Dataset Information

Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status.

ABSTRACT: In humans, the A1 (T) allele of the dopamine (DA) D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) TaqIA (rs1800497) single nucleotide polymorphism has been associated with reduced striatal DA D2/D3 receptor (D2/D3R) availability. However, radioligands used to estimate D2/D3R are displaceable by endogenous DA and are nonselective for D2R, leaving the relationship between TaqIA genotype and D2R specific binding uncertain. Using the positron emission tomography (PET) radioligand, (N-[(11) C]methyl)benperidol ([(11) C]NMB), which is highly selective for D2R over D3R and is not displaceable by endogenous DA, the current study examined whether DRD2/ANKK1 TaqIA genotype predicts D2R specific binding in two independent samples. Sample 1 (n?=?39) was composed of obese and nonobese adults; sample 2 (n?=?18) was composed of healthy controls, unmedicated individuals with schizophrenia, and siblings of individuals with schizophrenia. Across both samples, A1 allele carriers (A1+) had 5 to 12% less striatal D2R specific binding relative to individuals homozygous for the A2 allele (A1-), regardless of body mass index or diagnostic group. This reduction is comparable to previous PET studies of D2/D3R availability (10-14%). The pooled effect size for the difference in total striatal D2R binding between A1+ and A1- was large (0.84). In summary, in line with studies using displaceable D2/D3R radioligands, our results indicate that DRD2/ANKK1 TaqIA allele status predicts striatal D2R specific binding as measured by D2R-selective [(11) C]NMB. These findings support the hypothesis that DRD2/ANKK1 TaqIA allele status may modify D2R, perhaps conferring risk for certain disease states.

SUBMITTER: Eisenstein SA

PROVIDER: S-EPMC4980198 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status.

Eisenstein Sarah A SA Bogdan Ryan R Love-Gregory Latisha L Corral-Frías Nadia S NS Koller Jonathan M JM Black Kevin J KJ Moerlein Stephen M SM Perlmutter Joel S JS Barch Deanna M DM Hershey Tamara T

Synapse (New York, N.Y.) 20160617 10

In humans, the A1 (T) allele of the dopamine (DA) D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) TaqIA (rs1800497) single nucleotide polymorphism has been associated with reduced striatal DA D2/D3 receptor (D2/D3R) availability. However, radioligands used to estimate D2/D3R are displaceable by endogenous DA and are nonselective for D2R, leaving the relationship between TaqIA genotype and D2R specific binding uncertain. Using the positron emission tomography (PET) radiolig ...[more]

PMID: 27241797

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Project description:BackgroundGenetic factors are important in the pathogenesis of Tourette syndrome (TS). Notably, Dopamine receptor D2 (DRD2) gene has been suggested as a possible candidate gene for this disorder. Several studies have demonstrated that DRD2/ANKK1 TaqIA polymorphism is associated with an increased risk of developing TS. However, past results remain conflicting. We addressed this controversy by performing a meta-analysis of the relationship between DRD2/ANKK1 TaqIA polymorphism and TS.MethodsLiterature was searched in multiple databases including PUBMED, COCHRANE and WEB OF SCIENCE up to July 2014. The number of the genotypes for DRD2/ANKK1 TaqIA in the TS and control subjects was extracted and statistical analysis was performed using Review Manager 5.0.16 and Stata 12.0 software. Summary odds ratios (ORs) and 95% confidence intervals (95%CIs) were utilized to calculate the risk of TS with DRD2/ANKK1 TaqIA. Stratified analysis based on ethnicity was also conducted.Results523 patients with TS, 564 controls and 87 probands plus 152 relatives from five published studies were finally involved in this meta-analysis. Combined analysis revealed that the overall ORs for the DRD2/ANKK1 TaqIA A1 allele were 1.69 (95%CIs = 1.42-2.00) in the fixed-effect model and 1.66 (95%CIs = 1.33-2.08) in the random-effects model. Stratification by ethnicity indicated the TaqIA A1 allele was significantly associated with TS in Caucasians (fixed-effect model: OR=1.75, 95%CI = 1.43-2.16; random-effect model: OR=1.69, 95%CI = 1.25-2.28) and in Asians (OR=1.54, 95%CI = 1.12-2.10). Meta-analysis of the A1A1 vs. A2A2 (homozygous model), A1A2 vs. A2A2 (heterozygous model) and A1A1+A1A2 vs. A2A2 (dominant model) of this polymorphism revealed a significant association with TS in overall populations and Caucasians.ConclusionsThis meta-analysis suggested that the DRD2/ANKK1 TaqIA polymorphism might contribute to TS susceptibility, especially in Caucasian population. However, further investigation with a larger number of worldwide studies should be conducted to verify the association.

Project description:ObjectiveDopamine is an endogenous neuromodulator in cortical circuits and the basal ganglia. In animal models of temporal lobe epilepsy (TLE), seizure threshold is modulated to some extent by dopamine, with D1-receptors having a pro- and D2-receptors an anticonvulsant effect. We aimed to extend our previously reported results on decreased D2/D3 receptor binding in the lateral epileptogenic temporal lobe and to correlate them with demographic and seizure variables to gain a more comprehensive understanding of the underlying involvement of the dopaminergic system in the epileptogenesis of TLE.MethodsTo quantify D2/D3 receptor binding, we studied 21 patients with TLE and hippocampal sclerosis (13 left- and eight right-sided) and 18 controls using PET with the high-affinity dopamine D2/D3-receptor ligand 18F-Fallypride to image striatal and extrastriatal binding. TLE was defined by interictal and ictal video-EEG, MRI and 18F-Fluorodeoxyglucose PET. Voxel-based statistical and regions-of-interest analyses were performed.Results18F-Fallypride binding potential was significantly reduced in the affected temporal lobe and bilateral putamen. A positive correlation between age at onset of epilepsy and [18F]FP BPnd (binding potential non-displaceable) in temporal regions on the epileptogenic side was found, as well as a negative correlation between epilepsy duration and [18F]FP BPnd in the temporal pole on the epileptogenic side and a positive correlation between the estimated number of lifetime GTCS and [18F]FP BPnd in the hippocampus on the epileptogenic side.SignificanceThe areas of reduced D2/D3 receptor availability correspond to "the irritative zone" surrounding the epileptogenic area. Moreover, reduced D2/D3 receptor availability was detectable in the basal ganglia, which are suspected to be involved in a control circuit for epileptic seizures. The correlational analysis additionally suggests that increased epilepsy duration leads to increasing impairment of the dopaminergic system.

Dataset Information

Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status.

Publications

Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status.

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