Genetic Variation in KCNH2 Associated With Expression in the Brain of a Unique hERG Isoform Modulates Treatment Response in Patients With Schizophrenia
Genetic Variation in KCNH2 Associated With Expression in the Brain of a Unique hERG Isoform Modulates Treatment Response in Patients With Schizophrenia
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DOI：
10.1176/appi.ajp.2012.11081214
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发表时间：
2012-07-01
影响因子：
17.7
通讯作者：
Weinberger, Daniel R.
中科院分区：
文献类型：
--
作者：
Apud, Jose A.;Zhang, Fengyu;Weinberger, Daniel R.
目的：抗多巴胺能药物与KCNH2基因编码的hERG1钾通道结合，导致QT间期延长的副作用。KCNH2也与精神分裂症风险相关，风险等位基因预测具有独特生理特性的脑选择性亚型KCNH2 3.1的表达增加。作者评估了与KCNH2 3.1表达相关的遗传变异是否会影响抗精神病药物的治疗效果。方法：作者使用两项独立研究的数据对精神分裂症患者的抗精神病药物治疗反应进行药理学分析：国家精神卫生研究所（NIMH）双盲、安慰剂对照住院交叉试验（N=54）和多中心门诊临床抗精神病药物干预效果试验（CATIE）研究（N=364）。KCNH2基因型先前与大脑中KCNH2 3.1表达增加相关，被视为预测变量。用阳性和阴性综合征量表评估两组患者治疗相关症状的改变。作者还分析了CATIE研究中奥氮平组的停药时间。结果：在NIMH研究中，rs1036145 KCNH2 3.1表达相关T等位基因纯合子个体在阳性症状、一般精神病理和思维障碍方面均有显著改善，而其他基因型患者变化不大。在CATIE研究中，观察到类似的显著基因型效应。此外，T等位基因rs1036145纯合子的个体有五分之一的可能性停止使用奥氮平。结论：在两项明显不同的治疗研究中，这些一致的发现支持了这样的假设，即herg1介导的抗精神病药物的作用可能不仅限于其潜在的心血管副作用，还可能涉及与KCNH2脑特异性3.1亚型相关的治疗作用。（美国精神病学杂志2012；169:725-734）
Objective: Antidopaminergic drugs bind to hERG1 potassium channels encoded by the gene KCNH2, which accounts for the side effect of QT interval prolongation. KCNH2 has also been associated with schizophrenia risk, and risk alleles predict increased expression of a brain-selective isoform, KCNH2 3.1, that has unique physiological properties. The authors assessed whether genetic variation associated with KCNH2 3.1 expression influences the therapeutic effects of antipsychotic drugs.Method: The authors performed a pharmacogenetic analysis of antipsychotic treatment response in patients with schizophrenia using data from two independent studies: a National Institute of Mental Health (NIMH) double-blind, placebo-controlled inpatient crossover trial (N=54) and the multicenter outpatient Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study (N=364). The KCNH2 genotype that was previously associated with increased expression of KCNH2 3.1 in the brain was treated as a predictor variable. Treatment-associated changes in symptoms were evaluated in both groups with the Positive and Negative Syndrome Scale. The authors also analyzed time to discontinuation in the olanzapine arm of the CATIE study.Results: In the NIMH study, individuals who were homozygous for the KCNH2 3.1 increased expression-associated T allele of rs1036145 showed significant improvement in positive symptoms, general psychopathology, and thought disturbance, while patients with other genotypes showed little change. In the CATIE study, analogous significant genotypic effects were observed. Moreover, individuals who were homozygous for the T allele at rs1036145 were one-fifth as likely to discontinue olanzapine.Conclusions: These consistent findings in two markedly different treatment studies support the hypothesis that hERG1-mediated effects of antipsychotics may not be limited to their potential cardiovascular side effects but may also involve therapeutic actions related to the brainspecific 3.1 isoform of KCNH2. (Am J Psychiatry 2012; 169:725-734)