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

Saito, Takeo, Ikeda, Masashi, Mushiroda, Taisei, Ozeki, Takeshi, Kondo, Kenji, Shimasaki, Ayu, Kawase, Kohei, Hashimoto, Shuji, Yamamori, Hidenaga, Yasuda, Yuka, Fujimoto, Michiko, Ohi, Kazutaka, Takeda, Masatoshi, Kamatani, Yoichiro, 沼田, 周助, 大森, 哲郎, Ueno, Shu-ichi, Makinodan, Manabu, Nishihata, Yosuke, Kubota, Masaharu, Kimura, Takemi, Kanahara, Nobuhisa, Hashimoto, Naoki, Fujita, Kiyoshi, Nemoto, Kiyotaka, Fukao, Taku, Suwa, Taro, Noda, Tetsuro, Yada, Yuji, Takaki, Manabu, Kida, Naoya, Otsuru, Taku, Murakami, Masaru, Takahashi, Atsushi, Kubo, Michiaki, Hashimoto, Ryota, Iwata, Nakao

doi:10.1016/j.biopsych.2016.08.007

Background: 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.

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

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