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Una variante genética asociada con cinco enfermedades vasculares es un regulador distal de la expresión del gen

Rajat M Gupta1, Joseph Hadaya2, Aditi Trehan2

  • 1Broad Institute of MIT and Harvard University, Cambridge, MA, USA; Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

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|July 29, 2017
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Resumen
Este resumen es generado por máquina.

Una variante genética común cerca del gen PHACTR1 (rs9349379) influye en el riesgo de cinco enfermedades vasculares mediante la regulación de la expresión de la endotelina 1 (EDN1) en la aorta. Este descubrimiento destaca un mecanismo de regulación distal en la patogénesis de la enfermedad vascular.

Palabras clave:
El PNVEnfermedades cardiovascularesEnfermedad arterial coronariacélulas endotelialesEndotelina-1 también incluye:La epigenomíaelementos potenciadores genéticosEstudio de asociación de todo el genomahipertensióntrastornos de la migraña

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Área de la Ciencia:

  • La genética
  • Biología vascular
  • La epigenética

Sus antecedentes:

  • Los estudios de asociación de todo el genoma (GWAS) vinculan el locus PHACTR1 (6p24) con un mayor riesgo de cinco enfermedades vasculares distintas: enfermedad arterial coronaria, dolor de cabeza por migraña, disección de la arteria cervical, displasia fibromuscular e hipertensión.
  • La identificación de las variantes causales específicas y los mecanismos biológicos subyacentes a estas asociaciones sigue siendo un desafío importante en la genética humana.

Objetivo del estudio:

  • Determinar la variante genética causal en el locus PHACTR1 responsable de las asociaciones observadas con múltiples enfermedades vasculares.
  • Aclarar los mecanismos moleculares y celulares por los que esta variante contribuye a la patogénesis de las enfermedades vasculares.

Principales métodos:

  • Se utilizó el mapeo genético fino para priorizar los polimorfismos de nucleótido único (SNPs) dentro del locus PHACTR1.
  • Se analizaron datos epigenómicos de tejidos humanos para identificar elementos reguladores funcionales.
  • Se emplearon células endoteliales derivadas de células madre editadas por CRISPR para evaluar los efectos reguladores del SNP priorizado en la expresión génica.

Principales resultados:

  • rs9349379, un SNP común en el tercer intrón del gen PHACTR1, fue identificado como la variante causal putativa.
  • El análisis epigenómico reveló una firma de potenciador en rs9349379 específicamente en el tejido aórtico, lo que indica una función reguladora específica vascular.
  • La validación experimental demostró que rs9349379 regula la expresión de la endotelina 1 (EDN1), un gen localizado 600 kb aguas arriba de PHACTR1.

Conclusiones:

  • La variante común no codificante rs9349379 actúa como un regulador distal de la expresión de EDN1, proporcionando un vínculo mecánico entre la genética y las enfermedades vasculares múltiples.
  • Los efectos fisiológicos de EDN1 en la vasculatura probablemente explican el riesgo genético compartido a través de la enfermedad arterial coronaria, la migraña, la disección de la arteria cervical, la displasia fibromuscular y la hipertensión.
  • Este estudio ejemplifica el poder de integrar datos genéticos, fenotípicos y epigenómicos para descubrir la base biológica de enfermedades complejas impulsadas por variantes comunes.