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El riesgo genético del receptor TNF 1 refleja el resultado de la terapia anti-TNF en la esclerosis múltiple
Adam P Gregory1, Calliope A Dendrou2, Kathrine E Attfield2
1MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Nature
|July 18, 2012
Resumen
Los estudios de asociación de todo el genoma identificaron una variante genética, rs1800693, vinculada a la esclerosis múltiple (EM). Esta variante en el gen TNFRSF1A produce una forma soluble del receptor 1 del factor de necrosis tumoral (TNFR1), imitando los fármacos bloqueadores del TNF utilizados en otras enfermedades autoinmunes.
Área de la Ciencia:
- Genética La genética.
- Inmunología Inmunología.
- Farmacología Farmacología.
Sus antecedentes:
- Los estudios de asociación genómica (GWAS) identifican variantes genéticas asociadas a enfermedades, pero determinar la causalidad y la relevancia clínica sigue siendo un desafío.
- Un polimorfismo específico de un solo nucleótido (SNP), rs1800693, en el gen TNFRSF1A (que codifica el receptor 1 del factor de necrosis tumoral, TNFR1) está asociado con la esclerosis múltiple (EM), pero no con otras enfermedades autoinmunes.
Objetivo del estudio:
- Identificar la variante genética causal en la región TNFRSF1A asociada con la EM.
- Aclarar el papel funcional de la variante asociada a la EM y su relación con la señalización del factor de necrosis tumoral (TNF) y las intervenciones terapéuticas.
Principales métodos:
- Análisis de los datos de MS GWAS combinados con los datos del Proyecto 1000 Genomas para identificar el SNP causal.
- Estudios funcionales para investigar el efecto del alelo de riesgo de EM en la expresión de TNFR1 y el bloqueo del TNF.
- Comparación de los resultados clínicos con los fármacos bloqueadores del TNF en diferentes enfermedades autoinmunes.
Principales resultados:
- El análisis genético implica fuertemente rs1800693 como la variante causal en la región TNFRSF1A para la EM.
- El alelo de riesgo de EM conduce a la expresión de un TNFR1 soluble que inhibe el TNF.
- Los datos clínicos muestran que los fármacos bloqueadores del TNF exacerban la EM, pero son efectivos en enfermedades autoinmunes que carecen de asociación rs1800693, reflejando el efecto de la variante.
Conclusiones:
- La variante rs1800693 de TNFRSF1A asociada a la esclerosis múltiple imita funcionalmente los fármacos bloqueadores del TNF.
- Comparar GWAS entre enfermedades autoinmunes e investigar las consecuencias funcionales de las variantes puede informar la práctica clínica y el desarrollo de fármacos.
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