Unit on the Genetic Basis of Mood and Anxiety Disorders, National Institute of Mental Health, Bethesda, MD 20892-3719, USA.
Int J Neuropsychopharmacol. 2010 Jul;13(6):715-24. doi: 10.1017/S1461145709991027. Epub 2010 Jan 5.
In a previous study we showed that genetic variation in HTR2A, which encodes the serotonin 2A receptor, influenced outcome of citalopram treatment in patients with major depressive disorder. Since chronic administration of citalopram, which selectively and potently inhibits the serotonin transporter (5-HTT), putatively enhances serotonergic transmission, it is conceivable that genetic variation within HTR2A also influences pretreatment 5-HTT function or serotonergic transmission. The present study used positron emission tomography (PET) and the selective 5-HTT ligand, [11C]DASB, to investigate whether the HTR2A marker alleles that predict treatment outcome also predict differences in 5-HTT binding. Brain levels of 5-HTT were assessed in vivo using PET measures of the non-displaceable component of the [11C]DASB binding potential (BPND). DNA from 43 patients and healthy volunteers, all unmedicated, was genotyped with 14 single nucleotide polymorphisms located within or around HTR2A. Allelic association with BPND was assessed in eight brain regions, with covariates to control for race and ethnicity. We detected allelic association between [11C]DASB BPND in thalamus and three markers in a region spanning the 3' untranslated region and second intron of HTR2A (rs7333412, p=0.000045; rs7997012, p=0.000086; rs977003, p=0.000069). The association signal at rs7333412 remained significant (p<0.05) after applying corrections for multiple testing via permutation. Genetic variation in HTR2A that was previously associated with citalopram treatment outcome was also associated with thalamic 5-HTT binding. While further work is needed to identify the actual functional genetic variants involved, these results suggest that a relationship exists between genetic variation in HTR2A and either 5-HTT expression or central serotonergic transmission that influences the therapeutic response to 5-HTT inhibition in major depression.
在之前的研究中，我们发现编码 5-羟色胺 2A 受体的 HTR2A 中的遗传变异影响了接受西酞普兰治疗的重度抑郁症患者的治疗效果。由于西酞普兰（选择性和强效地抑制 5-羟色胺转运体[5-HTT]）的慢性给药推测增强了 5-羟色胺能传递，因此 HTR2A 内的遗传变异也可能影响 5-HTT 功能或 5-羟色胺能传递的预处理。本研究使用正电子发射断层扫描（PET）和选择性 5-HTT 配体 [11C]DASB 来研究是否预测治疗效果的 HTR2A 标记等位基因也预测 5-HTT 结合的差异。使用 [11C]DASB 结合潜能（BPND）的不可置换成分的 PET 测量值，在体内评估 5-HTT 的脑水平。从 43 名患者和未用药的健康志愿者中提取 DNA，并用位于 HTR2A 内或周围的 14 个单核苷酸多态性进行基因分型。用协变量来控制种族和民族，评估与 BPND 的等位基因关联。我们在 8 个脑区检测到丘脑与跨越 HTR2A 3'非翻译区和第二内含子的三个标记之间的等位基因关联(rs7333412，p=0.000045；rs7997012，p=0.000086；rs977003，p=0.000069)。在通过置换进行多次测试校正后，rs7333412 的关联信号仍然显著（p<0.05）。与西酞普兰治疗效果相关的 HTR2A 中的遗传变异也与丘脑 5-HTT 结合相关。虽然需要进一步的工作来确定实际涉及的功能性遗传变异，但这些结果表明 HTR2A 中的遗传变异与 5-HTT 表达或中枢 5-羟色胺传递之间存在关系，这影响了重度抑郁症中对 5-HTT 抑制的治疗反应。
