PGxHealth, 5 Science Park, New Haven, CT 06511, USA.
J Clin Psychiatry. 2011 Apr;72(4):458-63. doi: 10.4088/JCP.09m05527yel. Epub 2010 Sep 21.
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).
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).
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.
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.
氯氮平被认为是治疗精神分裂症最有效的药物，尽管它的应用并不广泛，部分原因是其会引起粒细胞缺乏症。本研究分析了 74 个候选基因，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。
2002 年 4 月至 2003 年 12 月期间，共纳入 33 例 CIA 病例和 54 例氯氮平治疗对照者，收集其血液和病史。然后，在 2002 年 4 月至 2003 年 12 月期间，在一个独立的病例对照队列（49 例 CIA 病例，78 例对照者）中评估 4 个基因中的显著标志物。
在第一个队列中，发现 5 个基因中的序列变异与 CIA 相关：HLA-DQB1、HLA-C、DRD1、NTSR1 和 CSF2RB。在第二个队列中，还发现 HLA-DQB1 中的序列变异与 CIA 相关。在 HLA-DQB1 中的序列变异的精细化分析后，发现一个单核苷酸多态性（SNP），6672G>C，与 CIA 的风险相关；与不携带该标志物的患者相比，携带该标志物的患者 CIA 的风险增加 16.9 倍。
HLA-DQB1 中的序列变异（6672G>C）与 CIA 风险增加相关。该标志物确定了 CIA 风险极高的患者亚群，比当前血液监测系统下的氯氮平治疗总体人群高 117.5%。通过检测该标志物和其他尚未确定的遗传变异来评估 CIA 的风险，在决定是否开始或继续氯氮平治疗时可能具有临床意义。
