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Las variantes genéticas que regulan la expresión de ORMDL3 contribuyen al riesgo de asma infantil
Miriam F Moffatt1, Michael Kabesch, Liming Liang
1National Heart and Lung Institute, Imperial College, London SW3 6LY, UK.
Nature
|July 6, 2007
Resumen
Los factores genéticos influyen en el asma infantil. Los estudios de asociación de todo el genoma identificaron polimorfismos de un solo nucleótido (SNP) en el cromosoma 17q21 fuertemente vinculados al asma infantil, particularmente la regulación del gen ORMDL3.
Área de la Ciencia:
- Genética La genética.
- Inmunología Inmunología.
- La pediatría es la medicina de los niños.
Sus antecedentes:
- El asma infantil surge de complejas interacciones genéticas y ambientales.
- Los fundamentos genéticos de la susceptibilidad al asma aún no se comprenden por completo.
- Los estudios de asociación de todo el genoma (GWAS) son cruciales para identificar los factores de riesgo genéticos.
Objetivo del estudio:
- Trazar un mapa sistemático de los efectos de los polimorfismos de un solo nucleótido (SNP) en el asma infantil.
- Para identificar los loci genéticos específicos asociados con el riesgo de asma.
- Para investigar la relación entre las variantes genéticas y los niveles de expresión génica.
Principales métodos:
- Estudio de asociación de todo el genoma (GWAS) que analiza más de 317.000 SNPs.
- Se utilizaron paneles basados en familias y casos de referencia que incluían a 994 pacientes con asma y 1.243 controles.
- Estudios de replicación independientes en poblaciones de cohorte de nacimiento alemanas y británicas.
- Se evaluaron los niveles de expresión génica en las líneas celulares linfoblastoides transformadas por el virus de Epstein-Barr (EBV).
Principales resultados:
- Se identificó una asociación fuerte y reproducible entre los marcadores del cromosoma 17q21 y el asma infantil (P < 10(-12)).
- Los estudios de replicación confirmaron la asociación del locus 17q21 en cohortes independientes (P = 0,0003 y P = 0,0005).
- Los SNPs en 17q21 se asociaron significativamente con los niveles de transcripción de ORMDL3 (P < 10(-22)), un gen que codifica las proteínas transmembranares del retículo endoplasmático.
Conclusiones:
- Las variantes genéticas que regulan la expresión de ORMDL3 son determinantes clave de la susceptibilidad al asma infantil.
- El locus 17q21 representa un factor de riesgo genético significativo para el asma infantil.
- Este estudio proporciona un vínculo molecular entre la variación genética, la expresión génica y la patogénesis del asma.
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