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

被引：116

作者：

Goldstein, Jacqueline I. ^{[1
]}

Jarskog, L. Fredrik

Hilliard, Chris

Alfirevic, Ana ^{[2
]}

Duncan, Laramie ^{[1
]}

Fourches, Denis ^{[3
]}

Huang, Hailiang ^{[1
]}

Lek, Monkol ^{[1
]}

Neale, Benjamin M. ^{[1
,4
,5
]}

Ripke, Stephan ^{[1
,5
]}

Shianna, Kevin ^{[6
]}

Szatkiewicz, Jin P. ^{[7
]}

Tropsha, Alexander ^{[3
]}

van den Oord, Edwin J. C. G. ^{[8
]}

Cascorbi, Ingolf ^{[9
]}

Dettling, Michael ^{[10
]}

Gazit, Ephraim ^{[11
]}

Goff, Donald C. ^{[12
]}

Holden, Arthur L. ^{[13
]}

Kelly, Deanna L. ^{[14
]}

Malhotra, Anil K. ^{[15
,16
,17
]}

Nielsen, Jimmi ^{[18
,19
]}

Pirmohamed, Munir ^{[2
]}

Rujescu, Dan ^{[20
,21
]}

Werge, Thomas ^{[22
,23
,24
]}

Levy, Deborah L. ^{[25
,26
]}

Josiassen, Richard C. ^{[27
]}

Kennedy, James L. ^{[28
]}

Lieberman, Jeffrey A. ^{[29
,30
]}

Daly, Mark J. ^{[1
]}

Sullivan, Patrick F. ^{[7
,31
]}

机构：

[1] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[2] Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool L69 3BX, Merseyside, England

[3] Univ N Carolina, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Lab Mol Modeling, Chapel Hill, NC 27599 USA

[4] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA

[5] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[6] New York Genome Ctr, New York, NY 10013 USA

[7] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA

[8] Virginia Commonwealth Univ, Ctr Biomarker Res & Personalized Med, Richmond, VA 23298 USA

[9] Univ Hosp Schleswig Holstein, Inst Expt & Clin Pharmacol, D-24105 Kiel, Germany

[10] Charite, Dept Psychiat & Psychotherapy, D-14050 Berlin, Germany

[11] Tel Aviv Univ, Chaim Sheba Med Ctr, Tissue Typing Lab, IL-6997801 Ramat Aviv, Israel

[12] NYU, Dept Psychiat, New York, NY 10016 USA

[13] Int SAE Consortium Ltd, Chicago, IL 60631 USA

[14] Univ Maryland, Maryland Psychiat Res Ctr, Baltimore, MD 21228 USA

[15] Feinstein Inst Med Res, Manhasset, NY 11030 USA

[16] Hofstra NS LIJ Sch Med, Hempstead, NY 11549 USA

[17] Zucker Hillside Hosp, Glen Oaks, NY 11004 USA

[18] Aalborg Univ Hosp, DK-9000 Aalborg, Denmark

[19] Aalborg Univ, Dept Clin Med, DK-9000 Aalborg, Denmark

[20] Univ Halle, Dept Psychiat, D-06112 Halle, Germany

[21] Univ Munich, Dept Psychiat, D-80336 Munich, Germany

[22] Univ Copenhagen, Dept Clin Med, DK-1165 Copenhagen, Denmark

[23] Mental Hlth Serv Copenhagen, MHC Sct Hans, Inst Biol Psychiat, DK-4000 Copenhagen, Denmark

[24] iPSYCH, Lundbeck Fdn Initiat Integrat Psychiat Res, DK-8000 Roskilde, Denmark

[25] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA

[26] McLean Hosp, Psychol Res Lab, Belmont, MA 02478 USA

[27] Drexel Univ, Dept Psychiat, Philadelphia, PA 19104 USA

[28] Ctr Addict & Mental Hlth, Toronto, ON M5T 1R8, Canada

[29] Columbia Univ, Dept Psychiat, New York, NY 10032 USA

[30] New York State Psychiat Inst & Hosp, New York, NY 10032 USA

[31] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden

来源：

NATURE COMMUNICATIONS | 2014年 / 5卷

基金：

美国国家科学基金会;

关键词：

GENOME-WIDE ASSOCIATION; RHEUMATOID-ARTHRITIS; GENOTYPE IMPUTATION; VARIANTS; RISK; HLA-B38; GENE;

D O I：

10.1038/ncomms5757

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：9

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