rs1800497 in ANKK1,DRD2

Clinical Annotations

PharmGKB clinical annotations provide information about variant-drug pairs based on a summary of the individual variant annotations in the database. Therefore, each clinical annotation could represent information from a single paper or multiple papers. The rating system used to assign "Strength of Evidence" levels is described here. The individual variant annotations, including the PMID for each supporting PubMed publication, can be found on the "PGx Research" tab above.

This information is manually curated by PharmGKB. All alleles are displayed on the positive chromosomal strand.

PharmGKB variant annotations provide information about variant-drug pairs or variant-disease pairs based on individual PubMed publications. Each annotation represents information from a single paper and the goal is to report the information that the author states, not an interpretation of the paper. The PMID for supporting PubMed publications is found in the "Evidence" field.

Information presented, including study size, allele frequencies and statistics is taken directly from the publication. However, if the author does not correct p-values in cases of multiple hypotheses, curators may apply a Bonferroni correction. Curators attempt to report study size based on the actual number of participants used for the calculation of the association statistics, so the number may vary slightly from what is reported in the abstract of the paper. OMB Race Category information is derived from the paper and mapped to standardized categories. Category definitions may be found by clicking on the "OMB Race Category" link.

List of all variant annotations for this variant.

Variant Overview

VIP Variant in DRD2

The Taq1A polymorphism is the most studied polymorphism in association with the DRD2 gene. It is not clear whether it is associated with effects of antipsychotic drugs, although some reports support such a conclusion. It is, however, quite clear that it is associated with nicotine dependency and treatment. The frequency of the minor T allele differs among ethnic populations. It occurs in about 22% of the European Caucasian population but is more frequent in Asian and African populations (42%) HapMap data set at dbSNP. The Taq1A site is a SNP in a Taq1 restriction site located 10 kb downstream of the DRD2 gene [Article:2573278]. Neville et al. demonstrated that the variation is an amino acid changing polymorphism (Glu713Lys) within the 11th ankyrin repeat of ANKK1 gene [Article:15146457]. Neville et al. showed low level expression of ANKK1 in placenta and whole spinal cord RNA [Article:15146457], while Hoenicka et al. demonstrate that ANKK1 mRNA and protein were expressed in the adult central nervous system in human and rodents, exclusively in astrocytes [Article:19853839]. On the other hand, this variation is also associated with the DRD2 gene. Zhang et al. found that the Taq1A A1 allele was in linkage disequilibrium (LD) with the minor allele of the intronic SNPs (rs2283265) (G > T) and (rs1076560) (G > T) [Article:18077373]. Both intronic SNPs were involved in splicing modification of the DRD2 gene and affected working memory [Article:18077373]. Taq1A was also part of DRD2 haplotypes associated with vulnerability to heroin dependence [Article:15184239], risk of opiate addiction [Article:19373123], alcohol dependence [Article:19603545], and clozapine treatment response [Article:15830237]. In addition, this variation was associated with reduced DRD2 gene expression and lower glucose metabolic rate in dopaminergic regions in the human brain [Articles:12587665, 9672901, 10395223]. In this overview we refer to the DRD2 gene for consistency with the majority of the existing literature.

Taq1A variation was associated with clinical response to antipsychotic drug treatment and adverse effects. Individual studies have shown that after short-term treatment, the effects of antipsychotic drugs (haloperidol [Article:11329406], nemonapride [Article:10862524], ripiprazole [Article:18926547], risperidone [Article:18855532]) on positive psychotic symptoms are better in patients with the A1 allele than in patients homozygous for A2/A2. In contrast, a meta-analysis focusing on the relationship of DRD2 variants and antipsychotic drug response was not able to detect an association between clinical response and the Taq1A variant [Article:20194480]. The analysis included eight studies, which assessed the Taq1A polymorphism and antipsychotic response (risperidone, haloperidol, chlorpromazine, clozapine, nemonapride, bromperidol, and aripiprazole), with a total sample size of 748 patients [Article:20194480].

Antipsychotic agents have been associated with hyperprolactinemia, or elevated prolactin levels. This effect is particularly frequent with first generation antipsychotics and with the second generation antipsychotic risperidone and paliperidone [Article:19944883]. A study of 25 Japanese schizophrenic inpatients suggested that female patients with the A1 allele showed a greater prolactin response to nemonapride. These subjects may be at high risk for adverse effects associated with neuroleptic-induced hyperprolactinemia [Article:10823405]. Another study including several antipsychotics showed also that patients carrying the A1 allele had higher prolactin levels and were overrepresented among those with hyperprolactinaemia [Article:15286066]. Calarge et al. also concluded that the Taq1A and -241A>G (rs1799978) variants of the DRD2 gene could be useful in predicting the emergence of hyperprolactinemia [Article:19339912]. The study determined that the Taq1A A1 and the -241G alleles were associated with higher prolactin concentration in children and adolescents in long-term treatment with risperidone [Article:19339912]. Alenius et al. found that patients with one or two A1 alleles had a greater risk of significant side effects [Article:18086475]. (This study did not report the specific side effects observed.) Tardive dyskinesia (TD) is a movement disorder often caused by a history of neuroleptic use. Thelma et al. review the possible pharmacogenetic influences on TD in association with antipsychotics [Article:18781856]. A meta-analysis indicated an association of the A2 with TD by showing that TD-positive patients have a higher A2 allele frequency [Article:17767146]. Another meta-analysis suggests multiple genetic influences on TD, including the DRD2 Taq1A SNP with A2 as the risk-increasing allele [Article:18180754].

Different DRD2 variants have been reported to be associated with nicotine dependence and the efficacy of bupropion and NRT. Several studies found no evidence for an association of Taq1A with smoking behavior [Article:19246443] or nicotine dependence [Articles:18354387, 19494806]. The DRD2 Taq1A was implicated in association with response to bupropin and NRT. Johnstone et al. found that in the first week of use, smokers with the T variant allele (A1) showed the greatest benefit from the nicotine transdermal patch [Article:15077009]. Results of a NRT randomized trial did not support the association of the T allele with improved response to NRT [Article:19273465]. However, Swan et al. reported that the DRD2 gene Taq1A polymorphism was associated with 12-month smoking cessation outcomes following treatment with a combination of bupropion SR and behavioral counseling in women [Article:15492764]. In this study women carrying at least one A1 allele were more likely to report that they stopped taking bupropion due to medication side effects [Article:15492764]. An analysis of pooled data from two clinical trials found also that smokers carrying the A2/A2 genotype using bupropion were more than three times as likely, relative to placebo, to be abstinent at end of treatment [Article:18058343]. David and Munafo reviewed the association of variation in the dopamine pathway with smoking cessation with the conclusion that there is some degree of replication regarding the association of the rs1800497 CC genotype with improved response to bupropion [Article:18781857].

An association of Taq1A with alcoholism was first identified by Blum et al. [Article:1969501] with an even more robust association of the A1 allele in case of severe alcoholism [Article:1839129]. A recent meta-analysis by Smith et al., which included 44 studies with 9,382 participants, found only a small but significant association of the Taq1A polymorphism with alcohol dependency [Article:17989061]. The authors point out that the relatively small effect for this association indicates a multigene causality [Article:17989061]. Another meta-analysis regarding the association of Taq1A and alcoholism is part of a recent review by Le Foll et al., which conclude a significant association [Article:19179847]. The authors also summarize studies related to DRD2 variants and nicotine, opiates, and psychostimulants [Article:19179847]. Doehring et al. showed that opiate addicts had a higher frequency of the T allele, as well as a number of other minor alleles of DRD2 (e.g. rs1076560G>T SNP or the ATCT haplotype of DRD2 rs1799978A>G, rs1076560G>T, rs6277C>T, and ANKK1 rs1800497C>T) relative to controls [Article:19373123].

Dopamine agonists are part of the pharmacotherapeutic management of patients with PD. Paus et al. concluded that TaqIA polymorphism alone had no effect on interindividual variability of dopaminergic requirement in PD. A study exploring the effect of several DRD2 variants for the discontinuation of non-ergoline dopamine agonists ropinirole and pramipexole found no association with Taq1A or -141C Ins/Del polymorphism [Article:19669131]. The study identified the 15x DRD2 CA repeat allele as genetic determinants for the discontinuation [Article:19669131]. Liu et al. found no impact of the TaqIA SNP on the efficacy of pramipexole in treating patients with PD [Article:19396436].

Note: The DRD2 gene is found on the minus chromosomal strand. Please note that for standardization, the PharmGKB presents all allele base pairs on the positive chromosomal strand, therefore the alleles within our variant annotations will differ (in a complementary manner) from those in this VIP summary that are given on the minus strand as reported in the literature.

Citation	PharmGKB summary: dopamine receptor D2. Pharmacogenetics and genomics. 2010. Mi Huaiyu, Thomas Paul D, Ring Huijun Z, Jiang Ruhong, Sangkuhl Katrin, Klein Teri E, Altman Russ B.
Reviewed	07/30/2010
Key Publications:
Drugs / Other Molecules	Drug (3) bupropion 1 haloperidol 2 nemonapride 3

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