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La secuenciación de todo el genoma revela variantes raras y estructurales que contribuyen a la psoriasis e identifica

Kyuto Sonehara¹, Rei Watanabe², Yutaka Matsumura³

¹Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan; Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

|August 23, 2025

Resumen

Este estudio revela nuevos factores genéticos que contribuyen a la psoriasis vulgar (PsV) mediante el análisis de variantes raras y estructurales en una población japonesa. Los hallazgos destacan IFIH1 y CERCAM como genes clave de susceptibilidad, avanzando en nuestra comprensión de la genética del PsV.

Área de la Ciencia:

La genética
Inmunodermatología
La genómica

Sus antecedentes:

La psoriasis vulgaris (PsV) es una enfermedad compleja de la piel mediada por el sistema inmunológico.
Los estudios genéticos anteriores se centraron principalmente en las variantes comunes en las poblaciones europeas, lo que limitó las ideas sobre diversos factores genéticos.
Es necesario explorar las variantes raras (RV) y las variantes estructurales (SV) para una comprensión completa de la etiología de PsV.

Objetivo del estudio:

Investigar el papel de las variantes raras y estructurales en la base genética de la psoriasis vulgar.
Identificar nuevos genes de susceptibilidad para el PsV en una cohorte japonesa.
Para aclarar la arquitectura genética de PsV más allá de las variantes comunes.

Principales métodos:

Secuenciación del genoma completo de 1.415 casos de PsV y 3.968 controles de la población japonesa.
Mapeo fino de una señal de estudio de asociación de todo el genoma (GWAS) en IFNLR1 utilizando análisis de variantes estructurales de eliminación.
Análisis de asociación de variantes raras basadas en genes y validación mediante secuenciación de larga lectura de PacBio.
Validación funcional en un modelo de ratón con psoriasis con knockout de Cercam.

Principales resultados:

Se identificó una variante estructural de deleción de 3,3 kb que interrumpe un potenciador específico del epitelio en IFNLR1.
Dos nuevos genes de susceptibilidad, IFIH1 y CERCAM, se asociaron con PsV a través de análisis de variantes raras.
El gen IL36RN, vinculado a la psoriasis pustulosa generalizada, mostró una asociación con el PsV común.
El knockout de Cercam en ratones exacerbó la dermatitis inducida por imiquimod, lo que indica su papel en la inflamación de la piel.

Conclusiones:

Este estudio revela la contribución significativa de las variantes raras y estructurales a la genética de la psoriasis vulgar.
IFIH1 y CERCAM se identifican como nuevos genes de susceptibilidad para PsV.
Los hallazgos amplían la comprensión de la patogénesis de PsV y resaltan la importancia de diversos análisis genéticos.

Palabras clave:

análisis basado en genes Estudio de asociación de todo el genoma Modelo de ratón nocaut Enfermedad de la piel Variante poco común ADN de una sola célula Análisis del transcriptoma espacial variante estructural secuenciación del genoma completo

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