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Asociación de la placa de ateroma carotídea con los niveles plasmáticos de IL-18 y con polimorfismos en el gen del receptor de la IL-18 en la población mediterránea
Association of carotid atheroma plaque with IL-18 levels and with polymorphisms in the IL-18 receptor gene in a Mediterranean population
Ana Palancaa,b, Amparo Bartual-Rodrigoa, Carolina Cuencab, Oscar D. Mayo-Lópezb, Francisco Javier Ampudia-Blascoa,b,d,e, Herminia González-Navarrob,c,d, Juan F. Ascasob,e, Ana Bárbara García-Garcíab,d,f, Felipe Javier Chavesb,d,f, José T. Reala,b,d,e, Sergio Martínez-Hervása,b,d,e,
Autor para correspondencia
sergio.martinez@uv.es

Autor para correspondencia.
a Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valencia, Valencia, España
b INCLIVA, Instituto de Investigación Sanitaria, Valencia, España
c Departamento de Bioquímica y Biología Molecular, Universitat de València, Valencia, España
d CIBER de Diabetes y Enfermedades Metabólicas asociadas, Instituto de Salud Carlos III, Madrid, España
e Departament de Medicina, Universitat de València, Valencia, España
f Unidad de Genómica y Diabetes, INCLIVA, Instituto de Investigación Sanitaria, Valencia, España
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    "titulosAlternativos" => array:1 [
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        "titulo" => "Association of carotid atheroma plaque with IL-18 levels and with polymorphisms in the IL-18 receptor gene in a Mediterranean population"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Introducci&#243;n</span><p id="par0005" class="elsevierStylePara elsevierViewall">La arteriosclerosis es una enfermedad inflamatoria cr&#243;nica<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a>&#46; Estudios en animales de experimentaci&#243;n han demostrado la importancia de diferentes mediadores inflamatorios tanto en el inicio como en el desarrollo de la arteriosclerosis<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a>&#46; M&#250;ltiples estudios en humanos han mostrado la estrecha asociaci&#243;n entre marcadores inflamatorios y el desarrollo de enfermedad cardiovascular<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a>&#46; Adem&#225;s&#44; recientemente se ha demostrado que el uso de f&#225;rmacos capaces de reducir el estado inflamatorio&#44; sin modificar otros factores de riesgo cardiovascular&#44; disminuye la incidencia de enfermedad cardiovascular<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">4&#8211;6</span></a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">El grado de inflamaci&#243;n&#44; as&#237; como el desarrollo de arteriosclerosis y la subsecuente enfermedad cardiovascular&#44; est&#225;n modulados tanto por factores ambientales como gen&#233;ticos&#46; La regulaci&#243;n del proceso inflamatorio por factores gen&#233;ticos podr&#237;a explicar la gran variabilidad existente en la respuesta inflamatoria<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a>&#46; Sin embargo&#44; la contribuci&#243;n gen&#233;tica tanto al desarrollo de inflamaci&#243;n como de arteriosclerosis no es completamente conocida&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Una de las mol&#233;culas inflamatorias que se ha relacionado con el desarrollo de arteriosclerosis es la interleucina 18 &#40;IL-18&#41;&#46; En modelos animales se ha observado que los niveles plasm&#225;ticos de IL-18 desempe&#241;an un importante papel tanto en la formaci&#243;n como en el desarrollo de la placa de ateroma&#44; as&#237; como en la estabilidad y la severidad de la misma<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">8</span></a>&#46; Resultados similares se han observado tambi&#233;n en humanos&#46; Diferentes estudios han demostrado la asociaci&#243;n entre los niveles de IL-18 y el desarrollo de enfermedad cardiovascular<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">9&#8211;11</span></a>&#46; Adem&#225;s&#44; algunos estudios han identificado la influencia de algunas variaciones gen&#233;ticas en los genes implicados en el sistema IL-18 sobre la enfermedad cardiovascular y la severidad de la misma<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">7&#44;12</span></a>&#44; si bien hay menos datos sobre los Single Nucleotide Polymorphisms &#40;SNPs&#41; localizados en receptor 1 de IL-18 &#40;IL18R1&#41; y prote&#237;na accesoria del receptor de IL-18 &#40;IL18RAP&#41;&#44; aunque existen resultados contradictorios y no se ha evaluado su efecto sobre la placa de ateroma<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">13&#44;14</span></a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">En este sentido&#44; nuestra hip&#243;tesis fue que los niveles plasm&#225;ticos de IL-18 se asocian con la presencia de arteriosclerosis&#44; pudiendo existir variaciones gen&#233;ticas que podr&#237;an influir el desarrollo de la placa de ateroma&#46; Por ello&#44; el objetivo de nuestro estudio fue evaluar la posible relaci&#243;n entre los niveles plasm&#225;ticos de IL-18 y la presencia de arteriosclerosis evaluada a nivel carot&#237;deo&#44; as&#237; como analizar la posible influencia de diferentes polimorfismos en los genes IL18R1 e IL18RAP en una poblaci&#243;n mediterr&#225;nea&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Material y m&#233;todos</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Sujetos</span><p id="par0025" class="elsevierStylePara elsevierViewall">Se incluyeron 746 pacientes procedentes del estudio VALencian CArdiovascular Risk &#40;VALCAR&#41;&#46; Se trata de un estudio transversal dise&#241;ado para evaluar la prevalencia de factores de riesgo cardiovascular en una poblaci&#243;n urbana&#44; y su asociaci&#243;n con la presencia de arteriosclerosis evaluada mediante ecograf&#237;a carot&#237;dea&#46; Los individuos participantes se incluyeron durante dos a&#241;os por muestreo consecutivo oportun&#237;stico de entre aquellos que acud&#237;an a diferentes consultas de nuestro departamento de salud en un &#225;rea metropolitana de Valencia&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Los criterios de exclusi&#243;n para nuestro estudio fueron&#58; pacientes con enfermedades inflamatorias cr&#243;nicas &#40;tanto de tipo digestivo como reum&#225;tico&#41;&#44; la presencia de niveles plasm&#225;ticos de prote&#237;na C reactiva de alta sensibilidad &#40;PCRas&#41;<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>mg&#47;l y haber presentado alg&#250;n episodio infeccioso o inflamatorio en las 2 semanas previas&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">El estudio fue aprobado por el Comit&#233; &#201;tico de nuestro centro&#46; Todos los participantes otorgaron su consentimiento por escrito para participar en el estudio&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Par&#225;metros cl&#237;nicos</span><p id="par0040" class="elsevierStylePara elsevierViewall">Se realiz&#243; una anamnesis a todos los participantes en la que se prest&#243; especial inter&#233;s al uso de f&#225;rmacos de consumo habitual u ocasional durante el periodo del estudio&#44; al h&#225;bito tab&#225;quico &#40;n&#250;mero de cigarrillos&#47;d&#237;a&#41; y al consumo de alcohol &#40;gramos de alcohol&#47;d&#237;a&#41;&#46; Se recogieron tambi&#233;n los antecedentes de enfermedad cardiovascular previa a la fecha de inclusi&#243;n en el estudio&#46; La presi&#243;n arterial se determin&#243; tras 10 minutos de dec&#250;bito supino&#44; utilizando el valor medio de 3 determinaciones separadas entre s&#237; 5<span class="elsevierStyleHsp" style=""></span>min&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Par&#225;metros antropom&#233;tricos</span><p id="par0050" class="elsevierStylePara elsevierViewall">Los par&#225;metros evaluados fueron&#58; peso en kilogramos &#40;kg&#41;&#44; talla en metros &#40;m&#41;&#44; &#237;ndice de masa corporal &#40;IMC&#41; en kg&#47;m<span class="elsevierStyleSup">2</span> y per&#237;metro de cintura en cent&#237;metros &#40;cm&#41;&#44; medido en el punto medio entre la espina il&#237;aca anterosuperior y el reborde costal inferior&#44; con el sujeto en bipedestaci&#243;n y los brazos en posici&#243;n anat&#243;mica&#46; La medida se obtuvo con una cinta m&#233;trica graduada en cm&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Par&#225;metros bioqu&#237;micos</span><p id="par0055" class="elsevierStylePara elsevierViewall">Se extrajo una muestra de sangre tras ayuno nocturno de 12<span class="elsevierStyleHsp" style=""></span>h&#46; La metodolog&#237;a fue similar a la previamente descrita<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">15</span></a>&#46; En concreto&#44; los niveles plasm&#225;ticos de colesterol total &#40;CT&#41;&#44; triglic&#233;ridos &#40;TG&#41; y glucosa se determinaron por m&#233;todos enzim&#225;ticos&#46; El colesterol HDL &#40;cHDL&#41; tras precipitaci&#243;n con &#225;cido fosfot&#250;ngstico cloruro de magnesio&#46; El colesterol LDL &#40;cLDL&#41; se calcul&#243; por la f&#243;rmula de Friedewald&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Los niveles plasm&#225;ticos de IL-18 se determinaron mediante la t&#233;cnica ELISA con &#171;Human IL-18 ELISA Kit&#187; &#40;Medical &#603;t BIologicalLaboratories Co&#46; Ltd&#46;&#41; y se cuantificaron por medici&#243;n de absorbancia con el aparato GloMax&#174;-Multi<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>DetectionSystem &#40;Promega&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Ecograf&#237;a carot&#237;dea</span><p id="par0065" class="elsevierStylePara elsevierViewall">La ecograf&#237;a se realiz&#243; mediante un equipo Siemens Sonoline G40&#44; con transductor lineal de alta resoluci&#243;n de 8<span class="elsevierStyleHsp" style=""></span>MHz de frecuencia&#46; La exploraci&#243;n se realiz&#243; con los sujetos en dec&#250;bito supino con la cabeza a 45&#730; girada hacia el lado contrario del lado explorado&#46; Se evaluaron 3 segmentos predeterminados de ambos lados&#58; car&#243;tida com&#250;n &#40;1<span class="elsevierStyleHsp" style=""></span>cm proximal al bulbo carot&#237;deo&#41;&#44; bulbo carot&#237;deo &#40;1-2<span class="elsevierStyleHsp" style=""></span>cm&#41; y car&#243;tida interna &#40;1<span class="elsevierStyleHsp" style=""></span>cm distal a la bifurcaci&#243;n&#41;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">16</span></a>&#46; Se realizaron 6 medidas a intervalos regulares de forma bilateral en 3 proyecciones diferentes &#40;ACCD&#58; 90-120 y 150&#730;&#59; ACCI&#58; 210&#44; 240 y 270&#730;&#41;&#46; Para el an&#225;lisis estad&#237;stico se utilizaron todas las mediciones&#46; El grosor &#237;ntima media &#40;GIM&#41;&#44; definido como la distancia entre la interfaz luz carot&#237;dea-&#237;ntima y la interfaz media-adventicia de la pared distal&#44; se determin&#243; en secciones longitudinales la regi&#243;n previa a la bifurcaci&#243;n de la arteria car&#243;tida com&#250;n &#40;1<span class="elsevierStyleHsp" style=""></span>cm&#41;&#46; Se consider&#243; placa carotidea al engrosamiento focal mayor del 50&#37; de la pared del vaso que lo rodea&#44; o a un GIM mayor a 1&#44;5<span class="elsevierStyleHsp" style=""></span>mm que protruye en la luz adyacente<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">17</span></a>&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Todas las exploraciones fueron realizadas por un &#250;nico investigador &#40;SM-H&#41; entrenado en la realizaci&#243;n de ecograf&#237;as carot&#237;deas y siguiendo siempre el mismo protocolo previamente descrito&#46; El coeficiente de variabilidad se estudi&#243; en 20 sujetos&#44; y fue del 5&#44;2&#37; para el GIM medio de ambas car&#243;tidas comunes&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Selecci&#243;n de SNP y genotipado</span><p id="par0075" class="elsevierStylePara elsevierViewall">Se obtuvo ADN gen&#243;mico a partir de c&#233;lulas sangu&#237;neas de sangre venosa&#44; utilizando el sistema Chemagic&#174; &#40;Chemagen&#44; Baesweiler&#44; Alemania&#41;&#46; El ADN fue cuantificado y diluido hasta una concentraci&#243;n final de 100<span class="elsevierStyleHsp" style=""></span>ng&#47;&#956;l&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Los SNP del receptor de IL-18 para el genotipado fueron seleccionados en base a una conjunci&#243;n de diferentes par&#225;metros&#58; heterocigosidad &#40;&#62;<span class="elsevierStyleHsp" style=""></span>10&#37; para el alelo de menor frecuencia&#41; en poblaci&#243;n cauc&#225;sica&#44; posici&#243;n y espaciado a lo largo del gen y posible efecto funcional &#40;<a href="http://www.%20ensembl.org/index.html">http&#58;&#47;&#47;www&#46; ensembl&#46;org&#47;index&#46;html</a>&#41;&#46; Cuatro de ellos fueron seleccionados finalmente&#58; rs2270297 y rs2287037 localizados en IL18R1&#59; rs2293224 y rs7559479 localizados en IL18RAP&#46; Los SNP fueron genotipados usando un ensayo de SNPlex&#174; &#40;Applied Biosystems&#44; Foster City&#44; CA&#44; EE&#46; UU&#46;&#41; siguiendo las recomendaciones del fabricante&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">M&#233;todos estad&#237;sticos</span><p id="par0085" class="elsevierStylePara elsevierViewall">Las variables cuantitativas han sido expresadas como media<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>desviaci&#243;n est&#225;ndar y las cualitativas como porcentajes y&#47;o n&#250;mero total&#46; Para la comparaci&#243;n de las variables cuantitativas entre grupos se ha utilizado el test de la t de Student y la prueba de ANOVA &#40;2 o m&#225;s variables&#44; respectivamente&#41; para las variables de distribuci&#243;n normal&#46; Para las variables de distribuci&#243;n no normal se utilizaron el test de Mann-Whitney y el test de Kruskal-Wallis &#40;2 o m&#225;s variables&#44; respectivamente&#41;&#46; Para corregir factores de confusi&#243;n en algunos estudios de comparaci&#243;n se ha utilizado el an&#225;lisis por ANCOVA&#46; Para la comparaci&#243;n de las variables cualitativas entre grupos se ha utilizado el test de Chi-cuadrado&#44; o el test de Fisher cuando el n&#250;mero era inferior a 5&#46; Las correlaciones bivariadas entre variables se estudiaron con la prueba de Pearson para variables con distribuci&#243;n normal y prueba de Spearman para variables sin distribuci&#243;n normal&#46; Para evaluar los factores asociados al GIM carot&#237;deo y a la presencia de placa de ateroma se realizaron an&#225;lisis de regresi&#243;n lineal y log&#237;stica respectivamente&#46; Se consider&#243; que las diferencias eran estad&#237;sticamente significativas si el valor de p era inferior a 0&#44;05&#46; Se utiliz&#243; el paquete estad&#237;stico SPSS&#174; para Windows versi&#243;n 15&#46;0 &#40;SPSS&#174;&#44; Chicago&#44; IL&#44; EE&#46; UU&#46;&#41;&#46; Las frecuencias de los alelos y los genotipos fueron calculadas para cada SNP utilizando SPSS&#174; y SNPstats &#40;<a href="http://bioinfo.iconcologia.net/index.php">http&#58;&#47;&#47;bioinfo&#46;iconcologia&#46;net&#47;index&#46;php</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">18</span></a>&#46; El equilibrio de Hardy-Weinberg &#40;HWE&#41; fue calculado mediante el test de Chi-cuadrado con un grado de libertad utilizando el <span class="elsevierStyleItalic">software</span> SNPstat&#46; Los desequilibrios de ligamiento fueron calculados usando la estad&#237;stica de R2&#46; La asociaci&#243;n entre los polimorfismos y los niveles de IL-18 fue analizada usando un modelo de herencia codominante mediante SPSS&#174; y SNPstat&#46; Para la comparaci&#243;n de las variables cuantitativas entre genotipos se ha utilizado la prueba de ANOVA&#46; La edad y el sexo&#44; como 2 potenciales factores de confusi&#243;n&#44; se utilizaron como covariables&#46; Se consider&#243; que las diferencias eran estad&#237;sticamente significativas si el valor de p era inferior a 0&#44;05&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Resultados</span><p id="par0090" class="elsevierStylePara elsevierViewall">Las caracter&#237;sticas generales de la poblaci&#243;n estudiada se incluyen en la <a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>&#46; Se encontraron diferencias estad&#237;sticamente significativas entre ambos g&#233;neros en el IMC&#44; per&#237;metro abdominal&#44; presi&#243;n arterial sist&#243;lica y diast&#243;lica&#44; par&#225;metros del metabolismo hidrocarbonado&#44; as&#237; como en el cHDL y triglic&#233;ridos plasm&#225;ticos&#46; As&#237; mismo&#44; los niveles de IL-18 &#40;472&#44;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>205&#44;5 vs&#46; 389&#44;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>185&#44;5<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#41; y el GIM carot&#237;deo &#40;0&#44;599<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;185 vs&#46; 0&#44;542<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;174<span class="elsevierStyleHsp" style=""></span>mm&#41; fueron significativamente superiores en los hombres&#46; Tambi&#233;n hubo una mayor frecuencia de placas de ateroma en los varones con respecto a las mujeres&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">En la <a class="elsevierStyleCrossRef" href="#tbl0010">tabla 2</a> se muestran las caracter&#237;sticas de la poblaci&#243;n dividida en funci&#243;n de los cuartiles de los niveles plasm&#225;ticos de IL-18&#46; Se observa que a medida que aumentan los niveles de IL-18 aumentan de forma significativa los niveles de los par&#225;metros asociados con la presencia de resistencia a la insulina&#44; as&#237; como el GIM carot&#237;deo&#46; La prevalencia de placas de ateroma fue significativamente inferior en los sujetos incluidos en el cuartil con niveles m&#225;s bajos de IL-18&#44; comparado con los otros 3&#44; no habiendo diferencias significativas entre los otros 3 grupos&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Al analizar la asociaci&#243;n de IL-18 con otros par&#225;metros &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">tabla 3</a>&#41; se observaron correlaciones significativas con los par&#225;metros asociados a la presencia de resistencia a la insulina&#44; as&#237; como a los componentes incluidos en la definici&#243;n de s&#237;ndrome metab&#243;lico y&#44; adem&#225;s&#44; con el GIM carot&#237;deo y con la presencia de placa de ateroma&#46; No hubo correlaci&#243;n significativa entre los SNPs estudiados y los niveles de IL-18&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">Adem&#225;s&#44; se analiz&#243; la posible asociaci&#243;n entre la presencia de alteraciones a nivel carot&#237;deo y los polimorfismos analizados &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">tabla 4</a>&#41;&#46; El equilibrio de Hardy-Weinberg se mantuvo para todos los polimorfismos analizados&#46; Los portadores del alelo menor de rs2287037 presentaron un incremento del riesgo de presentar placa de ateroma&#44; mientras que los portadores del alelo menor de rs2293224 presentaron una reducci&#243;n significativa de dicho riesgo&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">Finalmente&#44; se realizaron an&#225;lisis de regresi&#243;n&#46; Mediante regresi&#243;n lineal se evaluaron cu&#225;les eran los factores asociados con el incremento del GIM carot&#237;deo&#44; observando correlaci&#243;n significativa &#250;nicamente con la edad y con los niveles de colesterol &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">tabla 5</a>&#41;&#46; Mediante regresi&#243;n log&#237;stica se evaluaron los factores asociados a la presencia de placa de ateroma&#44; observando una asociaci&#243;n significativa con la edad&#44; el g&#233;nero y uno de los SNPs evaluados&#44; rs2287037 &#40;<a class="elsevierStyleCrossRef" href="#tbl0030">tabla 6</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><elsevierMultimedia ident="tbl0030"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Discusi&#243;n</span><p id="par0115" class="elsevierStylePara elsevierViewall">En este estudio se demuestra que los pacientes con niveles plasm&#225;ticos m&#225;s elevados de IL-18 presentan factores de riesgo cardiovascular asociados&#46; Adem&#225;s&#44; los niveles elevados de IL-18 se asociaron de forma significativa con un mayor GIM carot&#237;deo y con la presencia de placas de ateroma&#46; Esta asociaci&#243;n parece estar influenciada por factores gen&#233;ticos&#44; como lo demuestran las asociaciones encontradas entre los SNPs en el gen del receptor de IL-18 y la presencia de placa de ateroma&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">La arteriosclerosis es una enfermedad cr&#243;nica en cuya patog&#233;nesis intervienen diferentes mol&#233;culas inflamatorias&#46; Dentro de estas&#44; la IL-18 es una citocina que juega un importante papel en el desarrollo del proceso inflamatorio<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">19</span></a>&#46; De hecho&#44; se considera que&#44; junto con la IL-1&#946;&#44; es una de las 2 citocinas inflamatorias m&#225;s destacadas del inflamasoma que promueven el desarrollo de la aterosclerosis<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">20</span></a>&#46; Sin embargo&#44; en relaci&#243;n a este hallazgo parecen existir datos contradictorios&#46; Fan et al&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">21</span></a> en un metaan&#225;lisis&#44; aplicando metodolog&#237;a de aleatorizaci&#243;n mendeliana&#44; no encontraron relaci&#243;n entre los niveles de IL-18 y el riesgo de enfermedad cardiovascular&#46; Por tanto&#44; el conocimiento del papel de IL-18&#44; as&#237; como de los posibles mecanismos implicados en la modulaci&#243;n del proceso arterioscler&#243;tico tienen gran inter&#233;s&#44; sobre todo porque podr&#237;a ser una posible v&#237;a sobre la que incidir para reducir el riesgo de desarrollar arteriosclerosis y enfermedad cardiovascular<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a>&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">En el presente estudio&#44; los pacientes con niveles m&#225;s elevados de IL-18 presentaron mayor GIM carot&#237;deo&#44; as&#237; como una mayor asociaci&#243;n con otros factores de riesgo cardiovascular&#46; Adem&#225;s&#44; aqu&#233;llos con menores niveles de IL-18 presentan una menor proporci&#243;n de placas de ateroma &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">tabla 2</a>&#41;&#46; Estos hallazgos van en la misma l&#237;nea que estudios previos en los que se observ&#243; que la IL-18 ten&#237;a un papel proaterog&#233;nico&#46; As&#237;&#44; los niveles plasm&#225;ticos de IL-18 demostraron ser un buen predictor tanto del desarrollo de enfermedad cardiovascular como de mortalidad por dicha causa<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">11&#44;23</span></a>&#46; Por el contrario&#44; modelos animales deficientes en IL-18 tienen menor presencia de arteriosclerosis<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">24</span></a>&#46; Adem&#225;s&#44; datos experimentales indican que la v&#237;a de se&#241;alizaci&#243;n de IL-18 est&#225; involucrada en la inestabilidad de la placa<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">25&#44;26</span></a>&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Sin embargo&#44; existe gran variabilidad en el desarrollo de arteriosclerosis y enfermedad cardiovascular entre los pacientes con niveles elevados de IL-18&#46; La presencia de diferentes variaciones gen&#233;ticas podr&#237;a explicar esto&#44; al menos&#44; en parte<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">27</span></a>&#46; Estudios previos han mostrado que polimorfismos en el gen de la IL-18 se asocian con el desarrollo de enfermedad coronaria y la severidad de la misma<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">7&#44;12</span></a>&#44; aunque existen datos contradictorios<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">14&#44;28</span></a>&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">La se&#241;alizaci&#243;n de IL-18 se induce mediante la uni&#243;n de esta citoquina a un receptor heterodim&#233;rico llamado IL-18R&#46; Este&#44; est&#225; formado por 2 cadenas&#44; IL-18R1 &#40;con funci&#243;n de uni&#243;n&#41; e IL18RAP &#40;prote&#237;na accesoria del receptor&#44; con funci&#243;n de transducci&#243;n de se&#241;ales&#41;&#46; La interacci&#243;n de ambas cadenas de IL-18R es necesaria para inducir la se&#241;alizaci&#243;n de IL-18<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">29&#44;30</span></a>&#46; En nuestro estudio hemos analizado 2 SNPs de IL-18R1 &#40;rs2270297 y rs2287037&#41; y 2 SNPs de IL-18RAP &#40;rs2293224 y rs7559479&#41;&#46; Observamos que el genotipo con el alelo A del SNP rs2287037 de IL-18R1 se asocia con mayor prevalencia de placa de ateroma carot&#237;dea&#46; Por la localizaci&#243;n&#44; este SNP podr&#237;a ser funcional&#46; Adem&#225;s&#44; en el an&#225;lisis de regresi&#243;n este SNPs se asoci&#243; de forma significativa con la presencia de placa de ateroma&#46; Por el contrario&#44; el genotipo con el alelo C del SNP rs2293224 de IL-18RAP se asocia con una menor prevalencia de placa de ateroma&#46; Sin embargo&#44; no existen estudios previos relacionando variaciones de estos SNPs con la presencia de arteriosclerosis&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Este estudio presenta algunas limitaciones&#46; Por un lado&#44; es un estudio transversal&#46; Por tanto&#44; no es posible establecer relaciones de causalidad&#46; Adem&#225;s&#44; no se han replicado los resultados en otra poblaci&#243;n&#46; Por &#250;ltimo&#44; no existen datos en este estudio de la presencia de placas de ateroma a nivel femoral&#46; Tampoco se ha evaluado si existe asociaci&#243;n entre las caracter&#237;sticas de la placa de ateroma o el n&#250;mero de territorios vasculares afectados y los niveles de IL-18 y las variaciones gen&#233;ticas estudiadas&#46; No obstante&#44; los hallazgos encontrados apoyan la participaci&#243;n de la IL-18 en el desarrollo de la arteriosclerosis&#44; as&#237; como su posible regulaci&#243;n&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">En conclusi&#243;n&#44; este estudio realizado en poblaci&#243;n mediterr&#225;nea sugiere que los niveles plasm&#225;ticos de IL-18 est&#225;n relacionados con otros factores de riesgo cardiovascular&#44; especialmente con los relacionados con la presencia de resistencia a la insulina&#46; Adem&#225;s&#44; niveles m&#225;s elevados de IL-18 se relacionan con la presencia de placas de ateroma&#44; existiendo variaciones gen&#233;ticas en el gen del receptor de IL-18 que podr&#237;an estar asociadas con el desarrollo de dichas placas de ateroma&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Financiaci&#243;n</span><p id="par0150" class="elsevierStylePara elsevierViewall">Consorcio Centro de Investigaci&#243;n Biom&#233;dica en Red &#40;CIBER&#41; CB07&#47;08&#47;0018&#44; Instituto de Salud Carlos III&#44; Ministerio de Ciencia e Innovaci&#243;n y Uni&#243;n Europea &#40;Fondos Europeos de desarrollo Regional&#41;&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">AP es receptora de un contrato postdoctoral Sara Borrell del Instituto de Salud Carlos III &#40;CD22&#47;00012&#41;&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conflicto de intereses</span><p id="par0160" class="elsevierStylePara elsevierViewall">Los autores declaran no tener ning&#250;n conflicto de intereses&#46;</p></span></span>"
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          "titulo" => "Abstract"
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              "titulo" => "Background"
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              "titulo" => "Par&#225;metros cl&#237;nicos"
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              "titulo" => "Ecograf&#237;a carot&#237;dea"
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              "titulo" => "Selecci&#243;n de SNP y genotipado"
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    "fechaRecibido" => "2023-11-11"
    "fechaAceptado" => "2023-12-15"
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            0 => "IL-18"
            1 => "Arteriosclerosis"
            2 => "Inflamaci&#243;n"
            3 => "Polimorfismo"
            4 => "Placa de ateroma"
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            0 => "IL-18"
            1 => "Atherosclerosis"
            2 => "Inflammation"
            3 => "Polymorphism"
            4 => "Atheroma plaque"
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    "resumen" => array:2 [
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Antecedentes</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">La arteriosclerosis es una enfermedad inflamatoria&#46; La interleucina 18 &#40;IL-18&#41; es una mol&#233;cula inflamatoria que se ha relacionado con el desarrollo de arteriosclerosis y enfermedad cardiovascular&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objetivo</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Evaluar la posible relaci&#243;n entre los niveles plasm&#225;ticos de IL-18 y la presencia de arteriosclerosis evaluada a nivel carot&#237;deo&#44; as&#237; como analizar la posible modulaci&#243;n por diferentes polimorfismos en una poblaci&#243;n mediterr&#225;nea&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Material y m&#233;todos</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Se incluyeron 746 individuos procedentes del &#225;rea metropolitana de Valencia&#44; reclutados durante un per&#237;odo de 2 a&#241;os&#46; Se determinaron par&#225;metros del metabolismo hidrocarbonado y lip&#237;dico mediante metodolog&#237;a est&#225;ndar e IL-18 mediante ELISA&#46; Adem&#225;s&#44; se realiz&#243; ecograf&#237;a carot&#237;dea y se analiz&#243; el genotipo de 4 Single Nucleotide Polymorphisms &#40;SNPs&#41; relacionados con la v&#237;a de se&#241;alizaci&#243;n de IL-18&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Resultados</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Los pacientes con niveles plasm&#225;ticos m&#225;s elevados de IL-18 presentaron otros factores de riesgo cardiovascular asociados&#46; Los niveles elevados de IL-18 se asociaron de forma significativa con un mayor GIM carot&#237;deo y con la presencia de placas de ateroma&#46; El genotipo con el alelo A del SNP rs2287037 se asoci&#243; con mayor prevalencia de placa de ateroma carot&#237;dea&#46; Por el contrario&#44; el genotipo con el alelo C del SNP rs2293224 se asoci&#243; con una menor prevalencia de placa de ateroma&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusiones</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Los niveles elevados de IL-18 se asociaron de forma significativa con un mayor GIM carot&#237;deo y con la presencia de placas de ateroma&#44; que parecen estar influenciados por factores gen&#233;ticos&#44; como lo demuestran las asociaciones entre los SNPs en el gen del receptor de IL-18 y la presencia de placa de ateroma&#46;</p></span>"
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        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Background</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Atherosclerosis is an inflammatory disease&#46; Interleukin 18 &#40;IL-18&#41; is an inflammatory molecule that has been linked to the development of atherosclerosis and cardiovascular disease&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objective</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">To evaluate the possible relationship between plasma levels of IL-18 and the presence of atherosclerosis evaluated at the carotid level&#44; as well as to analyze the possible modulation by different polymorphisms in a Mediterranean population&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Material and methods</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Seven hundred and forty-six individuals from the metropolitan area of Valencia were included&#44; recruited over a period of 2 years&#46; Hydrocarbon and lipid metabolism parameters were determined using standard methodology and IL-18 using ELISA&#46; In addition&#44; carotid ultrasound was performed and the genotype of four SNPs related to the IL-18 signaling pathway was analyzed&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Results</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Patients with higher plasma levels of IL-18 had other associated cardiovascular risk factors&#46; Elevated IL-18 levels were significantly associated with higher carotid IMT and the presence of atheromatous plaques&#46; The genotype with the A allele of the SNP rs2287037 was associated with a higher prevalence of carotid atheromatous plaque&#46; On the contrary&#44; the genotype with the C allele of the SNP rs2293224 was associated with a lower prevalence of atheromatous plaque&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusions</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">High levels of IL-18 were significantly associated with a higher carotid IMT and the presence of atheromatous plaques&#44; which appear to be influenced by genetic factors&#44; as evidenced by associations between SNPs in the IL-18 receptor gene and the presence of atheroma plaque&#46;</p></span>"
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Edad &#40;a&#241;os&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">45&#44;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&#44;3&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
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                  \t\t\t\t">45&#44;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>15&#44;2&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">44&#44;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>13&#44;3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#44;267&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">IMC &#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  " align="left" valign="\n
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                  \t\t\t\t">27&#44;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#44;8&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">28&#44;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#44;2&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">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">PC &#40;cm&#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
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                  \t\t\t\t">91&#44;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>13&#44;1&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">87&#44;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>13&#44;1&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">96&#44;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#44;2&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
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                  \t\t\t\t">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">PAS &#40;mmHg&#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
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                  \t\t\t\t">125&#44;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&#44;2&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">121&#44;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>17&#44;1&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
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                  \t\t\t\t">129&#44;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&#44;2&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
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                  \t\t\t\t">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">PAD &#40;mmHg&#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
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                  \t\t\t\t">77&#44;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#44;4&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  " align="left" valign="\n
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                  \t\t\t\t">75&#44;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#44;1&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  " align="left" valign="\n
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                  \t\t\t\t">78&#44;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&#44;2&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">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Glucosa &#40;mg&#47;dl&#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
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                  \t\t\t\t">99&#44;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>24&#44;7&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
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                  \t\t\t\t">95&#44;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>20&#44;4&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">102&#44;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>28&#44;1&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
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                  \t\t\t\t">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Insulina &#40;mcU&#47;ml&#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">11&#44;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#44;3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">12&#44;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#44;3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">&#205;ndice HOMA&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2&#44;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#44;5&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">3&#44;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#44;4&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#44;031&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">CT &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">227&#44;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>61&#44;0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">224&#44;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>65&#44;3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#44;517&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">cHDL &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">49&#44;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#44;7&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">cLDL &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#44;667&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TG &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">164&#44;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>259&#44;4&nbsp;\t\t\t\t\t\t\n
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        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">HWE&#58; Hardy-Weinberg equilibrium&#59; MAF&#58; minor allele frequency&#59; SNP&#58; single-nucleotide polymorphism&#46;</p><p id="spar0125" class="elsevierStyleSimplePara elsevierViewall">En negrita se muestran los datos estad&#237;sticamente significativos&#46;</p>"
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">dbSNP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Genotipo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">N&#46;&#176;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Placa</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col"><span class="elsevierStyleItalic">Odds ratio</span> &#40;IC95&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">S&#237; &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">rs2270297&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HWE&#58; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;12&#59; MAF&#58; 0&#44;24&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">GG<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>GA&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">592&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">&#40;91&#44;8&#37;&#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">&#40;96&#44;8&#37;&#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">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;21&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">AA&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">49&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">&#40;8&#44;2&#37;&#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">&#40;3&#44;2&#37;&#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">0&#44;4 &#40;0&#44;08-1&#44;92&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">rs2287037&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HWE&#58; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;26&#59; MAF&#58; 0&#44;46&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">GG&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">266&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">&#40;44&#44;4&#37;&#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">&#40;27&#37;&#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">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0052&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">GA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>AA&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">371&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">&#40;55&#44;6&#37;&#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">&#40;73&#37;&#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"><span class="elsevierStyleBold">2&#44;46 &#40;1&#44;28-4&#44;73&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">rs2293224&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HWE&#58; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;074&#59; MAF&#58; 0&#44;42&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">TT&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">171&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">&#40;25&#44;6&#37;&#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">&#40;38&#44;7&#37;&#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">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0069&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">TC<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>CC&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">453&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">&#40;74&#44;4&#37;&#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">&#40;61&#44;3&#37;&#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"><span class="elsevierStyleBold">0&#44;41 &#40;0&#44;21-0&#44;78&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">rs7559479&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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
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                  """
              ]
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          "es" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Asociaci&#243;n entre la presencia de placa de ateroma carot&#237;dea y los SNPs de IL-18 ajustado por edad y g&#233;nero</p>"
        ]
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Coeficienteno estandarizado&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">0&#44;680&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">CT &#40;mg&#47;dl&#41;&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 ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">IL-18 &#40;pg&#47;ml&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#44;00006&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#44;157&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t">rs2287037&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">rs2293224&nbsp;\t\t\t\t\t\t\n
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                  """
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        ]
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0120" class="elsevierStyleSimplePara elsevierViewall">CT&#58; colesterol total&#59; GIM&#58; grosor &#237;ntima-media&#59; IL-18&#58; interleucina 18&#59; IMC&#58; &#237;ndice de masa corporal&#59; PAD&#58; presi&#243;n arterial diast&#243;lica&#59; PAS&#58; presi&#243;n arterial sist&#243;lica&#46;</p>"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Coeficienteno estandarizado&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" scope="col" style="border-bottom: 2px solid black">Exp &#40;B&#41;&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" scope="col" style="border-bottom: 2px solid black">p valor&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Edad &#40;a&#241;os&#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
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                  \t\t\t\t">0&#44;081&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
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                  \t\t\t\t">1&#44;085&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
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                  \t\t\t\t">&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">G&#233;nero&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
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                  \t\t\t\t">0&#44;952&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  " align="left" valign="\n
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                  \t\t\t\t">2&#44;591&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
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                  \t\t\t\t">0&#44;012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">IMC &#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
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8722;0&#44;048&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">0&#44;953&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
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                  \t\t\t\t">0&#44;301&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">PAS &#40;mmHg&#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
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                  \t\t\t\t">0&#44;007&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  " align="left" valign="\n
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                  \t\t\t\t">1&#44;007&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  " align="left" valign="\n
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                  \t\t\t\t">0&#44;651&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">PAD &#40;mmHg&#41;&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\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#44;996&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
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                  \t\t\t\t">0&#44;877&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">&#205;ndice HOMA&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  " align="left" valign="\n
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                  \t\t\t\t">0&#44;053&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
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                  \t\t\t\t">1&#44;055&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
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                  \t\t\t\t">0&#44;145&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">CT &#40;mg&#47;dl&#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
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                  \t\t\t\t">0&#44;005&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">0&#44;062&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">IL-18 &#40;pg&#47;ml&#41;&nbsp;\t\t\t\t\t\t\n
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          "es" => "<p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">Modelo de regresi&#243;n que eval&#250;a los determinantes independientes de la placa de ateroma &#40;variable dependiente&#41;</p>"
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Información del artículo
ISSN: 02149168
Idioma original: Español
DOI:10.1016/j.arteri.2023.12.005
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