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HLA-DQB1 6672G>C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry

HLA-DQB1 6672G>C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry

Title: HLA-DQB1 6672G>C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry
Author: Konte, Bettina
Walters, James T.R.
Rujescu, Dan
Legge, Sophie E.
Pardiñas, Antonio F.
Cohen, Dan
Pirmohamed, Munir
Tiihonen, Jari
Hartmann, Annette M.
Bogers, Jan P.
... 17 more authors Show all authors
Date: 2021-04-12
Language: English
Scope: 214
University/Institute: Landspitali - The National University Hospital of Iceland
Department: Faculty of Medicine
Mental Health Services
Series: Translational Psychiatry; 11(1)
ISSN: 2158-3188
DOI: https://doi.org/10.1038/s41398-021-01322-w
Subject: Geðrof; Lyfjameðferð; Aukaverkanir lyfja; Antipsychotic Agents/adverse effects; Clozapine/adverse effects; HLA-DQ beta-Chains/genetics; Humans; Neutropenia/chemically induced
URI: https://hdl.handle.net/20.500.11815/3231

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Konte , B , Walters , J T R , Rujescu , D , Legge , S E , Pardiñas , A F , Cohen , D , Pirmohamed , M , Tiihonen , J , Hartmann , A M , Bogers , J P , van der Weide , J , van der Weide , K , Putkonen , A , Repo-Tiihonen , E , Hallikainen , T , Silva , E , Ingimarsson , O , Sigurðsson , E , Kennedy , J L , Sullivan , P F , Rietschel , M , Breen , G , Stefansson , H , Stefansson , K , Collier , D A , O’Donovan , M C & Giegling , I 2021 , ' HLA-DQB1 6672G >C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry ' , Translational Psychiatry , vol. 11 , no. 1 , 214 , pp. 214 . https://doi.org/10.1038/s41398-021-01322-w


The atypical antipsychotic clozapine is the only effective medication for treatment-resistant schizophrenia. However, it can also induce serious adverse drug reactions, including agranulocytosis and neutropenia. The mechanism by which it does so is largely unknown, but there is evidence for contributing genetic factors. Several studies identified HLA-DQB1 variants and especially a polymorphism located in HLA-DQB1 (6672G>C, rs113332494) as associated with clozapine-induced agranulocytosis and neutropenia. We analysed the risk allele distribution of SNP rs113332494 in a sample of 1396 controls and 178 neutropenia cases of which 60 developed agranulocytosis. Absolute neutrophil counts of 500/mm3 and 1500/mm3 were used for defining agranulocytosis and neutropenia cases, respectively. We also performed association analyses and analysed local ancestry patterns in individuals of European ancestry, seeking replication and extension of earlier findings. HLA-DQB1 (6672G>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), with effect sizes being considerably larger for agranulocytosis. Using local ancestry estimates for prediction, the sensitivity of rs113332494 increased from 11.28 to 55.64% for neutropenia and from 16.67 to 53.70% for agranulocytosis. Our study further strengthens the evidence implicating HLA-DQB1 in agranulocytosis and neutropenia, suggesting components of the immune system as contributing to this serious adverse drug reaction. Using local ancestry estimates might help in identifying risk variants and improve prediction of haematological adverse effects.


Funding Information: The authors thank all participants, clinicians and researchers for making this study possible. This CRESTAR project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement #279227. M.P. wishes to thank the MRC Centre for Drug Safety Science (grant code MR/L006758/1) for support. A.F.P. acknowledges support by a “Springboard” award (ref: SBF005 \1083) from the Academy of Medical Sciences. J.T.R.W. and M.C.O. acknowledge support by a collaborative research grant from Takeda (Takeda played no part in the conception, design, implementation or interpretation of this study). Genome-wide data of CIAC used for identifying overlapping individuals were obtained from NIMH Repository & Genomics Resource, a centralized national biorepository for genetic studies of psychiatric disorders (www.nimhgenetics. org). The collection of data and biomaterials for this study was supported by funding provided by R01 MH080403 (PIs: P.F.S., Edwin J.C.G. van den Oord) from the US National Institute of Mental Health via the American Recovery and Reinvestment Act of 2009. Dr. Denis Fourches and Dr. Alexander Tropsha acknowledge the support from National Science Foundation grant ABI 10-567. The study was led by P.F.S., L. Fredrik Jarskog, Jeffrey A. Lieberman, J.L.K. and Mark J. Daly. Dr. Thomas Lehner (NIMH) and Dr. David Goldstein (Duke University) were also involved in assisting with this project. The authors acknowledge the assistance of Dr. Michael Karukin (Teva Pharmaceuticals) and Dr. Rafael Muniz and Dr. Vinod Kumar (Novartis) for help in accessing US national clozapine registries. Dr. Stanton Gerson (Department of Hematology, Case Western Reserve), Dr. Armond Goldman (Department of Immunology, University of Texas Galveston) and Dr. Nancy Berliner (Department of Hematology, Harvard University) provided input on mechanisms of agranulocytosis. Publisher Copyright: © 2021, The Author(s).

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