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Un QTL dependiente de estatinas para la expresión de GATM se asocia con miopatía inducida por estatinas
Lara M Mangravite1, Barbara E Engelhardt, Marisa W Medina
1Sage Bionetworks, 1100 Fairview Avenue North, Seattle, Washington 98109, USA. lara.mangravite@sagebase.org
Nature
|September 3, 2013
Resumen
Las estatinas reducen el colesterol, pero pueden causar miopatía. Se encontró un vínculo genético que involucra el gen GATM, lo que potencialmente explica el daño muscular inducido por las estatinas y ofrece nuevos objetivos terapéuticos.
Área de la Ciencia:
- La farmacogenómica es la farmacogenómica.
- Biología Molecular Biología Molecular
- Investigación de Enfermedades Cardiovasculares Investigación de Enfermedades Cardiovasculares
Sus antecedentes:
- Las estatinas se recetan ampliamente para reducir el riesgo de lipoproteínas de baja densidad (LDL) y enfermedades cardiovasculares (ECV).
- A pesar de los beneficios, las estatinas conllevan riesgos como la miopatía y la diabetes tipo 2.
- Los factores genéticos que influyen en la respuesta a las estatinas no se comprenden bien, lo que limita el tratamiento personalizado.
Objetivo del estudio:
- Para identificar objetivos posteriores del tratamiento con estatinas.
- Para investigar las variaciones genéticas que modulan la respuesta a las estatinas y la toxicidad.
- Explorar el mecanismo que vincula el uso de estatinas con la miopatía.
Principales métodos:
- Detección de cambios en la expresión génica en respuesta a la exposición in vitro a estatinas.
- Analizando las asociaciones genéticas con la expresión génica en las líneas celulares linfoblastoides de los participantes en el ensayo de estatinas.
- Investigando el papel de los genes identificados en la miotoxicidad inducida por estatinas utilizando modelos celulares.
Principales resultados:
- Se identificaron seis loci de rasgos cuantitativos de expresión (eQTL) que interactúan con la simvastatina.
- Un cis-eQTL para el gen de la glicina amidinotransferasa (GATM), rs9806699, se relacionó con la reducción de la miotoxicidad inducida por estatinas.
- El knockdown de GATM deterioró la respuesta celular al agotamiento de esteroles, lo que sugiere un papel en el metabolismo del colesterol y la miopatía.
Conclusiones:
- El gen GATM es un objetivo posterior del tratamiento con estatinas y un potencial mediador de la miopatía inducida por estatinas.
- Las variaciones genéticas en GATM pueden influir en la susceptibilidad a la toxicidad muscular inducida por estatinas.
- GATM representa un vínculo funcional entre la regulación del colesterol y los efectos secundarios de las estatinas.
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