脑源性神经营养因子、磷脂酶C基因与环境因素及其相互作用对抗抑郁剂临床疗效的影响
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摘要
目的
临床抗抑郁剂治愈率低、潜伏期长,但其作用机理尚不明确。近年来的研究显示,抗抑郁剂可以作用于单胺类受体影响细胞内信号传导,调节神经细胞生长、增殖、存活和神经可塑性,从而发挥抗抑郁作用。脑源性营养因子(brain-derived neurotrophic factor,BDNF)在调节神经可塑性中起着重要作用,被认为是抗抑郁剂的作用靶点。BDNF也可以通过与酪氨酸激酶(tyrosine kinase,Trk)受体结合激活细胞内促分裂原活化蛋白激酶(mitogenactivated protein kinase,MAPK)等参与抗抑郁剂作用机制的信号传导通路。有研究表明磷脂酰肌醇(phosphoinositide,PI)信号传导通路可能参与抗抑郁剂的作用机制,其中磷脂酶C(phospholipase C,PLC)是调节PI代谢的主要蛋白酶。PLCε蛋白(phospholipase C epsilon)是PLC家族的一员,与Ras蛋白特异性结合。PLCε蛋白不仅参与PI信号传导,还可以通过Ras蛋白参与MAPK信号通路,从而参与抗抑郁剂的作用机制。探讨BDNF、PLCε的PLCE1基因和环境因素及其相互作用对抗抑郁剂治疗抑郁症临床疗效的影响。
方法
按照美国诊断和统计手册第4版(Diagnostic and statisticalmanual of mental disorder-IV,DSM-Ⅳ)入组340例抑郁症患者,共302例完成8周抗抑郁剂治疗。治疗前、治疗2周、4周、6周、8周采用汉密尔顿抑郁量表(Hamilton depression rating scale,HDRS)评定抑郁严重程度和治疗疗效,其中188例抑郁症患者完成儿童期创伤问卷(childhood trauma questionnaire,28 item short form,CTQ-SF)及生活事件量表(life events scale,LES),分别评定早期负性生活事件及发病前应激事件刺激量;采用Illumina GoldenGate定制芯片分析患者BDNFVal66Met基因多态性和PLCE1基因各单核苷酸多态性(single nucleotide polymorphism,SNP)(SNP1:rs17109671、SNP2:rs17109674、SNP3:rs17417407、SNP4:rs2274224、SNP5:rs3765524和SNP6:rs2274223)。以4周后HDRS分值减分率≥50%为界,分为有效组和无效组;以8周后HDRS分值≤7为界,分为痊愈组和未痊愈组。采用SPSS11.0、Haploview 4.0、Unphased3.0.13和多因素维降法(multifactor dimensionality r eduction,MDR)软件包进行统计分析。
结果
4周抗抑郁剂治疗有效组和无效组间、8周抗抑郁剂治疗痊愈组和未痊愈组间,BDNF Val66Met基因型和等位基因分布频率差异均无统计学意义(P=0.943,0.754;P=0.890,0.845)。PLCE1基因中rs17109671 A等位基因分布频率在无效组中显著高于有效组(P=0.048),而在未痊愈组中AA基因型和A等位基因显著高于痊愈组(P=0.013,0.004);rs1710974 G等位基因和GG基因型分布频率在未痊愈组中显著高于痊愈组(P=0.001,0.008)。在4周有效组-无效组中,单倍型A-C(SNP1-4)、A-G-C (SNP1-2-4)、A-C-G (SNP1-4-5)、G-C-G(SNP2-4-5)和A-C-G-A(SNP1-4-5-6)分布频率在有效组中显著高于无效组(PA-C=0.005,PA-G-C=0.003,PA-C-G=0.003,PG-C-G=0.007,PA-C-G-A=0.004);而在8周痊愈-未愈组中单倍型G-C(SNP1-4)、G-A-C(SNP1-2-6)、G-C-G(SNP1-4-5)、A-C-G-A(SNP2-4-5-6)在痊愈组中分布频率显著高于未愈组(PG-C=0.003,PG-A-C=0.002,PG-C-G=0.003,PA-C-G-A=0.001)。BDNF Val66Met基因多态性与PLCE1基因多态性联合作用对抗抑郁疗效并无统计学意义。CTQ-SF及LES分值在4周有效组与无效组间、8周痊愈组与未痊愈组间的差异无统计学意义。多因素Logistic回归模型分析显示BDNF Val66Met基因多态性与各量表赋值交互作用对短期抗抑郁剂疗效无统计学意义,而PLCE1基因rs2274224基因多态性与CTQ总分交互作用对8周抗抑郁剂疗效具有统计学意义(P=0.041)。
结论
携带PLCE1基因rs17109671 A等位基因的患者4周抗抑郁剂治疗疗效差,而分别携带rs17109671(AA基因型和A等位基因)和rs1710974(GG基因型和G等位基因)的患者8周抗抑郁剂疗效差。单倍型A-C(SNP1-4)、A-G-C (SNP1-2-4),A-C-G (SNP1-4-5)、G-C-G(SNP2-4-5)和A-C-G-A(SNP1-4-5-6)与4周抗抑郁剂治疗疗效较好有关。单倍型G-C(SNP1-4)、G-A-C(SNP1-2-6)、G-C-G(SNP1-4-5)和A-C-G-A(SNP2-4-5-6)与8周抗抑郁疗效较好有关。rs2274224基因多态性与儿童期创伤经历对8周抗抑郁剂疗效存在交互作用。而发病前生活事件应激和儿童期创伤经历、BDNF Val66Met基因多态性及两环境因素与BDNF基因交互作用对短期抗抑郁剂疗效没有明显影响。
Objective
The clinical remission of antidepressant treatment was low with a long incubation period, but the mechanism is unclear. Several studies showed antidepressant could influence intracellular signal transduction, regulate of nerve cell growth, proliferation, survival and neural plasticity by acting on monoamine receptors. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic family known to regulate neuronal plasticity and survival, may play an important role in the mechanisms underlying antidepressant therapeutic action. BDNF could active mitogenactivated protein kinase (MAPK) pathway, which participated in the mechinsim of antidepressant, through coupling with tyrosine kinase (Trk). Recent studies showed antidepressant could modulate phosphoinositide (PI) by interacting with the phospholipase C (PLC). Phospholipase C epsilon (PLCε) is a member of PLC families, which was initially characterized as a novel Ras-binding protein. PLCεwas not only the enzyme to odulate PI signal transduction, but also a indirect mediator of MAPK signal transduction though Ras, which participate in the mechanism of depression and may be the target of the antidepressant action. The aim of this study was to examine the associations of antidepressant treatment with BDNF Val66Met polymorphism, PLCE1 gene, environment factors and their interactions.
Methods
We recruited 340 patients of major depressive disorder (MDD) who met the diagnosis criteria of MDD (DSM-IV Axis I). 302 patients of them were finished 8 weeks antidepressant treatment. The severity of depression was measured with the Hamilton Depression Rating Scale (HDRS) before and after 2 weeks, 4 weeks, 6 weeks and 8 weeks antidepressant treatment. 188 patients finished Childhood Trauma Questionnaire, 28 item Short Form (CTQ-SF) and Life Events Scale (LES) which were used to evaluate childhood adverse and life stress before onset. Using Illumina GoldenGate genotyping to determine BDNF Val66Met polymorphism and the 6 SNPs (1: rs17109671, 2: rs17109674, 3: rs17417407, 4: rs2274224, 5: rs3765524 and 6: rs2274223) of PLCE1 gene. Clinical response to 4 weeks antidepressant treatment was considered when a decrease of at least 50% in the baseline HDRS scores. The remission criterion was HDRS scores equal to or less than 7 scores by the end of 8 weeks of treatment. We doing the statistical analysis used by SPSS package software for Windows version 11.0, UNPHASE the version 3.0.13 program and Multifactor Dimensionality Reduction (MDR) program.
Results
There was no significant difference of genotype and allele distributions for the BDNF Val66Met polymorphism between responders and non-responders or remitters and non-remitters (P=0.943 and 0.754, P=0.890 and 0.845, respectively). The frequencies of rs17109671 A allele carriers were significant higher in non-responders than responders (P=0.048), but the AA genotype and A allele carries were significant more in non-remitters than remitters (P=0.013 and 0.004, respectively). The frequencies of rs17109674 G allele and GG genotype carriers were significant higher in non-remitters than remitters (P=0.001 and 008, respectively). Haplotypes A-C (SNP1-4), A-G-C (SNP1-2-4), A-C-G (SNP1-4-5), G-C-G (SNP2-4-5) and A-C-G-A (SNP1-4-5-6) displayed higher frequencies in responders and non-responders (PA-C=0.0049, PA-G-C=0.0033, PA-C-G=0.0031, PG-C-G=0.0065 and PA-C-G-A=0.0043, respectively). 4 haplotypes [G-C (SNP1-4), G-A-C (SNP1-2-6), G-C-G (SNP1-4-5) and A-C-G-A (SNP2-4-5-6)] frequencies were significantly higher in remitters than in non-remitters (PG-C=0.0025, PG-A-C=0.0020, PG-C-G=0.0026 and PA-C-G-A=0.0013, respectively). No significant unification between BDNF Val66Met polymorphism and PLCE1 gene was found effect on antidepressant treatment. But there was no significant difference of CTQ scores and LES scores between responders and non-responders or remitters and non-remitters. The binary logistic regression analysis showed no interaction between BDNF Val66Met polymorphism and environment significantly effect on antidepressant treatment. But an interaction of rs2274224 polymorphism with childhood adversity factors was found significantly associated with remission to antidepressant.
Conclusions
The rs17109671 A allele carriers were with a poor response efficacy of 4 weeks antidepressant treatment. The rs17109671 (AA genotype and A allele) and rs1710974 (GG genotype and G allele) carriers were with a poor remission of 8 weeks antidepressant. Haplotypes A-C (SNP1-4), A-G-C (SNP1-2-4), A-C-G (SNP1-4-5), G-C-G (SNP2-4-5) and A-C-G-A (SNP1-4-5-6) were asocciated with better response efficacy of 4 weeks antidepressant treatment. 4 haplotypes G-C (SNP1-4), G-A-C (SNP1-2-6), G-C-G (SNP1-4-5) and A-C-G-A (SNP2-4-5-6) were associated with better remission of 8 weeks antidepressant. The interaction of rs2274224 polymorphism and child adversity might be effect on 8 weeks antidepressant outcome. But there were no effect of BDNF Val66Met polymorphism, recently life adverse events, childhood adversity, and the interactions of BDNF Val66Met polymorphism and environment factors on short term antidepressant outcome.
临床抗抑郁剂治愈率低、潜伏期长,但其作用机理尚不明确。近年来的研究显示,抗抑郁剂可以作用于单胺类受体影响细胞内信号传导,调节神经细胞生长、增殖、存活和神经可塑性,从而发挥抗抑郁作用。脑源性营养因子(brain-derived neurotrophic factor,BDNF)在调节神经可塑性中起着重要作用,被认为是抗抑郁剂的作用靶点。BDNF也可以通过与酪氨酸激酶(tyrosine kinase,Trk)受体结合激活细胞内促分裂原活化蛋白激酶(mitogenactivated protein kinase,MAPK)等参与抗抑郁剂作用机制的信号传导通路。有研究表明磷脂酰肌醇(phosphoinositide,PI)信号传导通路可能参与抗抑郁剂的作用机制,其中磷脂酶C(phospholipase C,PLC)是调节PI代谢的主要蛋白酶。PLCε蛋白(phospholipase C epsilon)是PLC家族的一员,与Ras蛋白特异性结合。PLCε蛋白不仅参与PI信号传导,还可以通过Ras蛋白参与MAPK信号通路,从而参与抗抑郁剂的作用机制。探讨BDNF、PLCε的PLCE1基因和环境因素及其相互作用对抗抑郁剂治疗抑郁症临床疗效的影响。
方法
按照美国诊断和统计手册第4版(Diagnostic and statisticalmanual of mental disorder-IV,DSM-Ⅳ)入组340例抑郁症患者,共302例完成8周抗抑郁剂治疗。治疗前、治疗2周、4周、6周、8周采用汉密尔顿抑郁量表(Hamilton depression rating scale,HDRS)评定抑郁严重程度和治疗疗效,其中188例抑郁症患者完成儿童期创伤问卷(childhood trauma questionnaire,28 item short form,CTQ-SF)及生活事件量表(life events scale,LES),分别评定早期负性生活事件及发病前应激事件刺激量;采用Illumina GoldenGate定制芯片分析患者BDNFVal66Met基因多态性和PLCE1基因各单核苷酸多态性(single nucleotide polymorphism,SNP)(SNP1:rs17109671、SNP2:rs17109674、SNP3:rs17417407、SNP4:rs2274224、SNP5:rs3765524和SNP6:rs2274223)。以4周后HDRS分值减分率≥50%为界,分为有效组和无效组;以8周后HDRS分值≤7为界,分为痊愈组和未痊愈组。采用SPSS11.0、Haploview 4.0、Unphased3.0.13和多因素维降法(multifactor dimensionality r eduction,MDR)软件包进行统计分析。
结果
4周抗抑郁剂治疗有效组和无效组间、8周抗抑郁剂治疗痊愈组和未痊愈组间,BDNF Val66Met基因型和等位基因分布频率差异均无统计学意义(P=0.943,0.754;P=0.890,0.845)。PLCE1基因中rs17109671 A等位基因分布频率在无效组中显著高于有效组(P=0.048),而在未痊愈组中AA基因型和A等位基因显著高于痊愈组(P=0.013,0.004);rs1710974 G等位基因和GG基因型分布频率在未痊愈组中显著高于痊愈组(P=0.001,0.008)。在4周有效组-无效组中,单倍型A-C(SNP1-4)、A-G-C (SNP1-2-4)、A-C-G (SNP1-4-5)、G-C-G(SNP2-4-5)和A-C-G-A(SNP1-4-5-6)分布频率在有效组中显著高于无效组(PA-C=0.005,PA-G-C=0.003,PA-C-G=0.003,PG-C-G=0.007,PA-C-G-A=0.004);而在8周痊愈-未愈组中单倍型G-C(SNP1-4)、G-A-C(SNP1-2-6)、G-C-G(SNP1-4-5)、A-C-G-A(SNP2-4-5-6)在痊愈组中分布频率显著高于未愈组(PG-C=0.003,PG-A-C=0.002,PG-C-G=0.003,PA-C-G-A=0.001)。BDNF Val66Met基因多态性与PLCE1基因多态性联合作用对抗抑郁疗效并无统计学意义。CTQ-SF及LES分值在4周有效组与无效组间、8周痊愈组与未痊愈组间的差异无统计学意义。多因素Logistic回归模型分析显示BDNF Val66Met基因多态性与各量表赋值交互作用对短期抗抑郁剂疗效无统计学意义,而PLCE1基因rs2274224基因多态性与CTQ总分交互作用对8周抗抑郁剂疗效具有统计学意义(P=0.041)。
结论
携带PLCE1基因rs17109671 A等位基因的患者4周抗抑郁剂治疗疗效差,而分别携带rs17109671(AA基因型和A等位基因)和rs1710974(GG基因型和G等位基因)的患者8周抗抑郁剂疗效差。单倍型A-C(SNP1-4)、A-G-C (SNP1-2-4),A-C-G (SNP1-4-5)、G-C-G(SNP2-4-5)和A-C-G-A(SNP1-4-5-6)与4周抗抑郁剂治疗疗效较好有关。单倍型G-C(SNP1-4)、G-A-C(SNP1-2-6)、G-C-G(SNP1-4-5)和A-C-G-A(SNP2-4-5-6)与8周抗抑郁疗效较好有关。rs2274224基因多态性与儿童期创伤经历对8周抗抑郁剂疗效存在交互作用。而发病前生活事件应激和儿童期创伤经历、BDNF Val66Met基因多态性及两环境因素与BDNF基因交互作用对短期抗抑郁剂疗效没有明显影响。
Objective
The clinical remission of antidepressant treatment was low with a long incubation period, but the mechanism is unclear. Several studies showed antidepressant could influence intracellular signal transduction, regulate of nerve cell growth, proliferation, survival and neural plasticity by acting on monoamine receptors. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic family known to regulate neuronal plasticity and survival, may play an important role in the mechanisms underlying antidepressant therapeutic action. BDNF could active mitogenactivated protein kinase (MAPK) pathway, which participated in the mechinsim of antidepressant, through coupling with tyrosine kinase (Trk). Recent studies showed antidepressant could modulate phosphoinositide (PI) by interacting with the phospholipase C (PLC). Phospholipase C epsilon (PLCε) is a member of PLC families, which was initially characterized as a novel Ras-binding protein. PLCεwas not only the enzyme to odulate PI signal transduction, but also a indirect mediator of MAPK signal transduction though Ras, which participate in the mechanism of depression and may be the target of the antidepressant action. The aim of this study was to examine the associations of antidepressant treatment with BDNF Val66Met polymorphism, PLCE1 gene, environment factors and their interactions.
Methods
We recruited 340 patients of major depressive disorder (MDD) who met the diagnosis criteria of MDD (DSM-IV Axis I). 302 patients of them were finished 8 weeks antidepressant treatment. The severity of depression was measured with the Hamilton Depression Rating Scale (HDRS) before and after 2 weeks, 4 weeks, 6 weeks and 8 weeks antidepressant treatment. 188 patients finished Childhood Trauma Questionnaire, 28 item Short Form (CTQ-SF) and Life Events Scale (LES) which were used to evaluate childhood adverse and life stress before onset. Using Illumina GoldenGate genotyping to determine BDNF Val66Met polymorphism and the 6 SNPs (1: rs17109671, 2: rs17109674, 3: rs17417407, 4: rs2274224, 5: rs3765524 and 6: rs2274223) of PLCE1 gene. Clinical response to 4 weeks antidepressant treatment was considered when a decrease of at least 50% in the baseline HDRS scores. The remission criterion was HDRS scores equal to or less than 7 scores by the end of 8 weeks of treatment. We doing the statistical analysis used by SPSS package software for Windows version 11.0, UNPHASE the version 3.0.13 program and Multifactor Dimensionality Reduction (MDR) program.
Results
There was no significant difference of genotype and allele distributions for the BDNF Val66Met polymorphism between responders and non-responders or remitters and non-remitters (P=0.943 and 0.754, P=0.890 and 0.845, respectively). The frequencies of rs17109671 A allele carriers were significant higher in non-responders than responders (P=0.048), but the AA genotype and A allele carries were significant more in non-remitters than remitters (P=0.013 and 0.004, respectively). The frequencies of rs17109674 G allele and GG genotype carriers were significant higher in non-remitters than remitters (P=0.001 and 008, respectively). Haplotypes A-C (SNP1-4), A-G-C (SNP1-2-4), A-C-G (SNP1-4-5), G-C-G (SNP2-4-5) and A-C-G-A (SNP1-4-5-6) displayed higher frequencies in responders and non-responders (PA-C=0.0049, PA-G-C=0.0033, PA-C-G=0.0031, PG-C-G=0.0065 and PA-C-G-A=0.0043, respectively). 4 haplotypes [G-C (SNP1-4), G-A-C (SNP1-2-6), G-C-G (SNP1-4-5) and A-C-G-A (SNP2-4-5-6)] frequencies were significantly higher in remitters than in non-remitters (PG-C=0.0025, PG-A-C=0.0020, PG-C-G=0.0026 and PA-C-G-A=0.0013, respectively). No significant unification between BDNF Val66Met polymorphism and PLCE1 gene was found effect on antidepressant treatment. But there was no significant difference of CTQ scores and LES scores between responders and non-responders or remitters and non-remitters. The binary logistic regression analysis showed no interaction between BDNF Val66Met polymorphism and environment significantly effect on antidepressant treatment. But an interaction of rs2274224 polymorphism with childhood adversity factors was found significantly associated with remission to antidepressant.
Conclusions
The rs17109671 A allele carriers were with a poor response efficacy of 4 weeks antidepressant treatment. The rs17109671 (AA genotype and A allele) and rs1710974 (GG genotype and G allele) carriers were with a poor remission of 8 weeks antidepressant. Haplotypes A-C (SNP1-4), A-G-C (SNP1-2-4), A-C-G (SNP1-4-5), G-C-G (SNP2-4-5) and A-C-G-A (SNP1-4-5-6) were asocciated with better response efficacy of 4 weeks antidepressant treatment. 4 haplotypes G-C (SNP1-4), G-A-C (SNP1-2-6), G-C-G (SNP1-4-5) and A-C-G-A (SNP2-4-5-6) were associated with better remission of 8 weeks antidepressant. The interaction of rs2274224 polymorphism and child adversity might be effect on 8 weeks antidepressant outcome. But there were no effect of BDNF Val66Met polymorphism, recently life adverse events, childhood adversity, and the interactions of BDNF Val66Met polymorphism and environment factors on short term antidepressant outcome.
引文
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[35] Harkness KL, Wildes JE. Childhood adversity and anxiety versus dysthymia co-morbidity in major depression. Psychol Med, 2002, 32 (7): 1239-1249.
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[37] Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science, 2003, 18(301): 386-389.
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[43] El Hage W, Powell JF, Surguladze SA. Vulnerability to depression: what is the role of stress genes in gene x environment interaction? Psychol Med, 2009, 39(9): 1407-1411.
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[46] Musazzi L, Mallei A, Tardito D, Gruber SH et al. Early-life stress and antidepressant treatment involve synaptic signaling and Erk kinases in a gene-environment model of depression. J Psychiatr Res 2009 [Epub ahead of print].
[47] El Khoury A, Gruber SHM, M?rk A, et al. Adult life behavioral consequences of early maternal separation are alleviated by escitalopram treatment in a rat model of depression. Prog Neuropsychopharmacol Biol Psychiatry, 2006, 30(3):535-540.
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[59] Schumacher J, Jamra RA, Becker T, et al. Evidence for a relationship between genetic variants at the brain-derived neurotrophic factor (BDNF) locus and major depression. Biol Psychiatry, 2005, 58(4): 307–314.
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