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基因差异影响抗精神病药物治疗效果

来源:Biological Psychiatry 2008-01-08 09:19

生物谷报道:美国科学家在一项遗传分析中发现,精神分裂症患者特定基因的差异可能决定抗精神病药物的治疗效果,这种决定作用在不同人种患者身上的显著程度也不同。该文章发表在2008年1月的爱思唯尔期刊《生物精神病学》(Biological  Psychiatry)上。  

最新研究基于一项早期由北卡罗来纳大学发起的名为“临床安定药物干涉效力试验”的研究,该项目中获取了678名精神病患者的数据和DNA样本。文章作者之一、美国北卡罗来纳大学医学院精神病学教授Scott  Stroup  说:“我们发现患者对抗精神病药物的反应有很大不同。”  

研究人员发现,一种名为“G-蛋白信号转导调节子4”(RGS4)  的基因的编码差异可能决定患者对传统抗精神病药物的反应。相应的RGS4蛋白能够对神经传递素受体的激活进行调节。  

在678名患者中,198名患者(29%)自称是纯非洲血统,397名患者(59%)自称是纯欧洲血统,83名患者(12%)属于其他血统。通过用基因分析的方法调查这些患者的数据,研究人员发现,非洲裔患者中出现的几种治疗反应在欧洲裔患者中没有出现。  

例如,具有某种RGS4基因特征的非洲裔患者服用奋乃静(perphenazine)的时间要比服用奎硫平(quetiapine)或齐拉西酮(ziprasidone)的时间长得多。这种差异在欧洲裔患者中并不存在。  

该研究结论还需要进一步的研究来验证。研究人员也强调了在实验设计时考虑到患者民族特征,以及采集更大规模少数民族患者样本的重要性。(科学网  荔涛/编译)

生物谷推荐原始出处:

Biological Psychiatry
Volume 63, Issue 1, 1 January 2008, Pages 32-41

doi:10.1016/j.biopsych.2007.04.018      

Ethnic Stratification of the Association of RGS4 Variants with Antipsychotic Treatment Response in Schizophrenia

Daniel B. Campbella, , , Philip J. Eberta, Tara Skellyc, T. Scott Stroupd, Jeffrey Liebermane, Pat Levitta, b and Patrick F. Sullivanc, f
aDepartment of Pharmacology, Vanderbilt University, Nashville, Tennessee
bVanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee
cDepartment of Genetics, University of North Carolina at Chapel Hill, North Carolina, New York
dDepartment of Psychiatry, University of North Carolina at Chapel Hill, North Carolina, New York
eDepartment of Psychiatry, Columbia University, New York, New York
fDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Received 29 January 2007;  revised 2 April 2007;  accepted 14 April 2007.  Available online 22 June 2007.

Background

Genetic association studies, including a large meta-analysis, report association of regulator of G protein signaling 4 (RGS4) with schizophrenia in the context of heterogeneity. The central role of RGS4 in regulating signaling via Gi/o coupled neurotransmitter receptors led us to hypothesize that there may be RGS4 genotypes predictive of specific disease phenotypes and antipsychotic treatment responses.

Methods

Subjects were 678 individuals with schizophrenia who participated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Among the 678 subjects, the inferred ancestries were 198 (29%) “Africa only,” 397 (59%) “Europe only,” and 83 (12%) “Other.” Eight single nucleotide polymorphisms (SNPs) spanning RGS4 were genotyped. Multiple linear regression was used to analyze association of RGS4 markers with Positive and Negative Symptoms Scale (PANSS) scores at baseline and throughout antipsychotic treatment.

Results

Two consecutive markers within RGS4, rs2661319 and rs2842030, were associated with more severe baseline PANSS total score. Treatment with perphenazine was more effective than treatment with quetiapine (p = .010) or ziprasidone (p = .002) in individuals of inferred African ancestry and homozygous for the rs951439 C allele.

Conclusions

RGS4 genotypes predicted both the severity of baseline symptoms and relative responsiveness to antipsychotic treatment. Although these analyses are exploratory and replication is required, these data provide support for RGS4 in schizophrenia pathogenesis and suggest a functional role for RGS4 in differential antipsychotic treatment efficacy of schizophrenia.

Key Words: Brain; candidate gene; cerebral cortex; G-protein coupled receptors; genetics; pharmacogenetics

Address reprint requests to Daniel B. Campbell, Ph.D., 8114 MRB3; 465 21st Avenue South; Department of Pharmacology; Vanderbilt University; Nashville, TN 37232

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