Association of Polymorphisms in Genes Regulating the Corticotropin-Releasing Factor System With Antidepressant Treatment Response
Association of Polymorphisms in Genes Regulating the Corticotropin-Releasing Factor System With Antidepressant Treatment Response
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DOI：
10.1001/archgenpsychiatry.2010.18
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发表时间：
2010-04-01
影响因子：
--
通讯作者：
Nemeroff, Charles B.
中科院分区：
文献类型：
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作者：
Binder, Elisabeth B.;Owens, Michael J.;Nemeroff, Charles B.
背景：促肾上腺皮质激素释放因子（CRF，或促肾上腺皮质激素释放激素）和精氨酸加压素系统与焦虑和抑郁症的病理生理学以及抗抑郁治疗的反应有关。 目的：研究调节 CRF 和精氨酸加压素系统的 10 个基因的遗传变异与西酞普兰治疗反应的关系。 缓解抑郁症的序贯治疗替代方案 (STAR*D) 样本 (N=1768)。设计：源自 STAR*D 研究的药物遗传学关联研究，这是一项多中心、前瞻性、开放、为期 12 周的有效性试验。地点：门诊初级保健和精神科诊所。患者：有 DNA 可用的非精神病性重度抑郁症患者，随后接受西酞普兰氢溴酸治疗 4 至 12 年 干预措施：灵活剂量的西酞普兰。主要结果指标：编码CRF系统的基因中的遗传多态性与出院访视时对西酞普兰治疗的反应和缓解之间的关联。结果：CRHBP位点内的一个单核苷酸多态性（SNP）（rs10473984）显示与两种缓解显着相关（P=6.0 x 10(-6)； 纠正后，P=.0026），并减少西酞普兰的抑郁症状（P=7.0 x 10(-7)；纠正后，P=.00031）。尽管次要等位基因频率存在很大差异，但该 SNP 的 T 等位基因与 3 个种族子样本中的 2 个（非裔美国人和西班牙裔）的较差治疗结果相关。这种关联在具有焦虑抑郁特征的患者中更为明显 (P=.008)。无反应等位基因被证明与总体较高的血浆促肾上腺皮质激素水平和更明显的地塞米松对促肾上腺皮质激素的抑制有关。结论：这些数据表明，CRHBP 基因座内的遗传变异影响非裔美国人和西班牙裔患者对西酞普兰的反应，表明该基因和 CRF 系统在抗抑郁治疗反应中发挥作用。
Context: The corticotropin-releasing factor (CRF, or corticotropin-releasing hormone) and arginine vasopressin systems have been implicated in the pathophysiology of anxiety and depressive disorders and response to antidepressant treatment.Objective: To study the association of genetic variants in 10 genes that regulate the CRF and arginine vasopressin systems with treatment response to citalopram in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) sample (N=1768).Design: Pharmacogenetic association study derived from the STAR*D study, a multicenter, prospective, open, 12-week effectiveness trial.Setting: Out patient primary care and psychiatric clinics.Patients: Individuals with nonpsychotic major depressive disorder for whom DNA was available who were subsequently treated with citalopram hydrobromide for 4 to 12 weeks.Intervention: Flexible doses of citalopram.Main Outcome Measure: Association of genetic polymorphisms in genes encoding the CRF system with response and remission to citalopram treatment at exit visit.Results: One single-nucleotide polymorphism (SNP) (rs10473984) within the CRHBP locus showed a significant association with both remission (P=6.0 x 10(-6); corrected, P=.0026) and reduction in depressive symptoms (P=7.0 x 10(-7); corrected, P=.00031) in response to citalopram. The T allele of this SNP was associated with poorer treatment outcome in 2 of the 3 ethnic subsamples (African American and Hispanic), despite large differences in minor allele frequency. This association was more pronounced in patients with features of anxious depression (P=.008). The nonresponse allele was shown to be associated with overall higher plasma corticotropin levels and more pronounced dexamethasone suppression of corticotropin.Conclusions: These data indicate that a genetic variant within the CRHBP locus affects response to citalopram in African American and Hispanic patients, suggesting a role for this gene and for the CRF system in antidepressant treatment response.