ANKK1 and DRD2 pharmacogenetics of disulfiram treatment for cocaine abuse

Pharmacogenet Genomics. 2013 Jul;23(7):333-40. doi: 10.1097/FPC.0b013e328361c39d.

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.

Materials and 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).

Conclusion: 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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Alleles
  • Cocaine-Related Disorders / drug therapy*
  • Cocaine-Related Disorders / genetics
  • Disulfiram / therapeutic use*
  • Disulfiram / urine
  • Female
  • Genotype
  • Humans
  • Male
  • Methadone / therapeutic use
  • Polymorphism, Genetic
  • Protein-Serine-Threonine Kinases / genetics*
  • Receptors, Dopamine D2 / genetics*

Substances

  • DRD2 protein, human
  • Receptors, Dopamine D2
  • ANKK1 protein, human
  • Protein-Serine-Threonine Kinases
  • Disulfiram
  • Methadone