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Genetic variants altering dopamine D2 receptor expression or function modulate the risk of opiate addiction and the dosage requirements of methadone substitution

Doehring, Alexandraa; Hentig, Nils vona; Graff, Jochena; Salamat, Syavasha; Schmidt, Michaelb; Geisslinger, Gerda; Harder, Sebastiana; Lötsch, Jörna

Pharmacogenetics and Genomics: June 2009 - Volume 19 - Issue 6 - pp 407-414
doi: 10.1097/FPC.0b013e328320a3fd
Original Articles

Aim: Addictive behavior is importantly mediated by mesolimbic dopaminergic signaling. Here, we comprehensively analyzed the DRD2 gene locus, and in addition, the ANKK1 rs1800497C>T single nucleotide polymorphism (SNP), formerly known as ‘dopamine D2 receptor Taq1A C>T polymorphism', for associations with the risk of opiate addiction and the methadone dosage requirements.

Methods: Allelic frequencies of DRD2/ANKK1 polymorphisms were compared between 85 methadone-substituted Caucasian patients and a random sample of 99 healthy Caucasian controls. Within patients, the average and maximum daily methadone dose during the first year of treatment and the time when that maximum dose was reached were analyzed for an association with DRD2/ANKK1 genetics.

Results: Compared with the control group, drug users carried more frequently the minor allele of DRD2 SNP rs1076560G>T SNP (P=0.022, odds ratio 2.343) or the ATCT haplotype of DRD2 rs1799978A>G, rs1076560G>T, rs6277C>T, ANKK1 rs1800497C>T (P=0.048, odds ratio 2.23), with similar tendencies for ANKK1 rs1800497C>T (P=0.056, odds ratio 2.12) and the TCCTCTT haplotype of DRD2 rs12364283T>C, rs1799732C del, rs4648317C>T, rs1076560G>T, rs6275C>T, rs6277C>T, and ANKK1 rs1800497C>T (P=0.059, odds ratio 2.31). The average and maximum daily methadone doses were significantly associated with the DRD2 rs6275C>T SNP (P=0.016 and 0.005 for average and maximum dose, respectively). Carriers of the variant rs6275T allele needed higher methadone doses than noncarriers. In addition, this variant was associated with a longer time to reach the maximum methadone dose (P=0.025).

Conclusion: On the basis of an analysis spanning the whole gene locus, from the DRD2 promoter to the ANKK1 rs1800497C>T polymorphism, DRD2 genetic polymorphisms modulate both the risk of opiate addiction, leading to the necessity of methadone substitution therapy, and the course of this therapy in terms of dosage requirements.

aPharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University

bMalteser Drogenambulanz Schielestraße, Schielestraße, Frankfurt am Main, Germany

Correspondence to Jörn Lötsch, Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe University, Theodor Stern Kai 7, D-60590 Frankfurt am Main, Germany

Tel: +49 69 6301 4589; fax: +49 69 6301 7636;

e-mail: j.loetsch@em.uni-frankfurt.de

Alexandra Doehring and Nils von Hentig contributed equally to this study

Received 12 August 2008 Accepted 4 November 2008

© 2009 Lippincott Williams & Wilkins, Inc.