Candidate Gene Analysis Identifies a Polymorphism in HLA-DQB1 Associated With Clozapine-Induced Agranulocytosis
Candidate Gene Analysis Identifies a Polymorphism in HLA-DQB1 Associated With Clozapine-Induced Agranulocytosis
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DOI：
10.4088/jcp.09m05527yel
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发表时间：
2011-04-01
影响因子：
5.3
通讯作者：
Reed, Carol R.
中科院分区：
文献类型：
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作者：
Athanasiou, Maria C.;Dettling, Michael;Reed, Carol R.
目的：氯氮平被认为是治疗精神分裂症最有效的药物，尽管它未被充分利用，部分原因是粒细胞缺乏症的副作用。对 74 个候选基因的分析旨在确定序列变异与氯氮平诱导的粒细胞缺乏症 (CIA) 之间的关联。方法：收集 2002 年 4 月至 2003 年 12 月期间登记的 33 名 CIA 病例和 54 名接受氯氮平治疗的对照者的血液和病史。然后在独立收集的病例对照队列（49 名 CIA 病例，78 名对照）中评估来自 4 个基因的显着标志物。结果：5 名 CIA 病例中的序列变异在第一组中发现与 CIA 相关的基因：HLA-DQB1、HLA-C、DRD1、NTSR1 和 CSF2RB。在第二组中，HLA-DQB1 的序列变异也被发现与 CIA 相关。对 HLA-DQB1 中的序列变异进行精细分析后，发现单个 SNP（单核苷酸多态性）6672G>C 与 CIA 风险相关；携带该标志物的患者患 CIA 的几率是不携带该标志物的患者的 16.9 倍。结论：HLA-DQB1 中的序列变异 (6672G>C) 与 CIA 风险增加相关。该标志物识别出 CIA 风险极高的患者子集，比当前血液监测系统下接受氯氮平治疗的总体人群高 1,175%。在决定是否开始或继续氯氮平治疗时，通过测试该基因变异和其他尚未确定的基因变异来评估 CIA 风险可能在临床上有用。 J Clin Psychiatry 2011；72(4):458-463 (C) 版权所有 2010 Physicians Postgraduate Press, Inc.
Objective: Clozapine is considered to be the most efficacious drug to treat schizophrenia, although it is underutilized, partially due to a side effect of agranulocytosis. This analysis of 74 candidate genes was designed to identify an association between sequence variants and clozapine-induced agranulocytosis (CIA).Method: Blood and medical history were collected for 33 CIA cases and 54 clozapine-treated controls enrolled between April 2002 and December 2003. Significant markers from 4 genes were then assessed in an independently collected case-control cohort (49 CIA cases, 78 controls).Results: Sequence variants in 5 genes were found to be associated with CIA in the first cohort: HLA-DQB1, HLA-C, DRD1, NTSR1, and CSF2RB. Sequence variants in HLA-DQB1 were also found to be associated with CIA in the second cohort. After refinement analyses of sequence variants in HLA-DQB1, a single SNP (single nucleotide polymorphism), 6672G>C, was found to be associated with risk for CIA; the odds of CIA are 16.9 times greater in patients who carry this marker compared to those who do not.Conclusions: A sequence variant (6672G>C) in HLA-DQB1 is associated with increased risk for CIA. This marker identifies a subset of patients with an exceptionally high risk of CIA, 1,175% higher than the overall clozapine-treated population under the current blood-monitoring system. Assessing risk for CIA by testing for this and other genetic variants yet to be determined may be clinically useful when deciding whether to begin or continue treatment with clozapine. J Clin Psychiatry 2011;72(4):458-463 (C) Copyright 2010 Physicians Postgraduate Press, Inc.