Your browser doesn't support javascript.
loading
Identification of novel drug targets for multiple sclerosis by integrating plasma genetics and proteomes.
Liu, Yi; Wang, Qian; Zhao, Yuhui; Liu, Liu; Hu, Jingxi; Qiao, Yao; Chen, Jinyi; Qin, Chao.
Afiliación
  • Liu Y; Department of Neurology, First Affiliated Hospital of Guangxi Medical University, Nanning, China; Department of Neurology, Shanxi Provincial People's Hospital, The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, China. Electronic address: liuyi123@sxmu.edu.cn.
  • Wang Q; Department of Neurology, Shanxi Provincial People's Hospital, The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, China; Shanxi Medical University, Taiyuan, China.
  • Zhao Y; Department of Neurology, Shanxi Provincial People's Hospital, The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, China; Shanxi Medical University, Taiyuan, China.
  • Liu L; Department of Neurology, Shanxi Provincial People's Hospital, The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, China; Shanxi Medical University, Taiyuan, China.
  • Hu J; Department of Neurology, Shanxi Provincial People's Hospital, The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, China; Shanxi Medical University, Taiyuan, China.
  • Qiao Y; Department of Neurology, Shanxi Provincial People's Hospital, The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, China; Shanxi Medical University, Taiyuan, China.
  • Chen J; Department of Neurology, Shanxi Provincial People's Hospital, The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, China; Shanxi Medical University, Taiyuan, China.
  • Qin C; Department of Neurology, First Affiliated Hospital of Guangxi Medical University, Nanning, China. Electronic address: chaoqin620@aliyun.com.
Exp Gerontol ; 194: 112505, 2024 Sep.
Article en En | MEDLINE | ID: mdl-38964432
ABSTRACT

BACKGROUND:

Genome-wide association studies (GWAS) have revealed numerous loci associated with multiple sclerosis (MS). However, the challenge lies in deciphering the mechanisms by which these loci influence the target traits. Here, we employed an integrative analytical pipeline to efficiently transform genetic associations to identify novel proteins for MS.

METHODS:

We systematically integrated MS GWAS data (N = 115,803) with human plasma proteome data (N = 7213) and conducted proteome-wide association studies (PWAS) to identify MS-associated pathogenic proteins. Following this, we employed Mendelian randomization and Bayesian colocalization analyses to verify the causal relationship between these significant plasma proteins and MS. Lastly, we utilized the Drug-Gene Interaction Database (DGIdb) to identify potential drug targets for MS.

RESULTS:

The PWAS identified 25 statistically significant cis-regulated plasma proteins associated with MS at a false discovery rate of P < 0.05. Further analysis revealed that the abundance of 7 of these proteins (PLEK, TNXB, CASP3, CD59, CR1, TAPBPL, ATXN3) was causally related to the incidence of MS. Our findings indicated that genetically predicted higher levels of TNXB and CD59 were associated with a lower risk of MS, whereas higher levels of PLEK, CASP3, CR1, TAPBPL, and ATXN3 were associated with an increased risk of MS. Three plasma proteins (PLEK, CR1, CD59) were validated by colocalization analysis. Among these, CR1 was prioritized as a target for Eculizumab due to its significant association with MS risk. Additionally, PLEK, CR1, and CD59 were identified as druggable target genes.

CONCLUSIONS:

Our proteomic analysis has identified PLEK, CR1, and CD59 as potential drug targets for MS treatment. Developing pharmacological inducers or inhibitors for these proteins could pave the way for new therapeutic approaches, potentially improving outcomes for MS patients.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteoma / Estudio de Asociación del Genoma Completo / Esclerosis Múltiple Límite: Humans Idioma: En Revista: Exp Gerontol Año: 2024 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteoma / Estudio de Asociación del Genoma Completo / Esclerosis Múltiple Límite: Humans Idioma: En Revista: Exp Gerontol Año: 2024 Tipo del documento: Article Pais de publicación: Reino Unido