SU93 - REPLICATION OF TWO INDEPENDENT LOCI IN HLA-DQB1 AND HLA-B CONTRIBUTING TO THE RISK OF CLOZAPINE-INDUCED AGRANULOCYTOSIS

Bettina Konte,James L Kennedy,Jari Tiihonen,Gerome Breen,Marcella Rietschel,Dan Cohen,Dan Rujescu,Eila Repo-Tiihonen,Ina Giegling,Karen Van Der Weide ,Michael O׳Donovan ,Hreinn Stefánsson ,Jan Van Der Weide ,Annette M Hartmann ,Edward Silva ,Patrick M Sullivan ,Jp Bogers ,Engilbert Sigurðsson ,Munir Pirmohamed ,Tero Hallikainen ,Sophie E Legge ,Oddur Ingimarsson ,Anu Putkonen ,D A Collier

doi:10.1016/j.euroneuro.2017.08.282

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.

Full Text