title: ANKK1 and DRD2 pharmacogenetics of disulfiram treatment for cocaine abuse.
abstract: OBJECTIVE
  Disulfiram is a potential cocaine addiction pharmacotherapy. Since dopamine deficiency has been found with cocaine addiction, our objective was to examine whether functional variants in the ankyrin repeat and kinase domain-containing 1 (ANKK1) and/or the dopamine receptor D2 (DRD2) genes interact with response to treatment with disulfiram.
  
  
  METHODS
  Cocaine and opioid codependent (DSM-IV) patients were stabilized on methadone and subsequently randomized into treatment groups - disulfiram (250 mg/day, N=31) or placebo (N=37). They were genotyped for ANKK1 (rs1800497) and DRD2 (rs2283265) polymorphisms, and the data were evaluated for an association between a cocaine-free state, as assessed by cocaine-free urine samples, and disulfiram treatment. Data were analyzed using repeated measures analysis of variance corrected for population structure.
  
  
  RESULTS
  Patients with CT or TT ANKK1 genotypes dropped from 80 to 52% cocaine-positive urines on disulfiram (N=13; P≤0.0001), whereas those on placebo (N=20) showed no treatment effect. Patients carrying the CC ANKK1 genotype showed no effect on treatment with disulfiram (N=18) or placebo (N=17). The GT/TT DRD2 genotype group showed a significant decrease in the number of cocaine-positive urine samples on disulfiram (N=9; 67-48%; P ≤ 0.0001), whereas the GG DRD2 genotype group showed only a marginal decrease (N=23; 84-63%; P=0.04). Genotype pattern analysis revealed that individuals carrying at least one minor allele in either gene responded better to disulfiram treatment (N=13; P ≤ 0.0001) compared with individuals carrying only the major alleles (N=17).
  
  
  CONCLUSIONS
  A patient's genotype for ANKK1, DRD2, or both, may be used to identify individuals for whom disulfiram may be an effective pharmacotherapy for cocaine dependence.
authors: Menninger Department of Psychiatry and Behavioral Sciences, Michael E. DeBakey VA Medical Center, Baylor College of Medicine, Houston, Texas 77030, USA. spellicy@bcm.edu
authors: Catherine J
authors: CJ
authors: Spellicy
authors: Thomas R
authors: TR
authors: Kosten
authors: Sara C
authors: SC
authors: Hamon
authors: Mark J
authors: MJ
authors: Harding
authors: David A
authors: DA
authors: Nielsen
mesh_terms: D000328:Adult; D000483:Alleles; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000235:genetics; D004221:Disulfiram / Q000627:therapeutic use* / Q000652:urine; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008691:Methadone / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D017448:Receptors, Dopamine D2 / Q000235:genetics*
chemical_list: C581293:DRD2 protein, human; D017448:Receptors, Dopamine D2; C489948:ANKK1 protein, human; D017346:Protein Serine-Threonine Kinases; D004221:Disulfiram; D008691:Methadone
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