Risk allele for side effects induced by Clozapine identified

A stepping stone towards safe and appropriate treatment for patients

Feb 10, 2016

Associate Professor Dr. Ryota Hashimoto in Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University Department of Psychiatry, Osaka University Graduate School of Medicine, Professor Dr. Nakao Iwata in Fujita Health University School of Medicine and Group Director Taisei Mushiroda in RIKEN Center for Integrative Medical Sciences, conducted a genome-wide pharmacogenomic analysis and detected a significant association of HLA-B*59:01 with Clozapine-induced agranulocytosis/granulocytopenia (CIA/CIG; CIAG).

Clozapine (CLZ) is a gold standard drug for managing treatment-resistant schizophrenia (TRS). Despite its efficacy with TRS, the use of CLZ is significantly restricted by severe side effects such as CIA, which is rare but potentially life-threatening. CIA are observed in approximately 1% in CLZ-treatment patients.

This achievement will be helpful in establishing effective pharmacogenetics test for CIA and in clarifying mechanism of CIA.

Background: Clozapine-induced agranulocytosis/granulocytopenia (CIA/CIG; CIAG) is a life-threatening event for schizophrenics treated with clozapine.

Methods: To examine the genetic factor for CIAG, a genome-wide pharmacogenomic analysis was conducted using subjects with 50 CIAG and 2,905 controls.

Results: We identified a significant association in the 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 (N=380, P =2.97 ´ 10 −5 , OR =6.3). As we observed the OR of CIA (OR: 9.3~15.8) was approximately double of that in CIG (OR: 4.4~7.4), we hypothesized the CIG subjects were a mixed-population of those who potgeneentially would develop CIA (“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 non-risk 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.

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

To learn more about this research, please view the full research report entitled " Pharmacogenomic Study of Clozapine-Induced Agranulocytosis/Granulocytopenia in a Japanese Population " at this page of the Biological Psychiatry website.

Related links

Technical Glossary