HLA-DQB1 6672 G>C is associated with the risk of clozapine-induced agranulocytosis in individuals of European ancestry

Introduction 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 including 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 (e.g. Athanasiou et al. 2011) and especially a polymorphism located in HLA-DBQ1 (6672 G>C, rs113332494) as associated with clozapine-induced agranulocytosis or neutropenia. Our study was conducted to replicate previous findings on HLA-DBQ1 6672 G>C.

Methods The sample was comprised of individuals from sites of Finland, Germany, the Netherlands and the UK and was collected in the course of the CRESTAR project, which aimed at the development of pharmacogenetic biomarkers for schizophrenia. We analysed the risk allele distribution of rs113332494 in individuals of different ethnic background including 180 clozapine-induced neutropenia cases of which 61 developed agranulocytosis and 1396 controls treated with clozapine but not affected by this severe adverse drug response. We also performed association analyses and analysed local ancestry patterns in individuals of European ancestry, seeking replication and extension of earlier findings. This CRESTAR project was funded by the European Unionʼs Seventh Framework Programme for research, technological development and demonstration under grant agreement #279 227.

Results HLA-DBQ1 (6672 G>C, rs113332494) was associated with neutropenia (OR = 6.20, P = 2.20E-06) and agranulocytosis (OR = 10.49, P = 1.83E-06) in individuals of European ancestry. The association signal strengthened after including local ancestry estimates (neutropenia: OR = 10.38, P = 6.05E-08; agranulocytosis: OR = 16.31, P = 1.39E-06).

Conclusion HLA-DBQ1 (6672 G>C, rs113332494) was associated with neutropenia (OR = 6.20, P = 2.20E-06) and agranulocytosis (OR = 10.49, P = 1.83E-06) in individuals of European ancestry. The association signal strengthened after including local ancestry estimates (neutropenia: OR = 10.38, P = 6.05E-08; agranulocytosis: OR = 16.31, P = 1.39E-06).