Differential Genetic and Epigenetic Regulation of catechol-O-methyltransferase is Associated with Impaired Fear Inhibition in Posttraumatic Stress Disorder.
Differential Genetic and Epigenetic Regulation of catechol-O-methyltransferase is Associated with Impaired Fear Inhibition in Posttraumatic Stress Disorder.
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DOI：
10.3389/fnbeh.2013.00030
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发表时间：
2013
影响因子：
3
通讯作者：
Ressler KJ
中科院分区：
文献类型：
--
作者：
Norrholm SD;Jovanovic T;Smith AK;Binder E;Klengel T;Conneely K;Mercer KB;Davis JS;Kerley K;Winkler J;Gillespie CF;Bradley B;Ressler KJ
儿茶酚-O-甲基转移酶（COMT）对突触多巴胺的分解代谢调节至关重要，导致皮质功能改变。COMT Val 158 Met多态性与人类精神疾病有关，Met/Met纯合子与创伤后应激障碍（PTSD）易感性增加有关。我们的主要目的是通过COMT基因型（Met/Met、瓦尔/Met和瓦尔/瓦尔）和COMT启动子区CpG位点甲基化状态的差异性基因调控来检测PTSD中恐惧抑制的中间表型。更具体地说，我们研究了COMT基因型和PTSD诊断在恐惧条件反射和消退过程中对恐惧增强惊吓的潜在相互作用以及COMT DNA甲基化水平（使用从全血中分离的基因组DNA测定）。参与者是从美国佐治亚州亚特兰大市一家城市医院的内科和妇科诊所招募的。我们发现，与瓦尔/Met和瓦尔/瓦尔基因型相比，Met/Met基因型的个体对CS-（安全信号）和CS+（危险信号）的消退表现出更高的恐惧增强惊吓。与瓦尔携带者相比，PTSD+ Met/Met基因型组对CS-恐惧抑制的损害最大（p = 0.006）。此外，Met/Met基因型与四个CpG位点的DNA甲基化相关，其中两个与对安全信号的恐惧抑制受损相关。这些结果表明，调节COMT功能的多种差异机制-通过Val 158 Met基因型在蛋白质结构水平上和通过差异甲基化在基因调节水平上-与PTSD中恐惧抑制受损相关。
The catechol-O-methyltransferase (COMT) enzyme is critical for the catabolic regulation of synaptic dopamine, resulting in altered cortical functioning. The COMT Val158Met polymorphism has been implicated in human mental illness, with Met/Met homozygotes associated with increased susceptibility to posttraumatic stress disorder (PTSD). Our primary objective was to examine the intermediate phenotype of fear inhibition in PTSD stratified by COMT genotype (Met/Met, Val/Met, and Val/Val) and differential gene regulation via methylation status at CpG sites in the COMT promoter region. More specifically, we examined the potential interaction of COMT genotype and PTSD diagnosis on fear-potentiated startle during fear conditioning and extinction and COMT DNA methylation levels (as determined using genomic DNA isolated from whole blood). Participants were recruited from medical and gynecological clinics of an urban hospital in Atlanta, GA, USA. We found that individuals with the Met/Met genotype demonstrated higher fear-potentiated startle to the CS− (safety signal) and during extinction of the CS+ (danger signal) compared to Val/Met and Val/Val genotypes. The PTSD+ Met/Met genotype group had the greatest impairment in fear inhibition to the CS− (p = 0.006), compared to Val carriers. In addition, the Met/Met genotype was associated with DNA methylation at four CpG sites, two of which were associated with impaired fear inhibition to the safety signal. These results suggest that multiple differential mechanisms for regulating COMT function – at the level of protein structure via the Val158Met genotype and at the level of gene regulation via differential methylation – are associated with impaired fear inhibition in PTSD.
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影响因子：
17.7
作者：
Kilpatrick, Dean G.;Koenen, Karestan C.;Gelernter, Joel
通讯作者：
Gelernter, Joel
影响因子：
120.7
作者：
Binder, Elisabeth B.;Bradley, Rebekah G.;Ressler, Kerry J.
通讯作者：
Ressler, Kerry J.
DOI：
10.3109/10253890.2011.592880
发表时间：
2012-01-01
影响因子：
2.3
作者：
Jung, Ye-Ha;Kang, Do-Hyung;Kwon, Jun Soo
通讯作者：
Kwon, Jun Soo
影响因子：
10.6
作者：
Kolassa, Iris-Tatjana;Kolassa, Stephan;De Quervain, Dominique J. -F.
通讯作者：
De Quervain, Dominique J. -F.
影响因子：
2.5
作者：
Lewis, DA;Melchitzky, DS;Sampson, A
通讯作者：
Sampson, A