Abstract
Clozapine is the only effective antipsychotic for treatment-resistant schizophrenia but remains widely under prescribed, at least in part due to its potential to cause agranulocytosis and neutropenia. In this article, we provide an overview of the current understanding of the genetics of clozapine-associated agranulocytosis and neutropenia. We now know that the genetic etiology of clozapine-associated neutropenia is complex and is likely to involve variants from several genes including HLA-DQB1, HLA-B and SLCO1B3/SLCO1B7. We describe recent findings relating to the Duffy-null genotype and its association with benign neutropenia in individuals with African ancestry. Further advances will come from sequencing studies, large, cross-population studies and in understanding the molecular mechanisms underlying these associations.
Highlights
The mechanism by which clozapine induces neutropenia (CIN) and agranulocytosis (CIA) is still unclear but there is evidence it is caused by the activation of clozapine to a chemically reactive nitrenium ion, which could lead to neutropenia via direct toxicity, or by initiating an immune mechanism, or both
There is considerable support for the role of the amino acid polymorphism HLA-DQB1 (126Q) and HLA-DQB1 6672G>C in CIN
HLA-B*59:01 has been associated with CIN in the Japanese population
Summary
HLA genes located in the MHC on chromosome 6 (6p21.31-32) encode proteins that are responsible for regulating the immune system and were hypothesized to be involved in CIA [17]. In 2014, the Clozapine-Induced Agranulocytosis Consortium (CIAC) published a comprehensive genetic analysis including GWAS, whole exome sequencing, CNVs and imputed HLA alleles in up to 163 cases with CIN (ANC < 1000 cells/mm3), 249 clozapine-exposed controls without neutropenia and 7970 unexposed controls [14]. They found two amino acid polymorphisms in the MHC that were independently and significantly associated with CIN at the genome-wide significance level of p < 5 × 10-8: HLA-DQB1 (126Q) and HLA-B (158T) [14]. The CLOZUK study found that no single rare variant from the exome array was associated with CIN, gene-based analyses yielded association for two genes:
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