1. Phamacogenomics of Clozapine-Induced Agranulocytosis
- Author
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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, Numata, Shusuke, Ohmori, Tetsuro, 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, and Iwata, Nakao
- Subjects
musculoskeletal diseases ,Genome-wide association study ,Human leukocyte antigen ,Schizophrenia ,Side effect ,Pharmacogenomics ,Single nucleotide polymorphism - Abstract
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.
- Published
- 2016