Pharmacogenomic Study of Clozapine-Induced Agranulocytosis/Granulocytopenia in a Japanese Population

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• 作者：Takeo Saito¹ ; ^a ; Masashi Ikeda^a ; ¹ ; Taisei Mushiroda^b ; Takeshi Ozeki^b ; Kenji Kondo^a ; Ayu Shimasaki^a ; Kohei Kawase^a ; Shuji Hashimoto^c ; Hidenaga Yamamori^d ; Yuka Yasuda^d ; Michiko Fujimoto^d ; Kazutaka Ohi^d ; Masatoshi Takeda^d ; ^e ; Yoichiro Kamatani^f ; Shusuke Numata^g ; Tetsuro Ohmori^g ; Shu-ichi Ueno^h ; Manabu Makinodanⁱ ; Yosuke Nishihataⁱ ; Masaharu Kubota^j ; ^w ; Takemi Kimura^k ; Nobuhisa Kanahara^l ; Naoki Hashimoto^m ; Kiyoshi Fujitaⁿ ; Kiyotaka Nemoto^o ; Taku Fukao^p ; Taro Suwa^q ; Tetsuro Noda^r ; Yuji Yada^s ; Manabu Takaki^t ; Naoya Kida^u ; Taku Otsuru^u ; Masaru Murakami^u ; Atsushi Takahashi^f ; ^v ; Michiaki Kubo^w ; Ryota Hashimoto^d ; ^e ; ^{hashimor@psy.med.osaka-u.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Nakao Iwata^a
• 关键词：Genome-wide association study ; Human leukocyte antigen ; Pharmacogenomics ; Schizophrenia ; Side effect ; Single nucleotide polymorphism
• 刊名：Biological Psychiatry
• 出版年：2016
• 出版时间：15 October 2016
• 年：2016
• 卷：80
• 期：8
• 页码：636-642
• 全文大小：210 K

文摘

Clozapine-induced agranulocytosis (CIA)/clozapine-induced granulocytopenia (CIG) (CIAG) is a life-threatening event for schizophrenic subjects treated with clozapine.

Methods

To examine the genetic factor for CIAG, a genome-wide pharmacogenomic analysis was conducted using 50 subjects with CIAG and 2905 control subjects.

Results

We identified a significant association in the human leukocyte antigen (HLA) region (rs1800625, p = 3.46 × 10⁻⁹, odds ratio [OR] = 3.8); therefore, subsequent HLA typing was performed. We detected a significant association of HLA-B*59:01 with CIAG (p = 3.81 × 10⁻⁸, OR = 10.7) and confirmed this association by comparing with an independent clozapine-tolerant control group (n = 380, p = 2.97 × 10⁻⁵, OR = 6.3). As we observed that the OR of CIA (OR: 9.3~15.8) was approximately double that in CIG (OR: 4.4~7.4), we hypothesized that the CIG subjects were a mixed population of those who potentially would develop CIA and those who would not develop CIA (non-CIA). This hypothesis allowed the proportion of the CIG who were non-CIA to be calculated, enabling us to estimate the positive predictive value of the nonrisk allele on non-CIA in CIG subjects. Assuming this model, we estimated that 1) ~50% of CIG subjects would be non-CIA; and 2) ~60% of the CIG subjects without the risk allele would be non-CIA and therefore not expected to develop CIA.

Conclusions

Our results suggest that HLA-B*59:01 is a risk factor for CIAG in the Japanese population. Furthermore, if our model is true, the results suggest that rechallenging certain CIG subjects with clozapine may not be always contraindicated.