國家衛生研究院 NHRI:Item 3990099045/10531
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    题名: Apoptosis pathway CASP10 gene associated with methadone dose and interacted with GRK5
    作者: Liu, YL;Tsung, JH;Shie, FS;Chung, RH;Wang, SC;Liu, SW;Kuo, HW;Fang, CP
    贡献者: Center for Neuropsychiatric Research;Division of Biostatistics and Bioinformatics
    摘要: Background: Methadone is a synthetic opioid usually used as a maintenance therapy for heroin dependent patients. The methadone maintenance treatment (MMT) dosage is essential for the treatment outcome. The MMT dosage has been reported involving multiple genes in its regulatory mechanism [1,2]. In our previous genomewide association analyses, we have discovered that the G protein-coupled receptor kinase 5 (GRK5) was associated with methadone dose. In this further study, we discovered a mechanism contributed from the Fas apoptosis pathway of caspase 10 (CASP10) gene using pathway-based association analyses. CASP10 gene encodes a protein which belongs to a member of the cysteine-aspartic acid protease (caspase) family. After subsequent activations of caspases, this process may lead to the executionphase of cell apoptosis [3]. Methods: This study was approved by the institutional review boards of the National Health Research Institutes (Zhunan, Taiwan) and the six participating hospitals. A total of 344 MMT patients whom had passed the quality check of genomewide association analyses were used in this study. Their genomic DNA were genotyped by the Axiom® Genome-Wide CHB 1 Array Plate, which had population-optimized to have a better genomic coverage of common alleles (MAF >5%) for the Han Chinese genome. All sample call rates were greater than 98.8%, and the mean individual sample call rate was 99.7±0.18%. 344 samples and 615,216 SNPs passed the quality control. The clinical assessments for these patients included the dose and tolerance (subtraction the initial from the current dose records). The pathway-based association analyses were analyzed by Knowledge-based mining system for Genomewide Genetic studies (KGG 2.5). The CASP10 and GRK5 gene expressions were analyzed by real-time polymerase chain reaction. The CASP10 over expression were carried out using the human HEK293 and SK-N-SH cell lines. Results: CASP10, CFLAR and SPTAN1 genes within the Fas pathway showed significant associations with methadone dose in the pathway-based association analyses (P = 0.003). The rs7576306 and rs6435069 at 3 -end on the CASP10, rs7558911 at intron 8 on CFLAR, and the rs10988041 and rs2152833 at intron 2on SPTAN1 were significantly associated with methadone dose (p = 0.013 and 0.013 for CASP10, 0.001 for CFLAR, and 0.012 and 0.009 for SPTAN1), and tolerance (p = 0.022 and 0.022 for CASP10, 0.003 for CFLAR, and 0.002 and 0.002 for SPTAN1). These significant associations were contributed from both urine morphine test positive and negative outcome. The significance of SNPs on CASP10 and CFLAR genes was contributed from urine morphine test positive ofMMT patients, while the significance of SNPs on SPTAN1 were contributed from urine morphine test negative patients. The rs7576306 on CASP10 were interacted with G protein-coupled receptor kinase 5 (GRK5) rs10886472 (p = 0.003). Its GG genotype carrier had higher CASP10 gene expression than the AA genotype carrier (p = 0.01). Overexpression of CASP10 gene in cultured human HEK293 and SK-N-SH cell line showed suppression of GRK5 expression. Conclusions: The methadone dose and tolerance were associated with the apoptosis Fas pathway of CASP10, CFLAR, and SPTAN1 genes. The CASP10 gene expression increase may reduce the GRK5 gene expression.
    日期: 2016-10
    關聯: European Neuropsychopharmacology. 2016 Oct;26(Suppl. 2):S693-S694.
    Link to: http://dx.doi.org/10.1016/S0924-977X(16)31823-5
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0924-977X&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000398568302404
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