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. 2016 Oct 15;80(8):636-42.
doi: 10.1016/j.biopsych.2015.12.006. Epub 2016 Feb 11.

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

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

Takeo Saito et al. Biol Psychiatry. .

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.

Keywords: Genome-wide association study; Human leukocyte antigen; Pharmacogenomics; Schizophrenia; Side effect; Single nucleotide polymorphism.

Comment in

  • Psychiatric Pharmacogenomics: How Close Are We?
    Hirschtritt ME, Besterman AD, Ross DA. Hirschtritt ME, et al. Biol Psychiatry. 2016 Oct 15;80(8):e63-5. doi: 10.1016/j.biopsych.2016.08.007. Epub 2016 Aug 11. Biol Psychiatry. 2016. PMID: 27663067 Free PMC article. No abstract available.

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