Genetic determinants of cocaine-associated agranulocytosis

BMC Research Notes

Bruce Carleton⁴  Jennifer Gardy²  Roy Purssell¹  Despina Tzemis³  Colin Ross⁴  Margot Kuo³  John Omura²  Jane A Buxton² 

[1] Drug and Poison Information Centre, BC Centre for Disease Control, 655 West 12th Avenue, Vancouver V5Z 4R4, BC, Canada;School of Population and Public Health, University of British Columbia, 2206 East Mall, Vancouver V6T 1Z3, BC, Canada;BC Center for Disease Control, 655 West 12th Avenue, Vancouver V5Z 4R4, BC, Canada;Child and Family Research Institute, 950 West 28th Avenue, Vancouver V5Z 4H4, BC, Canada

关键词: Neutropenia;    Pharmacogenetics;    HLA-B27 antigen;    Cocaine;    Levamisole;    Agranulocytosis;   

Others  :  1231974
DOI  :  10.1186/s13104-015-1219-4

 received in 2014-06-26, accepted in 2015-06-01,  发布年份 2015

【 摘 要 】

Background

Drug-induced agranulocytosis is a recognized adverse drug event associated with serious infectious complications. Levamisole is an antihelminthic and immunomodulator withdrawn from North American markets in 2005 after reports of agranulocytosis. Previous studies of levamisole, suggest that the human leukocyte antigen (HLA)-B27 confers a genetic predisposition to this adverse drug event. Since 2009, emergency room visits due to agranulocytosis in individuals consuming levamisole-adulterated crack-cocaine have increased.

Methods

We performed a case–control study using a genotyping assay and novel gene chip to test the association between cocaine-associated agranulocytosis (CAA) and HLA-B27 and to identify pharmacokinetic and pharmacodynamic gene variants associated with the phenotype.

Results

Fifty-one CAA cases were identified through a provincial physician reporting system between 2008 and 2011. We examined eight of these cases and 26 matched controls. Genotyping revealed a significant association between HLA-B27 and CAA (odds ratio [OR] 9.2, 95% confidence interval [CI], 1.54–54.6). We also observed a similar association with the HLA-B27 tag single nucleotide polymorphism rs4349859 (OR 9.2, 95% CI 1.5–54.6) and rs13202464 (OR 6.7, 95% CI 1.1–41). Further associations were identified with variants in the ARBCC12 (OR 10.0, 95% CI 2.7–36.8) and CYP11A1 (OR 7.4, 95% CI 2.1–26.6) genes, while a novel protective association was observed with variants in the ARDB1 gene (OR 0.06, 95% CI 0.007–0.46).

Conclusions

We confirmed the association of HLA-B27 with CAA and identified additional susceptibility variants. Health care providers should inform people who are identified as having CAA that it is genetically determined and can recur with continued cocaine use. The severity of infections and subsequent hospitalization, and the risk of recurrence may prompt health-promoting behaviour changes of the affected individuals. These genetic associations warrant the attention of public health and knowledge translation efforts to highlight the implications for susceptibility to this severe adverse drug event.

【 授权许可】

   
2015 Buxton et al.

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