Institute of Psychiatry, King's College London, United Kingdom.
Biol Psychiatry. 2011 Feb 15;69(4):360-5. doi: 10.1016/j.biopsych.2010.08.011. Epub 2010 Oct 20.
Antidepressant drugs are used as first-line treatment in depression, but response has been shown to be highly heterogeneous, with drugs often failing to have the desired therapeutic effect. We report on an integrative analysis from the Genome-Based Therapeutic Drugs for Depression (GENDEP) study using gene expression from mice to inform prioritization in a human pharmacogenetic study.
The same two antidepressants were used in mice and humans: escitalopram (a serotonin reuptake inhibitor) and nortriptyline (a norepinephrine reuptake inhibitor). The animal study used four inbred strains of mice (129S1/SvlmJ, C57LB/6J, DBA/2J, and FVB/NJ). Hippocampus mRNA levels were measured in 144 animals using the Affymetrix MOE 430 v2 chip.
Based on gene-expression analysis of strain-by-drug interactions, 17 genes differentially expressed with nortriptyline or escitalopram versus saline were prioritized in the human pharmacogenetic analysis. Single nucleotide polymorphisms tagging common sequence variation in human orthologs of these genes were tested for association with response to antidepressants in 706 participants of the GENDEP human pharmacogenetic study, treated with escitalopram or nortriptyline for 12 weeks, with available high-quality Illumina 610 quad array genotyping. Several polymorphisms in the protein phosphatase 1A gene (PPM1A) remained significantly associated with response to nortriptyline in humans after correction for multiple comparisons within the gene. PPM1A encodes a phosphatase involved in mitogen-activated protein kinase signaling and cell stress response.
Convergent evidence from mice and humans suggests a role of the PPM1A in response to noradrenergic but not serotonergic antidepressants.
抗抑郁药被用作抑郁症的一线治疗药物，但反应高度异质，药物往往无法达到预期的治疗效果。我们报告了一项来自基于基因组的抗抑郁治疗药物（GENDEP）研究的综合分析，该研究使用来自小鼠的基因表达来为人类药物遗传学研究中的优先级排序提供信息。
在小鼠和人类中使用了两种相同的抗抑郁药：依他普仑（一种 5-羟色胺再摄取抑制剂）和去甲替林（一种去甲肾上腺素再摄取抑制剂）。该动物研究使用了四种近交系小鼠（129S1/SvlmJ、C57LB/6J、DBA/2J 和 FVB/NJ）。使用 Affymetrix MOE 430 v2 芯片测量了 144 只动物的海马 mRNA 水平。
基于药物与基因表达相互作用的基因表达分析，在人类药物遗传学分析中优先考虑了 17 个与去甲替林或依他普仑与生理盐水相比差异表达的基因。在 GENDEP 人类药物遗传学研究的 706 名参与者中，测试了这些基因的人类同源物的单核苷酸多态性（SNP）标记常见序列变异与依他普仑或去甲替林治疗 12 周的反应之间的关联，这些参与者可获得高质量的 Illumina 610 四重基因分型。在人类中，在基因内进行多次比较校正后，蛋白磷酸酶 1A 基因（PPM1A）中的几个多态性与去甲替林的反应仍然显著相关。PPM1A 编码一种参与丝裂原激活蛋白激酶信号转导和细胞应激反应的磷酸酶。
来自小鼠和人类的一致证据表明，PPM1A 在去甲肾上腺素能而非 5-羟色胺能抗抑郁药的反应中起作用。
