Elsevier

Psychiatry Research

Volume 219, Issue 3, 30 November 2014, Pages 690-692
Psychiatry Research

Brief report
Association between VNTR polymorphism in promoter region of prodynorphin (PDYN) gene and heroin dependence

https://doi.org/10.1016/j.psychres.2014.06.048Get rights and content

Highlights

  • Prodynorphin (PDYN) is the precursor of the dynorphin related peptides.

  • A VNTR polymorphism (with 1–5 repeats) in promoter region of PDYN was reported.

  • This VNTR has an important role in regulation of PDYN expression.

  • Our study revealed the existence of an ancestral nucleotide (A) at 29th position of the VNTR.

  • A male-limited association between PDYN VNTR and heroin dependence risk was revealed.

Abstract

Within the core promoter region of prodynorphin (PDYN), a 68-bp sequence was found to occur as a polymorphism element, either singular or as tandemly repeated two, three or four times. We report the sequence of a novel allele (5-repeats). Our study revealed the existence of an ancestral nucleotide (A) at 29th position of the VNTR in human. In total, 442 heroin addicts and 799 controls were included in this study. The present findings revealed a male-limited association between VNTR polymorphism and heroin dependence risk.

Introduction

Studies suggest that genetic factors have a strong impact on substance-dependence traits. Understanding of the molecular mechanisms of the etiology of heroin dependence is crucial for improving the prevention and treatment programs. Genes that could be risk factors for heroin dependence have not been consistently identified.

Prodynorphin (PDYN; OMIM: 131340) is the precursor of the dynorphin related peptides. The PDYN plays an important role in several complex traits such as drug abuse (Schwarzer, 2009). Within the core promoter region of PDYN, a 68-bp sequence was found to occur as a polymorphism element, either singular or as tandemly repeated two, three or four times (Zimprich et al., 2000). This VNTR has an important role in regulation of PDYN expression. Each repeat contains a putative activator protein transcription factor binding site. Alleles with three or four repeats, have an approximately 50% greater level of transcriptional activity compared to alleles with 1–2 repeats (Zimprich et al., 2000, Rouault et al., 2011). There is one study reported that the 3 and 4 repeats of VNTR increase heroin dependence risk (Wei et al., 2011). However another study did not found any significant association (Zimprich et al., 2000). The aims of this study are to introduce sequence of a novel allele for the VNTR polymorphism and study the association between this polymorphism and heroin dependence susceptibility.

Section snippets

Materials and methods

This study was performed in Shiraz (southern Iran) on 442 heroin addicts (42 females and 400 males) and 799 controls (137 females and 662 males). The patients were in methadone maintenance and all of them reported heroin as their primary drug of choice. Control individuals were blood donors, who declared that they did not suffer substance abuse. The mean±S.D. of age of the patients and controls were 38.3±10.0 and 38.5±12.7 years, respectively (t=0.3, d.f.=1239, and P=0.718). Considering the

Results

A new band (651 bp) above the band of the 4R allele was detected in two persons. According to the sequencing results, the newly identified sequences were the same and contained a new fragment similar to previously identified cis regulatory elements in the promoter region of the PDYN (Fig. 1). This allele was named 5R allele. This allele has very low frequency in our population (2 alleles from 2396 alleles).

Table 1 shows the genotype distribution of the VNTR polymorphism between cases and

Discussion

According to sequencing results, the newly identified sequences were the same and contained a new fragment similar to previously identified cis regulatory elements in the promoter region of the PDYN. Therefore, we identified five kinds of alleles, 1–5 copies of the 68-bp tandem repeat, of the polymorphism in the promoter region of the PDYN. It should be noted that previously, Rouault et al. (2011), reported that they found only one 5R allele among their subjects, but they did not report the

Acknowledgments

The authors are indebted to the participants for their close cooperation. This study was supported by Shiraz University.

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