Elsevier

Human Immunology

Volume 76, Issue 1, January 2015, Pages 42-51
Human Immunology

Association between DRD2/ANKK1 TaqIA polymorphism and common illicit drug dependence: Evidence from a meta-analysis

https://doi.org/10.1016/j.humimm.2014.12.005Get rights and content

Abstract

Background

Growing evidence indicated conflicting results about the dopamine receptor D2 (DRD2)/kinase domain containing 1 gene (ANKK1) TaqIA single nucleotide polymorphism (rs1800497) and common illicit drug dependence risk including stimulants, opioid and marijuana. We conducted a meta-analysis to evaluate the association between the polymorphism and common illicit drug dependence risk.

Method

A total of 25 available studies (26 subgroups) testing the association between the polymorphism and common illicit drug dependence were examined through Oct 2013. Pooled odds ratios (ORs) and 95% confidence intervals (CI) were estimated using fixed- and random-effects models when appropriate. Heterogeneity and publication bias were evaluated.

Results

We found the DRD2/ANKK1 TaqIA polymorphism was significantly associated with increased risk of opioid dependence under homozygote, dominant, and recessive genetic model, respectively (homozygote: OR = 1.546, 95%CI = 1.279–1.87; dominant: OR = 1.265, 95%CI = 1.055–1.516; recessive: OR = 1.409, 95%CI = 1.182–1.680). Subgroup analyses were similar to the results of the total population by ethnicity and quality score. Besides, we also found that Caucasian and low-quality studies were major sources of heterogeneity for opioid dependence. We failed to find any significant association between the polymorphism and stimulants or marijuana neither in total population nor subgroup analyses under any genetic model.

Conclusions

The current meta-analysis suggested that DRD2/ANKK1 TaqIA polymorphism might be associated with opioid dependence risk, but not associated with stimulants or marijuana dependence.

Introduction

Common illicit drug dependence brought great losses to the societies and individuals (http://www.unodc.org/wdr/index.html). It was classified as stimulants (e.g. cocaine, methamphetamine), hallucinogens (e.g. marijuana, ketamine), and depressants (e.g. opioid, heroin) according to the pharmacological mechanism [1], [2], which involved approximately 240 million people, and resulted in drug-related deaths from 102,000 to 247,000. Common illicit drug dependence was considered to be a multi-factorial disease, interacted by environmental factors, drug-induced physiological effects and genetic susceptibility [2]. And, the estimated heritability accounted for 60%, and environment about 40% in substance dependence [3]. Among genetic factors, dopamine (DA) system received a great deal of attention, which was related to processes of activation and reward-related behaviors, and played a key role in drug dependence [4], [5]. As was known to all, only DA interactions with membrane receptors has the ability to the formation of second messengers, and inhibit or activate specific signaling pathways. Hence, DA receptors were widely focused on drug dependence, especially the dopamine receptor D2 (DRD2) [6], [7], [8], [9], which was centrally involved in reward-mediating mesocorticolimbic pathways, and attributed to 27% of all the genetic factors to drug dependence [3].

DRD2 (11q23.2) is composed of 8 exons and 7 introns, which encodes a G protein-coupled receptor located on postsynaptic dopaminergic neurons, and plays important role in locomotion, hormone production, and drug dependence [10], [11]. The TaqIA polymorphism (rs1800497, 32806C/T) was originally associated with the DRD2 gene and located on 3′-untranslated region (3′-UTR), but later found to be located on exon 8 of ankyrin repeat and kinase domain containing 1 gene (ANKK1), which was one of the serine/threonine kinase family [12]. And, the polymorphism changed glutamate into lysine in ANKK1 (713Glu/Lys), which was unlikely to affect structural integrity, but may affect substrate-binding specificity [12].

Altered DRD2 receptor expression due to the DRD2/ANKK1 TaqIA polymorphism may confer vulnerability to substance (illicit drug, alcohol and nicotine) dependence [13]. The TaqIA polymorphism association with substance dependences has been widely studied [14], [15], [16], [17], [18]. In 2013, Wang et al. [19] and Ohmoto et al. [20] confirmed the association between the polymorphism and alcohol and nicotine dependences by large-scale meta-analysis, respectively. To common illicit drug dependence, some studies suggested that the polymorphism was associated with opioid, stimulants, and marijuana [14], [15], [16], [17], [18], [21], [22], [23], [24], [25]. Majority studies showed 1.5–3.0-folds increased risk of opioid, stimulants, or marijuana dependence in individuals with allele A1 or carriers A1 genotypes [17], [18], [23]. Nevertheless, conflicting results were also reported [26], [27], [28], [29], [30], [31], even within the same population. For example, Hou et al. [15] reported that the frequencies of the allele A1 of DRD2/ANKK1 TaqIA polymorphism in heroin abusers predicted a significantly higher heroin dependence risk compared with those of normal controls in a Chinese population (45.2% vs 39.8%, P = 0.014), whereas Li et al. [32] did not find similar relationship in the same Chinese population (29.8% vs 25.9%, P = 0.29). It might be that individual study had lower statistical power to limit the overall effects. Hence, it was necessary that a quantitative summary of the combined data from different studies was performed to assess the association between the TaqIA polymorphism and common illicit drug dependence. To our best knowledge, few of meta-analysis was available on the association between the polymorphism and common illicit drug dependence except Chen’s study [33], in which a meta-analysis was performed to estimate only the polymorphism association with opioid dependence, however, the influence of ethnic differences and quality score of literature were not considered. Of course, they also analyzed other locus association with opioid dependence. Up to date, 4 new studies evaluating the association of the Taq1A polymorphism with opioid dependence have been published since 2010. These studies included 2187 new subjects (1019 cases and 1168 controls). However, no further meta-analysis has been conducted to investigate whether the association between the TaqIA polymorphism and opioid remained significant or not. And, no meta-analysis estimated stimulants and marijuana dependence. To gain better insight into the impact of the polymorphism on the common illicit drug dependence, we performed a systematic review and meta-analysis on all available published studies to better clarify the association the DRD2/ANKK1 TaqIA polymorphism (rs1800497, 32806C/T) with opioid, stimulants, and marijuana dependence risk.

Section snippets

Publication search

Studies which investigated the association of the TaqIA polymorphism with common illicit drug dependence were selected from the electronic database PubMed, Medline, and Web of Science up to Oct, 2013. The following terms were used in this search: (D2 Dopamine receptor or dopamine receptor D2 or DRD2 or D2DR or ANKK1) and (polymorphisms or SNPs or mutation or variant or variation) and (narcotics or drug or substance) and (abuse or misuse or dependence or addiction). All searched publications

Study characteristics

Overall, 25 studies (26 subgroups) met the inclusion criteria for this meta-analysis. The main characteristics of the studies are summarized in Table 1. For opioid dependence, 13 studies (14 subgroups, 3423 cases and 3096 controls) evaluated the DRD2/ANKK1 TaqIA polymorphism association with opioid dependence including 8 subgroups in Caucasian [18], [22], [23], [24], [25], [27], [44], [45], 5 in the Asian [15], [21], [31], [32], [45], and 1 in the mixed population [46]. For stimulants

Discussion

A number of studies were conducted to investigate the association between the DRD2/ANKK1 TaqIA polymorphism and common illicit drug dependence in diverse populations, whereas, the results remained controversial and ambiguous [14], [15], [16], [17], [28], [30], [32], [50]. We performed systematic review and meta-analysis to better clarify the relationship between the polymorphism and common illicit drug dependence including opioid, stimulants, and marijuana.

In current meta-analysis, we found

Acknowledgments

This Project was Supported by Scientific Research Fund of Sichuan Provincial Education Department (Grant Number: 10ZA079 and 14ZA0191), Sichuan Provincial Department of Science and Technology Project (Grant Number: 2013JY0071), and Key Science Foundation of North Sichuan Medical College in 2013.

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