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Estudio de asociación multiancestral de la estenosis aórtica identifica múltiples loci nuevos en el programa de un

Aeron M Small^1,2, Gina M Peloso^3,4, Jason Linefsky^5,6

¹Cardiovascular Medicine Division, Department of Medicine, Brigham and Women's Hospital (A.M.S., C.J.O.), Harvard Medical School, Boston, MA.

|February 21, 2023

Resumen

Los estudios de asociación de todo el genoma identificaron seis nuevas regiones genómicas para la estenosis aórtica calcificada (CAS), una enfermedad cardíaca común. Los hallazgos destacan el metabolismo lipídico, la inflamación y la adiposidad en el desarrollo de CAS y sus vínculos genéticos con las enfermedades cardiovasculares.

Área de la Ciencia:

Genética y genómica
Investigación de las enfermedades cardiovasculares
Medicina de precisión

Sus antecedentes:

La estenosis aórtica calcificada (CAS) es la enfermedad valvular cardíaca más frecuente en adultos mayores.
Actualmente, no existen terapias preventivas efectivas para el CAS.
Los estudios de asociación de todo el genoma (GWAS) ofrecen una vía para identificar los factores genéticos que influyen en el CAS y los posibles objetivos terapéuticos.

Objetivo del estudio:

Realizar un estudio de asociación genómica a gran escala (GWAS) y un análisis de asociación génica para la estenosis aórtica calcificada (CAS).
Identificar nuevos loci de riesgo genético para el CAS en diversas ascendencias.
Investigar la arquitectura genética del CAS y su relación con la enfermedad cardiovascular aterosclerótica y los factores de riesgo cardiometabólicos.

Principales métodos:

Se realizó un estudio de asociación de todo el genoma (GWAS) en 14.451 pacientes con CAS y 398.944 controles del Programa Million Veteran.
Los hallazgos se repitieron en múltiples cohortes independientes, con un total de 12.889 casos y 348.094 controles.
Utilizó puntuación de prioridad poligénica, colocalización eQTL y métodos genéticos más cercanos para priorizar los genes causales. Utilizó la aleatorización mendeliana y los estudios de asociación de todo el fenómeno (PheWAS) para evaluar la causalidad y la pleiotropía.

Principales resultados:

Se identificaron 23 variantes de plomo significativas en todo el genoma en 17 regiones genómicas, con 14 variantes en 11 regiones replicadas.
Se descubrieron 6 nuevas regiones genómicas asociadas con CAS, incluidas las variantes específicas de los individuos no blancos (rs12740374 en *CELSR2*, rs1522387 en *SLMAP*).
La aleatorización mendeliana implicó la lipoproteína y el colesterol LDL en CAS; el locus * FTO * mostró una asociación independiente con CAS, incluso después de ajustar el IMC.

Conclusiones:

Un GWAS multiancestral identificó seis nuevas regiones genómicas que contribuyen a la susceptibilidad a la estenosis aórtica calcificada (CAS).
El estudio destaca las funciones del metabolismo lipídico, la inflamación, la senescencia celular y la adiposidad en la patobiología de CAS.
Se aclararon las arquitecturas genéticas compartidas y distintas entre el CAS y las enfermedades cardiovasculares ateroscleróticas.

Palabras clave:

Estenosis de la válvula aórtica Estudio de asociación de todo el genoma La genómica Proteínas lipídicas

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