Original article
Association between interleukin-10 polymorphisms and CD4+CD25+FOXP3+ T cells in asthmatic children
Magáli Mocellina, Lidiane Alves de Azeredo Leitãoa, Patrícia Dias de Araújoa, Marcus Herbert Jonesa, Renato Tetelbom Steina, Paulo Márcio Pitreza, Ana Paula Duarte de Souzab, Leonardo Araújo Pintoa,
Corresponding author
a Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Escola de Medicina, Núcleo de Pediatria, Centro Infantil, Porto Alegre, RS, Brazil
b Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Escola de Saúde e Ciências da Vida, Centro Infant, Laboratório de Imunologia Clínica e Experimental, Porto Alegre, RS, Brazil
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All qRT-PCR data are presented as the fold induction relative to the <span class="elsevierStyleItalic">Actb</span> mRNA level.</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">MMP, mycoplasma pneumoniae pneumonia.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Linlin Yin, Yajun Ma, Wenlong Wang, Yitang Zhu" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Linlin" "apellidos" => "Yin" ] 1 => array:2 [ "nombre" => "Yajun" "apellidos" => "Ma" ] 2 => array:2 [ "nombre" => "Wenlong" "apellidos" => "Wang" ] 3 => array:2 [ "nombre" => "Yitang" "apellidos" => "Zhu" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0021755720302515?idApp=UINPBA000049" "url" => "/00217557/0000009700000005/v1_202109160616/S0021755720302515/v1_202109160616/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S0021755720302461" "issn" => "00217557" "doi" => "10.1016/j.jped.2020.10.016" "estado" => "S300" "fechaPublicacion" => "2021-09-01" "aid" => "946" "copyright" => "Sociedade Brasileira de Pediatria" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "J Pediatr (Rio J). 2021;97:540-5" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Translation and cross-cultural adaptation of the <span class="elsevierStyleItalic">Childhood Bladder and Bowel Dysfunction Questionnaire</span> (CBBDQ)" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "540" "paginaFinal" => "545" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1117 "Ancho" => 1494 "Tamanyo" => 108484 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Bland-Altman plots comparing the results obtained during the two evaluation moments.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Rejane P. 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"apellidos" => "de Bie" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0021755720302461?idApp=UINPBA000049" "url" => "/00217557/0000009700000005/v1_202109160616/S0021755720302461/v1_202109160616/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "Association between interleukin-10 polymorphisms and CD4<span class="elsevierStyleSup">+</span>CD25<span class="elsevierStyleSup">+</span>FOXP3<span class="elsevierStyleSup">+</span> T cells in asthmatic children" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "546" "paginaFinal" => "551" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Magáli Mocellin, Lidiane Alves de Azeredo Leitão, Patrícia Dias de Araújo, Marcus Herbert Jones, Renato Tetelbom Stein, Paulo Márcio Pitrez, Ana Paula Duarte de Souza, Leonardo Araújo Pinto" "autores" => array:8 [ 0 => array:3 [ "nombre" => "Magáli" "apellidos" => "Mocellin" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Lidiane Alves" "apellidos" => "de Azeredo Leitão" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Patrícia Dias" "apellidos" => "de Araújo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Marcus Herbert" "apellidos" => "Jones" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "Renato Tetelbom" "apellidos" => "Stein" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 5 => array:3 [ "nombre" => "Paulo Márcio" "apellidos" => "Pitrez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 6 => array:3 [ "nombre" => "Ana Paula Duarte" "apellidos" => "de Souza" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 7 => array:4 [ "nombre" => "Leonardo Araújo" "apellidos" => "Pinto" "email" => array:1 [ 0 => "leonardo.pinto@pucrs.br" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Escola de Medicina, Núcleo de Pediatria, Centro Infantil, Porto Alegre, RS, Brazil" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Escola de Saúde e Ciências da Vida, Centro Infant, Laboratório de Imunologia Clínica e Experimental, Porto Alegre, RS, Brazil" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 988 "Ancho" => 2925 "Tamanyo" => 171163 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Association between IL-10 gene SNP rs3024491 and levels of IL-10 protein (a), asthma severity (b) and Tregs cells frequency (c).</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">GG genotype, TG genotype, TT genotype; SNP, single nucleotide polymorphism; Tregs, regulatory T cells.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Asthma is a chronic, multifactorial, and polygenic disease caused by a complex combination of environmental stimuli, host factors, and genetic susceptibility. It affects more than 300 million people worldwide<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> and is the most common chronic non-communicable disease in children.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> It is well-known that asthma often begins in childhood but can occur at all ages and at any time throughout life.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Asthma presents higher incidence and prevalence in children, with morbidity and mortality rates higher in adults. Childhood asthma is more common in boys while adult asthma is more common in women.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In the last few decades, a wide variety of environmental determinants and modern lifestyles have contributed to important changes in the epidemiology of asthma, such as an increase in environmental pollutants, obesity, and westernization. The International Study of Asthma and Allergies in Childhood (ISAAC) has been the most standardized methodology to provide worldwide comparable information on the epidemiology of asthma in children and adolescents. The population of interest in Phases One and Three was schoolchildren aged 6–7 years and adolescents 13–14 years. The ISAAC Phase Three research included 1.2 million children from 233 centers in 98 countries. This important study showed great variability in the prevalence of asthma between regions, continents, countries, and centers in the same country.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The highest prevalence (≥20%) was generally observed in English speaking language countries, and in parts of Latin America.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> In Brazil, Phase Three of this study showed an average asthma prevalence of 24.3% (ranging from 16.5 to 31.2%) for children and 19% (11.8% and 30.5%) for adolescents, unrelated to socioeconomic status.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In addition to environmental stimuli, genetic factors have a strong influence on the etiology of asthma. Studies with mono and dizygotic twins have shown that asthma has a heritability of approximately 60%.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,6</span></a> Moreover, inflammatory cytokines produced by Th2 cells play an important role in asthma. However, other subtypes of CD4<span class="elsevierStyleSup">+</span> T cells are also involved in its pathogenesis.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Interleukin-10 (IL-10) is a pleiotropic cytokine with an important anti-inflammatory and immunoregulatory function, playing a protective role in asthma.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Low levels of IL-10 have been associated with asthma.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Also, IL-10 may potentiate the differentiation of regulatory T cells (Tregs).<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Some studies have shown changes in the number and function of Tregs in asthma.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11–15</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Single Nucleotide Polymorphisms (SNPs) have been related to asthma pathogenesis. The IL-10 gene is located at chromosome 1 (1q31-32), a region associated with asthma susceptibility. The SNPs of the IL-10 gene most studied are in the promoter region and comprise the variants rs1800896 (-1082A/G), rs1800871 (−819<span class="elsevierStyleHsp" style=""></span>T/C) and rs1800872 (-592A/C). These SNPs show linkage disequilibrium (LD) with other polymorphisms of the gene and have been reported to have a regulatory role on IL-10 expression.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Three meta-analysis studied these three polymorphisms in children and adults, but the results were inconclusive.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17–19</span></a> A recent meta-analysis evaluated the association between IL-10 promoter polymorphisms and the risk of pediatric asthma. The results of this study indicated that the IL-10 -1082<span class="elsevierStyleHsp" style=""></span>G/A polymorphism might be a risk factor for asthma in children.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Thus, the objective of this study was to evaluate the association between possible functional IL-10 polymorphisms, IL-10 expression, Tregs cells frequency, and asthma severity in a sample of children and adolescents.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Study design and population sample</span><p id="par0030" class="elsevierStylePara elsevierViewall">This is a nested case-control genetic association study. The study sample consisted of children and adolescents aged 8–14 from public schools. The study was stratified into three phases: 1. ISAAC questionnaire to assess the prevalence of asthma in schoolchildren; 2. Assessment of asthma control and severity through simple procedures such as Global Initiative for Asthma (GINA)<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> questionnaires, and a pulmonary function test; 3. Blood collection for evaluation of atopy with specific IgE for analysis of inflammatory markers and for genotyping in a case-control sub-sample.</p><p id="par0035" class="elsevierStylePara elsevierViewall">The ISAAC questionnaire was used to select the population of asthmatics. The control group included children from the same schools, without diagnosis of asthma (ISAAC questionnaire). Afterwards, the children diagnosed with asthma and selected controls underwent a series of evaluation procedures in phases 2 and 3: spirometry, tests for specific IgE and analyses of inflammatory markers. Finally, the samples were genotyped for IL-10 SNPs. The severity of asthma was defined according to the GINA guideline<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> and the subjects were classified as having mild, moderate and severe asthma.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Exclusion criteria included cardiovascular disease, immunodeficiencies, chronic respiratory diseases, recent asthma/rhinitis exacerbation, acute respiratory infections or use of systemic steroids in the last four weeks.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Assessment of atopy and lung function</span><p id="par0045" class="elsevierStylePara elsevierViewall">Atopy was defined by specific IgE (ImmunoCAP, Phadia AB, Uppsala, Sweden) for the aeroallergens (<span class="elsevierStyleItalic">Dermatofagoides pteronyssinus, Dermatofagoides farinae,</span> Dust and <span class="elsevierStyleItalic">Blomia tropicalis, Periplaneta americana</span>, dog and cat, fungi, pollen and grass). Children with a detection level of at least 0.35kU/L of any of the allergens tested were considered atopic.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Trained professionals performed spirometry (Koko equipment, Ferraris Respiratory, Louisville, CO, USA) according to the ERS/ATS guidelines.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> At least three acceptable tests were obtained before and after the use of a bronchodilator (salbutamol, 400<span class="elsevierStyleHsp" style=""></span>μg). The results of the variables forced expiratory volume in the 1<span class="elsevierStyleHsp" style=""></span>st second (FEV<span class="elsevierStyleInf">1</span>), forced vital capacity (FVC), FEV<span class="elsevierStyleInf">1</span>/FVC ratio and forced expiratory flow between 25% and 75% (FEF 25% -75%) were described into z scores according to reference values of the Global Lung Function Initiative (GLI 2012), adjusted for height, age and sex.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Selection of IL-10 polymorphisms</span><p id="par0055" class="elsevierStylePara elsevierViewall">IL-10 polymorphisms were initially selected by project database (version 28.0) in order to include the most frequent genetic variations.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> For the present study, we identified the SNPs rs1518111, rs3024490, rs3024496 and rs3024491, with minor allele frequency (MAF) of 42%, 40%, 31%, 28%, respectively.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Blood collection for gDNA extraction</span><p id="par0060" class="elsevierStylePara elsevierViewall">Blood samples were collected during visits at the outpatient clinic. Ten mL of blood was collected from each study participant. Aliquots of 1<span class="elsevierStyleHsp" style=""></span>mL were stored in a freezer (-20<span class="elsevierStyleHsp" style=""></span>°C) for later use in the extraction of genomic DNA (gDNA), following the technique of phenol/ chloroform/ isoamyl alcohol extraction (25: 24: 1), already described.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Genotyping</span><p id="par0065" class="elsevierStylePara elsevierViewall">Sample genotyping was performed using the Real-Time PCR (TaqMan-Applied Biosystems, Thermo Fisher Scientific, Waltham, MA, USA) following the manufacturer's instructions. 0.1<span class="elsevierStyleHsp" style=""></span>ng or 0.25<span class="elsevierStyleHsp" style=""></span>ng of gDNA were used for the real-time PCR reaction. The genotyping master mix, catalog 4371355 (Applied Biosystems, Thermo Fisher Scientific, Waltham, MA, USA) and the primers of IL-10, SNP genotyping assays rs1518111, rs3024490, rs3024496 and rs3024491 (Applied Biosystems, Thermo Fisher Scientific, Waltham, MA, USA) were used for genotyping with the support of the StepOne ™ Real-Time PCR System (Applied Biosystems, Thermo Fisher Scientific, Waltham, MA, USA). The data obtained from the amplification (threshold cycle-CT) were analyzed by the StepOne program (version 2.3). The result was expressed as a frequent homozygous, heterozygous, rare homozygous or indeterminate.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Analysis of regulatory T cell frequency and IL-10 production</span><p id="par0070" class="elsevierStylePara elsevierViewall">For analysis of regulatory T cell frequency, peripheral blood mononuclear cells were purified from 9<span class="elsevierStyleHsp" style=""></span>mL of whole blood using Histopaque-1077 separation gradient (Sigma-Aldrich Corporation, St Louis, MO, USA) and frozen at −80<span class="elsevierStyleHsp" style=""></span>°C. After, 2<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">5</span> cells were labeled with anti-CD4 PE Cy7 (clone SK3-BD Biosciences, Franklin Lakes, NJ, USA) and anti-CD25 APC H7 antibodies (clone M-A251-BD Biosciences, Franklin Lakes, NJ, USA) for 30<span class="elsevierStyleHsp" style=""></span>min. Cells were permeabilized using FoxP3 buffer (BD Biosciences, Franklin Lakes, NJ, USA) and then labeled with anti-FoxP3 Alexa Fluor®488 antibody (clone 259d/ C7, BD Biosciences, Franklin Lakes, NJ, USA) for 20<span class="elsevierStyleHsp" style=""></span>min at room temperature. The cells were analyzed by flow cytometry (FACS Canto II, BD Biosciences, Franklin Lakes, NJ, USA), and data were analyzed with FlowJo software (Tree Star, Ashland, OR, USA). Isotype control antibodies were used to exclude non-labeled cells specifically. For analysis of IL-10 production, peripheral blood mononuclear cells were purified and cultured with anti-CD3 and anti-CD28 antibody for 24<span class="elsevierStyleHsp" style=""></span>h, and the supernatant was collected and analyzed using CBA (BD Bioscience, Franklin Lakes, NJ, USA) by flow cytometry.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Statistical analysis</span><p id="par0075" class="elsevierStylePara elsevierViewall">The quantitative variables were evaluated using the Kolmogorov-Smirnov test. Data that presented normal distribution were presented in mean and standard deviation and asymmetric data, in median and interquartile range. The qualitative variables were expressed in absolute and relative frequency. The comparison between the quantitative data was performed by Student's <span class="elsevierStyleItalic">t</span>-test for independent samples or by the Mann-Whitney <span class="elsevierStyleItalic">U</span> test The categorical variables were compared using the Pearson Chi-Square Test. For analysis of Tregs cells frequency and IL-10 production, the GraphPad Prism 5 program (San Diego, CA, USA) was used. The other analyses and data processing were performed with SPSS version 18.0 (SPSS Inc., USA). Differences were considered significant when p<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05.</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Ethical aspects</span><p id="par0080" class="elsevierStylePara elsevierViewall">All guardians of the children and participants signed the informed consent. The identity of all the participants was kept confidential. First, the project was approved by the University Scientific Board (number 6.139). Then, the study was registered at the Brazilian Research Database called <span class="elsevierStyleItalic">Plataforma Brasil</span> - CAAE number 19835913.8.0000.5336 (<a href="http://plataformabrasil.saude.gov.br">http://plataformabrasil.saude.gov.br</a>), and approved by the Human Ethics Committee of the Institution, under the number 10/04978.</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Results</span><p id="par0085" class="elsevierStylePara elsevierViewall">In this genetic association study, 123 cases and 58 controls were included and genotyped (N<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>181). There was no significant difference between the groups regarding the variables age, sex and birth weight (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Patients with asthma presented atopy more frequently (75.6% vs 54.4%, p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.004) and reduction in some lung function, such as FEV<span class="elsevierStyleInf">1</span>/FVC (-0.50<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.91 vs -0.13<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.70, p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.013) and FEF25% -75% (-0.43<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.06 vs -0.00<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.91, p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.015). Patients with asthma also had greater frequency of the FoxP3 in CD4<span class="elsevierStyleSup">+</span> and CD25<span class="elsevierStyleSup">+</span> T cells, presenting a CD4<span class="elsevierStyleSup">+</span>CD25<span class="elsevierStyleSup">+</span>Foxp3<span class="elsevierStyleSup">+</span> median frequency of 1.38 (0.39–3.25) compared to controls 0.25 (0.02−0.52); p<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.0001 (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">Four common IL-10 SNPs (rs1518111, rs3024490, rs3024496 and rs3024491) were selected for genotyping. The frequencies of the rare alleles for each SNP were 38.6%; (A allele, rs1518111), 40.6% (G allele, rs3024490), 29.8%, (T allele, rs3024496), 27.4% (G allele, rs3024491) (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). The selected SNPs are in LD with other polymorphisms of the gene and represent a large part of the loci variations.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">The IL-10 SNP rs3024491 showed a trend for association with disease severity when assessed for frequency in patients with moderate asthma, mild asthma and controls (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>b). However, when we analyzed mild asthmatic patients and controls versus moderate asthma, IL-10 rs3024491 SNP showed a significant association with asthma severity, presenting a higher frequency of T allele in patients in the moderate asthma group versus mild asthma and controls (71. 4% vs. 48.5%, chi-square test; p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.042).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">In the analysis with a dominant model, TT genotype (rs3024491) was shown to be associated with a reduction in IL-10 levels; p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.01 (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>a). In this same model, the TT genotype of the variant rs3024491 was shown to be more frequent in patients with moderate asthma than in controls and patients with mild asthma (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>b). Finally, the same rs3024491 TT genotype also demonstrated association with increased frequency of regulatory T cells; p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.01 (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>c). The variant rs3024496 showed an association only with increased frequency of Tregs cells (p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.01) in the C allele. The other variants of the IL-10 gene, rs1518111 and rs3024490, were not significantly associated with increased Tregs cells.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Discussion</span><p id="par0105" class="elsevierStylePara elsevierViewall">In this study, the rs3024491 variant of the IL-10 gene showed the most consistent and significant findings. The T allele of variant rs3024491 of the IL-10 gene showed association with asthma severity and was associated with lower expression of IL-10. This polymorphism (rs3024491) may influence the IL-10 expression or function. In addition to the association with asthma severity (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>b), this polymorphism also demonstrated to influence Tregs cell frequency (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>c).</p><p id="par0110" class="elsevierStylePara elsevierViewall">Our study also showed that children with asthma had a higher percentage of Tregs cells in peripheral blood than controls; p<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.0001 (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). In accordance with our findings, a few studies observed an increased frequency of Tregs cells in asthmatics compared to controls.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11–13</span></a> Raedler et al. also found increased Tregs cells in atopic asthmatics compared to healthy controls. This increase of Tregs cells in asthmatic patients is probably due to a mechanism of counterbalance, wherein an inflamed environment, the immune system reacts producing more Tregs to counterbalance or contain the inflammation.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> On the other hand, other studies show lower percentage of Tregs cells in asthmatic children.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14,15</span></a> Further studies are needed to confirm this hypothesis.</p><p id="par0115" class="elsevierStylePara elsevierViewall">IL-10 polymorphisms have been extensively studied in several inflammatory and auto-immune diseases. Associations of these three variants of the IL-10 gene with rheumatoid arthritis,<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> systemic lupus erythematosus,<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Crohn's disease,<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> and psoriasis<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> have been described. Some studies have identified an association between IL-10 gene polymorphisms and asthma risk, but the results were inconclusive. Three previous meta-analyses analyzed polymorphisms in the IL-10 gene promoter region (-1082/ -592/-819) and the risk of asthma.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17–19</span></a> Nie et al. evaluated 18 case-control studies (4478 asthmatics and 4803 controls) and found significant associations between the -1082A/G and -592A/C polymorphisms of the IL-10 gene and the risk of asthma in Asians and Caucasians. Individuals AA homozygosity (-1082A/G, in LD with rs3024491) had a 27% increase in disease risk. Carriers of the A allele in the -592A/C polymorphism also had an increased risk of asthma.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Hyun et al. evaluated 11 studies (2215 asthmatics and 2170 controls). Three of these studies were conducted in the European population and eight in the Asian population. Four studies were conducted only with children and an additional four with children and adults. This meta-analysis also demonstrated that the -1082<span class="elsevierStyleHsp" style=""></span>G/A polymorphism confer susceptibility to asthma. The polymorphisms -592C/A, and -819C/T were not associated with the disease.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> In the meta-analysis of Zheng et al., 23 studies (4716 asthmatics and 5093 controls) were evaluated. In the 23 studies, Asian, Caucasian and African population samples were analyzed. This meta-analysis found that the promoter polymorphisms -1028A/G and -592A/C are probably associated with asthma susceptibility, especially in Asian samples with atopic asthma.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Interestingly, there are high levels of LD between the promoter polymorphisms and the variants evaluated in our study (especially -1082 A and rs3024491<span class="elsevierStyleHsp" style=""></span>T). The IL-10 gene is highly polymorphic and several variations within it or close to it may influence the IL-10 expression.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> The variant rs3024491 was shown to be approximately 100% in LD with the promoter region variant, rs1800896 (-1082A/G).<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> Therefore, rare alleles may have the same functional consequences measured by the outcomes. Thus, one may suspect that only one of them causes the final effect, but the association between SNPs and asthma is probably the same. Most genetic association studies were performed with IL-10 promoter variants. In our study, we used four SNPs of the IL-10 gene that had high minor allele frequency (MAF) and were distributed along the gene structure. Some of them (especially rs3024491) are in LD with the IL-10 promoter SNPs.</p><p id="par0125" class="elsevierStylePara elsevierViewall">This study presented some limitations and sample size is probably the most important. However, the consistency of the association results found at different levels (genetics, IL-10 expression, Tregs and phenotype) demonstrate the strength and possible impact of the result, despite the small sample for a genetic association study. Another limitation is that we did not have patients with severe asthma and severe therapy-resistant asthma in the samples. A further possible limitation is that the Tregs cell analysis was performed only on peripheral blood. Ideally, biological samples should be taken directly at the site of inflammation, in bronchoalveolar lavage (BAL) or through bronchial biopsy. However, this type of sample requires an invasive procedure and has been often denied by ethics committees.</p><p id="par0130" class="elsevierStylePara elsevierViewall">In conclusion, IL-10 genetic polymorphisms may be one of the mechanisms related to the variation of the severity of asthma. Its association with asthma outcomes may be of great clinical relevance and may be a specific target for therapeutic strategies. Our results suggest that moderate asthma is associated with a higher frequency rs3024491<span class="elsevierStyleHsp" style=""></span>T. We showed that the rs3024491<span class="elsevierStyleHsp" style=""></span>T is associated with a reduction in IL-10 production, a high frequency of moderate asthma and a consequent increase in Tregs cells frequency. However, there is a need for more genetic association studies in different population samples.</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Funding</span><p id="par0135" class="elsevierStylePara elsevierViewall">This study was financed by the <span class="elsevierStyleItalic">Conselho Nacional de Desenvolvimento Científico e Tecnológico</span> (CNPq) and <span class="elsevierStyleItalic">Coordenação de Aperfeiçoamento de Pessoal de Nível Superior</span> – Brazil (CAPES) – Finance Code 001.</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conflicts of interest</span><p id="par0140" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres1572374" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1416574" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:8 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Study design and population sample" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Assessment of atopy and lung function" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Selection of IL-10 polymorphisms" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Blood collection for gDNA extraction" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Genotyping" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Analysis of regulatory T cell frequency and IL-10 production" ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Statistical analysis" ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Ethical aspects" ] ] ] 4 => array:2 [ "identificador" => "sec0055" "titulo" => "Results" ] 5 => array:2 [ "identificador" => "sec0060" "titulo" => "Discussion" ] 6 => array:2 [ "identificador" => "sec0065" "titulo" => "Funding" ] 7 => array:2 [ "identificador" => "sec0070" "titulo" => "Conflicts of interest" ] 8 => array:2 [ "identificador" => "xack555160" "titulo" => "Acknowledgments" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-04-30" "fechaAceptado" => "2020-11-05" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1416574" "palabras" => array:6 [ 0 => "Asthma" 1 => "Children and adolescents" 2 => "Immunology" 3 => "Interleukin-10" 4 => "Polymorphism" 5 => "Regulatory T cells" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">The aim of this study was to evaluate the association between possible functional interleukin-10 (IL-10) polymorphisms, IL-10 expression and regulatory T cells (Tregs) frequency, and/or asthma severity in a sample of children and adolescents.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">This is a nested case-control genetic association study. The study sample consisted of children and adolescents aged 8–14 from public schools. Four polymorphisms of the IL-10 gene (rs1518111, rs3024490, rs3024496, rs3024491) were genotyped in asthmatic subjects and controls using real-time PCR. Tregs cells and IL-10 were analyzed in peripheral blood mononuclear cells by flow cytometry. The severity of asthma was defined according to the Global Initiative for Asthma (GINA) guideline.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">One hundred twenty-three asthmatic subjects and fifty-eight controls participated in the study. The single nucleotide polymorphism (SNP) rs3024491 (T allele) showed association with asthma severity, presenting a higher frequency in patients in the moderate asthma group. The T allele of variant rs3024491 also showed an association with reduced IL-10 levels (p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.01) and with increased Tregs frequency (p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.01). The other variants did not present consistent associations.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Our results suggest that moderate asthma is associated with a higher frequency of the T allele in the SNP rs3024491. In addition, the variant rs3024491 (TT) was associated with a reduction in IL-10 production and an increased percentage of Tregs cells, suggesting possible mechanisms that influence asthma severity.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] ] "multimedia" => array:3 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 988 "Ancho" => 2925 "Tamanyo" => 171163 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Association between IL-10 gene SNP rs3024491 and levels of IL-10 protein (a), asthma severity (b) and Tregs cells frequency (c).</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">GG genotype, TG genotype, TT genotype; SNP, single nucleotide polymorphism; Tregs, regulatory T cells.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">FEV<span class="elsevierStyleInf">1</span>, forced expiratory volume in the 1<span class="elsevierStyleHsp" style=""></span>st second; FVC, forced vital capacity; FEV<span class="elsevierStyleInf">1</span>/FVC, Tiffenou index; FEF (25−75%), forced expiratory flow between 25 and 75%; CD4<span class="elsevierStyleSup">+</span>CD25<span class="elsevierStyleSup">+</span>FoxP3<span class="elsevierStyleSup">+</span>, Treg cells.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Variables \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Asthma(n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>123) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Controls(n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>58) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">p \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age, years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11.17<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.09 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11.28<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.537 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Male gender, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">63 (51.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">27 (46.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.558 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Birth weight, g \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.40<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.57 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.29<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.45 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.228 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Atopy, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">90 (75.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31 (54.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.004<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">FEV<span class="elsevierStyleInf">1</span>/FVC, Z score \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−0.50<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.91 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−0.13<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.70 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.013<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">FEF<span class="elsevierStyleInf">25−75%,</span> Z score \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−0.43<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.06 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">−0.00<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.91 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.015<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CD4<span class="elsevierStyleSup">+</span>CD25<span class="elsevierStyleSup">+</span>FoxP3<span class="elsevierStyleSup">+</span>,(% of cells) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.38 (0.39–3.25) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25 (0.02 – 0.52) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">< 0.0001<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2693998.png" ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">chi-square test (absolute and relative).</p>" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Student <span class="elsevierStyleItalic">t</span>-test (mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD).</p>" ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Mann-Whitney <span class="elsevierStyleItalic">U</span> test (median and interquartile range).</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Descriptive data of the sample comparing the study group versus the control group.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">HapMap, Haplotype Map; MAF, Minor Allele Frequency; SNP, Single Nucleotide Polymorphism.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">SNP \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Position on the chromosome \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gene location \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Allele \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MAF (HapMap) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MAF (Sample) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs1518111 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">206944645 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intron 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">A/G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">38.62 % (A) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs3024490 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">206945311 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intron 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">G/T \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">40.65% (G) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs3024496 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">206941864 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Exon 5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C/T \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">29.83% (T) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs3024491 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">206771701 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intron 2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">G/T \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">27.45% (G) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2693999.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">IL-10 gene variants included in the study.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:32 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "The Global Asthma Report 2018. Auckland, New Zealand: Global Asthma Network, 2018. [cited 14 July 2020]. Available from: www.globalasthmareport.org." ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Global variation in the prevalence and severity of asthma symptoms: phase three of the International Study of Asthma and Allergies in Childhood (ISAAC)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C.K. Lai" 1 => "R. Beasley" 2 => "J. Crane" 3 => "S. Foliaki" 4 => "J. Shah" 5 => "S. Weiland" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/thx.2008.106609" "Revista" => array:6 [ "tituloSerie" => "Thorax." 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| Year/Month | Html | Total | |
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| 2024 November | 6 | 4 | 10 |
| 2024 October | 28 | 21 | 49 |
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