Original article
Alpha-1 antitrypsin deficiency and Pi*S and Pi*Z SERPINA1 variants are associated with asthma exacerbations
Elena Martín-Gonzáleza, José M. Hernández-Pérezb,c, José A. Pérez Péreza,d, Javier Pérez-Garcíaa, Esther Herrera-Luisa, Ruperto González-Péreze,f, Orelvis González-Gonzálezg, Elena Mederos-Luise, Inmaculada Sánchez-Machíne, Paloma Poza-Guedese,f, Olaia Sardónh,i, Paula Corcuerah, María J. Cruzj,k, Francisco J. González-Barcalal, Carlos Martínez-Riverak,m, Joaquim Mullolk,n, Xavier Muñozj,k, José M. Olaguibelk,o, Vicente Plazak,p, Santiago Quircek,q..., Antonio Valerok,r, Joaquín Sastrek,s, Javier Korta-Muruah, Victoria del Pozok,t, Fabián Lorenzo-Díaza,d, Jesús Villark,u, María Pino-Yanesa,k,v,
, Mario A. González-Carracedoa,d,
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Corresponding author
mdelpino@ull.edu.es
Corresponding authors at: Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology, and Genetics, Universidad de La Laguna (ULL). Apartado 456, La Laguna, 38200 Santa Cruz de Tenerife, Spain.
Corresponding authors at: Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology, and Genetics, Universidad de La Laguna (ULL). Apartado 456, La Laguna, 38200 Santa Cruz de Tenerife, Spain.
Corresponding author
mgonzalc@ull.edu.es
Corresponding authors at: Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology, and Genetics, Universidad de La Laguna (ULL). Apartado 456, La Laguna, 38200 Santa Cruz de Tenerife, Spain.
Corresponding authors at: Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology, and Genetics, Universidad de La Laguna (ULL). Apartado 456, La Laguna, 38200 Santa Cruz de Tenerife, Spain.
a Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), 38200 La Laguna, Tenerife, Spain
b Department of Respiratory Medicine, Hospital Universitario de N.S de Candelaria, 38010 Santa Cruz de Tenerife, Spain
c Respiratory Medicine, Hospital Universitario de La Palma, 38713 Breña Alta, Santa Cruz de Tenerife, Spain
d Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna (ULL), La Laguna, Tenerife, Spain
e Allergy Department, Hospital Universitario de Canarias, 38320 La Laguna, Tenerife, Spain
f Severe Asthma Unit, Allergy Department, Hospital Universitario de Canarias, 38320 La Laguna, Spain
g Hospital Universitario de La Palma, 38713 Breña Alta, Santa Cruz de Tenerife, Spain
h Division of Pediatric Respiratory Medicine, Hospital Universitario Donostia, San Sebastián, Spain
i Department of Pediatrics, University of the Basque Country (UPV/EHU), San Sebastián, Spain
j Department of Respiratory Medicine, Hospital Vall d'Hebron, Barcelona, Spain
k CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
l Department of Respiratory Medicine, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, La Coruña, Spain
m Department of Respiratory Medicine, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain
n Rhinology Unit & Smell Clinic, ENT Department, Clinical and Experimental Respiratory Immunoallergy (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
o Department of Allergy, Hospital Universitario de Navarra, Pamplona, Navarra, Spain
p Department of Respiratory Medicine, Hospital de la Santa Creu i Sant Pau, Instituto de Investigación Biomédica Sant Pau (IIB Sant Pau), Barcelona, Spain
q Department of Allergy, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain
r Allergy Unit & Severe Asthma Unit, Pneumonology and Allergy Department, Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain
s Department of Allergy, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
t Department of Immunology, Instituto de Investigación Sanitaria Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
u Multidisciplinary Organ Dysfunction Evaluation Research Network (MODERN), Research Unit, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain
v Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna (ULL), San Cristóbal de La Laguna, Tenerife, Spain
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"apellidos" => "González-Carracedo" "email" => array:1 [ 0 => "mgonzalc@ull.edu.es" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0001" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0004" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0001" ] ] ] ] "afiliaciones" => array:22 [ 0 => array:3 [ "entidad" => "Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), 38200 La Laguna, Tenerife, Spain" "etiqueta" => "a" "identificador" => "aff0001" ] 1 => array:3 [ "entidad" => "Department of Respiratory Medicine, Hospital Universitario de N.S de Candelaria, 38010 Santa Cruz de Tenerife, Spain" "etiqueta" => "b" "identificador" => "aff0002" ] 2 => array:3 [ "entidad" => "Respiratory Medicine, Hospital Universitario de La Palma, 38713 Breña Alta, Santa Cruz de Tenerife, Spain" "etiqueta" => "c" "identificador" => "aff0003" ] 3 => array:3 [ "entidad" => "Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna (ULL), La Laguna, Tenerife, Spain" "etiqueta" => "d" "identificador" => "aff0004" ] 4 => array:3 [ "entidad" => "Allergy Department, Hospital Universitario de Canarias, 38320 La Laguna, Tenerife, Spain" "etiqueta" => "e" "identificador" => "aff0005" ] 5 => array:3 [ "entidad" => "Severe Asthma Unit, Allergy Department, Hospital Universitario de Canarias, 38320 La Laguna, Spain" "etiqueta" => "f" "identificador" => "aff0006" ] 6 => array:3 [ "entidad" => "Hospital Universitario de La Palma, 38713 Breña Alta, Santa Cruz de Tenerife, Spain" "etiqueta" => "g" "identificador" => "aff0007" ] 7 => array:3 [ "entidad" => "Division of Pediatric Respiratory Medicine, Hospital Universitario Donostia, San Sebastián, Spain" "etiqueta" => "h" "identificador" => "aff0008" ] 8 => array:3 [ "entidad" => "Department of Pediatrics, University of the Basque Country (UPV/EHU), San Sebastián, Spain" "etiqueta" => "i" "identificador" => "aff0009" ] 9 => array:3 [ "entidad" => "Department of Respiratory Medicine, Hospital Vall d'Hebron, Barcelona, Spain" "etiqueta" => "j" "identificador" => "aff0010" ] 10 => array:3 [ "entidad" => "CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain" "etiqueta" => "k" "identificador" => "aff0011" ] 11 => array:3 [ "entidad" => "Department of Respiratory Medicine, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, La Coruña, Spain" "etiqueta" => "l" "identificador" => "aff0012" ] 12 => array:3 [ "entidad" => "Department of Respiratory Medicine, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain" "etiqueta" => "m" "identificador" => "aff0013" ] 13 => array:3 [ "entidad" => "Rhinology Unit & Smell Clinic, ENT Department, Clinical and Experimental Respiratory Immunoallergy (IDIBAPS), Universitat de Barcelona, Barcelona, Spain" "etiqueta" => "n" "identificador" => "aff0014" ] 14 => array:3 [ "entidad" => "Department of Allergy, Hospital Universitario de Navarra, Pamplona, Navarra, Spain" "etiqueta" => "o" "identificador" => "aff0015" ] 15 => array:3 [ "entidad" => "Department of Respiratory Medicine, Hospital de la Santa Creu i Sant Pau, Instituto de Investigación Biomédica Sant Pau (IIB Sant Pau), Barcelona, Spain" "etiqueta" => "p" "identificador" => "aff0016" ] 16 => array:3 [ "entidad" => "Department of Allergy, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain" "etiqueta" => "q" "identificador" => "aff0017" ] 17 => array:3 [ "entidad" => "Allergy Unit & Severe Asthma Unit, Pneumonology and Allergy Department, Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain" "etiqueta" => "r" "identificador" => "aff0018" ] 18 => array:3 [ "entidad" => "Department of Allergy, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain" "etiqueta" => "s" "identificador" => "aff0019" ] 19 => array:3 [ "entidad" => "Department of Immunology, Instituto de Investigación Sanitaria Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain" "etiqueta" => "t" "identificador" => "aff0020" ] 20 => array:3 [ "entidad" => "Multidisciplinary Organ Dysfunction Evaluation Research Network (MODERN), Research Unit, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain" "etiqueta" => "u" "identificador" => "aff0021" ] 21 => array:3 [ "entidad" => "Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna (ULL), San Cristóbal de La Laguna, Tenerife, Spain" "etiqueta" => "v" "identificador" => "aff0022" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0001" "etiqueta" => "⁎" "correspondencia" => "Corresponding authors at: Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology, and Genetics, Universidad de La Laguna (ULL). Apartado 456, La Laguna, 38200 Santa Cruz de Tenerife, Spain." ] ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0001" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0007">Introduction</span><p id="para0005" class="elsevierStylePara elsevierViewall">Asthma is a common chronic respiratory disease characterized by episodes of wheezing, coughing, shortness of breath, and airflow limitation, which vary over time and intensity.<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a> Moreover, about 75% of asthma patients also present atopy.<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a> Asthma is considered a complex disease with a multifactorial background, in which genetic factors are known to play a significant role, with heritability ranging between 35% and 95%.<a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a> Among European countries, Spain exhibits variation in asthma prevalence, the Canary Islands having the highest prevalence (18%) compared to the rest of the Spanish regions (4% on average).<a class="elsevierStyleCrossRefs" href="#bib0003"><span class="elsevierStyleSup">3-5</span></a></p><p id="para0006" class="elsevierStylePara elsevierViewall">While asthma symptoms may resolve spontaneously or in response to preventive medication, some patients with asthma may experience episodic flare-ups, known as exacerbations. The most widely used definition of asthma exacerbations comprises the administration of systemic corticosteroids, emergency room visits, or hospitalizations.<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a> These episodes not only negatively impact the patient's quality of life, long-term lung function, work productivity, and/or school attendance, but can also be life-threatening.<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a> Likewise, the associated socioeconomic burden extends to caregivers, the healthcare system, and the whole community.<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a></p><p id="para0007" class="elsevierStylePara elsevierViewall">Among the asthma-associated genetic factors, the serpin family A member 1 gene (<span class="elsevierStyleItalic">SERPINA1</span>) participates in the development of several respiratory diseases, including asthma,<a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a> and it is also associated with atopy in asthma patients.<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a><span class="elsevierStyleItalic">SERPINA1</span> gene encodes alpha-1 antitrypsin (AAT), the most abundant antiprotease in the human serum,<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a> plays a fundamental role as a serine protease inhibitor, protecting the lower respiratory tract against neutrophil elastase, in addition to having other immunomodulatory and anti-inflammatory properties.<a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a> When serum levels of AAT decrease below a protective threshold,<a class="elsevierStyleCrossRef" href="#bib0012"><span class="elsevierStyleSup">12</span></a> reduced protection against elastase activity in the lung could lead to alveoli degradation.<a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a></p><p id="para0008" class="elsevierStylePara elsevierViewall">Different <span class="elsevierStyleItalic">SERPINA1</span> gene variants are known to produce AAT deficiency (AATD), which is considered one of the most common hereditary disorders of European descent populations.<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a> AATD is diagnosed by measurement of AAT serum levels and characterization of AAT isoforms by protein isoelectric focusing (Pi*AAT phenotypes). Pi*M is considered the reference AAT variant, associated with normal AAT levels, while two canonical Pi*AAT variants, known as Pi*Z and Pi*S, have been classically associated with AATD.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleItalic">Pi*Z</span> variant is related to severe AATD,<a class="elsevierStyleCrossRef" href="#bib0016"><span class="elsevierStyleSup">16</span></a> and is caused by a missense mutation (p.Glu342Lys, rs28929474) in the <span class="elsevierStyleItalic">SERPINA1</span> gene, with a minor allele frequency (MAF) < 1%, reaching the highest MAF in European populations (2%). <span class="elsevierStyleItalic">Pi*S</span> variant is related to moderate AATD and is produced by another missense mutation of the <span class="elsevierStyleItalic">SERPINA1</span> gene (p.Glu264Val, rs17580) with the highest MAF in European-descent populations (6%)<a class="elsevierStyleCrossRef" href="#bib0017"><span class="elsevierStyleSup">17</span></a>. Interestingly, the Spanish population shows the highest allele frequency for this polymorphism among the populations from the 1000 Genomes project (9.3%).<a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a></p><p id="para0009" class="elsevierStylePara elsevierViewall">To the best of our knowledge, the association of <span class="elsevierStyleItalic">SERPINA1</span> classic genetic variants with asthma exacerbations has not been studied yet. In this sense, populations of the Canary Islands are interesting due to the elevated asthma prevalence in this region, and the unique genomic features found in the different islands.<a class="elsevierStyleCrossRef" href="#bib0019"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">20</span></a> Indeed, novel defective <span class="elsevierStyleItalic">SERPINA1</span> alleles have been characterized in La Palma island,<a class="elsevierStyleCrossRef" href="#bib0021"><span class="elsevierStyleSup">21</span></a> where frequencies of <span class="elsevierStyleItalic">Pi*S</span> and <span class="elsevierStyleItalic">Pi*Z</span> alleles are higher than expected.<a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a> In the present work, we performed the first genetic association study of <span class="elsevierStyleItalic">SERPINA1</span> variants with asthma exacerbations, considering subjects with asthma from La Palma Island as a model. In addition, were attempted to replicate our findings in Canary Islanders, mainland Spanish subjects, and other European populations.</p></span><span id="sec0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0008">Methods</span><span id="sec0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0009">Discovery and replication populations</span><p id="para0010" class="elsevierStylePara elsevierViewall">Patients enrolled in <span class="elsevierStyleItalic">Characterizing Alpha-1-Antitrypsin Deficiency in patients with pulmonary diseases</span> (CAATDPUL)<a class="elsevierStyleCrossRef" href="#bib0023"><span class="elsevierStyleSup">23</span></a> study were included in the discovery cohort. The CAATDPUL study was approved by the Ethics Committee of La Palma General Hospital, with the reference/date HGLaPalma_2010_7/ September 26, 2010. Patients enrolled in The <span class="elsevierStyleItalic">Genomics and Metagenomics of Asthma Severity</span> (GEMAS)<a class="elsevierStyleCrossRef" href="#bib0024"><span class="elsevierStyleSup">24</span></a> cohort and in the <span class="elsevierStyleItalic">Study of the mechanisms involved in the genesis and evolution of asthma</span> (MEGA)<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">25</span></a> were included in the replication phase. The GEMAS and MEGA studies were approved by the respective Clinical Research Ethics Committee of participating centers (approvals 29/17 for the Canary Islands hospitals and PI2019077 Hospital Universitario Donostia in the GEMAS study, and EOH 2014/48 from Hospital Universitario Fundación Jiménez Díaz in the MEGA study). All patients under 18 years old provided their assent (with signature for those aged 12–17 years), and one of their legal guardians signed the informed consent. All participants older than 18 years old provided their informed consent to participate in the study. A full description of each cohort can be found elsewhere.<a class="elsevierStyleCrossRefs" href="#bib0023"><span class="elsevierStyleSup">23-25</span></a></p><p id="para0011" class="elsevierStylePara elsevierViewall">Details related to AAT quantification, genomic DNA extraction, genotyping, and quality control (e-Appendix 1) are described in the Supplementary Material. Moreover, the open-access integrative resource <span class="elsevierStyleItalic">Open Targets Genetics (version 7)</span>,<a class="elsevierStyleCrossRef" href="#bib0026"><span class="elsevierStyleSup">26</span></a> which integrates summary results of genetic association studies of the GWAS Catalog, FinnGen, and UK Biobank studies, was used for <span class="elsevierStyleItalic">in silico</span> assessment of replication in other European populations.</p></span><span id="sec0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0010">Statistical analyses</span><p id="para0012" class="elsevierStylePara elsevierViewall">Subjects who experienced hospitalizations, emergency room visits, and/or oral corticosteroids in the last 12 months were selected as cases.<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a> In contrast, controls did not experience any of these events for the same period. The definition of exacerbations was identical for the discovery and replication populations. The association of AATD, AAT levels, or <span class="elsevierStyleItalic">SERPINA1</span> genetic variants with asthma exacerbations was tested through logistic regression models following an additive genetic model for the rs17580 and rs28929474 polymorphisms.</p><p id="para0013" class="elsevierStylePara elsevierViewall">Deficient <span class="elsevierStyleItalic">SERPINA1</span> genotypes (<span class="elsevierStyleItalic">Pi*MS, Pi*SS, Pi*MZ, Pi*SZ,</span> and <span class="elsevierStyleItalic">Pi*ZZ</span>) were compared with the reference genotype (<span class="elsevierStyleItalic">Pi*MM</span>). AATD was defined as a binary variable based on the AAT protein levels (<80 or ≥80 mg/dl).<a class="elsevierStyleCrossRef" href="#bib0027"><span class="elsevierStyleSup">27</span></a> AAT levels were also analyzed as a continuous variable with a Box-Cox normalization to obtain a normal distribution. Age, sex, and PCs from the genotype data that summarized most of the genetic variability in allele frequencies were included in the regression models as covariates. The 29 subjects simultaneously genotyped from dried blood spots and fresh blood were considered in CAATDPUL and removed from further analysis in GEMAS. Statistical significance was declared after applying a Bonferroni correction for the two genetic variants tested (<span class="elsevierStyleItalic">p</span>-value ≤ 0.025). Sensitivity analyses were conducted and are explained in e-Appendix 2.</p><p id="para0014" class="elsevierStylePara elsevierViewall">In the replication phase, association analyses were performed following the same methodology as in the discovery phase. In the GEMAS study, replication analyses were conducted stratifying the subjects by having or not two generations of Canary Islander origin. All analyses were performed using the statistical program R 3.6.3.<a class="elsevierStyleCrossRef" href="#bib0028"><span class="elsevierStyleSup">28</span></a></p></span></span><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0011">Results</span><span id="sec0006" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0012">Quality control, demographic, and clinical characteristics of all study populations</span><p id="para0015" class="elsevierStylePara elsevierViewall">After QC, 369 subjects from CAATDPUL, 383 from GEMAS, and 138 from MEGA populations were retained for subsequent analyses (e-Appendix 2, e-Figure 1). For subjects simultaneously genotyped from dried blood spots and fresh blood, we observed a concordance rate of 99.2%, confirming the suitability of dried blood spot samples for genome-wide genotyping without loss of accuracy and coverage (total genotyping rate of 99.7%). The main demographic and clinical characteristics of the discovery population are shown in <a class="elsevierStyleCrossRef" href="#tbl0001">Table 1</a>. No significant differences were found between cases and controls for age, sex, smoking behavior, lung function measurements, and total IgE levels. Cases showed higher eosinophils levels (<span class="elsevierStyleItalic">p</span>-value=0.007), had a higher proportion of subjects requiring inhaled corticosteroids (ICS) (<span class="elsevierStyleItalic">p</span>-value=0.022), and more patients with AATD in comparison with controls (<span class="elsevierStyleItalic">p</span>-value=0.007). In contrast, controls showed higher AAT levels when subjects with chronic airway obstruction were excluded (<span class="elsevierStyleItalic">p</span>-value=0.038) and a higher proportion of controlled asthma (<span class="elsevierStyleItalic">p</span>-value<0.01).</p><elsevierMultimedia ident="tbl0001"></elsevierMultimedia><p id="para0016" class="elsevierStylePara elsevierViewall">Demographic and clinical characteristics available for the two replication datasets (GEMAS and MEGA) are shown in <a class="elsevierStyleCrossRef" href="#tbl0002">Table 2</a>. In the GEMAS whole study, controls were slightly older than cases (<span class="elsevierStyleItalic">p</span>-value=0.04), while this difference was not found in subjects with two generations of Canary Islands origin. In contrast, in the MEGA study, cases were older than controls (<span class="elsevierStyleItalic">p</span>-value=0.007). Similar to CAATDPUL, GEMAS cases had a higher proportion of ICS use than controls (<span class="elsevierStyleItalic">p</span>-value<0.001), but no difference was observed in MEGA. In addition, cases showed lower pulmonary function than controls in the MEGA population (<span class="elsevierStyleItalic">p</span>-value<0.01). Finally, cases presented a higher proportion of asthma partially or poorly controlled in all populations (<span class="elsevierStyleItalic">p</span>-value<0.001).</p><elsevierMultimedia ident="tbl0002"></elsevierMultimedia></span><span id="sec0007" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0013">Association analysis in the discovery phase</span><p id="para0017" class="elsevierStylePara elsevierViewall">In the CAATDPUL cohort, a significant association of AAT protein levels was found, showing higher levels a protective effect against asthma exacerbation (odds ratio [OR]= 0.72, 95%CI=0.57–0.91, <span class="elsevierStyleItalic">p</span>-value=0.005). AATD was associated with an increased risk for asthma exacerbations (OR=5.18, 95% CI: 1.58–16.92, <span class="elsevierStyleItalic">p</span>-value=0.007). <span class="elsevierStyleItalic">SERPINA1</span> deficient variants <span class="elsevierStyleItalic">Pi*S</span> (OR=2.38, 95%CI=1.40–4.04, <span class="elsevierStyleItalic">p</span>-value=0.001) and <span class="elsevierStyleItalic">Pi*Z</span> (OR=3.49, 95%CI=1.55–7.85, <span class="elsevierStyleItalic">p</span>-value=0.003) were associated with asthma exacerbations (<a class="elsevierStyleCrossRef" href="#tbl0003">Table 3</a>). Likewise, the associations of <span class="elsevierStyleItalic">Pi*S</span> and <span class="elsevierStyleItalic">Pi*Z</span> alleles, AAT levels, and AATD with asthma exacerbations were consistent in the analyses that excluded subjects with chronic airflow obstruction. Moreover, all the associations retained their significance in models adjusted for smoking history, BMI, and ICS use (e-Table 1).</p><elsevierMultimedia ident="tbl0003"></elsevierMultimedia><p id="para0018" class="elsevierStylePara elsevierViewall">In the assessment of alternative outcomes, associations were found (e-Table 2) for AATD with ACT level (<span class="elsevierStyleItalic">p</span>-value=0.017) and <span class="elsevierStyleItalic">Pi*MS</span> genotype with asthma severity (<span class="elsevierStyleItalic">p</span>-value=0.014), but not for other variables.</p></span><span id="sec0008" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0014">Association analysis in the replication phase</span><p id="para0019" class="elsevierStylePara elsevierViewall">We next examined deficient variants for association with asthma exacerbations in the replication cohorts. The association between the <span class="elsevierStyleItalic">Pi*Z</span> variant and asthma exacerbations was nominally replicated in a subset of GEMAS patients that had four grandparents from the Canary Islands (OR=3.79, 95%CI=1.16–12.43, <span class="elsevierStyleItalic">p</span>-value=0.028) (<a class="elsevierStyleCrossRef" href="#tbl0004">Table 4</a>). However, the association of <span class="elsevierStyleItalic">Pi*S</span> variant with asthma exacerbations was not significant in this subset of patients. Moreover, none of the associations between deficient variants and asthma exacerbations were validated when all subjects from GEMAS or MEGA were considered (<a class="elsevierStyleCrossRef" href="#tbl0004">Table 4</a>).</p><elsevierMultimedia ident="tbl0004"></elsevierMultimedia><p id="para0020" class="elsevierStylePara elsevierViewall">An <span class="elsevierStyleItalic">in-silico</span> assessment in other European populations via <span class="elsevierStyleItalic">Open Targets Genetics</span> revealed a significant association of the <span class="elsevierStyleItalic">Pi*Z</span> variant with asthma (OR=2.35, <span class="elsevierStyleItalic">p</span>-value=2.3 × 10<span class="elsevierStyleSup">−3</span>) and only in the Finnish population (OR=1.16, <span class="elsevierStyleItalic">p</span>-value=1.1 × 10<span class="elsevierStyleSup">−4</span>).<a class="elsevierStyleCrossRef" href="#bib0026"><span class="elsevierStyleSup">26</span></a> In addition, a significant association of <span class="elsevierStyleItalic">Pi*Z</span> with asthma hospitalizations (OR=1.12, <span class="elsevierStyleItalic">p</span>-value=6.5 × 10<span class="elsevierStyleSup">−3</span>) in Finnish population<a class="elsevierStyleCrossRef" href="#bib0026"><span class="elsevierStyleSup">26</span></a> was found but not in other European populations.</p></span></span><span id="sec0009" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0015">Discussion</span><p id="para0021" class="elsevierStylePara elsevierViewall">To the best of our knowledge, this is the first study examining the association of AATD and <span class="elsevierStyleItalic">SERPINA1</span> variants with asthma exacerbations. A higher level of AAT was associated with a protective effect for asthma exacerbations among Canary Islanders from La Palma. In addition, AATD, considered when serum protein level was below 80 mg/dl, was associated with a higher risk for asthma exacerbations. In the same population, the rs17580 (<span class="elsevierStyleItalic">Pi*S</span>) and rs28929474 (<span class="elsevierStyleItalic">Pi*Z</span>) <span class="elsevierStyleItalic">SERPINA1</span> variants were associated with a higher risk of asthma exacerbations. The rs28929474 signal was replicated in an independent sample of the Canary Islands and Finnish populations, but not in other Spanish or European populations.</p><p id="para0022" class="elsevierStylePara elsevierViewall">Several genes have been associated with predisposition to this flare-up episode,<a class="elsevierStyleCrossRefs" href="#bib0029"><span class="elsevierStyleSup">29-36</span></a> but in-depth studies, carried out in additional populations, are necessary to identify the whole genetic component involved in asthma exacerbations. Nevertheless, AATD is considered an underdiagnosed disease, as only about 10% of patients are estimated to be properly diagnosed.<a class="elsevierStyleCrossRef" href="#bib0037"><span class="elsevierStyleSup">37</span></a> Therefore, the scarce AATD diagnosis bias could underestimate its association with asthma. Since AAT is the main inhibitor of neutrophilic serine proteinase and acts as an important anti-inflammatory protein with pronounced immunomodulatory activity, the link between AATD and asthma might be represented by the elastase/antielastase imbalance caused by AATD. Alternatively, the proinflammatory effect caused by AAT serum levels reduction could also underlie the association found.<a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a> Interestingly, a previous study observed that protein levels of AAT are elevated during asthma exacerbations,<a class="elsevierStyleCrossRef" href="#bib0038"><span class="elsevierStyleSup">38</span></a> which agrees with our findings.</p><p id="para0023" class="elsevierStylePara elsevierViewall">Despite the important role of <span class="elsevierStyleItalic">SERPINA1</span> variants in COPD,<a class="elsevierStyleCrossRef" href="#bib0027"><span class="elsevierStyleSup">27</span></a> the associations found were not driven by this condition, as they remained significant when all asthmatic patients with pulmonary obstruction were excluded from the analysis. Moreover, the association of AATD with asthma severity was also confirmed by analyzing asthma control values as an alternative outcome. Given that IgE and eosinophil levels are related to allergic asthma,<a class="elsevierStyleCrossRef" href="#bib0039"><span class="elsevierStyleSup">39</span></a> and the high prevalence of atopy in the Canary Islands,<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a> we evaluated the association of <span class="elsevierStyleItalic">SERPINA1</span> variants and genotypes with these phenotypes. However, no associations were found in this case, suggesting the <span class="elsevierStyleItalic">SERPINA1</span> variants are not directly involved in the immunomodulation of the allergic response in these individuals. In previous studies, the <span class="elsevierStyleItalic">Pi*Z</span> variant has been associated with smoking behavior<a class="elsevierStyleCrossRef" href="#bib0017"><span class="elsevierStyleSup">17</span></a>, and the <span class="elsevierStyleItalic">Pi*S</span> variant has been mainly associated with the risk of developing COPD in smokers.<a class="elsevierStyleCrossRef" href="#bib0017"><span class="elsevierStyleSup">17</span></a> However, our associations of <span class="elsevierStyleItalic">Pi*S</span> and <span class="elsevierStyleItalic">Pi*Z</span> alleles, AAT levels, and AATD with asthma exacerbations were not explained by smoking history, body mass index, or ICS use.</p><p id="para0024" class="elsevierStylePara elsevierViewall">The associations found in the discovery population motivated us to assess the validation in Spanish subjects considering the overall population and a subset of individuals with two generations of Canary Islands origin. The latter comparison allowed us to evaluate the possible existence of a population-specific effect. It is known that populations from the Canary Islands present a recent admixture involving North African, European, and sub-Saharan African ancestry with variable ancestry, depending on the island.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">40</span></a> Although no relationship has been found between genetic ancestry and asthma when individuals from different islands of the Canary Archipelago were analyzed,<a class="elsevierStyleCrossRef" href="#bib0041"><span class="elsevierStyleSup">41</span></a> studies based on island-specific populations are yet to be addressed. In this sense, evidence of validation was found for the association of rs28929474 (<span class="elsevierStyleItalic">Pi*Z</span>) with asthma exacerbations in Canary Islanders, but not in other Spanish populations.</p><p id="para0025" class="elsevierStylePara elsevierViewall">The rs28929474 (<span class="elsevierStyleItalic">Pi*Z</span>) variant was also associated with asthma hospitalizations in the Finnish population, suggesting the possibility that a founder effect in certain isolated populations could cause an increase in <span class="elsevierStyleItalic">SERPINA1</span> deficient alleles associated with the risk of asthma exacerbations. In this sense, the lack of replication in the independent populations from mainland Spain may be due to differences in allele frequencies among the discovery and replication populations. In previous studies,<a class="elsevierStyleCrossRef" href="#bib0038"><span class="elsevierStyleSup">38</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0042"><span class="elsevierStyleSup">42</span></a> a high frequency of both polymorphisms was found among Spanish individuals, where the <span class="elsevierStyleItalic">Pi*S</span> and <span class="elsevierStyleItalic">Pi*Z</span> variants have a frequency of 10 and 2%, respectively.<a class="elsevierStyleCrossRef" href="#bib0043"><span class="elsevierStyleSup">43</span></a> Interestingly, the frequency of the <span class="elsevierStyleItalic">Pi*Z</span> variant in our study was higher in La Palma (3.8%), followed by Canary Islanders from GEMAS (3.1%), and mainland Spaniards from MEGA (1.1%). In the case of the Finnish population, the frequency of <span class="elsevierStyleItalic">Pi*Z</span> was only two times lower than in La Palma (1.9%), but the frequency of <span class="elsevierStyleItalic">Pi*S</span> was about 10 times lower (0.8%), which could explain the lack of replication of the <span class="elsevierStyleItalic">Pi*S</span> variant in this population.</p><p id="para0026" class="elsevierStylePara elsevierViewall">To the best of our knowledge, the present work represents the first evidence of the association of AATD and <span class="elsevierStyleItalic">SERPINA1</span> classic variants with asthma exacerbations. Moreover, we have demonstrated the robustness of the results by including strict quality control procedures and considering multiple demographic and clinical confounders in the association analyses. Additionally, we have analyzed different populations, not only genotyped in our study but also from different public databases queries.</p><p id="para0027" class="elsevierStylePara elsevierViewall">Nonetheless, some limitations must be considered. First, the <span class="elsevierStyleItalic">Pi*S</span> association with asthma exacerbations was not validated in all populations analyzed in the replication stage. Although the association found could be population specific, the lack of replication could also be due to the reduced statistical power derived from the smaller sample size in the non-Canary Islander replication set of samples. Second, different endotypes of asthma were not assessed and could underlie the different results obtained in the cohorts analyzed. Third, AAT serum levels were not available in GEMAS and MEGA. Therefore, it was not possible to confirm the association between AATD and asthma exacerbations in the replication phase. Fourth, other possible confounding factors were not evaluated, for example, atopy, rhinitis, or other individual or environmental conditions, since data was not available for all cohorts, and these uncontrolled conditions could mask the associations in the replication populations. Fifth, the recruitment of patients is heterogeneous between studies since CAATDPUL enrolled patients from the Pneumonology unit only, but GEMAS and MEGA enrolled patients from Pneumonology and Allergology units. Despite correcting the regression models by the recruitment center, this feature could be another reason for the lack of replication. Additionally, differences in the environment could also affect the associations through gene-environment interactions.</p><p id="para0028" class="elsevierStylePara elsevierViewall">Sixth, rare variants can also cause AATD, and such type of variation was not assessed. Therefore, future sequencing efforts analyzing the whole spectrum of genetic variation in the <span class="elsevierStyleItalic">SERPINA1</span> gene could reveal additional associations with asthma exacerbations.</p><p id="para0029" class="elsevierStylePara elsevierViewall">Personalized medicine has shown the existence of drugs with application to specific populations.<a class="elsevierStyleCrossRef" href="#bib0044"><span class="elsevierStyleSup">44</span></a> In this sense, it could be helpful to measure AAT serum levels and assess the <span class="elsevierStyleItalic">SERPINA1</span> genetic variants in asthmatic patients routinely in clinical practice to detect carriers of <span class="elsevierStyleItalic">SERPINA1</span> deficient variants, during which implementing AAT replacement therapy could be a potential treatment to reduce asthma exacerbations. This approach would especially be relevant to patients who do not respond to other asthma treatments, in order to decrease disease morbidity and mortality.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0016">Conclusions</span><p id="para0030" class="elsevierStylePara elsevierViewall">We describe for the first time the association of the <span class="elsevierStyleItalic">SERPINA1</span> gene <span class="elsevierStyleItalic">Pi*S</span> (rs17580) and <span class="elsevierStyleItalic">Pi*Z</span> (rs28929474) variants, AAT levels, and AATD with asthma exacerbations in patients from La Palma (Canary Islands, Spain). In addition, the association of the <span class="elsevierStyleItalic">Pi*Z</span> allele, the most important <span class="elsevierStyleItalic">SERPINA1</span> variant in clinical practice, was validated in another set of Canary Islanders and individuals from the Finnish population. This suggests AATD is a potential therapeutical target for treating asthma exacerbations in specific populations.</p></span><span id="sec0011" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0017">Author contributions</span><p id="para0031" class="elsevierStylePara elsevierViewall">M.P.Y. and M.G.C. are the guarantors of the paper, taking responsibility for the integrity of the work, from inception to the published article. E.M.G. was responsible for formal analysis and writing the original draft. J.M.H.P., M.P.Y., and M.G.C. contributed to the conceptualization, and M.P.Y. and M.G.C. also contributed to methodology and supervision. Resources were carried out by J.M.H.P., J.A.P.P., R.G.P., E.M.L., I.S.M., O.S., P.C., P.P.G., J.K.M., V.d.P., F.L.D., J.V., and M.P.Y. All the authors support with the investigation, writing-review, and editing. Funding acquisition was carried out by J.M.H.P. and M.P.Y.</p></span><span id="sec0012" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0018">Financial/nonfinancial disclosures</span><p id="para0032" class="elsevierStylePara elsevierViewall">This study was funded by the Spanish Ministry of Science and Innovation MCIN/AEI/10.13039/501100011033 (PID2020–116274RB-I00) and by Sociedad Española de Neumología y Cirugía Torácica (SEPAR <a href="http://www.separ.es">http://www.separ.es</a>), grant number 1264–2022. Authors declare they have no competing interests or other interests that might be perceived to influence the interpretation of the manuscript. No supporting institution may gain or lose financially through this publication. Genotyping of samples from GEMAS and MEGA studies was funded by the Spanish Ministry of Science and Innovation (SAF2017–87417R) at the Spanish National Cancer Research centre, in the Human Genotyping lab, a member of CeGen, PRB3, and was supported by grant PT17/0019, of the PE <span class="elsevierStyleItalic">I</span> + <span class="elsevierStyleItalic">D</span> + <span class="elsevierStyleItalic">i</span> 2013–2016, funded by Instituto de Salud Carlos III (ISCIII) and European Regional Development Fund. Genotyping of GEMAS was also partially funded by Fundación Canaria Instituto de Investigación Sanitaria de Canarias (PIFIISC19/17). E.M.G. was supported by a fellowship (TESIS2022010045) awarded by the Board of Economy, Industry, Trade, and Knowledge of the Canary Islands Government, with a European Social Fund co-financing rate managed by the Canary Islands Agency for Research, Innovation, Society, and Information (ACIISI). J.P.G. was funded by an FPU fellowship (FPU19/02,175) granted by the Spanish Ministry of Universities. E.H.L. was supported by a fellowship awarded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future” (PRE2018–083,837). V.P. has received grant support from MSD. V.d.P. was supported by CIBER de Enfermedades Respiratorias, ISCIII, Spain. M.P.Y. was funded by the Ramón y Cajal Program (RYC-2015–17,205) by MCIN/AEI/10.13039/501100011033 and by the European Social Fund “ESF Investing in your future”. M.P.Y. and J.V. were supported by CIBER de Enfermedades Respiratorias, ISCIII, Spain (CB/06/06/1088).</p></span><span id="sec0013" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0019">Role of sponsors</span><p id="para0033" class="elsevierStylePara elsevierViewall">The sponsor had no role in the design of the study, the collection, and analysis of the data, or the preparation of the manuscript.</p></span><span id="sec0014" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0020">Other contributions</span><p id="para0034" class="elsevierStylePara elsevierViewall">The authors thank the patients, families, recruiters, healthcare providers, and community clinics for their participation in the studies analyzed in this manuscript. The genotyping service was carried out at CEGEN-PRB3-ISCIII; it is supported by grant PT17/0019, of the PE <span class="elsevierStyleItalic">I</span> + <span class="elsevierStyleItalic">D</span> + <span class="elsevierStyleItalic">i</span> 2013–2016, funded by ISCIII and ERDF.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0021">Funding</span><p id="para0035" class="elsevierStylePara elsevierViewall">This study was funded by the Spanish Ministry of Science and Innovation MCIN/AEI/10.13039/501100011033 (PID2020–116274RB-I00) and by <span class="elsevierStyleGrantSponsor" id="gs0001">Sociedad Española de Neumología y Cirugía Torácica</span> (SEPAR <a href="http://www.separ.es">http://www.separ.es</a>), grant number <span class="elsevierStyleGrantNumber" refid="gs0001">1264–2022</span>.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres1904719" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abss0001" "titulo" => "Introduction and objectives" ] 1 => array:2 [ "identificador" => "abss0002" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abss0003" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abss0004" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1645637" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0001" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "sec0002" "titulo" => "Methods" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0003" "titulo" => "Discovery and replication populations" ] 1 => array:2 [ "identificador" => "sec0004" "titulo" => "Statistical analyses" ] ] ] 4 => array:3 [ "identificador" => "sec0005" "titulo" => "Results" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0006" "titulo" => "Quality control, demographic, and clinical characteristics of all study populations" ] 1 => array:2 [ "identificador" => "sec0007" "titulo" => "Association analysis in the discovery phase" ] 2 => array:2 [ "identificador" => "sec0008" "titulo" => "Association analysis in the replication phase" ] ] ] 5 => array:2 [ "identificador" => "sec0009" "titulo" => "Discussion" ] 6 => array:2 [ "identificador" => "sec0010" "titulo" => "Conclusions" ] 7 => array:2 [ "identificador" => "sec0011" "titulo" => "Author contributions" ] 8 => array:2 [ "identificador" => "sec0012" "titulo" => "Financial/nonfinancial disclosures" ] 9 => array:2 [ "identificador" => "sec0013" "titulo" => "Role of sponsors" ] 10 => array:2 [ "identificador" => "sec0014" "titulo" => "Other contributions" ] 11 => array:2 [ "identificador" => "sec0015" "titulo" => "Funding" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2022-12-14" "fechaAceptado" => "2023-05-06" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1645637" "palabras" => array:5 [ 0 => "Asthma" 1 => "Exacerbations" 2 => "<span class="elsevierStyleItalic">SERPINA1</span>" 3 => "Alpha-1 antitrypsin" 4 => "Alpha-1 antitrypsin deficiency" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abss0001" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0002">Introduction and objectives</span><p id="spara010" class="elsevierStyleSimplePara elsevierViewall">Asthma is a chronic inflammatory disease of the airways. Asthma patients may experience potentially life-threatening episodic flare-ups, known as exacerbations, which may significantly contribute to the asthma burden. The <span class="elsevierStyleItalic">Pi*S</span> and <span class="elsevierStyleItalic">Pi*Z</span> variants of the <span class="elsevierStyleItalic">SERPINA1</span> gene, which usually involve alpha-1 antitrypsin (AAT) deficiency, had previously been associated with asthma. The link between AAT deficiency and asthma might be represented by the elastase/antielastase imbalance. However, their role in asthma exacerbations remains unknown. Our objective was to assess whether <span class="elsevierStyleItalic">SERPINA1</span> genetic variants and reduced AAT protein levels are associated with asthma exacerbations.</p></span> <span id="abss0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0003">Materials and methods</span><p id="spara011" class="elsevierStyleSimplePara elsevierViewall">In the discovery analysis, <span class="elsevierStyleItalic">SERPINA1 Pi*S</span> and <span class="elsevierStyleItalic">Pi*Z</span> variants and serum AAT levels were analyzed in 369 subjects from La Palma (Canary Islands, Spain). As replication, genomic data from two studies focused on 525 Spaniards and publicly available data from UK Biobank, FinnGen, and GWAS Catalog (<span class="elsevierStyleItalic">Open Targets Genetics</span>) were analyzed. The associations between <span class="elsevierStyleItalic">SERPINA1 Pi*S</span> and <span class="elsevierStyleItalic">Pi*Z</span> variants and AAT deficiency with asthma exacerbations were analyzed with logistic regression models, including age, sex, and genotype principal components as covariates.</p></span> <span id="abss0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0004">Results</span><p id="spara012" class="elsevierStyleSimplePara elsevierViewall">In the discovery, a significant association with asthma exacerbations was found for both <span class="elsevierStyleItalic">Pi*S</span> (odds ratio [OR]=2.38, 95% confidence interval [CI]= 1.40–4.04, <span class="elsevierStyleItalic">p</span>-value=0.001) and <span class="elsevierStyleItalic">Pi*Z</span> (OR=3.49, 95%CI=1.55–7.85, <span class="elsevierStyleItalic">p</span>-value=0.003)Likewise, AAT deficiency was associated with a higher risk for asthma exacerbations (OR=5.18, 95%CI=1.58–16.92, <span class="elsevierStyleItalic">p</span>-value=0.007) as well as AAT protein levels (OR= 0.72, 95%CI=0.57–0.91, <span class="elsevierStyleItalic">p</span>-value=0.005). The <span class="elsevierStyleItalic">Pi*Z</span> association with exacerbations was replicated in samples from Spaniards with two generations of Canary Islander origin (OR=3.79, <span class="elsevierStyleItalic">p</span>-value=0.028), and a significant association with asthma hospitalizations was found in the Finnish population (OR=1.12, <span class="elsevierStyleItalic">p</span>-value=0.007).</p></span> <span id="abss0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0005">Conclusions</span><p id="spara013" class="elsevierStyleSimplePara elsevierViewall">AAT deficiency could be a potential therapeutic target for asthma exacerbations in specific populations.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abss0001" "titulo" => "Introduction and objectives" ] 1 => array:2 [ "identificador" => "abss0002" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abss0003" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abss0004" "titulo" => "Conclusions" ] ] ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "<p id="para0036a" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="ecom0001"></elsevierMultimedia></p>" "etiqueta" => "Appendix" "titulo" => "Supplementary materials" "identificador" => "sec0017" ] ] ] ] "multimedia" => array:5 [ 0 => array:8 [ "identificador" => "tbl0001" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0001" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spara002" class="elsevierStyleSimplePara elsevierViewall">A comparison of demographic and clinical characteristics between controls and cases was performed for all CAATDPUL subjects or excluding patients with chronic airway obstruction. The normality of continuous variables (age, pulmonary function variables, IgE levels, eosinophils counts, and AAT levels) was evaluated using the Shapiro-Wilk test and then summarized with the median and interquartile range (in brackets). Categorical variables (sex, ever smoker, asthma control, ICS use, and AATD) were summarized as counts for each group and percentages (in brackets). Predicted values of lung function measurements were estimated using the Global Lung Function Initiative (GLI) 2012 equations. Statistically significant differences between groups were evaluated either with Mann-Whitney U or Fisher's exact tests, for continuous and categorical variables, respectively. Statistically significant differences between groups (<span class="elsevierStyleItalic">p</span>-values<0.05) are depicted in boldface. <span class="elsevierStyleBold">Abbreviations:</span> AATD: Alpha-1-antitrypsin deficiency; ACT: Asthma control test; FEV<span class="elsevierStyleInf">1</span>: Forced expiratory volume in the first second; FVC: Forced vital capacity; ICS: inhaled corticosteroid; IgE: Immunoglobulin E; n: sample size.</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"><a name="en0001"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col">Characteristic \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0002"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_colgroup " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">All subjects <span class="elsevierStyleItalic">n</span> = 369</th><a name="en0003"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_colgroup " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Subjects without chronic airway obstruction <span class="elsevierStyleItalic">n</span> = 335</th></tr><tr title="table-row"><a name="en0004"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0005"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Controls (<span class="elsevierStyleItalic">n</span> = 231) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0006"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Cases (<span class="elsevierStyleItalic">n</span> = 138) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0007"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>-value \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0008"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Controls (<span class="elsevierStyleItalic">n</span> = 207) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0009"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Cases (<span class="elsevierStyleItalic">n</span> = 128) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0010"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>-value \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="en0011"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Age (years) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0012"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">47 (31–61) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0013"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">42 (32–65) \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">0.519 \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="char" valign="top">45 (30–60) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0016"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">41 (29–63) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0017"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.611 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0018"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Sex (females), n (%) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0019"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">150 (65) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0020"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">99 (72) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0021"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.207 \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="char" valign="top">135 (65) \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="char" valign="top">93 (73) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0024"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.185 \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">Ever smoker, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0026"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">79 (34) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0027"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">38 (28) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0028"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.204 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0029"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">68 (33) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0030"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">33 (28) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0031"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.180 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0032"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_colgroup " colspan="7" align="left" valign="top">Pulmonary function</td></tr><tr title="table-row"><a name="en0033"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>FEV<span class="elsevierStyleInf">1</span> (% predicted) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0034"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">95 (83–103) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0035"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">94 (83–103) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0036"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.872 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0037"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">95 (85–104) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0038"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">94 (85–104) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0039"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.716 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0040"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>FVC (% predicted) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0041"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">95 (86–104) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0042"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">94 (85–104) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0043"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.374 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0044"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">96 (86–104) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0045"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">94 (85–104) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0046"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.580 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0047"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>FEV<span class="elsevierStyleInf">1</span>/FVC (% predicted) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0048"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">80 (73–85) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0049"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">81 (75–86) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0050"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.587 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0051"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">80 (75–86) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0052"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">82 (76–86) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0053"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.605 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0054"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">IgE levels (UI/ml) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0055"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">93 (32–264) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0056"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">107 (35–305) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0057"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.300 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0058"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">92 (32–264) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0059"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">111 (37–307) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0060"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.267 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0061"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Eosinophil counts (cells/µl) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0062"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">200 (136–319) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0063"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">300 (200–400) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0064"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">0.007</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0065"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">200 (200–300) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0066"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">300 (200–450) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0067"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">0.021</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0068"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_colgroup " colspan="7" align="left" valign="top">Asthma control, n (%)</td></tr><tr title="table-row"><a name="en0069"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Well controlled \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0070"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">137 (62) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0071"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">47 (36) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0072"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">1.94×10<span class="elsevierStyleSup">−6</span></span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0073"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">121 (61) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0074"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">44 (36) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0075"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">1.15×10</span><span class="elsevierStyleSup">−5</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0076"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Partially/Poorly controlled \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0077"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">84 (38) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0078"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">85 (64) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0079"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">1.94×10<span class="elsevierStyleSup">−6</span></span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0080"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">76 (39) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0081"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">78 (64) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0082"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">1.15×10<span class="elsevierStyleSup">−5</span></span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0083"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">ICS use, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0084"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">215 (93) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0085"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">136 (99) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0086"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">0.022</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0087"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">193 (93) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0088"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">126 (98) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0089"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">0.034</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0090"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">AATD, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0091"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">4 (2) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0092"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">11 (8) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0093"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">0.007</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0094"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">4 (2) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0095"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">10 (8) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0096"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">0.022</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0097"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">AAT levels (mg/dl) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0098"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">128 (115–141) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0099"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">125 (109–139) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0100"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.057 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0101"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">129 (115–141) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0102"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">124 (110–139) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0103"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">0.038</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3179506.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall">Demographic and clinical variables of subjects from La Palma Island (enrolled by CAATDPUL between 2011 and 2015) included in the discovery phase.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0002" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0002" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spara004" class="elsevierStyleSimplePara elsevierViewall">Comparison of demographic and clinical characteristics between controls and cases was performed for GEMAS (including all subjects, or only patients with two generations of Canary Islander origin), and MEGA populations. The normality of continuous variables (age, pulmonary function variables, IgE levels, and eosinophils counts) was evaluated with the Shapiro-Wilk test, and then summarized with the median and interquartile range (in brackets). Categorical variables (sex, ever smoker, asthma control, and ICS use) were summarized as counts for each group and percentages (in brackets). Predicted values of lung function measurements were estimated using the Global Lung Function Initiative (GLI) 2012 equations.</p><p id="spara005" class="elsevierStyleSimplePara elsevierViewall">Statistically significant differences between groups were evaluated either with Mann-Whitney U or Fisher's exact tests, for continuous and categorical variables, respectively. Statistically significant differences between groups (<span class="elsevierStyleItalic">p</span>-values<0.05) are depicted in boldface. <span class="elsevierStyleBold">Abbreviations</span>: ACT: Asthma control test; FEV<span class="elsevierStyleInf">1</span>: Forced expiratory volume in the first second; FVC: Forced vital capacity; ICS: inhaled corticosteroid; IgE: Immunoglobulin E; n: sample size.</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"><a name="en0104"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col">Characteristic \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0105"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_colgroup " colspan="6" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">GEMAS</th><a name="en0106"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_colgroup " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">MEGA</th></tr><tr title="table-row"><a name="en0107"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0108"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_colgroup " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">All subjects <span class="elsevierStyleItalic">n</span> = 387</th><a name="en0109"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_colgroup " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Canary Islands origin <span class="elsevierStyleItalic">n</span> = 223</th><a name="en0110"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_colgroup " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">All subjects <span class="elsevierStyleItalic">n</span> = 138</th></tr><tr title="table-row"><a name="en0111"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0112"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Controls (<span class="elsevierStyleItalic">n</span> = 194) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0113"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Cases (<span class="elsevierStyleItalic">n</span> = 192) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0114"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>-value \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0115"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Controls (<span class="elsevierStyleItalic">n</span> = 135) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0116"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Cases (<span class="elsevierStyleItalic">n</span> = 88) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0117"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>-value \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0118"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Controls (<span class="elsevierStyleItalic">n</span> = 90) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0119"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Cases (<span class="elsevierStyleItalic">n</span> = 48) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0120"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>-value \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="en0121"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Age (years) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0122"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">33 (19–53) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0123"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">30 (13–48) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0124"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">0.040</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0125"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">38 (25–53) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0126"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">43 (22–51) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0127"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.691 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0128"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">44 (36–53) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0129"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">54 (44–60) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0130"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">0.007</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0131"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Sex (female), n (%) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0132"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">107 (55) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0133"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">118 (61) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0134"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.217 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0135"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">80 (59) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0136"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">59 (67) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0137"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.261 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0138"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">63 (70) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0139"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">35 (73) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0140"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.844 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0141"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Ever smoker, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0142"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">49 (25) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0143"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">46 (24) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0144"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.814 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0145"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">40 (30) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0146"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">30 (34) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0147"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.554 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0148"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">35 (39) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0149"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">23 (48) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0150"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.259 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0151"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_colgroup " colspan="10" align="left" valign="top">Pulmonary function</td></tr><tr title="table-row"><a name="en0152"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>FEV<span class="elsevierStyleInf">1</span> (% predicted) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0153"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">91 (82–102) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0154"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">89 (77–101) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0155"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.129 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0156"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">91 (77–100) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0157"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">87 (73–97) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0158"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.237 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0159"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">95 (81–93) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0160"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">78 (64–93) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0161"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">6.47×10<span class="elsevierStyleSup">−4</span></span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0162"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>FVC (% predicted) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0163"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">96 (84–104) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0164"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">93 (84–103) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0165"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.332 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0166"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">95 (82–104) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0167"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">88 (81–90) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0168"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.118 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0169"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">104 (94–112) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0170"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">95 (79–107) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0171"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">0.008</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0172"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>FEV<span class="elsevierStyleInf">1</span>/FVC (% predicted) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0173"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">80 (75–86) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0174"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">80 (72–85) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0175"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.548 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0176"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">78 (74–84) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0177"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">80 (71–85) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0178"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.908 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0179"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">80 (72–87) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0180"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">75 (67–79) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0181"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">0.009</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0182"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">IgE levels (UI/ml) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0183"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">215 (68–905) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0184"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">206 (60–674) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0185"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.317 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0186"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">184 (53–740) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0187"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">193 (63–750) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0188"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.910 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0189"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">164 (70–388) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0190"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">209 (70–536) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0191"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.416 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0192"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">Eosinophil counts (cells/µl) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0193"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">335 (200–600) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0194"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">345 (110–570) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0195"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.408 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0196"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">340 (22–610) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0197"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">400 (150–600) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0198"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.878 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0199"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">300 (200–500) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0200"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">400 (198–700) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0201"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.221 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0202"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_colgroup " colspan="10" align="left" valign="top">Asthma control, n (%)</td></tr><tr title="table-row"><a name="en0203"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Well controlled \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0204"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">84 (66) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0205"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">59 (39) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0206"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">1.36×10<span class="elsevierStyleSup">−5</span></span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0207"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">51 (64) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0208"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">19 (29) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0209"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">5.23×10<span class="elsevierStyleSup">−5</span></span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0210"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">69 (82) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0211"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">19 (42) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0212"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">7.50×10<span class="elsevierStyleSup">−6</span></span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0213"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>Partially/Poorly controlled \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0214"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">44 (34) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0215"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">92 (61) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0216"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">1.36×10<span class="elsevierStyleSup">−5</span></span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0217"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">29 (36) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0218"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">46 (71) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0219"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">5.23×10<span class="elsevierStyleSup">−5</span></span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0220"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">15 (18) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0221"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">26 (58) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0222"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">7.50×10<span class="elsevierStyleSup">−6</span></span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0223"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleHsp" style=""></span>ICS use, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0224"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">152 (78) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0225"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">177 (92) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0226"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">1.86×10<span class="elsevierStyleSup">−6</span></span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0227"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">108 (80) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0228"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">80 (91) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0229"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">0.010</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0230"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">87 (97) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0231"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">48 (100) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0232"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.551 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3179508.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spara003" class="elsevierStyleSimplePara elsevierViewall">Demographic and clinical variables in the replication populations (GEMAS and MEGA).</p>" ] ] 2 => array:8 [ "identificador" => "tbl0003" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0003" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spara007" class="elsevierStyleSimplePara elsevierViewall">AATD frequency was summarized as counts and% frequency (in brackets). The frequency of variants and genotypes were summarized as allele/genotype count and minor allele frequency/genotype percentages (in brackets). Statistically significant <span class="elsevierStyleItalic">p</span>-values after Bonferroni correction are depicted in boldface (<span class="elsevierStyleItalic">p</span>-value<0.025). <span class="elsevierStyleBold">Abbreviations:</span> AATD: Alpha-1 antitrypsin deficiency; CI: Confidence interval; NA: Not available (beta coefficient or standard deviation >10); n: sample size; OR: Odds ratio.</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"><a name="en0233"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">AAT levels/AATD/Variant/Genotype</th><a name="en0234"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_colgroup " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">All subjects <span class="elsevierStyleItalic">n</span> = 369</th><a name="en0235"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_colgroup " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Subjects without chronic airway obstruction <span class="elsevierStyleItalic">n</span> = 335</th></tr><tr title="table-row"><a name="en0237"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">OR (95%CI) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0238"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>-value \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0239"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Frequency \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0240"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">OR (95%CI) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0241"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>-value \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0242"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Frequency \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="en0243"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">AAT levels \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0244"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.72 (0.57–0.91) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0245"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">0.005</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0246"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0247"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.68 (0.53–0.87) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0248"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">0.002</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0249"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0250"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">AATD \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0251"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5.18 (1.58–16.92) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0252"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">0.007</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0253"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">15 (4.0) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0254"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5.18 (1.58–16.92) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0255"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">0.015</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0256"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">14 (4.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0257"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">Pi*S</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0258"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">2.38 (1.40–4.04) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0259"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">0.001</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0260"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">65 (8.8) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0261"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">2.38 (1.40–4.04) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0262"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">0.002</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0263"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">59 (8.8) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0264"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">Pi*Z</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0265"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">3.49 (1.55–7.85) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0266"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">0.003</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0267"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">28 (3.8) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0268"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">3.49 (1.55–7.85) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0269"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">0.003</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0270"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">26 (3.9) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0271"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">Pi*MS</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0272"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">1.93 (1.03–3.62) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0273"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.039 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0274"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">49 (13.3) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0275"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">1.93 (1.03–3.62) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0276"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.071 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0277"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">43 (12.8) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0278"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">Pi*MZ</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0279"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">2.64 (1.09–6.42) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0280"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.032 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0281"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">22 (6.0) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0282"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">2.64 (1.09–6.42) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0283"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.047 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0284"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">20 (6.0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0285"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">Pi*SS</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0286"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">8.90 (0.94–84.26) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0287"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.057 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0288"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5 (1.4) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0289"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">8.90 (0.94–84.26) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0290"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.064 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0291"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">5 (1.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0292"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleItalic">Pi*SZ</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0293"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0294"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0295"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">6 (1.6) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0296"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0297"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0298"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">6 (1.8) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3179509.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spara006" class="elsevierStyleSimplePara elsevierViewall">Association analysis results obtained between asthma exacerbations and <span class="elsevierStyleItalic">SERPINA1</span> genetic variants, classic genotypes, and AATD, as well as their frequencies in the discovery population and adjusting by age, sex, and principal components.</p>" ] ] 3 => array:8 [ "identificador" => "tbl0004" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0004" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spara009" class="elsevierStyleSimplePara elsevierViewall">The frequency of variants and genotypes were summarized as allele/genotype count and minor allele frequency/genotype percentages (in brackets). Statistically significant <span class="elsevierStyleItalic">p</span>-values are depicted in boldface (<span class="elsevierStyleItalic">p</span>-value<0.05). <span class="elsevierStyleBold">Abbreviations:</span> CI: Confidence interval; NA: Not available (beta coefficient or standard deviation >10); n: sample size; OR: Odds ratio.</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"><a name="en0299"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0300"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_colgroup " colspan="6" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">GEMAS</th><a name="en0301"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_colgroup " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">MEGA</th></tr><tr title="table-row"><a name="en0302"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Variant/Genotype</th><a name="en0303"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_colgroup " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">All subjects <span class="elsevierStyleItalic">n</span> = 387</th><a name="en0304"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_colgroup " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Canary Islands origin <span class="elsevierStyleItalic">n</span> = 223</th><a name="en0305"></a><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_colgroup " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">All subjects <span class="elsevierStyleItalic">n</span> = 138</th></tr><tr title="table-row"><a name="en0307"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">OR (95% CI) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0308"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>-value \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0309"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Frequency \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0310"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">OR (95% CI) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0311"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>-value \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0312"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Frequency \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0313"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">OR (95% CI) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0314"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>-value \t\t\t\t\t\t\n \t\t\t\t\t\t</th><a name="en0315"></a><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Frequency \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="en0316"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="top"><span class="elsevierStyleItalic">Pi*S</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0317"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.82 (0.51–1.32) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0318"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.414 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0319"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">86 (11.1) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0320"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.69 (0.37–1.31) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0321"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.261 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0322"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">54 (12.1) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0323"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.90 (0.34–2.40) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0324"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.830 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0325"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">23 (8.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><a name="en0326"></a><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="" valign="top"><span class="elsevierStyleItalic">Pi*Z</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0327"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">1.27 (0.53–3.06) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0328"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.597 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0329"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">20 (2.6) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0330"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">3.79 (1.16–12.43) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0331"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top"><span class="elsevierStyleBold">0.028</span> \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0332"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">14 (3.1) \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0333"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0334"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">0.991 \t\t\t\t\t\t\n \t\t\t\t</td><a name="en0335"></a><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="top">3 (1.1) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3179507.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spara008" class="elsevierStyleSimplePara elsevierViewall">Association of <span class="elsevierStyleItalic">SERPINA1</span> genetic variants and genotypes with exacerbations and their frequencies in the replication populations and adjusting by age, sex, and principal components.</p>" ] ] 4 => array:6 [ "identificador" => "ecom0001" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "detalles" => array:1 [ 0 => array:3 [ "identificador" => "alt0005" "detalle" => "Image, application " "rol" => "short" ] ] "Ecomponente" => array:2 [ "fichero" => "mmc1.docx" "ficheroTamanyo" => 216726 ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "cebibsec1" "bibliografiaReferencia" => array:44 [ 0 => array:3 [ "identificador" => "bib0001" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Global Initiative for Asthma. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 20 | 2 | 22 |
| 2024 October | 163 | 68 | 231 |
| 2024 September | 170 | 53 | 223 |
| 2024 August | 196 | 69 | 265 |
| 2024 July | 195 | 66 | 261 |
| 2024 June | 152 | 53 | 205 |
| 2024 May | 184 | 54 | 238 |
| 2024 April | 116 | 47 | 163 |
| 2024 March | 112 | 29 | 141 |
| 2024 February | 68 | 36 | 104 |
| 2024 January | 56 | 24 | 80 |
| 2023 December | 44 | 30 | 74 |
| 2023 November | 52 | 37 | 89 |
| 2023 October | 42 | 43 | 85 |
| 2023 September | 42 | 36 | 78 |
| 2023 August | 22 | 7 | 29 |
| 2023 July | 24 | 29 | 53 |
| 2023 June | 43 | 51 | 94 |
| 2023 May | 19 | 13 | 32 |
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