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

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

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Title: Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles
Author: Goldstein, Jacqueline I; Jarskog, L Fredrik; Hilliard, Chris; Alfirevic, Ana; Duncan, Laramie; Fourches, Denis; Huang, Hailiang; Lek, Monkol; Neale, Benjamin M; Ripke, Stephan; Shianna, Kevin; Szatkiewicz, Jin P; Tropsha, Alexander; van den Oord, Edwin JCG; Cascorbi, Ingolf; Dettling, Michael; Gazit, Ephraim; Goff, Donald C; Holden, Arthur L; Kelly, Deanna L; Malhotra, Anil K; Nielsen, Jimmi; Pirmohamed, Munir; Rujescu, Dan; Werge, Thomas; Levy, Deborah L; Josiassen, Richard C; Kennedy, James L; Lieberman, Jeffrey A; Daly, Mark J; Sullivan, Patrick F

Note: Order does not necessarily reflect citation order of authors.

Citation: Goldstein, J. I., L. F. Jarskog, C. Hilliard, A. Alfirevic, L. Duncan, D. Fourches, H. Huang, et al. 2014. “Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles.” Nature communications 5 (1): 4757. doi:10.1038/ncomms5757. http://dx.doi.org/10.1038/ncomms5757.
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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% 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.
Published Version: doi:10.1038/ncomms5757
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4155508/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:14351080
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