Publicado el 18/01/2020 por MAS para el AUTISMO (traducción)
La heterogeneidad genética puede ser una explicación de la ausencia de replicación de los estudios de asociación en autismo.
Sin embargo, estos resultados también podrían interpretarse dentro del marco de un modelo de interacción GxE.
Si, por ejemplo, se ha encontrado una asociación en una muestra con sujetos expuestos frecuentemente a un riesgo ambiental particular pero no en aquellos expuestos con poca frecuencia, y no se determinó la exposición, la fuente de no replicación seguirá siendo difícil de alcanzar.
La existencia de interacciones entre los antecedentes genéticos y los factores ambientales en el autismo se sugirió por primera vez para las complicaciones perinatales.
De hecho, en un estudio epidemiológico sobre el autismo que incluyó un grupo de comparación de hermanos, los hermanos no afectados tuvieron menos complicaciones prenatales y perinatales que sus hermanos afectados, pero más que los sujetos de control.
Esto sugirió que las personas con autismo pueden reaccionar de manera diferente a los mismos estímulos ambientales y pueden tener menos tolerancia a la experiencia prenatal en comparación con sus hermanos.
Además, los estudios de modelos animales han sugerido que los defectos genéticos en la función sináptica pueden alterar la sensibilidad al medio ambiente.
De hecho, un estudio ha demostrado que los mutantes deficientes en neuroligina de los nematodos de C. elegans son hipersensibles al estrés oxidativo.
Otro estudio informó que las rodajas de hipocampo de ratones con deficiencia de MecP2 son más susceptibles a la hipoxia.
Por el contrario, se demostró en modelos animales que la patología más importante del cerebro extremadamente prematuro es la interrupción del desarrollo sináptico.
Por lo tanto, se planteó la hipótesis de que los defectos genéticos sinápticos podrían interactuar con el factor ambiental para aumentar el riesgo de autismo.
Otra hipótesis es la interacción entre las variaciones genéticas de los genes de la vía de la melatonina y el estrés oxidativo. De hecho, la concentración baja de melatonina en plasma es un rasgo frecuente en pacientes con TEA, causada por un déficit primario en la actividad acetilserotonina-melil-transferasa (ASMT). Se sugirió que las variaciones genéticas contribuyen al déficit enzimático.
Varios estudios han sugerido un efecto antioxidante de la melatonina in vitro, y se demostró que la administración de melatonina reduce el estrés oxidativo en los recién nacidos expuestos a infección o sufrimiento fetal, y promueve la maduración oligodendroglial en la rata recién nacida con materia blanca anormal relacionada con hipoxia fetal .
Por lo tanto, podría tener un efecto neuroprotector en el recién nacido expuesto a sufrimiento fetal. Curiosamente, Gardener et al señalaron que varios de los factores de riesgo perinatales y neonatales que identificaron pueden estar asociados con un mayor riesgo de hipoxia.
Por lo tanto, podemos plantear la hipótesis de que un déficit de melatonina podría tenerse en cuenta en las consecuencias de la angustia perinatal.
Más allá de estas observaciones, la evidencia disponible para la contribución de GxE al riesgo de autismo proviene de modelos animales. En un primer estudio, los ratones haploinsuficientes para el gen TSC2 demostraron una falta de comportamiento de enfoque social normal solo cuando se exponen a la activación inmune materna.
Los autores proponen que la señalización desinhibida de TSC / mTOR aguas abajo de los mediadores de los efectos de la activación inmunitaria gestacional amplifica su impacto en el cerebro fetal de ratones mutantes; o que la activación inmune puede ser más pronunciada en mutantes debido al papel de la señalización de TSC / mTOR en la regulación de la respuesta inmune adaptativa.
Además, explorando más a fondo la posible interacción entre la esclerosis tuberosa y la activación inmune materna en una cohorte de individuos con esclerosis tuberosa, los autores encontraron una asociación entre la gestación tardía y la actividad máxima de la gripe estacional específicamente en individuos afectados por TEA.
Estos resultados sugieren que la gestación tardía es el principal período de vulnerabilidad del desarrollo neurológico a la infección por gripe, lo que está en contradicción con los resultados, discutidos anteriormente, lo que sugiere que el parto en verano y la infección materna durante el primer trimestre son factores de riesgo para TEA.
Sin embargo, podemos hipotetizar razonablemente que el período de vulnerabilidad principal a la infección durante la gestación puede variar según los factores genéticos, y que existe un período específico de vulnerabilidad del desarrollo neurológico durante la gestación tardía en la esclerosis tuberosa.
En otro modelo animal, la activación inmune materna prenatal y la expresión de una proteína DISC1 mutante interactuaron para producir un patrón alterado de sociabilidad.
Este perfil neuroconductual estaba ausente en ratones no tratados que expresaban el mutante.
Aunque estos resultados son muy alentadores, los estudios de asociación familiar y poblacional en autismo aún no se han extendido para la interacción GxE.
Uno de los principales problemas con este tipo de estudio es que el poder para detectar las interacciones GxE es incluso menor que el poder para detectar los principales efectos genéticos o ambientales, y el entusiasmo por la investigación de GxE en otros trastornos psiquiátricos se ha atenuado recientemente por la ausencia de replicación de Muchos resultados positivos.
Sin embargo, estos estudios son necesarios, ya que podrían ayudarnos a comprender la inconsistencia en los resultados encontrados en los estudios de asociación clásicos y proporcionar sugerencias útiles con respecto a la prevención.
Recientemente se lanzaron dos estudios epidemiológicos prospectivos a gran escala destinados a explorar factores ambientales y la interacción GxE. El estudio de National Children ‘s seguirá a 100 000 niños en los EE. UU. Desde la concepción hasta los 21 años.
La contribución de los factores ambientales a través del efecto aditivo o multiplicativo debe explorarse más a fondo.
Será necesario dedicar nuevos fondos a este campo de investigación, que ha sido escasamente financiado hasta hace muy poco.
Se recogen muestras biológicas de niños y sus padres. Curiosamente, un resultado alentador provino de un estudio de asociación sobre el déficit de atención con el trastorno de hiperactividad (TDAH), que encontró efectos GxE en los síntomas de TEA en niños con TDAH. Los análisis de regresión múltiple para los efectos de GxE mostraron que el genotipo 5-HTTLPR S / S interactuó con el tabaquismo materno durante el embarazo, aumentando los problemas en la interacción social, y también interactuó con bajo peso al nacer, aumentando el comportamiento rígido.
Por último, dada la nueva comprensión de la arquitectura genética del autismo, sería útil estudiar más a fondo la interacción de variantes raras asociadas con TEA y factores ambientales en poblaciones que portan mutaciones idénticas, pero son difíciles de realizar debido al pequeño número de portadores.
Contrariamente a la afirmación frecuente de que conocemos muy poco del riesgo de autismo, se han realizado importantes avances en la última década en este ámbito.
En particular, los recientes avances en genética han permitido una nueva conceptualización de los mecanismos moleculares y celulares de la patología.
Al mismo tiempo, se plantean nuevas preguntas, incluido el papel de las variantes comunes y la relación entre el genotipo y el fenotipo.
La contribución de los factores ambientales a través del efecto aditivo o multiplicativo debe explorarse más a fondo.
Será necesario dedicar nuevos fondos a este campo de investigación, que ha sido escasamente financiado hasta hace muy poco.
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