Pharmacogenomic Study of Clozapine-Induced Agranulocytosis/Granulocytopenia in a Japanese Population
| Autor: | Masatoshi Takeda, Kiyoshi Fujita, Yuji Yada, Kiyotaka Nemoto, Hidenaga Yamamori, Yuka Yasuda, Shuji Hashimoto, Nobuhisa Kanahara, Kohei Kawase, Shu-ichi Ueno, Kenji Kondo, Ayu Shimasaki, Taisei Mushiroda, Masaru Murakami, Takeo Saito, Taku Otsuru, Shusuke Numata, Tetsuro Ohmori, Naoya Kida, Tetsuro Noda, Michiko Fujimoto, Takeshi Ozeki, Nakao Iwata, Manabu Takaki, Masaharu Kubota, Yoichiro Kamatani, Manabu Makinodan, Ryota Hashimoto, Naoki Hashimoto, Michiaki Kubo, Takemi Kimura, Taku Fukao, Taro Suwa, Masashi Ikeda, Kazutaka Ohi, Yosuke Nishihata, Atsushi Takahashi |
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| Jazyk: | angličtina |
| Předmět: |
Adult
Male musculoskeletal diseases medicine.medical_specialty Genome-wide association study Genotype Population Human leukocyte antigen Side effect Bioinformatics Sensitivity and Specificity Gastroenterology Article Young Adult 03 medical and health sciences 0302 clinical medicine Asian People Risk Factors Internal medicine medicine Humans Genetic Predisposition to Disease Risk factor Allele education Clozapine Alleles Biological Psychiatry education.field_of_study business.industry Histocompatibility Testing Odds ratio Japanese population Pharmacogenomic Testing 030227 psychiatry Single nucleotide polymorphism HLA-B Antigens Case-Control Studies Schizophrenia Female business Pharmacogenomics 030217 neurology & neurosurgery Agranulocytosis Pharmacogenomic Study medicine.drug |
| Zdroj: | Biological Psychiatry. (8):636-642 |
| ISSN: | 0006-3223 |
| DOI: | 10.1016/j.biopsych.2015.12.006 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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