall">In&#160;2018&#44; Yang et al&#46; used nasal epithelium samples from African-American children with allergic asthma to compare methylation profiles of genomic DNA&#46; They were able to identify&#160;186&#160;genes with methylation changes&#44; including genes related to atopy&#44; asthma&#44; immunity&#44; airflow obstruction&#44; and epigenetic regulation&#46; By showing that the epigenetic marks on the respiratory epithelium are related to allergic asthma&#44; this study provided a basis for studies of nasal DNA in larger populations&#46;<a class="elsevierStyleCrossRef" href="#bib0016"><span class="elsevierStyleSup">16</span></a> In another study&#44; DeVries et al&#46; suggest that childhood asthma engages epigenetic alterations in immunoregulatory and pro-inflammatory pathways&#46;<a class="elsevierStyleCrossRef" href="#bib0017"><span class="elsevierStyleSup">17</span></a> Thus&#44; asthma has an epigenetic regulatory mechanism influenced by genetic variability and environmental exposures&#44; that can be used as a strong biomarker&#46;<a class="elsevierStyleCrossRef" href="#bib0012"><span class="elsevierStyleSup">12</span></a></p><p id="para0016" class="elsevierStylePara elsevierViewall">An important issue in these studies is the origin of the tissue being analyzed&#46; Most allergic biomarkers to date were extracted from whole blood DNA&#46; Also&#44; cord blood immune cells were adopted to establish &#40;in an effort to predict&#41; DNAm signatures related to allergy and asthma&#46;<a class="elsevierStyleCrossRef" href="#bib0017"><span class="elsevierStyleSup">17</span></a> Although manifested at birth&#44; these epigenetic signatures are still able to change&#44; as determined by physiological pathways&#46; It means that some gene alterations might be transient&#44; or disease-related&#46; Therefore&#44; DNAm mechanisms may present some malleability during lifespan&#46; Besides&#44; most indicators of allergic disease and asthma are related to epigenetic aging of cells collected from nasal epithelia&#46;<a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a> Data on the differences and changes in the methylation profiles of these different tissues and their implication in hypersensitivity reactions are still very few&#46;</p></span><span id="sec0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0008">Asthma&#58; an epigenetic outcome</span><p id="para0017" class="elsevierStylePara elsevierViewall">Asthma is one of the most common pulmonary chronic diseases&#46; It may start early in life and&#44; if not handled properly&#44; tends to cause loss of pulmonary function in adult life&#46;<a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a> It is characterized by reversible airflow obstruction and airway inflammation with symptoms such as wheezing&#44; shortness of breath&#44; cough&#44; and chest tightness&#44; that may vary over time and frequency&#44; intermittent or persistently&#46; Some of them are transient and tend to disappear at school age&#46; Other persistent symptoms are up to remain until adulthood&#46;<a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a> The onset and clinical progression are strongly connected to environmental exposures and genetic susceptibility&#46;<a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a> Environmental and genomic aspects as well as aberrant immune maturation early in life may engage the disease outbreak&#46;<a class="elsevierStyleCrossRef" href="#bib0019"><span class="elsevierStyleSup">19</span></a></p><p id="para0018" class="elsevierStylePara elsevierViewall">In the past decade&#44; the increase in morbidity and mortality related to respiratory diseases has reached the spotlight in several countries&#46;<a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a> Epidemiological evidence has shown that approximately 30&#37; of children will experience at least one episode of wheezing in their lifetime&#46;<a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a> Worldwide&#44; asthma is frequently diagnosed during pre-scholar years and affects more than 300 million people&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">20</span></a> The estimated heritability of the disease in certain studies starts from&#160;40&#37;&#160;to&#160;60&#37;<a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a> and can reach as high as&#160;80&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0021"><span class="elsevierStyleSup">21</span></a> However&#44; the timeline and mechanisms of asthma onset are not well described yet&#46;<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a></p><p id="para0019" class="elsevierStylePara elsevierViewall">To keep homeostasis in human lungs&#44; a healthy adaptation to the environment is needed and the lung epithelia must present a competent mucosal immunity&#46; The respiratory system provides mucociliary clearance and a barrier against pathogens and other particles that may affect the alveolar gas exchange&#46; An unbalanced immune system or deficient epithelial barrier can therefore result in respiratory illness&#44; as the respiratory system remains in unprotected contact with exogenous factors&#46;<a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a></p><p id="para0020" class="elsevierStylePara elsevierViewall">Protection factors are also described&#46; Some exposures can promote healthier airway development even in the presence of a genetic predisposition to the disease&#46; Recent studies propose that the use of fish oil and vitamin D throughout pregnancy may minimize the risk of early childhood wheezing&#46; Also&#44; children from a farm environment who are frequently exposed to allergens&#44; bacteria&#44; fungi&#44; and others from diverse microbiomes and the consumption of unprocessed cow milk may develop a strong protective barrier against asthma and allergy&#46; Indeed&#44; children from rural areas have shown a prevalence of allergic diseases lower than children from urban environments&#46;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0019"><span class="elsevierStyleSup">19</span></a></p><p id="para0021" class="elsevierStylePara elsevierViewall">Asthma management is based on the severity and risk profile of these children&#46; Many recent studies have evaluated the relationship of genetic polymorphisms as potential risk factors for the onset and severity of asthma symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0019"><span class="elsevierStyleSup">19</span></a> Even with the advance of asthma treatment&#44; there is still a group of patients that faces a low response to traditional approaches&#46; From this&#44; a better understanding of asthma and allergy mechanisms through the observation of DNAm and gene expression may provide a clue about reliable biomarkers associated with therapeutic responses in this population&#46;<a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a></p><p id="para0022" class="elsevierStylePara elsevierViewall">There is a strong connection between asthma and DNAm<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0023"><span class="elsevierStyleSup">23</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0001">Table 1</a>&#41;&#46; In&#160;2019&#44; Reese et al&#46; conducted a study with newborns and school-age children&#46; They evaluated the entire epigenome by observing the presence of CpG methylation in the blood of these two age groups both in prospective and cross-sectional analyses&#46; In&#160;8&#160;cohorts of newborns &#40;668&#160;cases&#41;&#44; 9&#160;CpGs islands and 35&#160;regions were differentially methylated in patients who developed asthma&#44; while in older children&#44; in a cross-sectional analysis&#44; 179&#160;CpGs islands and 36&#160;differentially methylated regions were identified in these cases&#46;</p><elsevierMultimedia ident="tbl0001"></elsevierMultimedia><p id="para0023" class="elsevierStylePara elsevierViewall">Another interesting fact is that DNAm is tissue-specific&#46; In the case of diseases whose local aspects are pronounced&#44; such as asthma&#44; the selection of tissues to carry out the DNA methylation profile can be an important variable in the analysis&#46;<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a> DNA methylation of the nasal epithelium may offer more information about changes in the airways&#44; once whole blood DNA does not perform a trustworthy complete agreement for pulmonary sample studies&#46;<a class="elsevierStyleCrossRef" href="#bib0024"><span class="elsevierStyleSup">24</span></a> Cardenas et al&#46; &#40;2019&#41; conducted an Epigenome-Wide Association Study &#40;EWAS&#41; with nasal samples of&#160;547&#160;children to analyze current asthma&#44; allergic sensitization&#44; and rhinitis&#44; Fractional exhaled Nitric Oxide &#40;FeNO&#41;&#44; and lung function&#44; where diverse differentially methylated CpG&#39;s and regions were found related to these diseases&#44; suggesting that the nasal cellular epigenome may be a good biomarker to airway inflammation in children&#46; Also&#44; in peripheral blood samples&#44; it is crucial to consider confounding factors&#44; such as leukocytes and eosinophils&#44; that may lead to biased results&#46;<a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a></p><p id="para0024" class="elsevierStylePara elsevierViewall">Some data contradict the tissue specificity theory in the analysis of patients with asthma&#46; A recent study by Vieira Braga et al&#46; &#40;2019&#41; was designed to find differences between asthmatic and healthy patients&#46; A wide overlapping of the cellular epigenetic profile of the different locations of the respiratory tree was observed&#46; In fact&#44; a diversity of immune cells was found in different parts of the respiratory unit&#46; Therefore&#44; it could be observed that&#44; in asthmatic patients&#44; airway wall remodeling was highly correlated with the presence of a chronic inflammatory response&#44; which may cause a cell-to-cell signaling network&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">25</span></a></p><p id="para0025" class="elsevierStylePara elsevierViewall">Also&#44; variations in innate and adaptive immune responses appear to precede the diagnosis of asthma in children&#46; This group of respiratory and immune modifications may characterize a window of susceptibility toward the disease and can contribute to asthma pathogenesis&#46; The disease trajectory can also be affected by post-translational histone modification that influences genetic regulation and its possible outcomes&#46;<a class="elsevierStyleCrossRef" href="#bib0023"><span class="elsevierStyleSup">23</span></a></p></span><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0009">Genes in sight</span><p id="para0026" class="elsevierStylePara elsevierViewall">Several genes whose altered DNA methylation has been described in asthmatic individuals have different pathophysiological aspects and relationships with components and functions of the immune system&#46;<a class="elsevierStyleCrossRef" href="#bib0026"><span class="elsevierStyleSup">26</span></a> Some of them deserve special attention &#40;<a class="elsevierStyleCrossRef" href="#tbl0001">Table 1</a>&#41;&#46;</p><span id="sec0006" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0010">IL5RA</span><p id="para0027" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">IL5RA</span> gene &#40;Interleukin&#160;5 Receptor Alpha subunit&#41; is found on the human chromosome&#160;3&#46; Hypomethylation of the <span class="elsevierStyleItalic">IL5RA</span> gene in Airway Epithelial Cells &#40;AECs&#41; and eosinophils has been shown to be a potential therapeutic target for asthma&#46; In an EWAS&#44; Arathimos et al&#46; &#40;2017&#41; used data from the Avon Longitudinal Study of Parents and Children &#40;ALSPAC&#41;&#44; with more than 1&#44;500&#160;patients&#44; identifying&#160;302&#160;CpGs related to asthma and 405&#160;to wheezing&#44; with a robust overlap between them&#46;<a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a> After adjusting for cell count&#44; there was a difference of&#160;2&#46;49 &#40;95&#37;&#160;CI -1&#46;56&#44; -3&#46;43&#41; percent of methylation in patients with asthma&#46; The <span class="elsevierStyleItalic">IL5RA</span> gene also showed an important link with the pathogenesis of asthma in a multi-omics approach&#46;<a class="elsevierStyleCrossRef" href="#bib0021"><span class="elsevierStyleSup">21</span></a> The hypomethylation of <span class="elsevierStyleItalic">IL5RA</span> gene on airway epithelial cells and eosinophils has shown to be a therapeutic target for asthma&#46; The epigenetic finding allowed the study and incorporation of the monoclonal antibody Benralizumab<a class="elsevierStyleCrossRef" href="#bib0021"><span class="elsevierStyleSup">21</span></a> &#40;Anti-IL-5Ra&#41; in clinical practice&#44; a drug that binds to <span class="elsevierStyleItalic">IL5RA</span>&#44; inducing a reduction in exacerbations and improvement in lung function in patients with severe asthma&#46;<a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0021"><span class="elsevierStyleSup">21</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0027"><span class="elsevierStyleSup">27</span></a></p></span><span id="sec0007" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0011">EPX</span><p id="para0028" class="elsevierStylePara elsevierViewall">Also common in eosinophils and AECs&#44; the <span class="elsevierStyleItalic">EPX</span> &#40;Eosinophil Peroxidase&#41; gene&#44; is involved in granulocyte functions&#44; notably neutrophils&#44; cytokine production and signaling&#46;<a class="elsevierStyleCrossRef" href="#bib0026"><span class="elsevierStyleSup">26</span></a> The enzyme expressed from eosinophil peroxidase is released to protect from parasitic infection and allergic stimuli&#46;<a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a> The gene is found clustered with other peroxidase genes on chromosome&#160;17&#46; Lower DNAm of the <span class="elsevierStyleItalic">EPX</span> is related to allergic asthma&#46; In a study with&#160;483 Puerto Rican children and adolescents&#44; the methylome from nasal epithelial cells was studied&#46; It was observed that&#160;61&#37; &#40;48&#47;79 CpGs&#41;&#44; including multiple CpGs annotated to EVL and <span class="elsevierStyleItalic">EPX</span> genes&#44; were associated with asthma outcomes&#44; such as allergic asthma&#44; environmental IgE sensitization&#44; FeNO&#44; and total IgE &#40;FDR&#160;&#60; 0&#46;05&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0016"><span class="elsevierStyleSup">16</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0024"><span class="elsevierStyleSup">24</span></a></p></span><span id="sec0008" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0012">SMAD3</span><p id="para0029" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">SMAD3</span> &#40;<span class="elsevierStyleItalic">SMAD Family Member</span> 3&#41; is a protein-coding gene located at chromosome 20p13&#46; It plays an important role in immune response regulation and acts together with other proteins to promote fibrosis regulation&#46;<a class="elsevierStyleCrossRef" href="#bib0023"><span class="elsevierStyleSup">23</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0028"><span class="elsevierStyleSup">28</span></a> The hypermethylation of the <span class="elsevierStyleItalic">SMAD3</span> gene promoter is associated with asthma&#44; particularly in children of asthmatic mothers&#46; A study by DeVries et al&#46; &#40;2017&#41; has shown that children from asthmatic mothers had <span class="elsevierStyleItalic">SMAD3</span> gene methylated at birth&#46; The methylation profile was analyzed from cord blood samples of children from three different cohorts&#46; Methylation levels measured by bisulfite sequencing over the entire DNA &#40;Spearman correlation coefficient &#91;&#961;&#160;&#61;&#160;0&#46;48&#93;&#44; p&#160;&#61;&#160;1&#46;2&#160;&#215;&#160;10&#8722;13&#41; and at intermediate DNA methylation levels &#40;8&#37;&#8211;92&#37;&#44; p&#160;&#61;&#160;0&#46;006&#41;&#44; <span class="elsevierStyleItalic">SMAD3</span> methylation was extremely correlated with asthma &#40;&#961;&#160;&#61;&#160;0&#46;46&#44; p&#160;&#61;&#160;0&#46;009&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a></p></span></span><span id="sec0009" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0013">Future perspectives</span><p id="para0030" class="elsevierStylePara elsevierViewall">Studies on epigenetics have advanced&#44; but despite this&#44; it is not yet clear whether changes in these pathways have a direct causal relationship in certain diseases&#46; For this reason&#44; it is essential to better understand the connection between the pathogenesis of pathologies&#44; and their environmental and developmental influences&#46; More systematic studies are needed to detect how DNAm paves the way for certain diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a> However&#44; integrative analysis with potent causal inference and longitudinal data is still a challenge&#46;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a></p><p id="para0031" class="elsevierStylePara elsevierViewall">A relevant point in carrying out these analyses is the origin of the biological material used for the study&#46; Although many surveys use blood&#44; samples from other locations can also be used&#46; Nasal epithelium&#44; for example&#44; has often been used to study airway diseases&#44; including cystic fibrosis&#44; allergic sensitization&#44; asthma&#44; and other obstructive respiratory disorders&#46;<a class="elsevierStyleCrossRef" href="#bib0024"><span class="elsevierStyleSup">24</span></a> Nasal epithelia is easier to access than blood samples and may be a profitable proxy for pathological changes in lung cells&#46;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0029"><span class="elsevierStyleSup">29</span></a></p><p id="para0032" class="elsevierStylePara elsevierViewall">In addition to the origin of the biological material used&#44; the association between environmental exposure and epigenetic variations is another challenge&#46; The ability to compare two or more samples at different time points with the same individuals in the cohort can ensure a strong approach to data analysis&#46;<a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a> Genetic predisposition&#44; epigenetics&#44; and exposure are perfectly suited to be studied through birth cohorts&#46; Currently&#44; the influence of intergenerational events on epigenetic mechanisms that can induce changes in the health-disease pattern is also evidenced&#46; Studies indicate that the health of offspring is influenced by intergenerational aspects related to maternal and grandparent&#39;s exposures and health status&#46;<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a></p><p id="para0033" class="elsevierStylePara elsevierViewall">The development of an &#8220;asthma phenotype index&#8221;&#44; considering molecular and clinical criteria&#44; with predictive values of management would be relevant for asthma diagnosis and modulated treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">30</span></a> On the other hand&#44; the small number of studies available today apply different designs and analysis techniques&#46; This fact precludes robust conclusions about DNAm and the epigenetic mechanisms of asthma&#46;<a class="elsevierStyleCrossRef" href="#bib0024"><span class="elsevierStyleSup">24</span></a> Machine learning analytics can provide substantial benefits in analyzing this heterogeneity&#44; but little data is available to allow the use of this technology&#46;<a class="elsevierStyleCrossRef" href="#bib0031"><span class="elsevierStyleSup">31</span></a> The characterization of epigenetic alterations with a homogeneous approach and standardized techniques for disease outbreak and progress remains needed&#46;<a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a> New studies in the areas of genomics&#44; biochemistry&#44; and genetics can facilitate the understanding of how epigenetic mechanisms influence the evolution of these patients&#44; promoting safer and more economical clinical approaches&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a> In addition&#44; these studies may seek to define how many aspects of life can influence the onset of inflammatory pathologies and asthma&#46; Epigenetics studies fit a new perspective in understanding pulmonary diseases&#46; It is possible that methylation profile analyses may soon be part of the diagnosis and risk stratification for childhood asthma&#46;</p></span></span>"
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          "titulo" => "Abbreviations"
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          "titulo" => "Introduction"
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          "titulo" => "Epigenetics and DNA methylation"
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        6 => array:2 [
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          "titulo" => "Epigenetic paths for hipersensibilization"
        ]
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          "identificador" => "sec0004"
          "titulo" => "Asthma&#58; an epigenetic outcome"
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          "titulo" => "Genes in sight"
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              "titulo" => "IL5RA"
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              "titulo" => "SMAD3"
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          "titulo" => "Future perspectives"
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            0 => "Asthma"
            1 => "Children"
            2 => "DNA methylation"
            3 => "Epigenetics"
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          "clase" => "abr"
          "titulo" => "Abbreviations"
          "identificador" => "xpalclavsec1869165"
          "palabras" => array:13 [
            0 => "DNAm"
            1 => "DOHaD"
            2 => "CpG"
            3 => "EWAS"
            4 => "ALSPAC"
            5 => "TSS"
            6 => "RNA pol II"
            7 => "AECs"
            8 => "IL5RA"
            9 => "EPX"
            10 => "EVL"
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            12 => "ADAM33"
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    "highlights" => array:2 [
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      "resumen" => "<span id="abss0001" class="elsevierStyleSection elsevierViewall"><p id="spara003" class="elsevierStyleSimplePara elsevierViewall"><ul class="elsevierStyleList" id="celist0001"><li class="elsevierStyleListItem" id="celistitem0001"><span class="elsevierStyleLabel">&#8226;</span><p id="para0001" class="elsevierStylePara elsevierViewall">Epigenetics&#44; hypersensibility and asthma&#58; what do we know so far&#63;</p></li><li class="elsevierStyleListItem" id="celistitem0002"><span class="elsevierStyleLabel">&#8226;</span><p id="para0002" class="elsevierStylePara elsevierViewall">Asthma can be triggered from epigenetic changes&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0003"><span class="elsevierStyleLabel">&#8226;</span><p id="para0003" class="elsevierStylePara elsevierViewall">Early life exposures can contribute to the development and exacerbation of asthma&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0004"><span class="elsevierStyleLabel">&#8226;</span><p id="para0004" class="elsevierStylePara elsevierViewall">DNA methylation profile of certain genes is related to asthma and allergy&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0005"><span class="elsevierStyleLabel">&#8226;</span><p id="para0005" class="elsevierStylePara elsevierViewall">Nasal epithelium samples have shown promise as a tissue for studying DNA methylation changes related to asthma&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0006"><span class="elsevierStyleLabel">&#8226;</span><p id="para0006" class="elsevierStylePara elsevierViewall">To find biomarkers and standardized assays to advance the field of epigenetics in respiratory disorders are still a challenge&#46;</p></li></ul></p></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abss0002" class="elsevierStyleSection elsevierViewall"><p id="spara004" class="elsevierStyleSimplePara elsevierViewall">In this review&#44; we describe recent advances in understanding the relationship between epigenetic changes&#44; especially DNA methylation &#40;DNAm&#41;&#44; with hypersensitivity and respiratory disorders such as asthma in childhood&#46; It is clearly described that epigenetic mechanisms can induce short to long-term changes in cells&#44; tissues&#44; and organs&#46; Through the growing number of studies on the Origins of Health Development and Diseases&#44; more and more data exist on how environmental and genomic aspects in early life can induce allergies and asthma&#46; The lack of biomarkers&#44; standardized assays&#44; and access to more accessible tools for data collection and analysis are still a challenge for future studies&#46; Through this review&#44; the authors draw a panorama with the available information that can assist in the establishment of an epigenetic approach for the risk analysis of these pathologies&#46;</p></span>"
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          "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; A methyl group addition to the cytosine carbon&#160;5 in cytosine-phosphate-guanine &#40;CpG&#41;&#59; &#40;B&#41; No CpG methylation in the gene&#39;s promoter region leads to active transcription&#59; &#40;C&#41; Methylation in the promoter region of genes leads to transcriptional repression&#46; TSS&#44; Transcription Start Site&#59; RNA pol&#160;II&#44; RNA polymerase&#160;II&#46;</p>"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0001"></a><th class="td" title="\n
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                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Author&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Patients&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Sample&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Main Results&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0005"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Reese et al&#46;&#44; 2019&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0006"></a><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="top">n&#160;&#61;&#160;1299 Age&#160;&#61;&#160;7-17 years old&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0007"></a><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="top">Whole blood&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0008"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Identified epigenetic variations related to asthma in newborns and children&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0009"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Cardenas et al&#46;&#44; 2019&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0010"></a><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="top">n&#160;&#61;&#160;1083 Age&#160;&#61;&#160;12 to 65 years old&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0011"></a><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="top">Nasal swab cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0012"></a><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="top">285 CpGs sites associated with asthma&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0013"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Arathimos et al&#46;&#44; 2017&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0014"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">n&#160;&#61;&#160;1529 Age&#160;&#61;&#160;7&#46;5 years and 16&#46;5years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0015"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Peripheral blood&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0016"></a><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleItalic">IL5RA</span> and <span class="elsevierStyleItalic">AP2A2</span> gene methylation related to asthma at&#160;16&#46;5&#160;years old&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0017"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Popovic et al&#46;&#44; 2019&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0018"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">n&#160;&#61;&#160;136 Age&#160;&#61;&#160;6 to 18 months&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">Saliva&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleItalic">PM20D1</span> gene hypermethylation associated with early childhood wheezing&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Yang et al&#46;&#44; 2018&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0022"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">n&#160;&#61;&#160;78&#46; Age&#160;&#61;&#160;10&#160;to 12&#160;years old&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0023"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Nasal epithelia&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">186 genes related to atopy&#44; asthma&#44; immunity&#44; airflow obstruction and epigenetic regulation&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0025"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Ning et al&#46;&#44; 201934&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0026"></a><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="top">n&#160;&#61;&#160;182 children&#46; 3&#160;to 14&#160;years old&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">Peripheral blood&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleItalic">ADAM33</span> polymorphism is correlated with increased susceptibility to asthma&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0029"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Nicodemus- Johnson et al&#46;&#44; 2016&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">n&#160;&#61;&#160;115 adults&#46; 26&#160;to 52&#160;years old&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">Airway epithelial cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0032"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Regulatory locus associated with asthma risk and epigenetic signatures of specific asthma endotypes&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                    0 => array:2 [
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                        "tituloSerie" => "Nature"
                        "fecha" => "2019"
                        "volumen" => "571"
                        "numero" => "7766"
                        "paginaInicial" => "489"
                        "paginaFinal" => "499"
                        "link" => array:1 [
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            1 => array:3 [
              "identificador" => "bib0002"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Epigenome-wide association study of asthma and wheeze in childhood and adolescence"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R Arathimos"
                            1 => "M Suderman"
                            2 => "GC Sharp"
                            3 => "K Burrows"
                            4 => "R Granell"
                            5 => "K Tilling"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s13148-016-0308-0"
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                        "tituloSerie" => "Clin Epigenetics"
                        "fecha" => "2017"
                        "volumen" => "9"
                        "numero" => "1"
                        "paginaInicial" => "1"
                        "paginaFinal" => "16"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28149329"
                            "web" => "Medline"
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              "identificador" => "bib0003"
              "etiqueta" => "3"
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                      "titulo" => "Differentially methylated DNA regions in early childhood wheezing&#58; an epigenome-wide study using saliva"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            1 => "V Fiano"
                            2 => "F Fasanelli"
                            3 => "M Trevisan"
                            4 => "C Grasso"
                            5 => "MB Assumma"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/pai.13023"
                      "Revista" => array:7 [
                        "tituloSerie" => "Pediatr Allergy Immunol"
                        "fecha" => "2019"
                        "volumen" => "30"
                        "numero" => "3"
                        "paginaInicial" => "305"
                        "paginaFinal" => "314"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30681197"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0004"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The nasal methylome as a biomarker of asthma and airway inflammation in children"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A Cardenas"
                            1 => "JE Sordillo"
                            2 => "SL Rifas-Shiman"
                            3 => "W Chung"
                            4 => "L Liang"
                            5 => "BA Coull"
                          ]
                        ]
                      ]
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                      "doi" => "10.1038/s41467-019-11058-3"
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                        "tituloSerie" => "Nat Commun"
                        "fecha" => "2019"
                        "volumen" => "10"
                        "numero" => "1"
                        "paginaInicial" => "3095"
                        "link" => array:1 [
                          0 => array:2 [
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                            "web" => "Medline"
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                      "titulo" => "The Bright and Dark Side of DNA Methylation&#58; a Matter of Balance"
                      "autores" => array:1 [
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                          "autores" => array:3 [
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                        "volumen" => "8"
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                        "paginaInicial" => "1243"
                        "link" => array:1 [
                          0 => array:2 [
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                            "web" => "Medline"
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                    0 => array:2 [
                      "doi" => "10.3389/fped.2019.00115"
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                        "tituloSerie" => "Front Pediatr"
                        "fecha" => "2019"
                        "volumen" => "7"
                        "paginaInicial" => "115"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31001502"
                            "web" => "Medline"
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                  ]
                ]
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "DNA methylation in lung cells is associated with asthma endotypes and genetic risk"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J Nicodemus-Johnson"
                            1 => "RA Myers"
                            2 => "NJ Sakabe"
                            3 => "DR Sobreira"
                            4 => "DK Hogarth"
                            5 => "ET Naureckas"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1172/jci.insight.90151"
                      "Revista" => array:6 [
                        "tituloSerie" => "JCI Insight"
                        "fecha" => "2016"
                        "volumen" => "1"
                        "numero" => "20"
                        "paginaInicial" => "e90151"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27942592"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0009"
              "etiqueta" => "9"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Establishing a birth cohort to investigate the course and aetiology of asthma and allergies across three generations &#8211; rationale&#44; design&#44; and methods of the ACROSSOLAR study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T Weinmann"
                            1 => "J Gerlich"
                            2 => "S Heinrich"
                            3 => "D Nowak"
                            4 => "J Gerdes"
                            5 => "J Schlichtiger"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s12889-015-2555-y"
                      "Revista" => array:5 [
                        "tituloSerie" => "BMC Public Health"
                        "fecha" => "2015"
                        "volumen" => "15"
                        "paginaInicial" => "1210"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26637409"
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                ]
              ]
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              "etiqueta" => "11"
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                    0 => array:2 [
                      "titulo" => "Wheezing phenotypes and risk factors in early life&#58; The ELFE cohort"
                      "autores" => array:1 [
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                          "etal" => true
                          "autores" => array:6 [
                            0 => "S Hallit"
                            1 => "B Leynaert"
                            2 => "MC Delmas"
                            3 => "S Rocchi"
                            4 => "J De Blic"
                            5 => "C Marguet"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "PLoS One"
                        "fecha" => "2018"
                        "volumen" => "13"
                        "numero" => "4"
                      ]
                    ]
                  ]
                ]
              ]
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            11 => array:3 [
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              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "Epigenome-wide association study reveals methylation pathways associated with childhood allergic sensitization"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C Peng"
                            1 => "ER Van Meel"
                            2 => "A Cardenas"
                            3 => "SL Rifas-Shiman"
                            4 => "AR Sonawane"
                            5 => "KR Glass"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1080/15592294.2019.1590085"
                      "Revista" => array:7 [
                        "tituloSerie" => "Epigenetics"
                        "fecha" => "2019"
                        "volumen" => "14"
                        "numero" => "5"
                        "paginaInicial" => "445"
                        "paginaFinal" => "466"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30876376"
                            "web" => "Medline"
                          ]
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                ]
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              "identificador" => "bib0013"
              "etiqueta" => "13&#46;"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Coordinated DNA Methylation and Gene Expression Data for Identification of the Critical Genes Associated with Childhood Atopic Asthma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "K Shi"
                            1 => "MN Ge"
                            2 => "XQ&#46; Chen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1089/cmb.2019.0194"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Comput Biol"
                        "fecha" => "2020"
                        "volumen" => "27"
                        "numero" => "1"
                        "paginaInicial" => "109"
                        "paginaFinal" => "120"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31460781"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0014"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Epigenetic regulation of AXL and risk of childhood asthma symptoms"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L Gao"
                            1 => "J Millstein"
                            2 => "KD Siegmund"
                            3 => "L Dubeau"
                            4 => "R Maguire"
                            5 => "FD Gilliland"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s13148-017-0421-8"
                      "Revista" => array:5 [
                        "tituloSerie" => "Clin Epigenetics"
                        "fecha" => "2017"
                        "volumen" => "9"
                        "paginaInicial" => "121"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29177020"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0015"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "DNA methylation in nasal epithelium&#44; atopy&#44; and atopic asthma in children&#58; a genome-wide study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E Forno"
                            1 => "T Wang"
                            2 => "C Qi"
                            3 => "Q Yan"
                            4 => "C-J Xu"
                            5 => "N Boutaoui"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S2213-2600(18)30466-1"
                      "Revista" => array:7 [
                        "tituloSerie" => "Lancet Respir Med"
                        "fecha" => "2019"
                        "volumen" => "7"
                        "numero" => "4"
                        "paginaInicial" => "336"
                        "paginaFinal" => "346"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30584054"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0016"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The nasal methylome and childhood atopic asthma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "IV Yang"
                            1 => "BS Pedersen"
                            2 => "AH Liu"
                            3 => "GT O&#39;Connor"
                            4 => "D Pillai"
                            5 => "M Kattan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaci.2016.07.036"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Allergy Clin Immunol"
                        "fecha" => "2017"
                        "volumen" => "139"
                        "numero" => "5"
                        "paginaInicial" => "1478"
                        "paginaFinal" => "1488"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27745942"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0017"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Early predictors of asthma and allergy in children&#58; the role of epigenetics"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "A DeVries"
                            1 => "D&#46; Vercelli"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/ACI.0000000000000201"
                      "Revista" => array:7 [
                        "tituloSerie" => "Curr Opin Allergy Clin Immunol"
                        "fecha" => "2015"
                        "volumen" => "15"
                        "numero" => "5"
                        "paginaInicial" => "435"
                        "paginaFinal" => "439"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26258923"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0018"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Impacto da asma no Brasil&#58; an&#225;lise longitudinal de dados extra&#237;dos de um banco de dados governamental brasileiro"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "TA Cardoso"
                            1 => "C Roncada"
                            2 => "E Rodrigues da Silva"
                            3 => "LA Pinto"
                            4 => "MH Jones"
                            5 => "RT Stein"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1590/S1806-37562016000000352"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Bras Pneumol"
                        "fecha" => "2017"
                        "volumen" => "43"
                        "numero" => "3"
                        "paginaInicial" => "163"
                        "paginaFinal" => "168"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28746526"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0019"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Primary prevention of asthma&#58; from risk and protective factors to targeted strategies for prevention"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "E von Mutius"
                            1 => "HH&#46; Smits"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(20)31861-4"
                      "Revista" => array:7 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2020"
                        "volumen" => "396"
                        "numero" => "10254"
                        "paginaInicial" => "854"
                        "paginaFinal" => "866"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32910907"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "DNA methylation in childhood asthma&#58; an epigenome-wide meta-analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "CJ Xu"
                            1 => "C S&#246;derh&#228;ll"
                            2 => "M Bustamante"
                            3 => "N Ba&#239;z"
                            4 => "O Gruzieva"
                            5 => "U Gehring"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S2213-2600(18)30052-3"
                      "Revista" => array:7 [
                        "tituloSerie" => "Lancet Respir Med"
                        "fecha" => "2018"
                        "volumen" => "6"
                        "numero" => "5"
                        "paginaInicial" => "379"
                        "paginaFinal" => "388"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29496485"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0021"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A multiomics approach to identify genes associated with childhood asthma risk and morbidity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E Forno"
                            1 => "T Wang"
                            2 => "Q Yan"
                            3 => "J Brehm"
                            4 => "E Acosta-Perez"
                            5 => "A Colon-Semidey"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1165/rcmb.2017-0002OC"
                      "Revista" => array:7 [
                        "tituloSerie" => "Am J Respir Cell Mol Biol"
                        "fecha" => "2017"
                        "volumen" => "57"
                        "numero" => "4"
                        "paginaInicial" => "439"
                        "paginaFinal" => "447"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28574721"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0022"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Epigenome-wide analysis links SMAD3 methylation at birth to asthma in children of asthmatic mothers"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A Devries"
                            1 => "G Wlasiuk"
                            2 => "SJ Miller"
                            3 => "A Bosco"
                            4 => "DA Stern"
                            5 => "IC Lohman"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaci.2016.10.041"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Allergy Clin Immunol"
                        "fecha" => "2017"
                        "volumen" => "140"
                        "numero" => "2"
                        "paginaInicial" => "534"
                        "paginaFinal" => "542"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28011059"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0023"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Atopic asthma after rhinovirus-induced wheezing is associated with DNA methylation change in the SMAD3 gene promoter"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "RJ Lund"
                            1 => "M Osmala"
                            2 => "M Malonzo"
                            3 => "M Lukkarinen"
                            4 => "A Leino"
                            5 => "J Salmi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Allergy Eur J Allergy Clin Immunol"
                        "fecha" => "2018"
                        "volumen" => "73"
                        "numero" => "8"
                        "paginaInicial" => "1735"
                        "paginaFinal" => "1740"
                      ]
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                  ]
                ]
              ]
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            23 => array:3 [
              "identificador" => "bib0024"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "DNA methylation in nasal epithelium&#58; strengths and limitations of an emergent biomarker for childhood asthma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "G Solazzo"
                            1 => "G Ferrante"
                            2 => "Grutta S La"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3389/fped.2020.00256"
                      "Revista" => array:5 [
                        "tituloSerie" => "Front Pediatr"
                        "fecha" => "2020"
                        "volumen" => "8"
                        "paginaInicial" => "256"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32500051"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0025"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A cellular census of human lungs identifies novel cell states in health and in asthma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "FA Vieira Braga"
                            1 => "G Kar"
                            2 => "M Berg"
                            3 => "OA Carpaij"
                            4 => "K Polanski"
                            5 => "LM Simon"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/s41591-019-0468-5"
                      "Revista" => array:7 [
                        "tituloSerie" => "Nat Med"
                        "fecha" => "2019"
                        "volumen" => "25"
                        "numero" => "7"
                        "paginaInicial" => "1153"
                        "paginaFinal" => "1163"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31209336"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
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                ]
              ]
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            25 => array:3 [
              "identificador" => "bib0026"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cell-specific DNA methylation signatures in asthma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "A-AH Thibeault"
                            1 => "C&#46; Laprise"
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                        "volumen" => "10"
                        "numero" => "11"
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                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31731604"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0027"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The genetics and genomics of asthma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "SAG Willis-Owen"
                            1 => "WOC Cookson"
                            2 => "MF Moffatt"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1146/annurev-genom-083117-021651"
                      "Revista" => array:6 [
                        "tituloSerie" => "Annu Rev Genomics Hum Genet"
                        "fecha" => "2018"
                        "volumen" => "19"
                        "paginaInicial" => "223"
                        "paginaFinal" => "246"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30169121"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0028"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The neonatal methylome as a gatekeeper in the trajectory to childhood asthma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "A DeVries"
                            1 => "D&#46; Vercelli"
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                    ]
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                    0 => array:2 [
                      "doi" => "10.2217/epi-2016-0149"
                      "Revista" => array:7 [
                        "tituloSerie" => "Epigenomics"
                        "fecha" => "2017"
                        "volumen" => "9"
                        "numero" => "4"
                        "paginaInicial" => "585"
                        "paginaFinal" => "593"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28322586"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0029"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The nasal methylome and childhood atopic asthma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "I V Yang"
                            1 => "BS Pedersen"
                            2 => "AH Liu"
                            3 => "GT O&#39;Connor"
                            4 => "D Pillai"
                            5 => "M Kattan"
                          ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaci.2016.07.036"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Allergy Clin Immunol"
                        "fecha" => "2016"
                        "volumen" => "139"
                        "numero" => "5"
                        "paginaInicial" => "1478"
                        "paginaFinal" => "1488"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27745942"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0030"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The puzzle of immune phenotypes of childhood asthma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "K Landgraf-Rauf"
                            1 => "B Anselm"
                            2 => "B Schaub"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s40348-016-0057-3"
                      "Revista" => array:6 [
                        "tituloSerie" => "Mol Cell Pediatr"
                        "fecha" => "2016"
                        "volumen" => "3"
                        "numero" => "1"
                        "paginaInicial" => "27"
                        "link" => array:1 [
                          0 => array:2 [
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Article information
ISSN: 18075932
Original language: English
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