Research reportAssociation between heroin dependence and prodynorphin gene polymorphisms
Research highlights
► PDYN 68bp VNTR was found to be associated with heroin dependence. ► Significantly more TCT haplotypes (rs1022563, rs2235749, rs910080 in 3′UTR) were found in heroin-dependent patients than in the controls. ► We found significant pointwise correlation of these three variants (rs1022563, rs2235749 and rs910080) with heroin dependence. ► These findings support the important role of PDYN polymorphism in heroin dependence.
Introduction
Heroin addiction is a chronic relapsing condition characterized by compulsive drug seeking, drug abuse, tolerance and physical dependence. An adoption study indicated a genetic component to substance dependence, especially opioid dependence [2]. Twin studies have suggested that genetic factors account for 30–60% of the overall variance in the risk of developing drug addiction [17], [31], [33]. Genetic component of opioid addition is even greater [31].
Prodynorphin (PDYN) is an opioid peptide precursor protein that gives rise to α- and β-neoendorphins, dynorphin A- and dynorphin B-related peptides [14]. These products of the PDYN genes have been shown to be able to inhibit neurotransmission by acting through kappa opioid receptors, and are implicated in reward, mood regulation, stress responses, and motor functions [7], [13], [16]. The dynorphins/kappa opioid receptors (Dyn/KOP) system plays a crucial role in addiction. Dysregulation of the Dyn/KOP system is induced by repeated drug abuse and involves the mesolimbic reward system. Thus, the dopaminergic pathway of the ventral tegmental area to the nucleus accumbens is seen as the main site of Dyn action in addiction. The importance of the Dyn/KOP systems is discussed not only with regard to habit learning and establishment, but also with regard to the reinstatement of addiction [28].
Several animal studies have shown that chronic administration of drugs of abuse, such as morphine [33], cocaine [1], [11], [18], [19], [26], [27], [37], amphetamine [32], nicotine and ethanol [9], [10], [20], [23], altered the activity of PDYN in the brain. Drugs of abuse can increase prodynorphin expression in clinical models. Postmortem studies of human cocaine addicts demonstrated an increase in both mRNA and protein levels of dynorphin compared to controls [8], [15]. Furthermore, polymorphisms in prodynorphin gene have been associated with opioid dependence in females [5]. In a human study, evidence suggested that dynorphin administered intravenously produced decreased withdrawal symptoms in heroin addicts [34]. It had been found that genetic variability of endogenous dynorphin opioid systems, which mediate dysphoria, may be related to opioid abuse, and thus has a strong heritability [12], [30], [31].
Human PDYN gene contains four exons and three introns. Zimprich et al. identified a functional polymorphism in PDYN gene promoter region with one to four repeats of a 68-bp element containing one binding site per repeat for transcription factor AP-1 (c-Fos/c-Jun) [39]. In vitro evidence has implied that this variable nucleotide tandem repeat (68-bp VNTR) polymorphism was able to induce transcriptional activation with four or three, but not less, copies of the repeats [38]. Such allelic variations could influence gene expression and contribute to individual psychophysiological variability [3], [6]. However, studies on genetic association have failed to produce consistent results with regards to potential involvement of PDYN 68bp VNTR polymorphism in cocaine, methamphetamine and heroin dependence [3], [6], [23], [25], [32], [39].
In addition to 68-bp VNTR polymorphism, the most well-studied one, other polymorphisms of PDYN genes in 3′UTR had also been associated with decreased PDYN mRNA expression in human brain tissues [37], suggesting that these PDYN gene variants might influence gene expression and thus PDYN function in human. Recent findings suggest that two SNPs (rs1022563 and rs1997794) in 3′UTR of this gene were associated with increased risk of developing opioid dependence in females [5]. In genotype and allelic tests, Yuferov et al. found experiment-wise significant association between three SNPs (rs910080, rs910079 and rs2235749) in 3′UTR and both cocaine dependence and cocaine/alcohol codependence in Caucasians, but not in African Americans [37]. However, genetic association studies have not been repeated in heroin dependence.
In view of the crucial role of the PDYN in addiction disorders, as well as the controversy in genetic association studies, we conducted a study with relatively large sample size and same ethnic origin to verify the putative association between PDYN polymorphisms and heroin dependence.
Section snippets
Subjects
Three hundred and four adult individuals with heroin addiction (mean age of 37.1 ± 6.3, 181 males and 123 females) receiving treatment in the Methadone Maintenance Treatment (MMT) Program at Xi’an Mental Health Center participated in this study. Opioid addiction was diagnosed based on the DSM-IV criteria from the medical history, along with urine test, and interview. A case vignette was made to assist with diagnosis, using a semistructured interview with questions on (a) the age at initiation and
Results
The distribution of genotypes, allelic frequencies and haplotype in control and patient groups, together with the results of statistical analysis were listed in Table 2, Table 3.
Significant differences were found in the distribution of genotype and allele frequencies of PDYN gene 68-bp VNTR between heroin-dependent subjects and healthy controls (p = 0.004 and 0.002, respectively). The frequency of the H allele in heroin-dependent subjects was significantly higher than in the controls (χ2 = 9.435, p =
Discussion
Dynorphin and k-opioid receptor (KOPr) are located in several areas of the dopaminergic nigrostriatal and mesolimbic–mesocortical systems, and play a modulatory role in heroin, cocaine and other rewarding stimuli [20]. The binding between PDYN and k-opioid receptors makes dopaminergic system important for the reinforcing and rewarding effects of drugs of abuse such as heroin [28].
After adjusting for multiple testing (threshold significance p value was set at 0.0125 in Table 2, Table 3), the
Acknowledgements
This research was partially supported by the fundamental research funds for central universities (08143020). The funding sources had input into the design of this study, the collection, analysis and interpretation of data, the writing of the report and the decision to submit the paper for publication.
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2018, Neuroscience LettersCitation Excerpt :c) SNPs with minor allele frequencies (MAFs) greater than 0.01 were selected based on a review of published literature and a search of HapMap and dbSNP (Han Chinese Beijing or Chinese Han Beijing populations). ( d) According to our previous research, PDYN 68-bp VNTR was related to HD [5]. These SNPs were further analyzed in an association study.
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2014, Psychiatry ResearchCitation Excerpt :For example, the DRD2 A1 allele associated with alcohol dependence only in male subjects (Limosin et al., 2002). Few studies investigated the association between heroin dependence and PDYN VNTR polymorphism with inconsistent results (Zimprich et al., 2000; Wei et al., 2011). Considering the fact that male-limited association between this polymorphism and risk of heroin dependence, the discrepancy between studies, at least in part might be interpreted by the sex proportion of the participants (cases and controls).
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The first two authors contributed equally to this study.
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