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ORIGINAL
Patrón de metilación en ADN de sujetos hipertrigliceridémicos
DNA methylation pattern of hypertriglyceridemic subjects
Montse Guardiolaa,b,c,
Autor para correspondencia
montse.guardiola@urv.cat

Autor para correspondencia.
, Daiana Ibarretxea,b,c,d, Núria Planaa,b,c,d, Lluís Masanaa,b,c,d, Josep Ribaltaa,b,c
a Unitat de Recerca en Lípids i Arteriosclerosi, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili, Reus, Tarragona, España
b Institut d’Investigació Sanitària Pere Virgili, Reus, Tarragona, España
c Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, España
d Unitat de Medicina Vascular i del Metabolisme, Hospital Universitari Sant Joan de Reus, Reus, Tarragona, España
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Actualmente hay 5 genes identificados como principales responsables que codifican para prote&#237;nas clave en el proceso de lip&#243;lisis de los TG&#58; son <span class="elsevierStyleItalic">LPL&#44; APOC2&#44; GPIHBP1&#44; APOA5</span> y <span class="elsevierStyleItalic">LMF1</span>&#46; Ciertas mutaciones en estos genes producen niveles elevados de TG de forma cr&#243;nica&#46; Las hipertrigliceridemias primarias tienen una prevalencia de 1&#58;100&#46;000-1&#58;1&#46;000&#46;000&#59; son de aparici&#243;n temprana&#59; su principal manifestaci&#243;n cl&#237;nica es la pancreatitis&#44; que puede llegar a ser fatal&#59; y no suelen asociarse a un elevado riesgo cardiovascular &#40;revisado en Dron y Hegele<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">2</span></a>&#41;&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Por otro lado&#44; las hipertrigliceridemias secundarias tienen una mayor prevalencia &#40;1&#58;6&#46;000&#41;&#59; suelen aparecen en adultos&#59; a nivel metab&#243;lico presentan un aumento del n&#250;mero de quilomicrones&#44; junto con VLDL&#44; y sus remanentes&#44; y esto hace que se asocien a un elevado riesgo cardiovascular&#59; encontramos una influencia significativa de factores secundarios &#40;como obesidad&#44; s&#237;ndrome metab&#243;lico&#44; diabetes o una ingesta elevada de alcohol&#44; entre otros&#41;&#59; y la causa gen&#233;tica es m&#225;s compleja&#44; con la participaci&#243;n de variantes gen&#233;ticas raras en forma heterocigota en los 5 genes diagn&#243;stico descritos anteriormente&#44; junto con variantes en otros genes asociados a TG<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">3</span></a>&#46; Cada vez parece m&#225;s claro que esta forma de quilomicronemia se suele presentar como una hipertrigliceridemia relativamente moderada pero asociada a descompensaciones hiperlip&#233;micas espor&#225;dicas que&#44; debido a ciertas situaciones de sobrecarga lip&#237;dica&#44; pueden multiplicar los niveles de TG hasta 10 veces o m&#225;s&#44; para volver a disminuir r&#225;pidamente<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">4</span></a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Por lo tanto&#44; existen diferencias claras entre ambas formas de hipertrigliceridemia grave&#44; y esto hace que conocer la causa gen&#233;tica responsable pueda ayudar a caracterizar mejor el fenotipo de cada paciente&#59; estratificar mejor su riesgo cardiovascular&#59; mejorar la identificaci&#243;n de nuevos pacientes&#44; y facilitar el tratamiento m&#225;s adecuado a cada paciente&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Hoy en d&#237;a&#44; la combinaci&#243;n de varias estrategias gen&#233;ticas&#44; como la identificaci&#243;n de nuevas mutaciones con gran efecto fenot&#237;pico gracias a la secuenciaci&#243;n masiva&#44; junto con el dise&#241;o de risk-score gen&#233;ticos que engloban varias variantes moduladoras de los TG&#44; han permitido mejorar la caracterizaci&#243;n de estos pacientes<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">5</span></a>&#44; pero aun as&#237;&#44; seguimos dejando cerca de un 30&#37; de los casos de quilomicronemia sin causa gen&#233;tica conocida<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">6&#44;7</span></a>&#46; Por ello&#44; no descartamos que otros componentes gen&#233;ticos tengan un papel en el desarrollo de estas dislipidemias&#46; En este trabajo hemos querido evaluar si la epigen&#233;tica puede estar implicada en la hipertrigliceridemia y por ello hemos realizado una estrategia no dirigida&#44; llevando a cabo un estudio de asociaci&#243;n del epigenoma completo en muestras de pacientes con hipertrigliceridemia severa sin causa gen&#233;tica conocida&#44; para identificar nuevas regiones en el genoma diferencialmente metiladas en comparaci&#243;n con un grupo de sujetos normolip&#233;micos&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Metodolog&#237;a</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Participantes</span><p id="par0030" class="elsevierStylePara elsevierViewall">El grupo de pacientes hipertriglicerid&#233;micos est&#225; compuesto por 16 sujetos remitidos a la Unidad de L&#237;pidos de nuestro centro para el estudio de hipertrigliceridemia severa&#46; Son pacientes que presentan niveles de TG superiores a 1&#46;000<span class="elsevierStyleHsp" style=""></span>mg&#47;dl y en los que no se detect&#243; ninguna de las principales mutaciones causales en los genes responsables de las formas m&#225;s severas de hipertrigliceridemia descritas en la bibliograf&#237;a &#40;7 mutaciones en <span class="elsevierStyleItalic">LPL</span>&#44; 5 en <span class="elsevierStyleItalic">APOA5</span>&#44; 5 en <span class="elsevierStyleItalic">GPIHBP1</span>&#44; una <span class="elsevierStyleItalic">en APOC2</span> y 2 en <span class="elsevierStyleItalic">LMF1</span>&#41;&#46; Estos pacientes fueron comparados con sujetos normolip&#233;micos emparejados por edad y sexo que formaron parte del proyecto europeo VITAGE<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">8</span></a>&#44; que incluy&#243; hombres aparentemente sanos de edades comprendidas entre los 20 y los 75 a&#241;os&#46; No se incluyeron sujetos con enfermedades cr&#243;nicas hep&#225;ticas&#44; renales&#44; cardiopulmonares o afectos de neoplasias&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">El estudio fue aprobado por el Comit&#233; de &#201;tica e Investigaci&#243;n Cl&#237;nica de nuestro centro y todos los participantes firmaron el consentimiento informado&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Muestras</span><p id="par0040" class="elsevierStylePara elsevierViewall">Se obtuvieron muestras de sangre en ayunas de todos los participantes y se recogieron en tubos EDTA de plasma &#40;Sarstedt&#44; Ltd&#46;&#44; N&#252;mbrecht&#44; Alemania&#41;&#44; protegidos de la luz&#44; y centrifugados inmediatamente a 1&#46;500<span class="elsevierStyleHsp" style=""></span>g durante 10<span class="elsevierStyleHsp" style=""></span>min a 8<span class="elsevierStyleHsp" style=""></span>&#176;<span class="elsevierStyleSmallCaps">C</span>&#46; El plasma fue separado y dividido en al&#237;cuotas&#46; El buffy coat fue recogido para la extracci&#243;n de ADN gen&#243;mico&#46; Todas las muestras fueron almacenadas a &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C hasta que se llevaron a cabo las determinaciones anal&#237;ticas&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Determinaci&#243;n de los l&#237;pidos en plasma</span><p id="par0045" class="elsevierStylePara elsevierViewall">Las concentraciones de TG y colesterol en plasma fueron medidas mediante kits enzim&#225;ticos &#40;F&#46; Hoffmann-La Roche&#44; Ltd&#46;&#41; adaptados para un autoanalizador Cobas Mira &#40;F&#46; Hoffmann-La Roche&#44; Ltd&#46;&#41;&#46; Mediante inmunoturbidometr&#237;a medimos las apolipoprote&#237;na B y la lipoprote&#237;na &#40;a&#41; utilizando anticuerpos espec&#237;ficos &#40;F&#46; Hoffmann-La Roche&#44; Ltd&#46; y Incstar Corp&#46;&#44; respectivamente&#41;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">El colesterol de las LDL fue calculado mediante la f&#243;rmula de Friedewald<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">9</span></a> y no pudo ser calculado en todos los pacientes hipertriglicerid&#233;micos&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Estudio de asociaci&#243;n de genoma completo</span><p id="par0055" class="elsevierStylePara elsevierViewall">Fueron tratados con bisulfito s&#243;dico 500<span class="elsevierStyleHsp" style=""></span>ng de ADN para convertir las citosinas en uracilos&#44; mientras que las citosinas con un grupo 5-metil no reaccionan ante el bisulfito de sodio&#46; El ADN fue seguidamente hibridado al array de Illumina&#174; &#40;Infinium MethylationEPIC BeadChip&#41; siguiendo las instrucciones del protocolo de la casa comercial&#46; Los datos de las intensidades de cada tipo de sonda del array &#40;archivos idat&#41; se procesaron utilizando el paquete R&#44; ChAMP versi&#243;n 2&#46;9&#46;10<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">10&#44;11</span></a>&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Se filtraron las sondas con un valor p de detecci&#243;n superior a 0&#44;01 en una o m&#225;s muestras&#44; sondas con un recuento de cuentas<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>3 en al menos el 5&#37; de las muestras&#44; sondas con SNP pr&#243;ximos tal como se identifica en Zhou et al&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">12</span></a>&#44; sondas que se alinean en m&#250;ltiples ubicaciones como se identifica en Nordlund et al&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">13</span></a>&#44; y sondas localizadas en los cromosomas X o Y&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Despu&#233;s de filtrar las sondas&#44; se realiz&#243; la normalizaci&#243;n del tipo intracelular utilizando el m&#233;todo de normalizaci&#243;n cuant&#237;lica de mezcla beta<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">14</span></a> para evitar el sesgo introducido por el dise&#241;o de la sonda Infinium tipo 2&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Despu&#233;s de la normalizaci&#243;n cuant&#237;lica de mezcla beta&#44; la magnitud de los efectos del lote se evalu&#243; utilizando la SVD&#46; Para corregir las diferencias en la metilaci&#243;n resultantes de las diferencias en la heterogeneidad celular&#44; se utiliz&#243; la correcci&#243;n de Houseman<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">15</span></a>&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">El an&#225;lisis de metilaci&#243;n diferencial se realiz&#243; utilizando el estad&#237;stico t moderado de eBayes &#40;para la variable de resultado&#41; mediante el paquete limma<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">16</span></a> del software estad&#237;stico R&#46; El valor &#946; en los experimentos de metilaci&#243;n es la estimaci&#243;n del nivel de metilaci&#243;n utilizando la relaci&#243;n entre la intensidad de la sonda de metilaci&#243;n y la intensidad general&#44; mientras que el valor M es una transformaci&#243;n logar&#237;tmica del valor &#946;&#46; El valor M se utiliz&#243; para el an&#225;lisis de metilaci&#243;n diferencial y el valor &#946; para reportar los resultados&#44; lo que proporcion&#243; una interpretaci&#243;n biol&#243;gica m&#225;s intuitiva&#46; Los valores de p brutos se ajustaron mediante el procedimiento de Benjamini-Hochberg&#44; y una tasa de descubrimientos falsos de corte de 0&#44;05 y deltaBeta<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>5&#37; en los an&#225;lisis relacionados con los resultados se utiliz&#243; como umbral estad&#237;sticamente significativo&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">An&#225;lisis estad&#237;stico</span><p id="par0080" class="elsevierStylePara elsevierViewall">Utilizamos la prueba de Kolmogorov-Smirnov para ver si las variables cuantitativas segu&#237;an o no una distribuci&#243;n normal&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Los datos descriptivos de las variables cuantitativas se presentan como media<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>desviaci&#243;n est&#225;ndar o mediana &#40;rango intercuart&#237;lico&#41;&#46; En el caso de las variables cualitativas&#44; se presentan como porcentaje&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Las correlaciones entre el porcentaje de metilaci&#243;n de las citosinas diferencialmente metiladas con las distintas variables cuantitativas fueron ajustadas por edad&#44; sexo e IMC&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Resultados y discusi&#243;n</span><p id="par0095" class="elsevierStylePara elsevierViewall">Actualmente ya existen muchas evidencias que indican que los mecanismos epigen&#233;ticos juegan un papel importante en la regulaci&#243;n de fenotipos metab&#243;licos y en enfermedades complejas como es el caso de las dislipidemias<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">17</span></a>&#44; aunque a&#250;n no est&#225; claro si la gran mayor&#237;a de los cambios descritos en la metilaci&#243;n del ADN son causales o consecuencia de las dislipidemias&#46; En el presente estudio hemos utilizado la epigen&#233;tica como una herramienta para la identificaci&#243;n de nuevas regiones gen&#243;micas relacionadas con la hipertrigliceridemia grave&#44; y para ello hemos querido conocer el patr&#243;n de metilaci&#243;n de ADN en un grupo de pacientes con hipertrigliceridemia grave que no tienen un claro diagn&#243;stico gen&#233;tico&#44; para compararlo con el que presentan un grupo de sujetos normolip&#233;micos&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Ambos grupos estaban emparejados por edad y sexo para minimizar la variabilidad biol&#243;gica entre grupos&#46; Los participantes presentaban mediana edad y eran mayoritariamente hombres&#46; Tal y como muestra la <a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>&#44; el grupo de pacientes hipertriglicerid&#233;micos presentaban de forma estad&#237;sticamente significativa un mayor IMC&#44; una mayor concentraci&#243;n de TG&#44; una menor concentraci&#243;n de colesterol HDL&#44; una mayor concentraci&#243;n de colesterol no-HDL y una mayor concentraci&#243;n de glucosa que los sujetos normolip&#233;micos&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">Comparamos los patrones de metilaci&#243;n global entre las muestras de los pacientes hipertriglicerid&#233;micos y los sujetos control normolip&#233;micos&#44; e identificamos 31 citosinas diferencialmente metiladas&#46; La mayor&#237;a de las asociaciones &#40;75&#37;&#41; representan citosinas que muestran un menor grado de metilaci&#243;n &#40;hipometiladas&#41; en las muestras hipertriglicerid&#233;micas en comparaci&#243;n con los sujetos normolip&#233;micos&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Todas las citosinas diferencialmente metiladas est&#225;n recogidas en las <a class="elsevierStyleCrossRefs" href="#tbl0010">tablas 2 y 3</a>&#46; Algunas de estas citosinas est&#225;n localizadas en regiones gen&#243;micas que corresponden a un gen conocido&#44; y otras se localizan en regiones interg&#233;nicas y no se han podido asignar a un gen&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">Destacamos 4 citosinas localizadas en regiones g&#233;nicas conocidas&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Los pacientes hipertriglicerid&#233;micos presentan un descenso del 10&#37; en el grado de metilaci&#243;n de la citosina cg03636183 que se localiza en el gen <span class="elsevierStyleItalic">F2RL3</span> &#63;F2R Like Thrombin or Trypsin Receptor 3&#63;&#46; Este gen est&#225; implicado en procesos asociados al riesgo cardiovascular&#44; como la activaci&#243;n plaquetar<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">18</span></a>&#44; la hiperplasia de la &#237;ntima y la inflamaci&#243;n asociada a tabaquismo<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">19</span></a>&#46; En concreto&#44; la hipometilaci&#243;n de esta citosina cg03636183 medida en ADN de c&#233;lulas sangu&#237;neas ha sido asociada a un mayor riesgo de mortalidad cardiovascular m&#225;s all&#225; de los factores de riesgo tradicionales en 2 grandes estudios prospectivos<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">20&#44;21</span></a>&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Tambi&#233;n hemos identificado 3 citosinas relacionadas con el transporte vesicular&#46; Los pacientes hipertriglicerid&#233;micos presentan un descenso del 10&#37; en el grado de metilaci&#243;n de la cg13824500 localizada en el gen <span class="elsevierStyleItalic">VTI1A</span> &#63;Vesicle Transport through Interaction with T-SNAREs 1A&#63;&#46; Este es un gen limitante en la formaci&#243;n de los quilomicrones&#44; y m&#225;s concretamente en el tr&#225;nsito de los quilomicrones a trav&#233;s del ret&#237;culo endopl&#225;smico hasta el aparato de Golgi en el enterocito<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">22</span></a>&#46; En resumen&#44; el proceso de formaci&#243;n de los quilomicrones tiene lugar durante la absorci&#243;n intestinal de l&#237;pidos&#46; En el ret&#237;culo endopl&#225;smico de la c&#233;lula se forma el prequilomicr&#243;n con la uni&#243;n de la apoB48 que se va sintetizando&#44; a los l&#237;pidos complejos que nos llegan de la dieta&#46; Estos prequilomicrones ahora tienen que llegar al aparato de Golgi para madurar&#44; y este es un proceso complejo y secuencial que involucra la participaci&#243;n de ves&#237;culas que se fusionan e interaccionan con varios ligandos y prote&#237;nas receptoras en el complejo de Golgi&#46; Los prequilomicrones van avanzando por las diferentes cisternas del complejo gracias a las ves&#237;culas transportadoras&#44; y van madurando&#44; adquiriendo prote&#237;nas esenciales y sufriendo las modificaciones necesarias hasta formar los quilomicrones que encontraremos en el torrente sangu&#237;neo<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">23&#44;24</span></a>&#46; Este proceso implica la participaci&#243;n de prote&#237;nas como las SNARE y las RAB&#44; entre otras&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">En este mismo sentido&#44; tambi&#233;n encontramos que la citosina cg26468118&#44; localizada en el gen <span class="elsevierStyleItalic">RAB20</span> &#63;Member RAS Oncogene Family&#63;&#44; presentaba un grado de metilaci&#243;n un 13&#37; menor en los sujetos hipertriglicerid&#233;micos&#46; Este gen est&#225; implicado en procesos de endocitosis apical y reciclaje de ves&#237;culas&#44; y recientemente tambi&#233;n se ha relacionado con el proceso arterioscler&#243;tico&#46; En un art&#237;culo dise&#241;ado para identificar nuevos genes implicados en el infarto de miocardio&#44; han identificado que <span class="elsevierStyleItalic">RAB20</span> est&#225; sobreexpresado en placas arterioscler&#243;ticas carot&#237;deas<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">25</span></a>&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Finalmente&#44; hay que destacar que la cg21560722 se encuentra hipermetilada en los pacientes hipertriglicerid&#233;micos y est&#225; localizada en el gen <span class="elsevierStyleItalic">SBF2</span> &#63;SET Binding Factor 2&#63;&#44; que regula la expresi&#243;n de varios miembros de la familia de las RAB y tambi&#233;n regula prote&#237;nas SNARE<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">26</span></a>&#46; Este gen&#44; adem&#225;s&#44; ha sido recientemente identificado en un estudio de asociaci&#243;n de genoma completo asociado a la concentraci&#243;n de part&#237;culas de HDL determinadas mediante resonancia magn&#233;tica nuclear en la cohorte del Women&#39;s Genome Health Study<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">27</span></a>&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">No hemos encontrado que las otras citosinas identificadas est&#233;n localizadas en genes o regiones que <span class="elsevierStyleItalic">a priori</span> ya hayan sido relacionados con el metabolismo de los TG o de los l&#237;pidos en general&#44; ni asociados a enfermedad cardiovascular o arteriosclerosis&#46; Aunque&#44; a falta de validar los presentes resultados&#44; no descartamos que estas citosinas puedan tener un papel relevante a tener en cuenta en futuros estudios&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">En conclusi&#243;n&#44; estos resultados apuntan a que hay nuevas regiones gen&#243;micas a considerar cuando llevamos a cabo la caracterizaci&#243;n gen&#233;tica de los sujetos que presentan hipertrigliceridemias graves&#44; destacando los genes relacionados con la formaci&#243;n y maduraci&#243;n de los quilomicrones en los enterocitos&#46; No obstante&#44; debemos tener en cuenta que este estudio presenta una serie de limitaciones&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Primero de todo&#44; estos resultados necesitan ser validados en otras cohortes m&#225;s grandes para confirmar su asociaci&#243;n y relevancia en el control de la hipertrigliceridemia&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Otra limitaci&#243;n a tener en cuenta es que la determinaci&#243;n del grado de metilaci&#243;n se ha llevado a cabo en ADN extra&#237;do de c&#233;lulas mononucleares de sangre perif&#233;rica y sabemos que el perfil de metilaci&#243;n del ADN y la regulaci&#243;n de la expresi&#243;n g&#233;nica son espec&#237;ficos de tejido&#46; Sin embargo&#44; existen estudios que demuestran que la metilaci&#243;n determinada en c&#233;lulas sangu&#237;neas&#44; utilizada como posible marcador en un tejido de f&#225;cil acceso&#44; tiene cierta capacidad de reflejar los efectos epigen&#233;ticos que tienen lugar en los tejidos diana&#46; Aun as&#237;&#44; no debemos descartar ciertas variaciones si se llevan a cabo estudios dirigidos en los &#243;rganos diana&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Tambi&#233;n debemos tener en cuenta que no conocemos qu&#233; funci&#243;n pueden tener estas metilaciones identificadas&#46; Generalmente&#44; sabemos que&#44; a mayor metilaci&#243;n de citosina&#44; mayor represi&#243;n de la expresi&#243;n de un gen&#44; pero tambi&#233;n est&#225; descrito que la metilaci&#243;n del ADN en diferentes regiones gen&#243;micas puede influir en la regulaci&#243;n g&#233;nica de diferentes formas<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">28</span></a>&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Financiaci&#243;n</span><p id="par0165" class="elsevierStylePara elsevierViewall">Este estudio ha sido subvencionado por una beca FEA 2018 para investigaci&#243;n clinicoepidemiol&#243;gica en arteriosclerosis&#44; y tambi&#233;n por el Instituto de Salud Carlos III mediante el proyecto PI19&#47;00832 &#40;cofinanciado por el Fondo Europeo de Desarrollo Regional&#47;Fondo Social Europeo&#46; &#171;Una manera de hacer Europa&#187;&#47;&#171;El FSE invierte en tu futuro&#187;&#41;&#46; Cerca Programme&#47;Generalitat de Catalunya&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conflicto de intereses</span><p id="par0170" class="elsevierStylePara elsevierViewall">Los autores declaran no tener ning&#250;n conflicto de intereses&#46;</p></span></span>"
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              "titulo" => "An&#225;lisis estad&#237;stico"
            ]
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          "identificador" => "sec0040"
          "titulo" => "Resultados y discusi&#243;n"
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          "identificador" => "sec0045"
          "titulo" => "Financiaci&#243;n"
        ]
        8 => array:2 [
          "identificador" => "sec0050"
          "titulo" => "Conflicto de intereses"
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        9 => array:1 [
          "titulo" => "Bibliograf&#237;a"
        ]
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    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2021-06-14"
    "fechaAceptado" => "2021-09-23"
    "PalabrasClave" => array:2 [
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1477674"
          "palabras" => array:3 [
            0 => "Metilaci&#243;n ADN"
            1 => "Epigenoma"
            2 => "Triglic&#233;ridos"
          ]
        ]
      ]
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
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          "palabras" => array:3 [
            0 => "DNA methylation"
            1 => "Epigenome"
            2 => "Triglycerides"
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    "resumen" => array:2 [
      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Antecedentes</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Las quilomicronemias generalmente se diagnostican gen&#233;ticamente mediante secuenciaci&#243;n gen&#243;mica o cribado de mutaciones en genes causales con un gran efecto fenot&#237;pico&#46; Esta estrategia ha permitido mejorar la caracterizaci&#243;n de estos pacientes&#44; pero a&#250;n tenemos un 30&#37; de ellos sin un diagn&#243;stico gen&#233;tico concluyente&#46; Es por esto que hipotetizamos que a&#241;adiendo el componente epigen&#233;tico podemos mejorar el diagn&#243;stico gen&#233;tico y para ello hemos explorado el grado de metilaci&#243;n en el ADN de pacientes hipertriglicerid&#233;micos&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Metodolog&#237;a</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El ADN de c&#233;lulas sangu&#237;neas fue obtenido de 16 pacientes hipertriglicerid&#233;micos y de 16 sujetos control emparejados por edad y sexo&#46; El grado de metilaci&#243;n en el ADN de todo el genoma fue determinado mediante el Illumina&#174; Infinium MethylationEPIC Array Analysis&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Resultados</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Identificamos 31 citosinas diferencialmente metiladas al comparar los patrones de metilaci&#243;n que presentaban los pacientes hipertriglicerid&#233;micos vs&#46; los sujetos control&#46; La cg03636183 en el gen <span class="elsevierStyleItalic">F2RL3</span> estaba un 10&#37; hipometilada en los pacientes hipertriglicerid&#233;micos&#44; y ha sido previamente asociada a un mayor riesgo cardiovascular&#46; La cg13824500 est&#225; un 10&#37; hipometilada en pacientes hipertriglicerid&#233;micos y se localiza en <span class="elsevierStyleItalic">VTI1A&#44;</span> que es un gen limitante en el tr&#225;nsito de los quilomicrones en el enterocito a trav&#233;s del ret&#237;culo endopl&#225;smico y el aparato de Golgi&#46; La cg26468118 en el gen <span class="elsevierStyleItalic">RAB20</span> &#40;13&#37; hipometilada&#41; y la cg21560722 en el gen <span class="elsevierStyleItalic">SBF2</span> &#40;33&#37; hipermetilada&#41; est&#225;n implicadas en la regulaci&#243;n de ves&#237;culas del aparato de Golgi&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusiones</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Nuestros resultados evidencian que existen regiones diferencialmente metiladas relacionadas con la formaci&#243;n de los quilomicrones en pacientes hipertriglicerid&#233;micos&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Antecedentes"
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          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Metodolog&#237;a"
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          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Resultados"
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          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Conclusiones"
          ]
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      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Background</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Chylomicronemias are generally diagnosed genetically by genomic sequencing or screening for mutations in causal genes with a large phenotypic effect&#46; This strategy has allowed to improve the characterization of these patients&#44; but we still have 30&#37; of the patients without a conclusive genetic diagnosis&#46; This is why we hypothesize that by adding the epigenetic component we can improve the genetic diagnosis&#44; and for this we have explored the degree of methylation in the DNA of hypertriglyceridemic patients&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Methodology</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Blood cell DNA was obtained from 16 hypertriglyceridemic patients and from 16 age- and sex-matched control subjects&#46; The degree of methylation in genome-wide DNA was determined using the Illumina&#174; Infinium Methylation EPIC Array Analysis&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Results</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">We identified 31 differentially methylated cytosines by comparing the methylation patterns presented by hypertriglyceridemic patients vs&#46; control subjects&#46; The cg03636183 in the <span class="elsevierStyleItalic">F2RL3</span> gene was 10&#37; hypomethylated in hypertriglyceridemic patients&#44; and has previously been associated with an increased cardiovascular risk&#46; Cg13824500 is 10&#37; hypomethylated in hypertriglyceridemic patients and is located in <span class="elsevierStyleItalic">VTI1A</span>&#44; which is a limiting gene in the transit of chylomicrons in the enterocyte through the endoplasmic reticulum and the Golgi apparatus&#46; Cg26468118 in the <span class="elsevierStyleItalic">RAB20</span> gene &#40;13&#37; hypomethylated&#41; and cg21560722 in the <span class="elsevierStyleItalic">SBF2</span> gene &#40;33&#37; hypermethylated&#41; are involved in the regulation of Golgi apparatus vesicles&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusions</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Our results suggest that there are differentially methylated regions related to the formation of chylomicrons in hypertriglyceridemic patients&#46;</p></span>"
        "secciones" => array:4 [
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            "identificador" => "abst0030"
            "titulo" => "Methodology"
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          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Results"
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          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusions"
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          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Datos representados como media<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>DE o mediana &#40;RIC&#41; para las variables cuantitativas&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" 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
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Hipertriglicerid&#233;micos &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>16&#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
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Normolip&#233;micos &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>16&#41;&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">Edad&#44; a&#241;os&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">50&#44;19<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#44;36&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">51&#44;95<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&#44;65&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">Sexo&#44; &#37; hombres&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">94&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">100&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">&#205;ndice de masa corporal&#44; kg&#47;m<span class="elsevierStyleSup">2</span>&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">29&#44;93<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#44;94&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">25&#44;95 &#40;2&#44;25&#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">Colesterol total&#44; mg&#47;dl&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">220&#44;50 &#40;77&#44;00&#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">215&#44;06<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>36&#44;68&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">Colesterol LDL&#44; mg&#47;dl&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">87&#44;00 &#40;95&#44;00&#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">140&#44;93<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>27&#44;03&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">Colesterol HDL&#44; mg&#47;dl&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">30&#44;00 &#40;13&#44;00&#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">54&#44;05<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&#44;67&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">Colesterol no-HDL&#44; mg&#47;dl&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">198&#44;00 &#40;82&#44;25&#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">161&#44;38<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>35&#44;22&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">Triglic&#233;ridos totales&#44; mg&#47;dl&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&#46;687&#44;50<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>905&#44;22&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">106&#44;19<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>57&#44;52&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">Apo B&#44; mg&#47;dl&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">124&#44;31<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>35&#44;14&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">80&#44;25<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>17&#44;99&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">Lp&#40;a&#41;&#44; mg&#47;dl&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">10&#44;00 &#40;41&#44;50&#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">14&#44;50 &#40;34&#44;75&#41;&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">Glucosa&#44; mg&#47;dl&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;12<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#44;79&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">97&#44;48<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#44;93&nbsp;\t\t\t\t\t\t\n
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          "es" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Caracter&#237;sticas antropom&#233;tricas y bioqu&#237;micas basales de los participantes</p>"
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                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2831024.png"
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        "descripcion" => array:1 [
          "es" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Citosinas diferencialmente hipermetiladas en pacientes hipertriglicerid&#233;micos en comparaci&#243;n con los sujetos normolip&#233;micos</p>"
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          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">C&#58; sujetos control normolip&#233;micos&#59; CHR&#58; cromosoma que contiene la CG &#40;Build 38&#41;&#59; HT&#58; pacientes hipertriglicerid&#233;micos&#59; ID&#58; identificador &#250;nico de la base de datos de CG de Illumina&#174;&#59; MAPINFO&#58; coordenadas de la CG &#40;Build 38&#41;&#59; Strand&#58; cadena Forward &#40;F&#41; o Reverse &#40;R&#41;&#46;</p>"
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es en pt

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