Genetic variants altering dopamine D2 receptor expression or function modulate the risk of opiate addiction and the dosage requirements of methadone substitution.
ABSTRACT Addictive behavior is importantly mediated by mesolimbic dopaminergic signaling. Here, we comprehensively analyzed the DRD2 gene locus, and in addition, the ANKK1 rs1800497C>T single nucleotide polymorphism (SNP), formerly known as 'dopamine D2 receptor Taq1A C>T polymorphism', for associations with the risk of opiate addiction and the methadone dosage requirements.
Allelic frequencies of DRD2/ANKK1 polymorphisms were compared between 85 methadone-substituted Caucasian patients and a random sample of 99 healthy Caucasian controls. Within patients, the average and maximum daily methadone dose during the first year of treatment and the time when that maximum dose was reached were analyzed for an association with DRD2/ANKK1 genetics.
Compared with the control group, drug users carried more frequently the minor allele of DRD2 SNP rs1076560G>T SNP (P=0.022, odds ratio 2.343) or the ATCT haplotype of DRD2 rs1799978A>G, rs1076560G>T, rs6277C>T, ANKK1 rs1800497C>T (P=0.048, odds ratio 2.23), with similar tendencies for ANKK1 rs1800497C>T (P=0.056, odds ratio 2.12) and the TCCTCTT haplotype of DRD2 rs12364283T>C, rs1799732C del, rs4648317C>T, rs1076560G>T, rs6275C>T, rs6277C>T, and ANKK1 rs1800497C>T (P=0.059, odds ratio 2.31). The average and maximum daily methadone doses were significantly associated with the DRD2 rs6275C>T SNP (P=0.016 and 0.005 for average and maximum dose, respectively). Carriers of the variant rs6275T allele needed higher methadone doses than noncarriers. In addition, this variant was associated with a longer time to reach the maximum methadone dose (P=0.025).
On the basis of an analysis spanning the whole gene locus, from the DRD2 promoter to the ANKK1 rs1800497C>T polymorphism, DRD2 genetic polymorphisms modulate both the risk of opiate addiction, leading to the necessity of methadone substitution therapy, and the course of this therapy in terms of dosage requirements.
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ABSTRACT: The role of dopamine neurotransmitter in attention deficit hyperactivity disorder (ADHD) remains controversial. Many molecular studies focusing on dopamine receptors have attempted to analyze the gene polymorphisms involved in dopaminergic transmission. Of these, rs1800497 (TaqIA) single nucleotide polymorphism (SNP) of the dopamine D2 receptor (DRD2) gene has been focused on by the most attention. However, this locus has recently been identified within the exon 8 of ankyrin repeat and kinase domain containing 1 (ANKK1), giving rise to a Glu713-to-Lys substitution in the putative ANKK1 protein. Thus, we performed a meta-analysis to determine whether ANKK1 polymorphism influences the risk of ADHD and examined the relationship between rs1800497 genetic variant and the etiology of ADHD. Relevant case-control studies were retrieved by database searches and selected according to established inclusion criteria. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. Meta-regression, subgroup analysis, sensitivity analysis and cumulative meta-analysis were performed. A total of 11 studies with 1645 cases and 1641 controls were included. In the dominant model, the rs1800497 locus was associated with ADHD, with a pooled OR of 1.785 (95% CI=1.068-2.984, p=0.027). Subgroup analysis for ethnicity indicated that the polymorphism was associated with ADHD in Africans (OR=3.286, 95% CI=1.434-7.527, p=0.005), but not in East Asians (OR=1.513, 95% CI=0.817-2.805, p=0.188) and Caucasians (OR=1.740, 95% CI=0.928-3.263, p=0.084). However, the results of meta-regression indicated that publication date (p=0.601), source of controls (p=0.685), ethnicity (p=0.755) and diagnostic criteria (p=0.104) could not explain the potential sources of heterogeneity. This meta-analysis indicates that the rs1800497 locus may be associated with ADHD. These data provide possible references for future case-control studies in childhood disorders. Copyright © 2015. Published by Elsevier Ireland Ltd.Neuroscience Letters 01/2015; 590. DOI:10.1016/j.neulet.2015.01.076 · 2.06 Impact Factor
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ABSTRACT: The role of dopamine D2 receptor (DRD2) polymorphisms in schizophrenia remains controversial. We performed a meta-analysis to determine whether DRD2 polymorphisms influence the risk of schizophrenia and examined the relationship between rs1799732, rs1801028, and rs1800rs028 and rs1800497 genetic variants and the etiology of schizophrenia. Relevant case-control studies were retrieved by database searches and selected according to established inclusion criteria. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. Meta-regression, subgroup analysis, sensitivity analysis, and cumulative meta-analysis were performed. A total of 76 studies with 16096 cases and 18965 controls were included. Specifically, 24 studies with 6075 cases and 6643 controls involved rs1799732, 36 studies with 8043 cases and 10194 controls involved rs1801028 and 16 studies with 1978 cases and 2128 controls involved rs1800497. No significant associations were observed between rs1799732 and rs1800rs732 and rs1800497 and schizophrenia. The rs1801028 locus was associated with schizophrenia, with a pooled OR of 1.221 (95% CI = 1.037–1.438, P = 0.016). This meta-analysis indicates that the rs1801028 locus may be associated with schizophrenia. These data provide possible references for future case-control studies related to schizophrenia. © 2014 Wiley Periodicals, Inc.American Journal of Medical Genetics Part B Neuropsychiatric Genetics 01/2015; 168(1). DOI:10.1002/ajmg.b.32281 · 3.27 Impact Factor
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ABSTRACT: Substance-related disorders (SRDs) are a major cause of morbidity and mortality worldwide. Family, twin, and adoption studies have demonstrated the substantial heritability of SRDs. To determine the impact of genetic variation on risk for SRD and the response to treatment, researchers have conducted a number of secondary data analyses and quasi-experimental studies that target one or more candidate gene variants. This review examines studies in which candidate polymorphisms were examined as mediator variables to identify pharmacogenetic effects on subjective responses to drug administration or cues or outcomes of medication trials for SRDs. Efforts to use a meta-analytic approach to quantify these effects are premature because the number of available studies using similar methods and outcomes is limited, so the present review is qualitative. Findings from these studies provide preliminary evidence of clinically relevant pharmacogenetic effects. However, independent replication of these findings has been sparse. Although this growing body of literature has produced conflicting results, improved statistical controls may help to clarify the findings. Additionally, the use of empirically derived sub-phenotypes (i.e., which serve to differentiate distinct groups of affected individuals) may also help to identify genetic mediators of pharmacologic response in relation to SRDs. The identification of genetic mediators can inform clinical care both by identifying risk factors for SRDs and predicting adverse events and therapeutic outcomes associated with specific pharmacotherapies. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.Drug and alcohol dependence 03/2015; DOI:10.1016/j.drugalcdep.2015.03.003 · 3.28 Impact Factor