Toll-like receptor 4 gene polymorphisms and acute coronary syndrome: No association in a Mexican population

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"apellidos" => "Peña-Duque" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 8 => array:4 [ "nombre" => "José Manuel" "apellidos" => "Fragoso" "email" => array:1 [ 0 => "mfragoso1275@yahoo.com.mx" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "¿" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Interventional Cardiology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Molecular Biology and Interventional Genetic Study Group in Cardiovascular Disease's, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Sociomedicine, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author. Juan Badiano No. 1, Tlalpan 14080, México DF, Mexico. Tel.: +52 55 5573 2911x1460; fax: +52 55 5573 0926." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "No existe asociación entre los polimorfismos del receptor tipo toll-4 y el síndrome coronario agudo" ] ] "textoCompleto" => "IntroductionAtherosclerosis is a multifactorial disorder that results from an excessive inflammatory response to various forms of injurious stimuli to the arterial wall.<a class="elsevierStyleCrossRefs" href="#bib0005">1–3</a> The inflammatory processes, genetic background, and various environmental factors, coupled to dyslipidemia, including hypertension, diabetes, obesity, and smoking play an important role in the progression of the atherosclerotic plaque.<a class="elsevierStyleCrossRefs" href="#bib0015">3–5</a> The transition of a stable coronary atherosclerotic lesion into a ruptured and eroded plaque results in the clinical manifestation of an acute coronary syndrome (ACS).<a class="elsevierStyleCrossRefs" href="#bib0025">5,6</a> The ACS includes unstable angina and myocardial infarction caused mainly by rupture or erosion of the atherosclerotic plaque, with subsequent thrombus formation.<a class="elsevierStyleCrossRefs" href="#bib0030">6–8</a> Mounting evidence suggests that specific agents enhance arterial inflammation during atherogenesis, based on their interaction with receptor signaling pathways of the innate immune systems.<a class="elsevierStyleCrossRefs" href="#bib0045">9,10</a> Toll-like receptor 4 (TLR-4) is part of the innate immunity response cascade. It has been associated as one of the factors contributing to the deleterious process of atherosclerosis.<a class="elsevierStyleCrossRefs" href="#bib0055">11–13</a>TLR-4 is well known as a pattern-recognition receptor for exogenous lipopolysacharide (LPS) derived from gram-negative bacterial infection.<a class="elsevierStyleCrossRefs" href="#bib0070">14,15</a> However, several studies showed that TLR-4 interacts with other ligands, such as fibrinogen,<a class="elsevierStyleCrossRef" href="#bib0080">16</a> fibronectin,<a class="elsevierStyleCrossRef" href="#bib0085">17</a> heat-shock protein,<a class="elsevierStyleCrossRef" href="#bib0090">18</a> hyaluronan oligosaccharide<a class="elsevierStyleCrossRef" href="#bib0095">19</a> and modified low-density lipoproteins (LDL),<a class="elsevierStyleCrossRefs" href="#bib0100">20,21</a> playing an important role in the development of the atherosclerotic plaque. The TLR-4 gene is located in the 9q32 region.<a class="elsevierStyleCrossRef" href="#bib0075">15</a>TLR-4 presents two single nucleotide polymorphisms (SNP), both polymorphisms, rs4986790 (Asp299Gly) and rs4986791 (Thr399Ile), are located in the coding region. These (SNPs) affect TLR-4 extracellular domain and result in amino acid exchanges: an aspartic acid for a glycine at position 299 (Asp299Gly) and a threonine for a isoleucine at position 399 (Thr399Ile).<a class="elsevierStyleCrossRefs" href="#bib0110">22,23</a> Several studies associate these polymorphisms with several inflammatory diseases, such as ACS, gastric cancer, carotid artery elasticity, chronic obstructive pulmonary disease, and atherosclerosis.<a class="elsevierStyleCrossRefs" href="#bib0120">24–28</a> Considering the prominent role of the TLR-4 as initiator of the inflammatory response, this study was based on the assumption that the TLR-4 gene polymorphisms have a measurable influence in the development of the atherosclerotic plaque and contributes to or increases the occurrence of ACS. The objective of this study was to establish the possible role of the TLR-4 gene polymorphisms as a risk factor for ACS in a group of Mexicans patients.MethodsStudy populationsThe study included 457 Mexican patients with ACS (368 males and 89 females, mean age 59.7±11.02) that were attended to our Institution. Three hundred forty-two presented myocardial infarction and 115 presented unstable angina. All subjects were diagnosed according to the World Health Organization and the American Heart Associated (AHA)/American College of Cardiology (ACC).<a class="elsevierStyleCrossRef" href="#bib0145">29</a> Basis in clinical history, physical examination with electrocardiography, chest radiography, echocardiography, and coronary angiography. The group of patients was compared with a group of 283 healthy unrelated individuals (202 males and 81 females, mean age 55.39±7.23). This group was selected from people arriving with the purpose to donation at the blood bank at our institute. According to the medical records, none of these had diabetes, dyslipidemia, hypertension or other pathology. On the other hand, subclinical atherosclerosis was discarded through determined calcium score by multi-detector computed tomography. The values were zero in these individuals. All subjects included in the study (patients and controls) were ethnically matched, and we considered as Mexican Mestizos only those individuals who had been born in Mexico for three generations, including their own. A Mexican Mestizo is defined as someone born in Mexico, who is a descendant of the original autochthonous inhabitants of the region and of individuals, mainly Spaniards, of Caucasian and African origin, who came to the American continent during the sixteenth century. The Institutional Ethics and Research Committees approved the study, and all subjects provided written, informed consent.DNA extractionGenomic DNA from whole blood containing EDTA was isolated with a standard technique.<a class="elsevierStyleCrossRef" href="#bib0150">30</a>Determination of the TLR-4 genotypesThe TLR-4 Asp299Gly (rs4986790) and TLR-4 Thr399Ile (rs4986791) single nucleotide polymorphisms were genotyped using 5′ exonuclease TaqMan genotyping assays on an 7900HT Fast real-time PCR system according to manufacturer's instructions (Applied Biosystems, Foster City, USA).Statistical analysisGene frequencies of TLR-4 polymorphisms in patients and controls were obtained by direct counting. Hardy–Weinberg equilibrium was evaluated by Chi2 test. Statistical analysis was carried out with the Stata 10.0 software for Windows. In the exploratory analysis, numerical data showed a different distribution from normal standard (Gaussian distribution) (Shapiro Wilk's test of normality, p>0.05), nominal and categorical variables were tabulated to estimate their proportions. Hypertension, altered lipid profile, smoking, and type 2 diabetes mellitus had two categories, yes or no, and all described the current condition of patients and healthy controls. Comparison of numerical variables, such as age and body mass index, between both groups was carried out with Mann–Whitney U test, data are presented as the 25th percentile, median, and 75th percentile. Categorical variables were analyzed with Chi2 tests and presented as absolute frequencies and proportions. Statistical significance was set at p≤0.05. Multiple logistic regression analysis was carried out to identify the variables that better explain the risk of developing ACS between patients and healthy controls. Models were constructed including one variable at a time to identify confounding bias; changes in estimated odds ratios (ORs) were less than 10%. When a main effect model was reached, effect modification was also tested, interaction terms were constructed between age and BMI, hypertension and type 2 diabetes mellitus, smoking and hypertension, and gender and BMI, no significant ORs (p ≤ 0.20) were identified and therefore these terms were not included in the final model. Hosmer–Lemeshow Goodness of fit test was performed for each multiple logistic model. Pairwise linkage disequilibrium (LD, D′) estimations between polymorphisms and haplotype reconstruction were performed with Haploview version 4.1 (Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA).ResultsCharacteristic of the study sampleBaseline characteristic of the ACS patients and healthy controls included in the study are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Allele and genotype frequenciesThe observed and expected frequencies in the two polymorphic sites of the toll-like receptor (TLR-4) were in Hardy–Weinberg equilibrium. The allele and genotype frequencies of the two studied polymorphisms (positions +896 A>G (Asp299Gly) and +1196 C>T (Thr399Ile)) were similar between patients with ACS and healthy controls (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). The multiple logistic regression analysis showed that the largest risk for ACS development was given by smoking (11.88-fold increased risk), hypertension (4.32-fold increased risk), type II diabetes (3.44-fold increased risk), gender (2.32-fold increased risk), and dyslipidemia (1.52-fold increased risk) (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). The +896 A>G (Asp299Gly) and +1196 C>T (Thr399Ile) polymorphisms showed a strong linkage disequilibrium (D′=0.82) and were used to construct two haplotypes (AC and GT). The haplotype “AC” showed a similar distribution in ACS patients and healthy controls (95.7% and 96.8%, respectively). Moreover, the “GT” haplotype showed a similar decreased in patients and control (4.3%, and 3.2%, respectively).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia>DiscussionIn the present work, we studied two polymorphisms (Asp299Gly and Thr399Ile) located in the TLR-4 gene in 457 patients with ACS and 283 healthy controls. In humans, both polymorphisms affect TLR-4 extracellular domain and individuals that possess these polymorphisms are hyporesponsive to several ligands.<a class="elsevierStyleCrossRefs" href="#bib0055">11–13</a> In this study, we observed that the distribution of the two polymorphisms were similar in patients with ACS and healthy controls. The association of the TLR-4 gene polymorphisms with several diseases in different populations is controversial with positive and negative results. For example, Koch et al. reported no association of the two TLR-4 gene polymorphisms with myocardial infarction in 3647 patients and 1211 individuals control with angiographic normal coronary and without signs or symptoms of myocardial infarction. In this work the authors showed that gender (women and men) did not sex-related associations and genotypes of polymorphisms in a Caucasian population,<a class="elsevierStyleCrossRef" href="#bib0155">31</a> agreeing with our results. Similar data were obtained by Labrum et al. who studied the two TLR-4 gene polymorphisms in a cohort 3000 individuals obtained of carotid atherosclerosis progression study. In this study showed no association between carotid artery intima-media thickness and polymorphisms of the TLR4 gene in 1460 males and 1540 females. However, there was no association between polymorphisms of TLR4 gene and baseline intima-media thickness. In addition, is reported there was no interactions between polymorphisms and the cardiovascular risk factors (C-reactive protein, smoking, body mass index and diabetes) in Caucasian population.<a class="elsevierStyleCrossRef" href="#bib0160">32</a> Moreover, Zee et al. reported that the Asp299Gly polymorphism is not associated with risk of incident myocardial infarction and stroke in 695 patients and 695 individuals control matched by age, smoking history, adjusted by body mass index, history of hypertension and presence or absence of diabetes, in a US population,<a class="elsevierStyleCrossRef" href="#bib0165">33</a> in line with our data. In contrast with these results, Ameziane et al. reported that the 299Gly allele is associated with decreased risk of developing ACS in 183 patients and 216 controls (OR=0.41). In addition, in controls the individuals with heterozygous (299 Asp/Gly) genotype was also associated with a significantly decrease in plasma fibrinogen and soluble vascular cellular adhesion molecule-1 levels in a French population.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> On the other hand, Hernesniemi et al. reported an association of the 299Gly allele with increased carotid artery elasticity in a cohort of 2201 young adults. In addition, according to multivariate linear regression analysis adjusted with potential confounders, the 299Gly allele carriers had significantly higher carotid arterial compliance, measured in increase of luminal diameter percentage in response to blood pressure. This increase has beneficial effects, because it reduces the risk of future cardiovascular events.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> Santini et al. reported in a case–control study that the CT (Thr/Ile) genotype of the Thr388Ile polymorphism increases susceptibility to gastric cancer (OR=5.38). In addition, according with regression analysis determine that the Thr/Ile genotype adjusted for age, sex (male), alcohol intake and smoking status increases susceptibility to gastric cancer (OR=3.62).<a class="elsevierStyleCrossRef" href="#bib0130">26</a> Similar data were reported by Speletas et al., who observed that the T (Ile) allele and CT (Thr/Ile) genotype (OR=2.4 and OR=2.0, respectively) are associated with risk of developing chronic obstructive pulmonary disease in a case–control study. Unfortunately, authors no determine differences between polymorphism and clinical and demographic data.<a class="elsevierStyleCrossRef" href="#bib0135">27</a> Nonetheless, the results obtained of the multiple logistic regression analysis showed that smoking, hypertension, type II diabetes, and gender increased more the risk of developing ACS. These data confirm the previous results obtained by our group in a small group of patients.<a class="elsevierStyleCrossRef" href="#bib0170">34</a> Moreover, this analysis showed no association between the TLR4 gene polymorphisms and clinical characteristics of the ACS in Mexican patients.Limitations of the studyWe recognize that our study has limitations; one was the limited samples number in controls group. Another limitation was pairing by gender between patients group and control group. Some experts consider that a proper analysis would need a relation between controls and patients of 1:1. Unfortunately for this report we could not meet this criterion. Nonetheless, the results from the present study are concordant with data reported in the international literature.ConclusionThe Asp299Gly and Thr399Ile gene polymorphisms were not associated with ACS in the present group of Mexican patients.FundingThis work was supported in part by grants from the Consejo Nacional de Ciencia y Tecnología (project 156911) and Fundación Gonzalo Rio Arronte, Mexico City, Mexico.DisclosureThe authors alone are responsible for the content and writing of the paper.Conflicts of interestThe authors report no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:2 [ "identificador" => "xres298634" "titulo" => array:5 [ 0 => "Abstract" 1 => "Objective" 2 => "Methods" 3 => "Results" 4 => "Conclusion" ] ] 1 => array:2 [ "identificador" => "xpalclavsec281665" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres298633" "titulo" => array:5 [ 0 => "Resumen" 1 => "Objetivo" 2 => "Métodos" 3 => "Resultados" 4 => "Conclusión" ] ] 3 => array:2 [ "identificador" => "xpalclavsec281664" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Study populations" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "DNA extraction" ] 2 => array:3 [ "identificador" => "sec0025" "titulo" => "Determination of the TLR-4 genotypes" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Statistical analysis" ] ] ] ] ] 6 => array:3 [ "identificador" => "sec0035" "titulo" => "Results" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Characteristic of the study sample" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Allele and genotype frequencies" ] ] ] 7 => array:3 [ "identificador" => "sec0050" "titulo" => "Discussion" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Limitations of the study" ] ] ] 8 => array:2 [ "identificador" => "sec0060" "titulo" => "Conclusion" ] 9 => array:2 [ "identificador" => "sec0065" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0070" "titulo" => "Disclosure" ] 11 => array:2 [ "identificador" => "sec0075" "titulo" => "Conflicts of interest" ] 12 => array:2 [ "identificador" => "xack70416" "titulo" => "Acknowledgment" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2012-11-27" "fechaAceptado" => "2013-09-09" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec281665" "palabras" => array:4 [ 0 => "Single nucleotide polymorphisms" 1 => "Acute coronary syndrome" 2 => "Genetics" 3 => "Mexico" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec281664" "palabras" => array:4 [ 0 => "Polimorfismos de un nucleótido" 1 => "Síndrome coronario agudo" 2 => "Genética" 3 => "México" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "ObjectiveThe objective of this study was to establish the role of the TLR-4 gene polymorphisms in individuals in risk of developing ACS. MethodsThe study included 457 Mexican patients with ACS and 283 control individuals. The TLR-4 Asp299Gly and TLR-4 Thr399Ile single nucleotide polymorphisms were genotyped using 5′ exonuclease TaqMan genotyping assays on an 7900HT Fast real-time PCR system according to manufacturer's instructions (Applied Biosystems, Foster City, USA). ResultsThe results obtained in this study showed that the frequency of the two polymorphisms (TLR-4 Asp299Gly and TLR-4 Thr399Ile) studied were similar between patients with ACS and healthy controls. Multiple logistic regression analysis showed that the largest risk factor for ACS development was given by smoking (11.88-fold increased risk), hypertension (4.32-fold increased risk), type II diabetes (3.44-fold increased risk), gender (2.32-fold increased risk), and dyslipidemia (1.52-fold increased risk). ConclusionThe Asp299Gly and Thr399Ile polymorphisms were not associated with susceptibility to ACS in the Mexican population." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "ObjetivoEl objetivo de este estudio fue establecer el papel de los polimorfismos del gen TLR-4 en individuos en riesgo de desarrollar síndrome coronario agudo (SCA). MétodosEl estudio incluyó a 457 pacientes mexicanos con SCA y 283 individuos como grupo control. Los polimorfismos de un solo nucleótido TLR-4 Asp299Gly y TLR-4 Thr399Ile fueron determinados usando ensayos TaqMan 5′ exonucleasa en un equipo tiempo real 7900HT (Fast real-time PCR system) de acuerdo con instrucciones del fabricante Applied Biosystems, Foster City, EE.UU. ResultadosLos resultados obtenidos mostraron que las frecuencias de los 2 polimorfismos (TLR-4 Asp299Gly y TLR-4 Thr399Ile) estudiados fueron similares entre pacientes con SCA e individuos control. No obstante, el análisis de regresión logística mostró que los factores de mayor riesgo para desarrollar SCA se debieron a tabaquismo (incrementa 11.88 veces el riesgo), hipertensión (incrementa 4.32 veces el riesgo), diabetes tipo 2 (incrementa 3.44 veces el riesgo), género (incrementa 2.32 veces el riesgo), y la dislipidemia (incrementa 1.52 veces el riesgo). ConclusiónDeterminamos que los polimorfismos Asp299Gly y Thr399Ile no se asocian con la susceptibilidad al SCA en la población mexicana." ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "Abbreviations: ACS, acute coronary syndrome; BMI, body index mass." "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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Clinical characteristics \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">ACS patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Healthy controls \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">P value \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Median (percentile 25–75) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Median (percentile 25–75) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age (years) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">59 (53–67) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">55 (50–60) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BMI (kg/m2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">26.7 (24.4–29.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">27.7 (25.5–30.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.0027 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n(%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n(%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Men<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">368 (80) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">202 (71) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypertension (mmHg)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">311 (68) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">94 (33) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Type 2 diabetes<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">191 (42) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">39 (14) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dyslipidemia<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">239 (52) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">119 (42) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.007 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Smoking<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">245 (54) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">59 (21) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab436967.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "n(%) number and proportion of subjects with the same clinical characteristic in both groups." ] ] ] "descripcion" => array:1 [ "en" => "Baseline clinical characteristics of the study group." ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Polymorphisms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Allele/genotype \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">ACS patients, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Controls, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">P value \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="5" align="left" valign="middle">TLR4-Asp299Gly</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">A (Asp) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">882 (97) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">550 (97) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="middle">NS</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">G (Gly) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">32 (3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16 (3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AA (Asp/Asp) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">425 (93) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">267 (94) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="middle">NS</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AG (Asp/Gly) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">32 (7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16 (6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GG (Gly/gly) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="5" align="left" valign="middle"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="5" align="left" valign="middle">TLR4-Thr399Ile</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C (Thr) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">881 (97) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">550 (97) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="middle">NS</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">G (Ile) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">33 (3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16 (3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CC (Thr/Thr) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">424 (97) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">267 (94) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="middle">NS</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CT (Thr/Ile) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">33 (7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16 (6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TT (Ile/Ile) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab436969.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Allele and genotype distribution between cases and controls." ] ] 2 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "Abbreviation: CVRF, cardiovascular risk factor." "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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">CVRF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">OR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">95% CI \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">P value \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gender (female/male) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.41–3.80 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age (years) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.03 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.01–1.05 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.003 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypertension (yes/no) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.80–6.64 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><10−3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dyslipidemia (yes/no) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.52 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.01–2.28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.043 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Current smoking (yes/no) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11.88 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7.26–19.42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><10−3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Type 2 diabetes mellitus (yes/no) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.44 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.13–5.55 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><10−3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Body mass index (kg/m2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.93 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.88–0.98 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.004 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab436968.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Estimated risk of ACS between case and controls." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:34 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Atherosclerosis an inflammatory disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "R. Ross" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM199901143400207" "Revista" => array:7 [ "tituloSerie" => "N Engl J Med" "fecha" => "1999" "volumen" => "340" "paginaInicial" => "115" "paginaFinal" => "126" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9887164" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S1521694211001598" "estado" => "S300" "issn" => "15216942" ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inflammatory and anti-inflammatory markers in acute coronary syndromes. Ready for use in the clinical setting?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "X. Garcia-Moll" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Rev Esp Cardiol" "fecha" => "2005" "volumen" => "58" "paginaInicial" => "615" "paginaFinal" => "617" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15970115" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Atherosclerosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "A.J. Lusis" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/35025203" "Revista" => array:6 [ "tituloSerie" => "Nature" "fecha" => "2000" "volumen" => "407" "paginaInicial" => "233" "paginaFinal" => "241" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11001066" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inflammation and atherosclerosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "P. Libby" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nature01323" "Revista" => array:6 [ "tituloSerie" => "Nature" "fecha" => "2002" "volumen" => "420" "paginaInicial" => "868" "paginaFinal" => "874" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12490960" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "R. Virmani" 1 => "F.D. Kolodgie" 2 => "A.P. 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"vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/14059940/0000008300000004/v1_201312121218/S1405994013001055/v1_201312121218/en/main.assets" "Apartado" => array:4 [ "identificador" => "9822" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Investigaciones clínicas" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/14059940/0000008300000004/v1_201312121218/S1405994013001055/v1_201312121218/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1405994013001055?idApp=UINPBA00004N"]

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Clinical Research

No existe asociación entre los polimorfismos del receptor tipo toll-4 y el síndrome coronario agudo

Marco A. Martínez-Ríosa, Gilberto Vargas-Alarcónb, Maite Vallejoc, Erick Cruz-Martíneza, Oscar Pérez-Méndezb, Ángel Medina-Andradeb, Mónica De la Torre-Garcíab, Marco A. Peña-Duquea, José Manuel Fragosob,

Corresponding author

mfragoso1275@yahoo.com.mx

Corresponding author. Juan Badiano No. 1, Tlalpan 14080, México DF, Mexico. Tel.: +52 55 5573 2911x1460; fax: +52 55 5573 0926.

a Interventional Cardiology, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico

b Department of Molecular Biology and Interventional Genetic Study Group in Cardiovascular Disease's, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico

c Department of Sociomedicine, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Atherosclerosis is a multifactorial disorder that results from an excessive inflammatory response to various forms of injurious stimuli to the arterial wall&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;3</span></a> The inflammatory processes&#44; genetic background&#44; and various environmental factors&#44; coupled to dyslipidemia&#44; including hypertension&#44; diabetes&#44; obesity&#44; and smoking play an important role in the progression of the atherosclerotic plaque&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#8211;5</span></a> The transition of a stable coronary atherosclerotic lesion into a ruptured and eroded plaque results in the clinical manifestation of an acute coronary syndrome &#40;ACS&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;6</span></a> The ACS includes unstable angina and myocardial infarction caused mainly by rupture or erosion of the atherosclerotic plaque&#44; with subsequent thrombus formation&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#8211;8</span></a> Mounting evidence suggests that specific agents enhance arterial inflammation during atherogenesis&#44; based on their interaction with receptor signaling pathways of the innate immune systems&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;10</span></a> Toll-like receptor 4 &#40;<span class="elsevierStyleItalic">TLR-4</span>&#41; is part of the innate immunity response cascade&#46; It has been associated as one of the factors contributing to the deleterious process of atherosclerosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#8211;13</span></a><span class="elsevierStyleItalic">TLR-4</span> is well known as a pattern-recognition receptor for exogenous lipopolysacharide &#40;LPS&#41; derived from gram-negative bacterial infection&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;15</span></a> However&#44; several studies showed that <span class="elsevierStyleItalic">TLR-4</span> interacts with other ligands&#44; such as fibrinogen&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> fibronectin&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> heat-shock protein&#44;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> hyaluronan oligosaccharide<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> and modified low-density lipoproteins &#40;LDL&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;21</span></a> playing an important role in the development of the atherosclerotic plaque&#46; The <span class="elsevierStyleItalic">TLR-4</span> gene is located in the 9q32 region&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleItalic">TLR-4</span> presents two single nucleotide polymorphisms &#40;SNP&#41;&#44; both polymorphisms&#44; rs4986790 &#40;<span class="elsevierStyleItalic">Asp299Gly</span>&#41; and rs4986791 &#40;<span class="elsevierStyleItalic">Thr399Ile</span>&#41;&#44; are located in the coding region&#46; These &#40;SNPs&#41; affect <span class="elsevierStyleItalic">TLR-4</span> extracellular domain and result in amino acid exchanges&#58; an aspartic acid for a glycine at position 299 &#40;<span class="elsevierStyleItalic">Asp299Gly</span>&#41; and a threonine for a isoleucine at position 399 &#40;<span class="elsevierStyleItalic">Thr399Ile</span>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</span></a> Several studies associate these polymorphisms with several inflammatory diseases&#44; such as ACS&#44; gastric cancer&#44; carotid artery elasticity&#44; chronic obstructive pulmonary disease&#44; and atherosclerosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#8211;28</span></a> Considering the prominent role of the <span class="elsevierStyleItalic">TLR-4</span> as initiator of the inflammatory response&#44; this study was based on the assumption that the <span class="elsevierStyleItalic">TLR-4</span> gene polymorphisms have a measurable influence in the development of the atherosclerotic plaque and contributes to or increases the occurrence of ACS&#46; The objective of this study was to establish the possible role of the <span class="elsevierStyleItalic">TLR-4</span> gene polymorphisms as a risk factor for ACS in a group of Mexicans patients&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Study populations</span><p id="par0010" class="elsevierStylePara elsevierViewall">The study included 457 Mexican patients with ACS &#40;368 males and 89 females&#44; mean age 59&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#46;02&#41; that were attended to our Institution&#46; Three hundred forty-two presented myocardial infarction and 115 presented unstable angina&#46; All subjects were diagnosed according to the World Health Organization and the American Heart Associated &#40;AHA&#41;&#47;American College of Cardiology &#40;ACC&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Basis in clinical history&#44; physical examination with electrocardiography&#44; chest radiography&#44; echocardiography&#44; and coronary angiography&#46; The group of patients was compared with a group of 283 healthy unrelated individuals &#40;202 males and 81 females&#44; mean age 55&#46;39<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;23&#41;&#46; This group was selected from people arriving with the purpose to donation at the blood bank at our institute&#46; According to the medical records&#44; none of these had diabetes&#44; dyslipidemia&#44; hypertension or other pathology&#46; On the other hand&#44; subclinical atherosclerosis was discarded through determined calcium score by multi-detector computed tomography&#46; The values were zero in these individuals&#46; All subjects included in the study &#40;patients and controls&#41; were ethnically matched&#44; and we considered as Mexican Mestizos only those individuals who had been born in Mexico for three generations&#44; including their own&#46; A Mexican Mestizo is defined as someone born in Mexico&#44; who is a descendant of the original autochthonous inhabitants of the region and of individuals&#44; mainly Spaniards&#44; of Caucasian and African origin&#44; who came to the American continent during the sixteenth century&#46; The Institutional Ethics and Research Committees approved the study&#44; and all subjects provided written&#44; informed consent&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">DNA extraction</span><p id="par0015" class="elsevierStylePara elsevierViewall">Genomic DNA from whole blood containing EDTA was isolated with a standard technique&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Determination of the TLR-4 genotypes</span><p id="par0020" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">TLR-4 Asp299Gly</span> &#40;rs4986790&#41; and <span class="elsevierStyleItalic">TLR-4 Thr399Ile</span> &#40;rs4986791&#41; single nucleotide polymorphisms were genotyped using 5&#8242; exonuclease TaqMan genotyping assays on an 7900HT Fast real-time PCR system according to manufacturer&#39;s instructions &#40;Applied Biosystems&#44; Foster City&#44; USA&#41;&#46;</p><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Statistical analysis</span><p id="par0025" class="elsevierStylePara elsevierViewall">Gene frequencies of <span class="elsevierStyleItalic">TLR-4</span> polymorphisms in patients and controls were obtained by direct counting&#46; Hardy&#8211;Weinberg equilibrium was evaluated by Chi<span class="elsevierStyleSup">2</span> test&#46; Statistical analysis was carried out with the Stata 10&#46;0 software for Windows&#46; In the exploratory analysis&#44; numerical data showed a different distribution from normal standard &#40;Gaussian distribution&#41; &#40;Shapiro Wilk&#39;s test of normality&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#44; nominal and categorical variables were tabulated to estimate their proportions&#46; Hypertension&#44; altered lipid profile&#44; smoking&#44; and type 2 diabetes mellitus had two categories&#44; yes or no&#44; and all described the current condition of patients and healthy controls&#46; Comparison of numerical variables&#44; such as age and body mass index&#44; between both groups was carried out with Mann&#8211;Whitney <span class="elsevierStyleItalic">U</span> test&#44; data are presented as the 25th percentile&#44; median&#44; and 75th percentile&#46; Categorical variables were analyzed with Chi<span class="elsevierStyleSup">2</span> tests and presented as absolute frequencies and proportions&#46; Statistical significance was set at <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46; Multiple logistic regression analysis was carried out to identify the variables that better explain the risk of developing ACS between patients and healthy controls&#46; Models were constructed including one variable at a time to identify confounding bias&#59; changes in estimated odds ratios &#40;ORs&#41; were less than 10&#37;&#46; When a main effect model was reached&#44; effect modification was also tested&#44; interaction terms were constructed between age and BMI&#44; hypertension and type 2 diabetes mellitus&#44; smoking and hypertension&#44; and gender and BMI&#44; no significant ORs &#40;<span class="elsevierStyleItalic">p</span> &#8804; 0&#46;20&#41; were identified and therefore these terms were not included in the final model&#46; Hosmer&#8211;Lemeshow Goodness of fit test was performed for each multiple logistic model&#46; Pairwise linkage disequilibrium &#40;LD&#44; D&#8242;&#41; estimations between polymorphisms and haplotype reconstruction were performed with Haploview version 4&#46;1 &#40;Broad Institute of Massachusetts Institute of Technology and Harvard University&#44; Cambridge&#44; MA&#44; USA&#41;&#46;</p></span></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Results</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Characteristic of the study sample</span><p id="par0030" class="elsevierStylePara elsevierViewall">Baseline characteristic of the ACS patients and healthy controls included in the study are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Allele and genotype frequencies</span><p id="par0035" class="elsevierStylePara elsevierViewall">The observed and expected frequencies in the two polymorphic sites of the toll-like receptor &#40;<span class="elsevierStyleItalic">TLR-4</span>&#41; were in Hardy&#8211;Weinberg equilibrium&#46; The allele and genotype frequencies of the two studied polymorphisms &#40;positions &#43;896 <span class="elsevierStyleItalic">A&#62;G</span> &#40;<span class="elsevierStyleItalic">Asp299Gly</span>&#41; and &#43;1196 <span class="elsevierStyleItalic">C&#62;T</span> &#40;<span class="elsevierStyleItalic">Thr399Ile</span>&#41;&#41; were similar between patients with ACS and healthy controls &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; The multiple logistic regression analysis showed that the largest risk for ACS development was given by smoking &#40;11&#46;88-fold increased risk&#41;&#44; hypertension &#40;4&#46;32-fold increased risk&#41;&#44; type II diabetes &#40;3&#46;44-fold increased risk&#41;&#44; gender &#40;2&#46;32-fold increased risk&#41;&#44; and dyslipidemia &#40;1&#46;52-fold increased risk&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; The &#43;896 <span class="elsevierStyleItalic">A&#62;G</span> &#40;<span class="elsevierStyleItalic">Asp299Gly</span>&#41; and &#43;1196 <span class="elsevierStyleItalic">C&#62;T</span> &#40;<span class="elsevierStyleItalic">Thr399Ile</span>&#41; polymorphisms showed a strong linkage disequilibrium &#40;<span class="elsevierStyleItalic">D</span>&#8242;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;82&#41; and were used to construct two haplotypes &#40;<span class="elsevierStyleItalic">AC</span> and <span class="elsevierStyleItalic">GT</span>&#41;&#46; The haplotype &#8220;<span class="elsevierStyleItalic">AC</span>&#8221; showed a similar distribution in ACS patients and healthy controls &#40;95&#46;7&#37; and 96&#46;8&#37;&#44; respectively&#41;&#46; Moreover&#44; the &#8220;<span class="elsevierStyleItalic">GT</span>&#8221; haplotype showed a similar decreased in patients and control &#40;4&#46;3&#37;&#44; and 3&#46;2&#37;&#44; respectively&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Discussion</span><p id="par0040" class="elsevierStylePara elsevierViewall">In the present work&#44; we studied two polymorphisms &#40;<span class="elsevierStyleItalic">Asp299Gly</span> and <span class="elsevierStyleItalic">Thr399Ile</span>&#41; located in the <span class="elsevierStyleItalic">TLR-4</span> gene in 457 patients with ACS and 283 healthy controls&#46; In humans&#44; both polymorphisms affect <span class="elsevierStyleItalic">TLR-4</span> extracellular domain and individuals that possess these polymorphisms are hyporesponsive to several ligands&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#8211;13</span></a> In this study&#44; we observed that the distribution of the two polymorphisms were similar in patients with ACS and healthy controls&#46; The association of the <span class="elsevierStyleItalic">TLR-4</span> gene polymorphisms with several diseases in different populations is controversial with positive and negative results&#46; For example&#44; Koch et al&#46; reported no association of the two <span class="elsevierStyleItalic">TLR-4</span> gene polymorphisms with myocardial infarction in 3647 patients and 1211 individuals control with angiographic normal coronary and without signs or symptoms of myocardial infarction&#46; In this work the authors showed that gender &#40;women and men&#41; did not sex-related associations and genotypes of polymorphisms in a Caucasian population&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> agreeing with our results&#46; Similar data were obtained by Labrum et al&#46; who studied the two <span class="elsevierStyleItalic">TLR-4</span> gene polymorphisms in a cohort 3000 individuals obtained of carotid atherosclerosis progression study&#46; In this study showed no association between carotid artery intima-media thickness and polymorphisms of the TLR4 gene in 1460 males and 1540 females&#46; However&#44; there was no association between polymorphisms of TLR4 gene and baseline intima-media thickness&#46; In addition&#44; is reported there was no interactions between polymorphisms and the cardiovascular risk factors &#40;C-reactive protein&#44; smoking&#44; body mass index and diabetes&#41; in Caucasian population&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> Moreover&#44; Zee et al&#46; reported that the <span class="elsevierStyleItalic">Asp299Gly</span> polymorphism is not associated with risk of incident myocardial infarction and stroke in 695 patients and 695 individuals control matched by age&#44; smoking history&#44; adjusted by body mass index&#44; history of hypertension and presence or absence of diabetes&#44; in a US population&#44;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> in line with our data&#46; In contrast with these results&#44; Ameziane et al&#46; reported that the <span class="elsevierStyleItalic">299Gly</span> allele is associated with decreased risk of developing ACS in 183 patients and 216 controls &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;41&#41;&#46; In addition&#44; in controls the individuals with heterozygous &#40;299 Asp&#47;Gly&#41; genotype was also associated with a significantly decrease in plasma fibrinogen and soluble vascular cellular adhesion molecule-1 levels in a French population&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> On the other hand&#44; Hernesniemi et al&#46; reported an association of the <span class="elsevierStyleItalic">299Gly</span> allele with increased carotid artery elasticity in a cohort of 2201 young adults&#46; In addition&#44; according to multivariate linear regression analysis adjusted with potential confounders&#44; the 299<span class="elsevierStyleItalic">Gly</span> allele carriers had significantly higher carotid arterial compliance&#44; measured in increase of luminal diameter percentage in response to blood pressure&#46; This increase has beneficial effects&#44; because it reduces the risk of future cardiovascular events&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> Santini et al&#46; reported in a case&#8211;control study that the <span class="elsevierStyleItalic">CT</span> &#40;<span class="elsevierStyleItalic">Thr&#47;Ile</span>&#41; genotype of the <span class="elsevierStyleItalic">Thr388Ile</span> polymorphism increases susceptibility to gastric cancer &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#46;38&#41;&#46; In addition&#44; according with regression analysis determine that the <span class="elsevierStyleItalic">Thr&#47;Ile</span> genotype adjusted for age&#44; sex &#40;male&#41;&#44; alcohol intake and smoking status increases susceptibility to gastric cancer &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;62&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Similar data were reported by Speletas et al&#46;&#44; who observed that the <span class="elsevierStyleItalic">T</span> &#40;<span class="elsevierStyleItalic">Ile</span>&#41; allele and <span class="elsevierStyleItalic">CT</span> &#40;<span class="elsevierStyleItalic">Thr&#47;Ile</span>&#41; genotype &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;4 and OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;0&#44; respectively&#41; are associated with risk of developing chronic obstructive pulmonary disease in a case&#8211;control study&#46; Unfortunately&#44; authors no determine differences between polymorphism and clinical and demographic data&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Nonetheless&#44; the results obtained of the multiple logistic regression analysis showed that smoking&#44; hypertension&#44; type II diabetes&#44; and gender increased more the risk of developing ACS&#46; These data confirm the previous results obtained by our group in a small group of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> Moreover&#44; this analysis showed no association between the <span class="elsevierStyleItalic">TLR4</span> gene polymorphisms and clinical characteristics of the ACS in Mexican patients&#46;</p><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Limitations of the study</span><p id="par0045" class="elsevierStylePara elsevierViewall">We recognize that our study has limitations&#59; one was the limited samples number in controls group&#46; Another limitation was pairing by gender between patients group and control group&#46; Some experts consider that a proper analysis would need a relation between controls and patients of 1&#58;1&#46; Unfortunately for this report we could not meet this criterion&#46; Nonetheless&#44; the results from the present study are concordant with data reported in the international literature&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conclusion</span><p id="par0050" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">Asp299Gly</span> and <span class="elsevierStyleItalic">Thr399Ile</span> gene polymorphisms were not associated with ACS in the present group of Mexican patients&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Funding</span><p id="par0055" class="elsevierStylePara elsevierViewall">This work was supported in part by grants from the <span class="elsevierStyleGrantSponsor" id="gs0005"><span class="elsevierStyleItalic">Consejo Nacional de Ciencia y Tecnolog&#237;a</span></span> &#40;project 156911&#41; and <span class="elsevierStyleGrantSponsor" id="gs0010"><span class="elsevierStyleItalic">Fundaci&#243;n Gonzalo Rio Arronte</span></span>&#44; Mexico City&#44; Mexico&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Disclosure</span><p id="par0060" class="elsevierStylePara elsevierViewall">The authors alone are responsible for the content and writing of the paper&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conflicts of interest</span><p id="par0065" class="elsevierStylePara elsevierViewall">The authors report no conflicts of interest&#46;</p></span></span>"
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              "titulo" => "Determination of the TLR-4 genotypes"
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    "fechaRecibido" => "2012-11-27"
    "fechaAceptado" => "2013-09-09"
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            1 => "Acute coronary syndrome"
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            3 => "Mexico"
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            0 => "Polimorfismos de un nucle&#243;tido"
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        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The objective of this study was to establish the role of the TLR-4 gene polymorphisms in individuals in risk of developing ACS&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The study included 457 Mexican patients with ACS and 283 control individuals&#46; The TLR-4 Asp299Gly and TLR-4 Thr399Ile single nucleotide polymorphisms were genotyped using 5&#8242; exonuclease TaqMan genotyping assays on an 7900HT Fast real-time PCR system according to manufacturer&#39;s instructions &#40;Applied Biosystems&#44; Foster City&#44; USA&#41;&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The results obtained in this study showed that the frequency of the two polymorphisms &#40;TLR-4 Asp299Gly and TLR-4 Thr399Ile&#41; studied were similar between patients with ACS and healthy controls&#46; Multiple logistic regression analysis showed that the largest risk factor for ACS development was given by smoking &#40;11&#46;88-fold increased risk&#41;&#44; hypertension &#40;4&#46;32-fold increased risk&#41;&#44; type II diabetes &#40;3&#46;44-fold increased risk&#41;&#44; gender &#40;2&#46;32-fold increased risk&#41;&#44; and dyslipidemia &#40;1&#46;52-fold increased risk&#41;&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The Asp299Gly and Thr399Ile polymorphisms were not associated with susceptibility to ACS in the Mexican population&#46;</p>"
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        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El objetivo de este estudio fue establecer el papel de los polimorfismos del gen <span class="elsevierStyleItalic">TLR-4</span> en individuos en riesgo de desarrollar s&#237;ndrome coronario agudo &#40;SCA&#41;&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">El estudio incluy&#243; a 457 pacientes mexicanos con SCA y 283 individuos como grupo control&#46; Los polimorfismos de un solo nucle&#243;tido <span class="elsevierStyleItalic">TLR-4 Asp299Gly</span> y <span class="elsevierStyleItalic">TLR-4 Thr399Ile</span> fueron determinados usando ensayos TaqMan 5&#8242; exonucleasa en un equipo tiempo real 7900HT &#40;Fast real-time PCR system&#41; de acuerdo con instrucciones del fabricante Applied Biosystems&#44; Foster City&#44; EE&#46;UU&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Los resultados obtenidos mostraron que las frecuencias de los 2 polimorfismos <span class="elsevierStyleItalic">&#40;TLR-4 Asp299Gly</span> y <span class="elsevierStyleItalic">TLR-4 Thr399Ile&#41;</span> estudiados fueron similares entre pacientes con SCA e individuos control&#46; No obstante&#44; el an&#225;lisis de regresi&#243;n log&#237;stica mostr&#243; que los factores de mayor riesgo para desarrollar SCA se debieron a tabaquismo &#40;incrementa 11&#46;88 veces el riesgo&#41;&#44; hipertensi&#243;n &#40;incrementa 4&#46;32 veces el riesgo&#41;&#44; diabetes tipo 2 &#40;incrementa 3&#46;44 veces el riesgo&#41;&#44; g&#233;nero &#40;incrementa 2&#46;32 veces el riesgo&#41;&#44; y la dislipidemia &#40;incrementa 1&#46;52 veces el riesgo&#41;&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Determinamos que los polimorfismos <span class="elsevierStyleItalic">Asp299Gly</span> y <span class="elsevierStyleItalic">Thr399Ile</span> no se asocian con la susceptibilidad al SCA en la poblaci&#243;n mexicana&#46;</p>"
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          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Abbreviations</span>&#58; ACS&#44; acute coronary syndrome&#59; BMI&#44; body index mass&#46;</p>"
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                  <table border="0" frame="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Clinical characteristics&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">ACS patients&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Healthy controls&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">55 &#40;50&#8211;60&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BMI &#40;kg&#47;m<span class="elsevierStyleSup">2</span>&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Men<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Hypertension &#40;mmHg&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">94 &#40;33&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Type 2 diabetes<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">191 &#40;42&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39 &#40;14&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dyslipidemia<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;007&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Smoking<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">59 &#40;21&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;001&nbsp;\t\t\t\t\t\t\n
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                  """
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Polymorphisms&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">550 &#40;97&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " rowspan="2" align="left" valign="middle">NS</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">16 &#40;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " rowspan="3" align="left" valign="middle">NS</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16 &#40;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
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Article information

ISSN: 14059940
Original language: English

DOI:10.1016/j.acmx.2013.09.001

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	2	0	2
2024 October	10	2	12
2024 September	21	3	24
2024 August	17	2	19
2024 July	8	4	12
2024 June	10	3	13
2024 May	20	2	22
2024 April	20	3	23
2024 March	121	3	124
2024 February	38	4	42
2024 January	30	1	31
2023 December	24	12	36
2023 November	22	1	23
2023 October	50	5	55
2023 September	16	2	18
2023 August	14	4	18
2023 July	16	4	20
2023 June	10	2	12
2023 May	20	3	23
2023 April	12	4	16
2023 March	9	3	12
2023 February	11	2	13
2023 January	8	8	16
2022 December	7	4	11
2022 November	10	6	16
2022 October	8	16	24
2022 September	15	5	20
2022 August	13	6	19
2022 July	13	9	22
2022 June	7	6	13
2022 May	9	6	15
2022 April	14	12	26
2022 March	13	11	24
2022 February	11	3	14
2022 January	23	9	32
2021 December	12	6	18
2021 November	8	10	18
2021 October	10	10	20
2021 September	15	12	27
2021 August	7	5	12
2021 July	10	6	16
2021 June	11	7	18
2021 May	7	7	14
2021 April	15	19	34
2021 March	16	6	22
2021 February	11	8	19
2021 January	15	9	24
2020 December	8	8	16
2020 November	6	8	14
2020 October	13	5	18
2020 September	15	12	27
2020 August	19	8	27
2020 July	9	8	17
2020 June	9	11	20
2020 May	10	8	18
2020 April	18	4	22
2020 March	14	3	17
2020 February	11	6	17
2020 January	8	3	11
2019 December	21	1	22
2019 November	10	9	19
2019 October	6	1	7
2019 September	12	3	15
2019 August	10	5	15
2019 July	7	9	16
2019 June	20	13	33
2019 May	58	28	86
2019 April	28	11	39
2019 March	15	3	18
2019 February	18	3	21
2019 January	21	1	22
2018 December	18	4	22
2018 November	27	3	30
2018 October	18	14	32
2018 September	14	3	17
2018 August	35	0	35
2018 July	15	2	17
2018 June	6	0	6
2018 May	4	5	9
2018 April	24	7	31
2018 March	83	1	84
2018 February	15	1	16
2018 January	82	2	84
2017 December	40	3	43
2017 November	11	2	13
2017 October	13	6	19
2017 September	12	0	12
2017 August	20	2	22
2017 July	12	3	15
2017 June	11	14	25
2017 May	17	3	20
2017 April	14	4	18
2017 March	13	34	47
2017 February	17	7	24
2017 January	23	2	25
2016 December	38	7	45
2016 November	45	12	57
2016 October	52	8	60
2016 September	23	12	35
2016 August	27	5	32
2016 July	30	3	33
2016 June	17	4	21
2016 May	18	12	30
2016 April	9	8	17
2016 March	16	17	33
2016 February	18	16	34
2016 January	16	12	28
2015 December	19	8	27
2015 November	10	5	15
2015 October	19	10	29
2015 September	14	4	18
2015 August	10	3	13
2015 July	11	0	11
2015 June	11	0	11
2015 May	20	1	21
2015 April	16	17	33
2015 March	20	12	32
2015 February	10	4	14
2015 January	15	5	20
2014 December	27	8	35
2014 November	12	3	15
2014 October	29	8	37
2014 September	34	9	43
2014 August	16	5	21
2014 July	13	7	20
2014 June	21	9	30
2014 May	19	8	27
2014 April	21	13	34
2014 March	58	30	88
2014 February	60	24	84
2014 January	48	29	77
2013 December	33	22	55

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