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            "entidad" => "Unidad de Medicina Molecular&#44; Departamento de Medicina&#44; Universidad de Salamanca&#46; Instituto de Investigaci&#243;n Biom&#233;dica de Salamanca-IBSAL&#44; Salamanca&#44; Espa&#241;a"
            "etiqueta" => "b"
            "identificador" => "aff0010"
          ]
          2 => array:3 [
            "entidad" => "Unidad de Alcoholismo&#44; Departamento de Medicina Interna&#44; Hospital Universitario de Salamanca&#46; Instituto de Investigaci&#243;n Biom&#233;dica de Salamanca-IBSAL&#44; Salamanca&#44; Espa&#241;a"
            "etiqueta" => "c"
            "identificador" => "aff0015"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cor0005"
            "etiqueta" => "&#63;"
            "correspondencia" => "Autor para correspondencia&#46;"
          ]
        ]
      ]
    ]
    "titulosAlternativos" => array:1 [
      "en" => array:1 [
        "titulo" => "Analysis of the relationship between interleukin polymorphisms within miRNA-binding regions and alcoholic liver disease"
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introducci&#243;n</span><p id="par0005" class="elsevierStylePara elsevierViewall">La predisposici&#243;n gen&#233;tica juega un papel importante en la susceptibilidad para el desarrollo de alcoholismo<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">1</span></a> o da&#241;os org&#225;nicos inducidos por el alcohol<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">2</span></a>&#46; En lo que respecta a la susceptibilidad para el desarrollo de alcoholismo&#44; estudios de asociaci&#243;n previos se han centrado&#44; en su mayor&#237;a&#44; en los genes candidatos con posible compromiso de sistemas de recompensa cerebral<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">3</span></a>&#46; En el caso de la enfermedad hep&#225;tica alcoh&#243;lica &#40;EHA&#41;&#44; anteriores estudios gen&#233;ticos se han ocupado&#44; principalmente&#44; de analizar las variantes de los genes codificadores de enzimas hep&#225;ticas<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">4&#44;5</span></a> o de mediadores de la respuesta inflamatoria<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">6</span></a>&#46; No obstante&#44; en ambos casos se desconoce el conjunto de genes implicados en la susceptibilidad gen&#233;tica a estas enfermedades&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Los polimorfismos de nucle&#243;tido &#250;nico &#40;SNP&#44; <span class="elsevierStyleItalic">Single Nucleotide Polymorphism</span>&#41; en los genes codificadores de las interleucinas &#40;IL&#41;&#44; o en los receptores interleuc&#237;nicos&#44; se han estudiado por su posible relaci&#243;n con la respuesta inflamatoria inducida por el alcohol&#46; En concreto&#44; se han estudiado los SNP de genes codificadores de IL implicadas en la v&#237;a de los receptores de tipo Toll<span class="elsevierStyleHsp" style=""></span>4 &#40;TLR4&#41; y el factor nuclear &#40;NF&#41;-&#63;B<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">7-9</span></a>&#44; que es activada por el lipopolisac&#225;rido &#40;LPS&#41; bacteriano&#46; El consumo de alcohol aumenta los niveles en sangre de LPS<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">10</span></a>&#44; y la activaci&#243;n de la v&#237;a TLR4&#47;NF-&#63;B determina la secreci&#243;n de algunas citoquinas inflamatorias tales como el factor de necrosis tumoral alfa &#40;TNF-a&#41;&#44; que&#44; a su vez&#44; son capaces de activar la apoptosis&#44; aumentar los niveles de estr&#233;s oxidativo y provocar da&#241;o hep&#225;tico mediante la activaci&#243;n de las c&#233;lulas de Kupffer<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">11-13</span></a>&#46; La importancia que tiene esta v&#237;a en la patog&#233;nesis de la EHA se ha establecido con claridad<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">14</span></a>&#44; y su posible relaci&#243;n con la dependencia del alcohol tambi&#233;n ha sido objeto de estudio<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">15</span></a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Algunas mol&#233;culas de micro-ARN &#40;miARN&#41; juegan importantes papeles en la inflamaci&#243;n a trav&#233;s de la regulaci&#243;n de los mediadores de la v&#237;a TLR4&#47;NF-&#63;B<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">16</span></a>&#46; Por consiguiente&#44; los SNP localizados en genes de miARN o genes codificadores de IL ubicados cerca de sitios espec&#237;ficos de uni&#243;n a miARN son capaces de modificar la respuesta inflamatoria a diversos est&#237;mulos&#44; incluida la ingesta de alcohol<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">17</span></a>&#46; En concreto&#44; la variante al&#233;lica rs1368439 del gen codificador de la IL-12B <span class="elsevierStyleItalic">&#40;IL12B&#41;</span> se halla cerca del sitio de uni&#243;n para miR-23&#44; cuya asociaci&#243;n con la respuesta inflamatoria es conocida<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">18-20</span></a>&#46; El polimorfismo rs1131445 del gen codificador de la IL-16 <span class="elsevierStyleItalic">&#40;IL16&#41;</span> se localiza en la regi&#243;n diana del miR-125&#44; que&#44; tambi&#233;n&#44; se asocia a la regulaci&#243;n de la inmunidad innata y la inflamaci&#243;n<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">21</span></a>&#46; La variante rs3917328 del gen codificador del receptor de IL-1 tipo 1 <span class="elsevierStyleItalic">&#40;IL1R1&#41;</span> se halla en una regi&#243;n diana del miR-19&#46; Potencialmente&#44; este SNP influye en la v&#237;a mediada por los receptores TLR4 por la similitud existente entre IL1R1 y dicho receptor<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">22&#44;23</span></a>&#46; Por &#250;ltimo&#44; la variante al&#233;lica rs4648143 del gen codificador del factor nuclear NF-&#63;B subunidad 1 <span class="elsevierStyleItalic">&#40;NFKB1&#41;</span> se encuentra cerca de la regi&#243;n diana del miR-557<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">22&#44;23</span></a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">A la luz de estos datos&#44; planteamos la hip&#243;tesis de que los citados SNP podr&#237;an&#44; por tanto&#44; modular la inflamaci&#243;n inducida por el alcohol y modificar el riesgo de da&#241;o inducido por el mismo&#46; El presente estudio se dise&#241;&#243;&#44; por todo ello&#44; para analizar posibles relaciones entre el alcoholismo o la EHA y los polimorfismos <span class="elsevierStyleItalic">IL12B</span> 2124 G&#62;T &#40;rs1368439&#41;&#44; <span class="elsevierStyleItalic">IL16</span> 5000 C&#62;T &#40;rs1131445&#41;&#44; <span class="elsevierStyleItalic">IL1R1</span> 3114 C&#62;T &#40;rs3917328&#41; y <span class="elsevierStyleItalic">NFKB1</span> 3400 A&#62;G &#40;rs4648143&#41;&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materiales y m&#233;todos</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Pacientes y controles</span><p id="par0025" class="elsevierStylePara elsevierViewall">Fueron incluidos 301 pacientes varones alcoh&#243;licos &#40;media de edad&#58; 52&#44;2<span class="elsevierStyleHsp" style=""></span>a&#241;os&#44; desviaci&#243;n est&#225;ndar &#91;DE&#93;&#58; 14&#44;4<span class="elsevierStyleHsp" style=""></span>a&#241;os&#41; seguidos en la Unidad de Alcoholismo del Hospital Universitario de Salamanca y que hab&#237;an consumido m&#225;s de 100<span class="elsevierStyleHsp" style=""></span>g de alcohol al d&#237;a durante al menos 10<span class="elsevierStyleHsp" style=""></span>a&#241;os&#46; De estos&#44; 189 presentaban dependencia alcoh&#243;lica &#40;DA&#41; y 112 abuso del alcohol &#40;AA&#41;&#44; seg&#250;n los criterios de la cuarta edici&#243;n del Manual Diagn&#243;stico y Estad&#237;stico de Trastornos Mentales &#40;DSM-IV&#41;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">24</span></a>&#46; Estos criterios eran los vigentes durante el per&#237;odo de estudio y se aplicaron mediante entrevistas semiestructuradas llevadas a cabo por personal experto&#46; Los pacientes con un diagn&#243;stico de adicci&#243;n a otras drogas &#40;aparte de la nicotina&#41;&#44; o con trastornos mayores del eje<span class="elsevierStyleHsp" style=""></span>I &#40;como&#44; por ejemplo&#44; esquizofrenia&#44; trastornos del estado de &#225;nimo o trastornos mayores de ansiedad&#41; establecidos tras examen psiqui&#225;trico integral&#44; fueron excluidos&#46; Un total de 103 pacientes presentaban cirrosis hep&#225;tica alcoh&#243;lica&#46; Se lleg&#243; al diagn&#243;stico de cirrosis tras biopsia hep&#225;tica en 93 pacientes y tras aplicar criterios cl&#237;nicos&#44; anal&#237;ticos y radiol&#243;gicos en 10 pacientes&#44; en los que la biopsia estaba contraindicada&#46; Los otros 198 pacientes alcoh&#243;licos fueron clasificados como sujetos sin EHA seg&#250;n criterios cl&#237;nicos&#44; anal&#237;ticos y radiol&#243;gicos&#46; Todos los pacientes dieron negativo en las determinaciones serol&#243;gicas para los virus de la hepatitis<span class="elsevierStyleHsp" style=""></span>C y<span class="elsevierStyleHsp" style=""></span>B&#46; Otras etiolog&#237;as de enfermedad hep&#225;tica fueron descartadas&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">El grupo de control lo formaban 156 voluntarios varones sanos &#40;media de edad&#58; 46&#44;7<span class="elsevierStyleHsp" style=""></span>a&#241;os&#44; DE&#58; 19&#44;5&#41;&#46; Todos ellos tomaban menos de 10<span class="elsevierStyleHsp" style=""></span>g de alcohol al d&#237;a&#46; Ni ellos ni ninguno de sus parientes de primera o segunda l&#237;nea consangu&#237;nea ten&#237;an antecedentes de AA o DA&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Todos los pacientes y los sujetos control proced&#237;an de Castilla y Le&#243;n &#40;noroeste de Espa&#241;a&#41; desde al menos tres generaciones y dieron su consentimiento informado para participar en el estudio&#46; El estudio se llev&#243; a cabo con la aprobaci&#243;n del Comit&#233; &#201;tico del Hospital Universitario de Salamanca&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">An&#225;lisis gen&#233;tico</span><p id="par0040" class="elsevierStylePara elsevierViewall">Se extrajo ADN gen&#243;mico de c&#233;lulas sangu&#237;neas nucleadas mediante digesti&#243;n con proteinasa<span class="elsevierStyleHsp" style=""></span>K&#44; extracci&#243;n con fenol-cloroformo y precipitaci&#243;n alcoh&#243;lica&#46; Las muestras se guardaron a -20<span class="elsevierStyleHsp" style=""></span>&#176;C hasta ser utilizadas&#44; posteriormente fueron analizadas simult&#225;neamente &#40;controles y pacientes con y sin EHA&#41; en placas de PCR&#44; a fin de garantizar la detecci&#243;n de forma ciega&#46; Los polimorfismos rs1368439&#44; rs1131445&#44; rs3917328 y rs4648143 fueron genotipados utilizando para ello las pruebas TaqMan MGB<span class="elsevierStyleSup"><span class="elsevierStyleBold">&#174;</span></span> de discriminaci&#243;n al&#233;lica con el sistema StepOnePlus<span class="elsevierStyleSup"><span class="elsevierStyleBold">&#174;</span></span> &#40;Applied Biosystems&#44; Foster City&#44; California&#44; EE&#46;UU&#46;&#41; y seg&#250;n el protocolo del fabricante&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">An&#225;lisis estad&#237;stico</span><p id="par0045" class="elsevierStylePara elsevierViewall">La distribuci&#243;n al&#233;lica y genot&#237;pica entre grupos se compar&#243; mediante el test &#63;<span class="elsevierStyleSup">2</span> o la prueba exacta de Fisher si el valor de frecuencia esperado &#60;<span class="elsevierStyleHsp" style=""></span>5&#46; La desviaci&#243;n del equilibrio de Hardy-Weinberg en las frecuencias genot&#237;picas entre los controles se analiz&#243; mediante la prueba &#63;<span class="elsevierStyleSup">2</span>&#46; Los valores p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05 se consideraron valores significativos&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Se realiz&#243; un an&#225;lisis comparativo entre pacientes alcoh&#243;licos y controles y tambi&#233;n entre pacientes con AA vs&#46; DA&#44; as&#237; como entre pacientes con cirrosis frente a pacientes sin EHA&#46; La contribuci&#243;n de las variantes gen&#233;ticas de cada fenotipo espec&#237;fico de forma significativa e independiente se valor&#243; mediante un an&#225;lisis de regresi&#243;n log&#237;stica&#44;a fin de determinar la herencia dominante o recesiva de los alelos espec&#237;ficos&#46; Utilizando como ejemplo el an&#225;lisis del polimorfismo <span class="elsevierStyleItalic">IL1R1</span>&#44; los efectos arbitrarios de los sujetos heterocigotos fueron incluidos en el modelo general&#46; Los tres posibles genotipos &#40;CC&#44; CT&#44; TT&#41; fueron denotados por tres variables simuladas &#40;0&#44; 1&#44; 2&#41;&#46; El modelo dominante se bas&#243; en la hip&#243;tesis de que los genotipos CT y TT contribu&#237;an por igual al riesgo de cirrosis alcoh&#243;lica&#44; siendo los genotipos codificados del siguiente modo&#58; CC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0 y CT y TT<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46; El modelo recesivo no se calcul&#243; por la ausencia del genotipo TT entre los controles&#46; La fuerza de la asociaci&#243;n se calcul&#243; mediante <span class="elsevierStyleItalic">odds ratio</span> &#40;OR&#41; e intervalos de confianza &#40;IC&#41; del 95&#37;&#46; Los valores p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05 se consideraron valores significativos&#46; Los an&#225;lisis se llevaron a cabo utilizando el software SPSS v&#46; 20&#46;0 &#40;IBM SPSS Statistics&#41;&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">La potencia estad&#237;stica del presente estudio para detectar un polimorfismo confiriendo un OR de 2 para la presencia de alcoholismo se calcul&#243; utilizando el software PS&#58; Power and Sample Size Calculations&#44; v&#46; 3&#46;0&#46;43 &#40;http&#58;&#47;&#47;biostat&#46;mc&#46;vanderbilt&#46;edu&#47;twiki&#47;bin&#47;view&#47;Main&#47;PowerSampleSize&#41;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">25</span></a>&#46; Asumiendo un valor a de 0&#44;05 y una prevalencia del alelo menos frecuente entre los controles de 0&#44;2&#44; la potencia estad&#237;stica fue del 81&#37; para la poblaci&#243;n del estudio &#40;pacientes alcoh&#243;licos&#44; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>301&#59; controles sanos&#44; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>156&#41;&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Resultados</span><p id="par0060" class="elsevierStylePara elsevierViewall">La distribuci&#243;n genot&#237;pica de los polimorfismos analizados entre los pacientes alcoh&#243;licos y los controles sanos puede verse en la <a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>&#46; Los individuos sanos presentaron frecuencias genot&#237;picas similares a las descritas previamente en poblaciones cauc&#225;sicas sanas&#46; No se hall&#243; desviaci&#243;n alguna del equilibrio de Hardy-Weinberg&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">Los polimorfismos <span class="elsevierStyleItalic">IL12B</span> 2124 G&#62;T &#40;rs1368439&#41;&#44; <span class="elsevierStyleItalic">IL16</span> 5000 C&#62;T &#40;rs1131445&#41; y <span class="elsevierStyleItalic">NFKB1</span> 3400 A&#62;G &#40;rs4648143&#41; no mostraron diferencia significativa alguna entre los grupos estudiados &#40;sujetos con trastornos por consumo de alcohol frente a controles sanos&#44; pacientes con AA frente a DA&#44; o pacientes con cirrosis alcoh&#243;lica frente a pacientes sin EHA&#41;&#46; En cambio&#44; la distribuci&#243;n al&#233;lica del polimorfismo <span class="elsevierStyleItalic">IL1R1</span> 3114 C&#62;T &#40;rs3917328&#41; revel&#243; que el porcentaje de portadores del alelo<span class="elsevierStyleHsp" style=""></span>T &#40;genotipos CT y TT&#41; fue mayor entre los controles &#40;9&#44;7&#37;&#41; que entre los pacientes alcoh&#243;licos &#40;6&#44;5&#37;&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;042&#41;&#46; En cualquier caso&#44; los an&#225;lisis de regresi&#243;n log&#237;stica multivariable no confirmaron esta diferencia &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">tabla 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Discusi&#243;n</span><p id="par0070" class="elsevierStylePara elsevierViewall">En el presente estudio analizamos la relaci&#243;n entre los polimorfismos gen&#233;ticos rs1368439&#44; rs1131445&#44; rs3917328 y rs4648143 y la presencia de alcoholismo o EHA&#46; Nuestro abordaje&#44; similar al seguido por otros autores<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">26&#44;27</span></a>&#44; se bas&#243; en seleccionar polimorfismos atendiendo a su ubicaci&#243;n cerca de sitios espec&#237;ficos de uni&#243;n miARN asociados&#44; potencialmente&#44; al alcoholismo o a la EHA<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">17&#44;28&#44;29</span></a>&#46; A pesar del posible papel que juegan estos polimorfismos en el alcoholismo y&#44; en concreto&#44; en el desarrollo de la EHA<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">30-32</span></a>&#44; no hallamos ninguna asociaci&#243;n significativa a este respecto&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Desde una perspectiva general&#44; nuestros resultados pueden explicarse&#44; en un principio&#44; por la verdadera ausencia de un nexo entre los polimorfismos analizados y estas enfermedades&#58; los polimorfismos seleccionados podr&#237;an no influir de manera significativa en la funci&#243;n de las citoquinas&#44; o ejercer una influencia que dependiera de otros posibles factores gen&#233;ticos o medioambientales asociados a la funci&#243;n de las interleucinas&#46; La complejidad de la regulaci&#243;n de los miARN podr&#237;a&#44; tambi&#233;n&#44; explicar nuestro resultado&#46; Cada miARN se une a varias dianas en diferentes genes&#44; y se sabe que cada sitio de uni&#243;n a trav&#233;s de los que ejercen su acci&#243;n es blanco de varios miARN<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">33</span></a>&#46; De ah&#237; que una variaci&#243;n en un &#250;nico SNP pudiera no ser suficiente para provocar una alteraci&#243;n en la funci&#243;n de las prote&#237;nas codificadas&#46; Por &#250;ltimo&#44; la ausencia de una relaci&#243;n significativa en nuestro estudio podr&#237;a deberse a las limitaciones espec&#237;ficas de los estudios de asociaci&#243;n caso-control&#46; En cualquier caso&#44; factores como la estratificaci&#243;n poblacional u otros posibles factores de confusi&#243;n parece poco probable&#46; Se realizaron ajustes en el an&#225;lisis estad&#237;stico para controlar posibles factores de confusi&#243;n &#40;como&#44; por ejemplo&#44; la edad o el sexo&#41;&#44; y las frecuencias al&#233;licas de nuestra poblaci&#243;n fueron similares a las descritas anteriormente en poblaciones cauc&#225;sicas&#46; Lamentablemente&#44; no se recogieron muestras serol&#243;gicas ni tisulares para determinar las interleucinas ni los miARN en sangre o h&#237;gado&#44; lo cual nos habr&#237;a permitido entender mejor el papel que juegan estos SNP en la inflamaci&#243;n inducida por el alcohol&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">En lo que a los polimorfismos <span class="elsevierStyleItalic">IL12B</span> y <span class="elsevierStyleItalic">IL16</span> hace referencia&#44; son pocos los estudios que han analizado la relaci&#243;n existente entre estas variantes gen&#233;ticas y el desarrollo de EHA o alcoholismo&#44; y en todo caso en ninguno de ellos se ha hallado una relaci&#243;n significativa<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">8</span></a>&#46; Aunque ambas citoquinas parecen jugar un papel en el da&#241;o inducido por el alcohol<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">34&#44;35</span></a>&#44; su relevancia podr&#237;a no ser suficiente para modular la susceptibilidad gen&#233;tica a estas enfermedades&#46; En cambio&#44; las variantes gen&#233;ticas del <span class="elsevierStyleItalic">NFKB1</span> s&#237; se han asociado al desarrollo de DA o EHA en anteriores estudios<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">32&#44;36</span></a>&#44; y la relaci&#243;n que existe entre el NF-&#63;B y la inflamaci&#243;n inducida por el alcohol es uno de los mecanismos fundamentales de regulaci&#243;n de la v&#237;a de los receptores TLR4 en estas enfermedades&#46; De ah&#237; que la falta de significaci&#243;n en el an&#225;lisis del polimorfismo <span class="elsevierStyleItalic">NFKB1</span> &#40;rs4648143&#41; pudiera explicarse por la baja frecuencia del alelo menor observado en este SNP&#44; o bien por la falta de efecto de esta variante gen&#233;tica espec&#237;fica&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">En lo que al polimorfismo <span class="elsevierStyleItalic">IL1R1</span> hace referencia&#44; se hall&#243; una frecuencia m&#225;s alta del alelo<span class="elsevierStyleHsp" style=""></span>T en controles sanos que en pacientes alcoh&#243;licos&#46; Este resultado no fue significativo tras el an&#225;lisis multivariable que se realiz&#243;&#44; en el que introdujimos la edad como posible factor de confusi&#243;n&#46; No obstante&#44; anteriores estudios han confirmado la implicaci&#243;n de la IL-1 y su receptor en la EHA y el alcoholismo<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">31&#44;37</span></a>&#44; y esta es una relaci&#243;n biol&#243;gicamente plausible&#46; La funci&#243;n del IL1R1 est&#225; &#237;ntimamente vinculada con la v&#237;a TLR4&#47;NF-&#63;B por las estructuras an&#225;logas de ambos receptores&#58; el IL1R1 puede verse estimulado por los mismos mediadores inflamatorios que los receptores TLR4&#44; como la quinasa<span class="elsevierStyleHsp" style=""></span>1 asociada al receptor<span class="elsevierStyleHsp" style=""></span>1 de la interleucina&#44; o el factor 6 asociado al receptor del TNF<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">38-40</span></a>&#46; Adem&#225;s&#44; el LPS bacteriano puede activar ambos receptores<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">41</span></a>&#46; La IL-1 tiene&#44; adem&#225;s&#44; una funci&#243;n relevante en la respuesta inflamatoria que lleva a desarrollar esteatohepatitis alcoh&#243;lica<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">42</span></a>&#46; A la luz de estos datos&#44; parece plausible que los cambios en la funci&#243;n de IL1R1&#44; como los inducidos por la presencia de SNP&#44; pudiesen acarrear un incremento de la respuesta inflamatoria&#46; La mayor frecuencia del alelo<span class="elsevierStyleHsp" style=""></span>T en los controles sanos podr&#237;a&#44; por lo tanto&#44; interpretarse como un posible factor protector del desarrollo de alcoholismo y EHA&#44; raz&#243;n por la cual estudios complementarios estar&#225;n plenamente justificados a fin de analizar esta relaci&#243;n junto con la de otros polimorfismos de IL-1 y IL1R1&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conclusiones</span><p id="par0090" class="elsevierStylePara elsevierViewall">Aunque negativos&#44; los resultados descritos en el presente estudio arrojan luz sobre la importancia de los miARN y los polimorfismos en sitios de uni&#243;n para miARN en el alcoholismo y la EHA&#46; Nuestro estudio describe&#44; por primera vez&#44; las frecuencias esperadas de ciertos polimorfismos en pacientes alcoh&#243;licos con y sin EHA&#46; Otras investigaciones&#44; a este respecto&#44; deber&#225;n aclarar su posible importancia en el desarrollo del alcoholismo y la EHA&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Financiaci&#243;n</span><p id="par0095" class="elsevierStylePara elsevierViewall">Estudio financiado por el Ministerio de Ciencia e Innovaci&#243;n de Espa&#241;a&#44; Instituto de Salud Carlos<span class="elsevierStyleHsp" style=""></span>III y los fondos FEDER de la Uni&#243;n Europea&#44; &#171;Una manera de hacer Europa&#187; &#40;becas n&#250;mero PI16&#47;01548 para M&#46;M&#46; y PI10&#47;00219 para RG-S&#41;&#44; Instituto de Investigaci&#243;n Biom&#233;dica de Salamanca II14&#47;0006 para M&#46;M&#46;&#44; Junta de Castilla y Le&#243;n INT&#47;M&#47;17&#47;17 para M&#46;M&#46; y la Red de Trastornos Adictivos-RTA &#40;beca n&#250;mero RD12&#47;0028&#47;0008 para F&#46;-J&#46;L&#46;&#41;&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conflicto de intereses</span><p id="par0100" class="elsevierStylePara elsevierViewall">Los autores declaran no tener ning&#250;n conflicto de intereses&#46;</p></span></span>"
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            1 => "Genetic polymorphism"
            2 => "Alcoholic liver disease"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introducci&#243;n</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">El consumo de alcohol induce una respuesta inflamatoria mediada por los receptores de tipo Toll<span class="elsevierStyleHsp" style=""></span>4 &#40;TLR4&#41; y el factor nuclear &#40;NF&#41;-&#63;B&#44; originando da&#241;o org&#225;nico&#46; Algunos micro-ARN &#40;miARN&#41; modulan la respuesta inflamatoria mediante retroalimentaci&#243;n negativa de mediadores como las interleucinas &#40;IL&#41;&#46; As&#237; pues&#44; polimorfismos en los genes de algunas IL localizados cerca de las dianas de los miARN podr&#237;an modificar el riesgo de da&#241;o org&#225;nico inducido por el alcohol&#46; Este estudio analiz&#243; la posible relaci&#243;n entre el alcoholismo o la enfermedad hep&#225;tica alcoh&#243;lica &#40;EHA&#41; y los polimorfismos <span class="elsevierStyleItalic">IL12B</span> 2124 G&#62;T &#40;rs1368439&#41;&#44; <span class="elsevierStyleItalic">IL16</span> 5000 <span class="elsevierStyleSmallCaps">C</span>&#62;T &#40;rs1131445&#41;&#44; <span class="elsevierStyleItalic">IL1R1</span> 3114 C&#62;T &#40;rs3917328&#41; y <span class="elsevierStyleItalic">NFKB1</span> 3400 A&#62;G &#40;rs4648143&#41;&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Pacientes y m&#233;todos</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Se incluyeron 301 pacientes alcoh&#243;licos varones y 156 voluntarios sanos varones&#46; Los polimorfismos fueron genotipados mediante discriminaci&#243;n al&#233;lica utilizando el sistema de PCR TaqMan<span class="elsevierStyleSup"><span class="elsevierStyleBold">&#174;</span></span>&#46; Se compararon las frecuencias al&#233;licas y genot&#237;picas entre grupos y se realiz&#243; un an&#225;lisis de regresi&#243;n log&#237;stica para dilucidar el modelo de herencia&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Resultados</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">El an&#225;lisis del polimorfismo de <span class="elsevierStyleItalic">IL1R1</span> &#40;rs3917328&#41; mostr&#243; que la proporci&#243;n de portadores del alelo<span class="elsevierStyleHsp" style=""></span>T &#40;genotipos CT y TT&#41; era mayor en los controles sanos &#40;9&#44;7&#37;&#41; que en pacientes alcoh&#243;licos &#40;6&#44;5&#37;&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;042&#41;&#46; Sin embargo el an&#225;lisis de regresi&#243;n log&#237;stica no mostr&#243; resultados significativos&#46; No se encontraron diferencias significativas entre grupos con respecto al resto de polimorfismos estudiados&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusiones</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Nuestro estudio describe&#44; por primera vez&#44; las frecuencias esperadas de polimorfismos en regiones diana de miARN en pacientes alcoh&#243;licos con y sin EHA&#46; Ser&#225;n necesarios nuevos estudios para aclarar la relevancia de estos polimorfismos en el desarrollo de alcoholismo o EHA&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introduction</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Alcohol consumption promotes inflammation through the Toll-like receptor 4 &#40;TLR4&#41;&#47;nuclear factor &#40;NF&#41;-&#63;B pathway&#44; leading to organic damage&#46; Some micro-RNA &#40;miRNA&#41; molecules modulate this inflammatory response by downregulating TLR4&#47;NF-&#63;B pathway mediators&#44; like interleukins &#40;ILs&#41;&#46; Thus&#44; polymorphisms within IL genes located near miRNA binding sites could modify the risk of ethanol-induced damage&#46; The present study analyzed potential relationships between alcoholism or alcoholic liver disease &#40;ALD&#41; and <span class="elsevierStyleItalic">IL12B</span> 2124 G&#62;T &#40;rs1368439&#41;&#44; <span class="elsevierStyleItalic">IL16</span> 5000 C&#62;T &#40;rs1131445&#41;&#44; <span class="elsevierStyleItalic">IL1R1</span> 3114 C&#62;T &#40;rs3917328&#41;&#44; and <span class="elsevierStyleItalic">NFKB1</span> 3400 A&#62;G &#40;rs4648143&#41; polymorphisms&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Patients and methods</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">The study included 301 male alcoholic patients and 156 male healthy volunteers&#46; Polymorphisms were genotyped using TaqMan<span class="elsevierStyleSup"><span class="elsevierStyleBold">&#174;</span></span> PCR assays for allelic discrimination&#46; Allele and genotype frequencies were compared between groups&#46; Logistic regression analysis was performed to analyze the inheritance model&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Results</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Analysis of the <span class="elsevierStyleItalic">IL1R1</span> &#40;rs3917328&#41; polymorphism showed that the proportion of allele<span class="elsevierStyleHsp" style=""></span>T carriers &#40;CT and TT genotypes&#41; was higher in healthy controls &#40;9&#46;7&#37;&#41; than in alcoholic patients &#40;6&#46;5&#37;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;042&#41;&#46; However&#44; multivariable logistic regression analyses did not yield a significant result&#46; No differences between groups were found for other analyzed polymorphisms&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusions</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Our study describes&#44; for the first time&#44; the expected frequencies of certain polymorphisms within miRNA-binding sites in alcoholic patients with and without ALD&#46; Further studies should be developed to clarify the potential relevance of these polymorphisms in alcoholism and ALD development&#46;</p></span>"
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          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">AC&#58; pacientes alcoh&#243;licos con cirrosis&#59; SEHA&#58; pacientes alcoh&#243;licos sin enfermedad hep&#225;tica alcoh&#243;lica&#59; TCA&#58; pacientes con trastornos por consumo de alcohol&#46;</p>"
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;2&#44;5&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>GT &#43; GG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">93 &#40;31&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">43 &#40;28&#44;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;741&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26 &#40;25&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">67 &#40;33&#44;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;756&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">IL16 rs1131445</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>TT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">109 &#40;36&#44;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">62 &#40;39&#44;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">0&#44;356</td><td class="td" title="table-entry  " align="left" valign="top">40 &#40;38&#44;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">69 &#40;34&#44;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">0&#44;431</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">146 &#40;48&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">65 &#40;41&#44;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">51 &#40;49&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">95 &#40;48&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46 &#40;15&#44;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">29 &#40;18&#44;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12 &#40;11&#44;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">34 &#40;17&#44;2&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CT &#43; CC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">192 &#40;63&#44;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">94 &#40;60&#44;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;460&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">63 &#40;61&#44;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">129 &#40;65&#44;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;495&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">IL1R1 rs3917328</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">264 &#40;87&#44;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">125 &#40;80&#44;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">0&#44;042</td><td class="td" title="table-entry  " align="left" valign="top">88 &#40;85&#44;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">176 &#40;88&#44;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">0&#44;236</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">35 &#40;11&#44;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30 &#40;19&#44;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15 &#40;14&#44;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20 &#40;10&#44;1&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>TT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;0&#44;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;1&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CT &#43; TT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">37 &#40;12&#44;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30 &#40;19&#44;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;044<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15 &#40;14&#44;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">22 &#40;11&#44;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;387&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">NFKB rs4648143</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>GG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">299 &#40;99&#44;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">152 &#40;98&#44;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">0&#44;217</td><td class="td" title="table-entry  " align="left" valign="top">102 &#40;99&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">197 &#40;99&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">0&#44;646</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>GA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;0&#44;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 &#40;1&#44;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;0&#44;5&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>AA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0 &#40;0&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>GA &#43; AA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;0&#44;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 &#40;1&#44;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;217&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;0&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;646&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1737882.png"
              ]
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          "notaPie" => array:1 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">La presencia del alelo T del polimorfismo <span class="elsevierStyleItalic">IL1R1</span> revel&#243; una distribuci&#243;n muy distinta en pacientes con TCA&#44; comparados con los controles &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;044&#41;&#46;</p> <p class="elsevierStyleNotepara" id="npar0010">Los datos se expresan en frecuencias absolutas &#40;&#37;&#41;&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "es" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Comparativa de frecuencias genot&#237;pica y al&#233;lica de los polimorfismos <span class="elsevierStyleItalic">IL12B</span>&#44; <span class="elsevierStyleItalic">IL16</span>&#44; <span class="elsevierStyleItalic">IL1R1</span> y <span class="elsevierStyleItalic">NFKB</span> entre pacientes con trastornos por consumo de alcohol y controles</p>"
        ]
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        "identificador" => "tbl0010"
        "etiqueta" => "Tabla 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
            "detalle" => "Tabla "
            "rol" => "short"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">IC&#58; intervalo de confianza&#59; NC&#58; no calculado por la ausencia del genotipo TT en los controles&#59; OR&#58; odds ratio&#59; TCA&#58; trastornos por consumo de alcohol&#46;</p><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Los datos se expresan en frecuencias absolutas &#40;&#37;&#41;&#46;</p><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">El modelo recesivo no se calcul&#243; por la ausencia del genotipo TT en los controles&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">An&#225;lisis multivariable</th></tr><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Modelo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Pacientes con TCA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Controles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">OR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">IC del 95&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="6" align="left" valign="top"><span class="elsevierStyleItalic">General</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">264 &#40;87&#44;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">125 &#40;80&#44;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Referencia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">35 &#40;11&#44;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30 &#40;19&#44;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;624&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;358-1&#44;087&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;096&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>TT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;0&#44;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;999&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="6" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="6" align="left" valign="top"><span class="elsevierStyleItalic">Dominante</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CC&nbsp;\t\t\t\t\t\t\n
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