No Association Between Antidepressant Efficacy and rs28365143 in Corticotropin-Releasing Hormone Binding Protein in a Large Meta-Analysis.
No Association Between Antidepressant Efficacy and rs28365143 in Corticotropin-Releasing Hormone Binding Protein in a Large Meta-Analysis.
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大型荟萃分析表明，抗抑郁功效与促肾上腺皮质激素释放激素结合蛋白的 rs28365143 之间没有关联。
DOI：
10.1176/appi.ajp.2018.18010070
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Uher,Rudolf
中科院分区：
文献类型：
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作者：
Fabbri,Chiara;Lewis,CathrynM;Perlis,RoyH;Uher,Rudolf
致编辑：O 'Connell等人(1)在2018年3月的《Journal》杂志上报道了促肾上腺皮质激素释放激素结合蛋白（CRHBP）基因rs28365143与重度抑郁症抗抑郁药物治疗效果之间的关联。这种关联仅在接受选择性血清素再摄取抑制剂（SSRIs）艾司西酞普兰和舍曲林治疗的患者中发现，而在文拉法辛治疗的患者中没有发现。在显性遗传模型下，携带小等位基因a的患者与GG纯合子相比，治疗效果更差。这篇文章使用了来自国际抑郁症优化治疗预测研究（iSPOT-D）的636名参与者，并复制了来自抑郁症缓解预测因子到个体和联合治疗（Predict）研究的141名参与者。这篇文章没有报道基于基因组的抑郁症治疗药物（GENDEP）项目、慕尼黑抗抑郁反应签名（MARS）项目和缓解抑郁症的测序治疗方案（STAR* D）研究（2256名参与者）的全基因组荟萃分析结果(2)。该荟萃分析显示rs28365143与抗抑郁缓解之间没有关联的证据（p50）。70)或症状改善（p50）。54)(3)。O 'Connell等人的研究强调了跨种族参与者分析候选基因研究的挑战。抗抑郁药反应的研究特别容易受到人群分层的影响，因为反应因种族而异（例如，STAR* D研究中非洲裔美国人的缓解率明显低于白种人[1]）。结合人群中等位基因频率的差异，种族差异可能导致反映遗传祖先而不是遗传关联的人为结果。在回归分析中加入祖先信息主成分作为协变量可以防止假阳性结果，但这在iSPOT-D的候选变异基因分型中是不可能的。作者进行了敏感性测试，结果显示rs28365143在高加索人iSPOT-D参与者（60.1%）和非高加索人（39.9%）中的效应量相似；见原始文章在线版随附的数据补充表S4。这可能不是一个充分的控制，因为非白种人组包括黑人、亚洲人、其他种族和缺失的种族（见文章中的表2）。此外，rs28365143 A等位基因的频率因祖先而异（欧洲人为3.5%）
TO THE EDITOR: In the March 2018 issue of the Journal, O’Connell et al.(1) report an association between rs28365143, which lies in the corticotropin-releasing hormone binding protein (CRHBP) gene, and efficacy of antidepressant treatment in major depressive disorder. The association was found only in patients treated with the selective serotonin reuptake inhibitors (SSRIs) escitalopram and sertraline, and not with venlafaxine. Under a dominant genetic model, patients carrying the minor allele A showed worse treatment outcomes compared with GG homozygotes. The article uses 636 participants from the International Study to Predict Optimized Treatment in Depression (iSPOT-D), with replication in 141 participants from the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study. The article does not report results from the genome-wide meta-analysis of the Genome-Based Therapeutic Drugs for Depression (GENDEP) project, the Munich Antidepressant Response Signature (MARS) project, and the Sequenced Treatment Alternatives to Relieve Depression (STAR* D) study (2,256 participants)(2). This metaanalysis shows no evidence of association between rs28365143 and antidepressant remission (p50. 70) or symptom improvement (p50. 54)(3).The study from O’Connell et al. highlights the challenges in analyzing candidate gene studies with participants across ethnic groups. Studies of antidepressant response are particularly susceptible to population stratification because response differs by ethnicity (for example, African Americans had substantially lower remission rates than Caucasians in the STAR* D study [4]). Combined with allele frequency differences across populations, ethnic differences can lead to artifactual results that reflect genetic ancestry and not genetic association. Adding ancestry-informative principal components as covariates in the regression analysis protects against false positive results, but this was not possible with the candidate variant genotyping in the iSPOT-D. The authors performed a sensitivity test showing that the effect size for rs28365143 was similar in Caucasian iSPOT-D participants (60.1%) and non-Caucasians (39.9%; see Table S4 in the data supplement accompanying the online edition of the original article). This may not be a sufficient control because the non-Caucasian group included black, Asian, other, and missing races (see Table 2 in the article). In addition, the frequency of the rs28365143 A allele differs by ancestry (3.5% in European