Association between DRD2/ANKK1 TaqIA polymorphism and common illicit drug dependence: Evidence from a meta-analysis
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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Common variant c.-22 + 155C > T of BDNF as a genetic risk factor of opium addiction
2022, Human GeneCitation Excerpt :Thereby, many functional and common variants have been associated with the addiction prevalence. In candidate gene-based studies, the rs1800497 and rs1079597 of DRD2 and the rs6265 of BDNF have been shown to be associated with Opioid use disorder (Cheng et al., 2005; Vereczkei et al., 2013; Deng et al., 2015). Genetic mutations present in different potassium voltage channels e.g. rs62103177 and rs60349741 of KCNG2 and KCNC1 have been also found in association in GWAS studies (Gelernter et al., 2014).
Epistatic effect of Ankyrin repeat and kinase domain containing 1 – Dopamine receptor D2 and catechol-o-methyltransferase single nucleotide polymorphisms on the risk for hazardous use of alcohol in Lithuanian population
2021, GeneCitation Excerpt :These findings largely agree with a meta-analysis examining the association of the ANKK1-DRD2 rs1800497 polymorphism with alcohol use disorder, where T allele was demonstrated to increase the risk of alcohol use disorder, but the effect was modest (Wang et al., 2012). T allele of the ANKK1-DRD2 rs1800497 was also found to increase the risk of smoking and opioid addiction, thus the role of T allele on the risk of substance use disorders seems to be not substance specific (Deng et al., 2015; Munafo et al., 2009). Moreover, there is evidence that lower density of the ANKK1-DRD2 receptors predicts increased alcohol craving and risk of alcohol addiction relapse (Heinz et al., 2005).
Molecular genetics of neurotransmitters and neuropeptides involved in Internet use disorders including first insights on a potential role of hypothalamus’ oxytocin hormone
2021, Handbook of Clinical NeurologyCitation Excerpt :Therefore the A1 allele associated with lower D2 receptor binding (potential) seems to be positively associated with Internet gaming disorder, hence, maybe also unspecified IUD and other specific IUDs. Interestingly, the same allele (A1) has also been associated with a risk for alcohol, smoking, and opioid dependence (Munafò et al., 2007; De Ruyck et al., 2010; Wang et al., 2013a,b; Deng et al., 2015). The COMT Val158Met SNP causes a valine to methionine substitution in the 158th codon of the COMT gene, thereby moderating the dopamine catabolism by the COMT enzyme in the synaptic cleft.
Genetic Factors Associated With Opioid Therapy and Opioid Addiction
2020, Fighting the Opioid Epidemic: The Role of Providers and the Clinical Laboratory in Understanding Who is VulnerableA review of opioid addiction genetics
2019, Current Opinion in PsychologyThe polymorphism of dopamine D2 receptor TaqIA gene is associated with brain response to drug cues in male heroin-dependent individuals during methadone maintenance treatment
2019, Drug and Alcohol DependenceCitation Excerpt :Since persons who carry the A1 allele show a reduced sensitivity to reward, they feel the increased urge to consume substances of abuse stimulating the dopamine (DA) system (Blum et al., 2000, 2017). Individuals with A1 allele significantly increased opioid dependence risk than patients without the A1 allele (Deng et al., 2015). The A1 allele has been associated with a higher heroin consumption and poor response to methadone treatment (Lawford et al., 2000).