Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles



Goldstein, Jacqueline I, Jarskog, L Fredrik, Hilliard, Chris, Alfirevic, Ana ORCID: 0000-0002-2801-9817, Duncan, Laramie, Fourches, Denis, Huang, Hailiang, Lek, Monkol, Neale, Benjamin M, Ripke, Stephan
et al (show 21 more authors) (2014) Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles. Nature Communications, 5.

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Abstract

Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the risk of clozapine-induced agranulocytosis/granulocytopenia (CIAG), a severe adverse drug reaction occurring in up to 1% of treated individuals. Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine. Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing. We find that two loci in the major histocompatibility complex are independently associated with CIAG: a single amino acid in HLA-DQB1 (126Q) (P=4.7 × 10−14, odds ratio (OR)=0.19, 95% confidence interval (CI)=0.12–0.29) and an amino acid change in the extracellular binding pocket of HLA-B (158T) (P=6.4 × 10−10, OR=3.3, 95% CI=2.3–4.9). These associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG.

Item Type: Article
Uncontrolled Keywords: Immunogenetics, Pharmacology
Depositing User: Symplectic Admin
Date Deposited: 31 Oct 2019 11:36
Last Modified: 12 Aug 2022 17:10
DOI: 10.1038/ncomms5757
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3060087