title: Kinase gene haplotypes and gene-gene interactions in the Ras-Raf-MAPK signaling pathway: association with antidepressant remission.
abstract: Signal transduction has been reported to be involved in antidepressant treatment outcomes; however, its mechanisms remain unclear. The aims of this study were to explore the associations between antidepressant remission and single nucleotide polymorphisms (SNPs), haplotypes, and gene-gene interactions in the Ras-Raf-MAPK intracellular signaling pathway. A total of 302 inpatients with major depressive disorder (DSM-IV Axis I) were assessed using the 17-item Hamilton Depression Rating Scale before and after 8 weeks of antidepressant treatment to determine the remission rate in the samples. Twenty-four SNPs at five kinase genes (Ras-Raf-MEK-ERK-RSK), which are a part of the Ras-Raf-MAPK signaling pathway, were identified to investigate a genetic association with antidepressant drug outcome. Correlations between 24 SNPs at the five kinase genes in the Ras-Raf-MAPK signaling pathway and antidepressant drug outcome were not found. The percentage of the CCAGA haplotype that RSK(2/3/4)-RSKL(1/2) gene loci SNPs constructed was markedly lower in the remitter group when compared with the nonremitter group in female depressed patients (P=0.04), whereas the proportion of AAAGGG haplotype that RSK(2/3/4)-RSKL(1/2) gene loci SNPs constructed in the remitter group was significantly greater than that in the nonremitter group in male patients (P=0.02). In addition, MEK1 (rs28730804) and RSK3 (rs2229712) in the Ras-Raf-MAPK signaling pathway showed a gene-gene interaction that affected antidepressant drug outcome in female depressed patients (P=0.041). Although this study did not find that SNPs at the five kinase genes in the Ras-Raf-MAPK signaling pathway are important markers for antidepressant outcome, certain haplotypes that SNPs at the RSK(2/3/4)-RSKL(1/2) gene constructed may be important markers for antidepressant drug efficacy. We observed a gene-gene interaction in this signaling pathway that influenced antidepressant efficacy in female depressed patients. Therefore, it is likely that in female depressed patients, different haplotypes and gene-gene interaction in the Ras-Raf-MAPK signaling pathway are involved in mediating the pharmacological action of an antidepressant, and eventually influence antidepressant efficacy.
authors.affiliation: Department of Psychiatry, Huai'an No. 3 People's Hospital, Huai'an, Jiangsu Province, China. congjiewang88@yahoo.com.cn
authors.forename: Cong-jie
authors.initials: CJ
authors.lastname: Wang
authors.forename: Zhi-jun
authors.initials: ZJ
authors.lastname: Zhang
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xu
authors.forename: Yan-yan
authors.initials: YY
authors.lastname: Shi
authors.forename: Meng-Jia
authors.initials: MJ
authors.lastname: Pu
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zheng
authors.forename: Xiu-zhen
authors.initials: XZ
authors.lastname: Wang
authors.forename: Yu-mei
authors.initials: YM
authors.lastname: Zhang
authors.forename: Ling-jiang
authors.initials: LJ
authors.lastname: Li
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use*; D044466:Asian People; D002681:China; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004843:Epistasis, Genetic; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011569:Psychiatric Status Rating Scales; D012074:Remission Induction; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics* / Q000378:metabolism; D012727:Sex Characteristics; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D048490:raf Kinases; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D018631:ras Proteins