Background The atypical antipsychotic drug clozapine is the only effective drug for treatment-resistant schizophrenia, but also bears the risk of inducing severe adverse drug responses like neutropenia and agranulocytosis. Agranulocytosis… Click to show full abstract
Background The atypical antipsychotic drug clozapine is the only effective drug for treatment-resistant schizophrenia, but also bears the risk of inducing severe adverse drug responses like neutropenia and agranulocytosis. Agranulocytosis and neutropenia occurs in about 1% and 3% of treated individuals. The aetiology is largely unknown, but there is evidence for contributing genetic factors. Identifying biomarkers could decrease blood monitoring effort and enable a more widespread use of clozapine. Several studies identified HLA variants contributing to the risk of agranulocytosis. The Clozapine-Induced Agranulocytosis Consortium (CIAC) identified two independent loci in the major histocompatibility complex genome-wide associated with clozapine-induced agranulocytosis: A single amino acid in HLA-DQB1 (126Q) (OR=0.19, P=4.7E−14) and an amino acid change in HLA-B (158 T) (OR=3.3, P=6.4E−10). Our study was performed to replicate these interesting findings. Methods The atypical antipsychotic drug clozapine is the only effective drug for treatment-resistant schizophrenia, but also bears the risk of inducing severe adverse drug responses like neutropenia and agranulocytosis. Agranulocytosis and neutropenia occurs in about 1% and 3% of treated individuals. The aetiology is largely unknown, but there is evidence for contributing genetic factors. Identifying biomarkers could decrease blood monitoring effort and enable a more widespread use of clozapine. Several studies identified HLA variants contributing to the risk of agranulocytosis. The Clozapine-Induced Agranulocytosis Consortium (CIAC) identified two independent loci in the major histocompatibility complex genome-wide associated with clozapine-induced agranulocytosis: A single amino acid in HLA-DQB1 (126Q) (OR=0.19, P=4.7E−14) and an amino acid change in HLA-B (158 T) (OR=3.3, P=6.4E−10). Our study was performed to replicate these interesting findings. Results HLA-DQB1 (126Q) was associated with agranulocytosis (OR=0.12, P=5.25E-05) and neutropenia (OR=0.18, P=7.34E-06), whereas HLA-B (158 T) was associated with neutropenia only (OR=2.45, P=1.32E-02). The HLA-DQB1 signal was mainly driven by agranulocytosis cases. Discussion We were able to replicate previous findings. Our study gives further evidence for the implication of immunological pathways and especially HLA-DQB1 in agranulocytosis and neutropenia.
               
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