Brief report 295 A functional prodynorphin promoter polymorphism and opioid dependence Riju Ray a , Glenn A. Doyle b , James J. Crowley a , Russell J. Buono b , David W. Oslin b,c , Ashwin A. Patkar d , Paolo Mannelli d , Peter A. DeMaria Jr d , Charles P. O’Brien b,c and Wade H. Berrettini b Objectives The prodynorphin gene (PDYN) promoter has a repeat polymorphism that is functionally important in association with substance abuse. We examined this polymorphism for association in our sample of 168 opioid- dependent patients and 122 ethnically and geographically matched controls. Methods Patients were selected from university-affiliated residential and non-residential addiction treatment pro- grams in the Philadelphia area. A sample of blood was drawn from consenting individuals and genomic DNA was isolated. Polymerase chain reaction amplification of the PDYN promoter was performed and various genotypes were determined on the basis of differing sizes of the polymerase chain reaction products. The genotype and allele data were analyzed by Fisher’s exact test. Result A significant difference in genotype (P < 0.0006) and allele (P < 10 –5 ) frequencies was found between the African American and European American populations. We did not detect any significant difference in genotype or allele frequencies between the patients and controls within the European American ethnic group. However, we de- tected a weak association (P = 0.013) when we compared allele frequencies of patients and controls in the African American population. Conclusions These data suggest that the PDYN repeat polymorphism should be studied in additional opioid- dependent populations. Psychiatr Genet 15:295–298  c 2005 Lippincott Williams & Wilkins. Psychiatric Genetics 2005, 15:295–298 Keywords: addiction and genetics, dynorphin, opioid, polymorphism a Department of Pharmacology, University of Pennsylvania, Philadelphia, b Department of Psychiatry, University of Pennsylvania, Philadelphia, c Philadelphia Veterans Affairs Medical Center, Philadelphia and d Department of Psychiatry and Human Behavior, Jefferson Medical College, Philadelphia, Pennsylvania, USA. Correspondence to Riju Ray, Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania School of Medicine, 415 Curie Boulevard, Clinical Research Building, Room 130, Philadelphia, PA 19104, USA. Tel: +1 215 898 0092; fax: +1 215 573 2041; e-mail: rijuray@mail.med.upenn.edu Requests for reprints to Dr Wade Berrettini, Karl E. Rickels, Professor of Psychiatry, Director, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Room 111, 415 Curie Blvd., Philadelphia, PA 19104, USA. Tel: +1 215 898 0092; fax: +1 215 573 2041; e-mail: wadeb@mail.med.upenn.edu Sponsorships: This work was supported by a Mental Illness Research, Education and Clinical Center grant at the Philadelphia Veterans Affairs Medical Center (C.P.O’B. D.W.O., W.H.B. O’Brien, Oslin and Berrettini) and NIDA Grant P60-05186 (C.P.O’B., D.W.O., W.H.B.). Accepted 12 April 2005 Introduction Prodynorphin is the precursor for the opioid peptides dynorphin A, dynorphin B and a-neoendorphin. It is expressed in the central and peripheral nervous systems and has been shown to inhibit neurotransmission by acting through kappa opioid receptors. Dynorphin re- duces dopaminergic tone in the mesocortical–limbic projections. In human studies, evidence suggests that dynorphin administered intravenously produces de- creased withdrawal symptoms in heroin addicts (Wen and Ho, 1982). Furthermore, dynorphin A suppresses naloxone-induced opiate withdrawal and development of morphine tolerance in morphine-dependent mice (Take- mori et al., 1993). Studies in animal models also show that dynorphin attenuates synaptic dopamine increases caused by the administration of cocaine (Kreek, 1996). Horikawa et al. (1983) cloned and sequenced the 5 0 region of the prodynorphin gene (PDYN) located on the short arm of chromosome 20. Zimprich et al. (2000) later described a 68-basepair (bp) repeat polymorphism within the PDYN promoter that altered response to external stimuli. This 68-bp repeat polymorphism can be present in 1–4 copies. The polymorphism is functionally important as each of the repeats contains an active activating protein-1 (AP1) site and transcription of PDYN is dependent on these AP1 sites (Messersmith et al., 1998). Thus, the presence of 3 or 4 repeats increases transcriptional efficiency of the promoter in response to phorbol esters which may mimic, partially, a pain stimulus (Zimprich et al., 2000). Zimprich et al. (2000) found no significant associa- tion between German heroin abusers and this repeat polymorphism. Chen et al. (2002) demonstrated that cocaine-dependent individuals had more alleles of low number of repeats whereas controls had more alleles of high number of repeats; thus, a higher number of repeats may reduce risk for cocaine dependence. Given the 0955-8829  c 2005 Lippincott Williams & Wilkins Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.