title: Genetic determinants of cocaine-associated agranulocytosis.
abstract: 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 Levamisole is an antihelminthic and immunomodulator withdrawn from North American markets in 2005 after reports of agranulocytosis.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.
authors.affiliation: BC Center for Disease Control, 655 West 12th Avenue, Vancouver, BC, V5Z 4R4, Canada. jane.buxton@bccdc.ca.|School of Population and Public Health, University of British Columbia, 2206 East Mall, Vancouver, BC, V6T 1Z3, Canada. jane.buxton@bccdc.ca.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Buxton
authors.affiliation: School of Population and Public Health, University of British Columbia, 2206 East Mall, Vancouver, BC, V6T 1Z3, Canada. john@johnomura.com.
authors.forename: John
authors.initials: J
authors.lastname: Omura
authors.affiliation: BC Center for Disease Control, 655 West 12th Avenue, Vancouver, BC, V5Z 4R4, Canada. margot.kuo@bccdc.ca.
authors.forename: Margot
authors.initials: M
authors.lastname: Kuo
authors.affiliation: Child and Family Research Institute, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada. colin.ross@ubc.ca.
authors.forename: Colin
authors.initials: C
authors.lastname: Ross
authors.affiliation: BC Center for Disease Control, 655 West 12th Avenue, Vancouver, BC, V5Z 4R4, Canada. despinatzemis@hotmail.com.
authors.forename: Despina
authors.initials: D
authors.lastname: Tzemis
authors.affiliation: Drug and Poison Information Centre, BC Centre for Disease Control, 655 West 12th Avenue, Vancouver, BC, V5Z 4R4, Canada. roy.purssell@bccdc.ca.
authors.forename: Roy
authors.initials: R
authors.lastname: Purssell
authors.affiliation: BC Center for Disease Control, 655 West 12th Avenue, Vancouver, BC, V5Z 4R4, Canada. jennifer.gardy@bccdc.ca.|School of Population and Public Health, University of British Columbia, 2206 East Mall, Vancouver, BC, V6T 1Z3, Canada. jennifer.gardy@bccdc.ca.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gardy
authors.affiliation: Child and Family Research Institute, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada. bcarleton@popi.ubc.ca.
authors.forename: Bruce
authors.initials: B
authors.lastname: Carleton
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000380:Agranulocytosis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001955:British Columbia; D016022:Case-Control Studies; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage / Q000009:adverse effects*; D019970:Cocaine-Related Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D015796:HLA-B27 Antigen / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007978:Levamisole / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000378:metabolism
chemical_list: C435501:ABCC12 protein, human; C547787:ADRB1 protein, human; D018528:ATP-Binding Cassette Transporters; D015796:HLA-B27 Antigen; D018342:Receptors, Adrenergic, beta-1; D007978:Levamisole; D002786:Cholesterol Side-Chain Cleavage Enzyme; D003042:Cocaine