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La puntuación de riesgo de la variante genética común está asociada con la prolongación del intervalo QT inducida por

David G Strauss¹, Jose Vicente², Lars Johannesen²

¹From Office of Clinical Pharmacology, Center for Drug Evaluation and Research (D.G.S., J.V., L.J.) and Office of Science and Engineering Laboratories, Center for Devices and Radiological Health (D.G.S., J.V., L.J., K.B.), US Food and Drug Administration, Silver Spring, MD; BSICoS Group, Aragón Institute for Engineering Research (I3A), IIS Aragón, University of Zaragoza, Spain (J.V.); Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden (L.J.); Division of Cardiology, University of Utah, Salt Lake City (J.W.M.); Spaulding Clinical Research, West Bend, WI (J.W.M.); Departments of Medicine (P.W., D.R.), Pharmacology (D.R.), and Biomedical Informatics (D.R.), Vanderbilt University Medical Center, Nashville, TN; Department of Cardiology, Copenhagen University Hospital, Gentofte, Denmark (P.W.); Cardiology Clinical Academic Group, St. George's University of London, London, UK (E.R.B.); AZCERT, Inc, Oro Valley, AZ (R.W.); Center for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA (G.K., M.A.R., C.N.-C.); Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (G.K., M.A.R., C.N.-C.); and Division of Cardiac Electrophysiology, Veterans Administration Hospital System of Boston, Harvard Medical School, West Roxbury, MA (M.A.R.). david.strauss@fda.hhs.gov cnewtoncheh@mgh.harvard.edu.

|February 19, 2017

Resumen

Una puntuación genética del intervalo QT, utilizando 61 variantes comunes, predice la prolongación del intervalo QT inducida por el fármaco y el riesgo de torsadas. Esta visión genética ayuda a la medicina personalizada al evaluar las respuestas individuales a los medicamentos que prolongan el intervalo QT.

Área de la Ciencia:

Farmacogenómica
Cardiología
La genética

Sus antecedentes:

La prolongación del intervalo QT inducida por fármacos es un factor de riesgo para las arritmias ventriculares que amenazan la vida.
No se comprende bien el papel de las variantes genéticas comunes en la prolongación del intervalo QT inducida por medicamentos.

Objetivo del estudio:

Para comprobar si una puntuación genética ponderada del intervalo QT predice respuestas individuales a medicamentos que prolongan el intervalo QT.
Evaluar la correlación entre una puntuación genética del intervalo QT y la prolongación del QTc inducida por fármacos.

Principales métodos:

Análisis secundario de un ensayo cruzado aleatorizado, doble ciego y controlado con placebo.
Análisis genético de 22 sujetos que recibieron dofetilida, quinidina, ranolazina y placebo.
Correlación de una puntuación genética de QT de 61 variantes con la prolongación del QTc frente a la concentración del fármaco.

Principales resultados:

La puntuación genética del intervalo QT explicó el 23-30% de la variabilidad en la prolongación del intervalo QT inducida por fármacos en sujetos blancos.
La puntuación genética QT predijo significativamente los puntos de torsión inducidos por el fármaco en una muestra independiente de casos y controles (P=1x10^-7).

Conclusiones:

Una puntuación genética del intervalo QT que comprende 61 variantes comunes predice significativamente la prolongación del intervalo QT inducida por el fármaco y los torsados.
Los descubrimientos genéticos ofrecen un potencial para mejorar la evaluación individualizada de los riesgos y beneficios de los medicamentos.
Se necesita una replicación adicional en muestras más grandes para validar los hallazgos e identificar variantes causales específicas.

Palabras clave:

Agentes antiarrítmicos tratamiento farmacológico pruebas genéticas genética La genómica farmacogenética Torsado de punta

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