Journal article
Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles
Nature communications, v 5(1), pp 4757-4757
04 Sep 2014
PMID: 25187353
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 genomewide 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 x 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 x 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.
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Details
- Title
- Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles
- Creators
- Jacqueline I. Goldstein - Massachusetts General HospitalL. Fredrik Jarskog - University of North Carolina at Chapel HillChris Hilliard - University of North Carolina at Chapel HillAna Alfirevic - University of LiverpoolLaramie Duncan - Massachusetts General HospitalDenis Fourches - University of North Carolina at Chapel HillHailiang Huang - Massachusetts General HospitalMonkol Lek - Massachusetts General HospitalBenjamin M. Neale - Massachusetts General HospitalStephan Ripke - Massachusetts General HospitalKevin Shianna - New York Genome CenterJin P. Szatkiewicz - University of North Carolina at Chapel HillAlexander Tropsha - University of North Carolina at Chapel HillEdwin J. C. G. van den Oord - Virginia Commonwealth UniversityIngolf Cascorbi - University of LübeckMichael Dettling - Charité - Universitätsmedizin BerlinEphraim Gazit - Sheba Medical CenterDonald C. Goff - New York UniversityArthur L. Holden - Society of Automotive Engineers InternationalDeanna L. Kelly - University of Maryland, BaltimoreAnil K. Malhotra - Zucker Hillside HospitalJimmi Nielsen - Aalborg University HospitalMunir Pirmohamed - University of LiverpoolDan Rujescu - Ludwig-Maximilians-Universität MünchenThomas Werge - Lundbeck FoundationDeborah L. Levy - Harvard UniversityRichard C. Josiassen - Drexel UniversityJames L. Kennedy - Centre for Addiction and Mental HealthJeffrey A. Lieberman - New York Psychoanalytic Society and InstituteMark J. Daly - Broad InstitutePatrick F. Sullivan - University of North Carolina at Chapel Hill
- Publication Details
- Nature communications, v 5(1), pp 4757-4757
- Publisher
- Springer Nature
- Number of pages
- 9
- Grant note
- NF-SI-0512-10064 / National Institute for Health Research; National Institute for Health Research (NIHR) ABI 10-567 / National Science Foundation; National Science Foundation (NSF) R01MH097281 / NATIONAL INSTITUTE OF MENTAL HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH) MR/L006758/1 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); European Commission R01 MH080403 / US National Institute of Mental Health via the American Recovery and Reinvestment Act R155-2014-1724 / Lundbeck Foundation; Lundbeckfonden MR/L006758/1 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Psychiatry
- Web of Science ID
- WOS:000342927300001
- Scopus ID
- 2-s2.0-84923091172
- Other Identifier
- 991021890007304721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Genetics & Heredity