ReviewEthnic-specific meta-analyses of association between the OPRM1 A118G polymorphism and alcohol dependence among Asians and Caucasians
Introduction
Alcohol dependence is one of the major psychiatric disorders. It involves physical and psychological dependence on alcohol and loss of control over drinking despite recurrent adverse consequences (Nishizawa et al., 2006, Zintzaras, 2011). Worldwide, 76 million people are affected (World Health Organization, 2004), making it one of the most prevalent adult psychiatric disorders (van der Zwaluw et al., 2007). Unfortunately, its etiology remains unclear. However, family, twin pair, half sibling, and adoption studies have suggested that heritability of alcohol dependence ranged between 49 and 64% (Du and Wan, 2009). Therefore, genetic factors may contribute to the development of alcohol dependence.
The endogenous opioid system has been implicated in the development of alcohol dependence for its prominent role in the central rewarding mechanism (Loh el et al., 2004). Studies have shown that pharmacological antagonism of μ-opioid receptors can reduce alcohol consumption in both animal and human (Bart et al., 2005, Soyka and Rosner, 2008, Ulm et al., 1995). Hence the gene encoding the μ-opioid receptor, genetic locus OPRM1, might be a good candidate for genetic studies on alcohol dependence. The human OPRM1 gene is located on chromosome 6q24–q25, and spans over 200 kb, containing at least 9 exons (Mague and Blendy, 2010). The exon 1 A118G (rs1799971) is located at the coding region of OPRM1, causing an Asn40Asp amino acid substitution. Among all identified single nucleotide polymorphisms (SNPs) of OPRM1, it is the best known variant for its potential functional significance both in vitro and in vivo. An initial study reported that in AV-12 cells, the μ-opioid receptors encoded by the 118G variant resulted in a three-fold increase in receptor binding affinity of the endogenous opioid β-endorphin (Bond et al., 1998). However, subsequent studies failed to confirm this finding in other cell lines, such as COS cells (Simian fibroblasts; Befort et al., 2001) or HEK293 cells (human embryonic kidney 293; Beyer et al., 2004). Moreover, one study even presented opposite finding by observing a reduced receptor expression due to 118G variant in CHO cells (Chinese hamster ovary; Zhang et al., 2005).
Studies in healthy participants also showed the functional effects of the A118G polymorphism. In these studies, individuals with the 118G allele displayed a significantly greater cortisol response to the opioid receptor antagonist naloxone (Chong et al., 2006, Hernandez-Avila et al., 2007, Hernandez-Avila et al., 2003, Wand et al., 2002).
Although a number of studies have investigated the association of OPRM1 A118G polymorphism with alcohol dependence, no consensus has been reached. For example, no significant association was identified in the initial study by Bergen et al. (1997), but a significant relationship was reported in two recent studies (Miranda et al., 2010, Deb et al., 2010). There are several possible reasons for these inconsistent findings, such as small sample sizes and ethnic background differences. Meta-analysis is a statistical procedure that can create more powerful estimates of the true effect by combining evidences from multiple studies (Munafo and Flint, 2004). The minor allele frequency of A118G polymorphism was significantly different between healthy Asians and Caucasians (31.1–47.4% and 7.4–15.3%, respectively; Arias et al., 2006). Therefore, we performed ethnicity-specific meta-analyses to study the association between the A118G polymorphism and alcohol dependence in Asians and Caucasians, the two major ethnic groups that had been studied.
Section snippets
Identification and eligibility of relevant studies
We searched the following electronic databases: PubMed/MEDLINE (US National Library of Medicine), EMBASE (Elsevier B.V., Amsterdam, the Netherlands), and ISI Web of Science (Thomson Reuters, New York, NY, USA), for all studies published up to April 12, 2011. The search strategy was based on the combination of the terms “OPRM1 or opiate receptor or opioid”, “alcohol or alcoholism or substance”, and “polymorphism or variant”. All references in the retrieved articles were also screened for
Characteristics of eligible studies
Sixteen relevant publications matched the search terms, and were used for further examination (as of April 12, 2011). Among them, one was conducted in Mexican Americans (Du and Wan, 2009), and the other three had overlapping data (Gscheidel et al., 2000, Rommelspacher et al., 2001, Town et al., 1999). Therefore, a total of twelve separate studies were retrieved. Each study was reviewed independently by two investigators (D. Chen and L. Liu), and few disagreements were resolved by consensus.
Discussion
With a total of 1900 cases and 2382 controls, we investigated the role of OPRM1 A118G polymorphism in alcohol dependence among Asians and Caucasians through ethnicity-specific meta-analyses. The results showed that the 118G allele might be associated with alcohol dependence in Asians, but not in Caucasians.
Given the importance of the μ-opioid receptor in the central rewarding mechanism, it is biologically plausible that OPRM1 polymorphisms may modulate the risk of alcohol dependence. Previous
Role of funding source
This study was partly supported by the National Natural Science Foundation of China (No. 30872175). The funding source had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Contributors
Zengzhen Wang, Dingyan Chen, and Li Liu designed the study and wrote the protocol. Dingyan Chen and Li Liu managed the literature searches and analyses, undertook the statistical analysis and wrote the first draft of the manuscript. Zengzhen Wang, Chengwu Yang, Yang Xiao, and Yuehua Peng provided critical revision of the manuscript for important intellectual content. All authors contributed to and have approved the final manuscript.
Conflict of interest
No conflict declared.
Acknowledgement
We would like to express our gratitude to all the people who give the help for this study.
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These authors contributed equally to this work.