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Original Research

Candidate Gene Analysis Identifies a Polymorphism in HLA-DQB1 Associated With Clozapine-Induced Agranulocytosis

Maria C. Athanasiou, PhD; Michael Dettling, MD; Ingolf Cascorbi, MD, PhD; Igor Mosyagin, PhD; Benjamin A. Salisbury, PhD; Kerri A. Pierz, PhD; Wei Zou, PhD; Heidi Whalen, MHS; Anil K. Malhotra, MD; Todd Lencz, PhD; Stanton L. Gerson, MD; John M. Kane, MD; and Carol R. Reed, MD

Published: September 21, 2010

Article Abstract

Objective: Clozapine is considered to be the most efficacious drug to treat schizophrenia, although it is underutilized, partially due to a side effect of agranulocytosis. This analysis of 74 candidate genes was designed to identify an association between sequence variants and clozapine-induced agranulocytosis (CIA).

Method: Blood and medical history were collected for 33 CIA cases and 54 clozapine-treated controls enrolled between April 2002 and December 2003. Significant markers from 4 genes were then assessed in an independently collected case-control cohort (49 CIA cases, 78 controls).

Results: Sequence variants in 5 genes were found to be associated with CIA in the first cohort: HLA-DQB1, HLA-C, DRD1, NTSR1, and CSF2RB. Sequence variants in HLA-DQB1 were also found to be associated with CIA in the second cohort. After refinement analyses of sequence variants in HLA-DQB1, a single SNP (single nucleotide polymorphism), 6672G>C, was found to be associated with risk for CIA; the odds of CIA are 16.9 times greater in patients who carry this marker compared to those who do not.

Conclusions: A sequence variant (6672G>C) in HLA-DQB1 is associated with increased risk for CIA. This marker identifies a subset of patients with an exceptionally high risk of CIA, 1,175% higher than the overall clozapine-treated population under the current blood-monitoring system. Assessing risk for CIA by testing for this and other genetic variants yet to be determined may be clinically useful when deciding whether to begin or continue treatment with clozapine.

J Clin Psychiatry

Submitted: June 25, 2009; accepted September 16, 2009.

Online ahead of print: September 21, 2010 (doi:10.4088/JCP.09m05527yel).

Corresponding author: Maria C. Athanasiou, PhD, PGxHealth, 5 Science Park, New Haven, CT 06511 (

Volume: 71

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