Genetic variation in the calcium/calmodulin-dependent protein kinase (CaMK) pathway is associated with antidepressant response in females.
Genetic variation in the calcium/calmodulin-dependent protein kinase (CaMK) pathway is associated with antidepressant response in females.
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DOI：
10.1016/j.jad.2011.10.030
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发表时间：
2012-02
影响因子：
6.6
通讯作者：
Yan-yan Shi;Yonggui Yuan;Zhi Xu;M. Pu;Congjie Wang;Yu-mei Zhang;Zhening Liu;Chuanyue Wang;Lingjiang Li;Zhijun Zhang
中科院分区：
文献类型：
--
作者：
Yan-yan Shi;Yonggui Yuan;Zhi Xu;M. Pu;Congjie Wang;Yu-mei Zhang;Zhening Liu;Chuanyue Wang;Lingjiang Li;Zhijun Zhang
抗抑郁药对单胺神经传递的作用可能受到细胞内信号转导途径的遗传变异的影响，如环磷酸腺苷（cAMP）-蛋白激酶A（PKA）途径，Ras-丝裂原活化蛋白激酶（MAPK）途径和钙/钙调蛋白依赖性蛋白激酶（CaMK）途径。本研究的目的是研究这三个信号转导通路的候选基因的多态性与抗抑郁药治疗的反应，并确定的影响，和相互作用，环境factors.METHODSWe招募了412例符合诊断标准的抑郁症（MDD）（DSM-IV轴I）。284例患者用选择性5-羟色胺再摄取抑制剂（SSRIs）或5-羟色胺和去甲肾上腺素能再摄取抑制剂（SNRIs）治疗8周。采用汉密尔顿抑郁量表（HDRS）评定治疗前后抑郁程度。209例患者完成了儿童期创伤问卷，28项简表（CTQ-SF），用于评估儿童期不良事件。218例患者在发病前完成生活事件量表（LES），用于评估生活应激。采用Illumina GoldenGate对66个候选基因的155个SNP进行分型，其中cAMP-PKA通路15个基因28个SNP，Ras-MAPK通路17个基因37个SNP，CaMK通路34个基因90个SNP。缓解标准为HDRS评分≤ 7分。通过UNPHASED 3.3.13分析单个SNP和单倍型关联。用SPSS 11.0软件对基因-环境交互作用进行二项logistic回归分析，发现ITPR 2的rs 2230372、PRKCZ的rs 2280272、PLCE 1的rs 17109671和rs 17109674 SNP与缓解显著相关，PRKCZ和PLCE 1的单倍型也是如此。所有这些正相关都存在于CaMK通路的基因中，而不是cAMP-PKA或Ras-MAPK通路。缓解者和非缓解者的CTQ评分和LES评分无显著差异。结论CaMK通路可能在抗抑郁反应中起重要作用。但最近的不良生活事件，童年逆境，候选基因和环境因素之间的相互作用似乎不会影响短期抗抑郁药的结果。
OBJECTIVEAntidepressant effects on monoamine neurotransmission may be influenced by genetic variation in intracellular signal transduction pathways, such as the cyclic adenosine monophosphate (cAMP) — protein kinase A (PKA) pathway, Ras-mitogen activated protein kinase (MAPK) pathway and calcium/calmodulin-dependent protein kinase (CaMK) pathway. The aims of this study were to examine the association of polymorphisms in candidate genes of these three signal transduction pathways with response to antidepressant treatment, and to determine the effects of, and interactions with, environment factors.METHODSWe recruited 412 patients who met diagnosis criteria for major depressive disorder (MDD) (DSM-IV Axis I). 284 patients completed 8weeks treatment with selective serotonin reuptake inhibitors (SSRIs) or serotonin and noradrenergic reuptake inhibitors (SNRIs). Severity of depression was measured with the Hamilton Depression Rating Scale (HDRS) before and after 8weeks antidepressant treatment. 209 patients completed the Childhood Trauma Questionnaire, 28 item Short Form (CTQ-SF) which was used to evaluate childhood adverse events. 218 patients completed the Life Events Scale (LES) which were used to evaluate life stress before onset. 155 SNPs in 66 candidate genes were genotyping by Illumina GoldenGate, including 28 SNPs in 15 genes of cAMP-PKA pathway, 37 SNPs in 17 genes of Ras-MAPK pathway and 90 SNPs in 34 genes of CaMK pathway. The remission criterion was HDRS score equal to or less than 7. Single SNP and haplotype associations were analyzed by UNPHASED 3.3.13. Gene-environment interactions were analyzed by binary logistic regression with SPSS 11.0 software.RESULTSThe rs2230372 SNP in ITPR2, rs2280272 in PRKCZ, rs17109671, and rs17109674 in PLCE1 were significant associated with remission, as were haplotypes in PRKCZ and PLCE1. All these positive associations were found in genes of the CaMK pathway, but not the cAMP-PKA or Ras-MAPK pathways. There were no significant differences in CTQ scores and LES scores between remitters and non-remitters. No significantly interactions between candidate genes and environment effects were observed.CONCLUSIONThe CaMK pathway may be important in determining antidepressant response. But recent adverse life events, childhood adversity, and interactions between candidate genes and environment factors appear not to influence short term antidepressant outcome.