Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment
Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment
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DOI：
10.1086/503820
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发表时间：
2006-05-01
影响因子：
9.8
通讯作者：
Manji, H
中科院分区：
文献类型：
--
作者：
McMahon, FJ;Buervenich, S;Manji, H
抑郁症占全球疾病负担的很大，而且还在不断增加。尽管许多患者的病情随着药物的治疗而改善，但只有少数患者完全缓解，对一种药物有反应的患者可能对其他药物没有反应。目前，抗抑郁药物治疗结果的个体差异是不可预测的，但可能有部分遗传基础。在《抑郁症替代疗法序列研究》(STAR*D)研究中，我们在1,953名接受抗抑郁剂西酞普兰治疗的重度抑郁症患者中寻找治疗结果的遗传预测因素，并进行了前瞻性评估。在分裂样本设计中，选择了68个候选基因进行了基因分型，选择了768个单核苷酸多态标记来检测常见的遗传变异。我们检测到治疗结果与HTR2A中的一个标记物(在总样本中的P范围为1×10(-6)至3.7×10(-5))之间存在显著且可重复性的关联。在总样本中，HTR2A中的其他标记物也显示出与治疗结果相关的证据。HTR2A编码5-羟色胺2A受体，该受体被西酞普兰下调。与其他等位基因纯合的参与者相比，A等位基因纯合的参与者对治疗无反应的绝对风险降低了18%。白人受试者中A等位基因的频率是黑人受试者的6倍以上，黑人受试者的治疗效果较差。A等位基因可能与抗抑郁药物治疗结果的种族差异有关。结合以前的神经生物学发现，这些新的遗传数据为HTR2A在抗抑郁作用机制中的关键作用提供了一个令人信服的理由。
Depressive disorders account for a large and increasing global burden of disease. Although the condition of many patients improves with medication, only a minority experience full remission, and patients whose condition responds to one medication may not have a response to others. Individual variation in antidepressant treatment outcome is, at present, unpredictable but may have a partial genetic basis. We searched for genetic predictors of treatment outcome in 1,953 patients with major depressive disorder who were treated with the antidepressant citalopram in the Sequenced Treatment Alternatives for Depression (STAR*D) study and were prospectively assessed. In a split-sample design, a selection of 68 candidate genes was genotyped, with 768 single-nucleotide-polymorphism markers chosen to detect common genetic variation. We detected significant and reproducible association between treatment outcome and a marker in HTR2A (P range 1 x 10(-6) to 3.7 x 10(-5) in the total sample). Other markers in HTR2A also showed evidence of association with treatment outcome in the total sample. HTR2A encodes the serotonin 2A receptor, which is downregulated by citalopram. Participants who were homozygous for the A allele had an 18% reduction in absolute risk of having no response to treatment, compared with those homozygous for the other allele. The A allele was over six times more frequent in white than in black participants, and treatment was less effective among black participants. The A allele may contribute to racial differences in outcomes of antidepressant treatment. Taken together with prior neurobiological findings, these new genetic data make a compelling case for a key role of HTR2A in the mechanism of antidepressant action.