Association study of dopamine D2, D3 receptor gene polymorphisms with motor fluctuations in PD.

The authors investigated the association between dopamine receptor D2, D3 gene polymorphisms, and the risk of developing motor fluctuations in PD. DRD3 BalI and MspI polymorphisms were not associated with risk of developing motor fluctuations. However, the genotypic distribution of DRD2 TaqIA polymorphism was significantly different in motor fluctuators and nonmotor fluctuators. These findings suggest that DRD2 TaqIA polymorphism may be associated with an increased risk for developing motor fluctuations in PD.     

Genetic polymorphism of dopamine D2 receptors in Parkinson's disease and interactions with cigarette smoking and MAO-B intron 13 polymorphism

Genetic polymorphisms of dopamine D2 receptors (DRD2) may be susceptibility factors for Parkinson's disease due to their influence on dopamine response and association with cigarette smoking, which is inversely related to risk of Parkinson's disease. Relations of TaqIA and TaqIB DRD2 genotypes with Parkinson's disease were investigated and tested for interactive effects with smoking and the monoamine oxidase B (MAO-B) intron 13 polymorphism previously found to be related to smoking. Study subjects were 152 cases of idiopathic Parkinson's disease and 231 controls. The smoking history of all genotyped subjects was known. Subjects of genotype B12 were more frequent among cases than controls (27% and 23.8%, respectively), and were more frequent among "ever smokers" than "never smokers", among controls (27.8% and 17.2%, respectively), although these associations were not statistically significant. Neither TaqIA or TaqIB genotypes modified the inverse relation of smoking and Parkinson's disease. When genotypes for DRD2 were considered in combination with genotypes for intron 13 of MAO-B, genotype combinations with high risk of Parkinson's disease were found; although the MAO-B/DRD2 interaction did not reach statistical significance after Bonferroni correction for multiple comparisons, these results are suggestive of a possible synergism between MAOB and DRD2 genes with respect to Parkinson's disease.     

Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers.

The density of striatal dopamine D2 receptors has been shown to vary considerably among healthy subjects. This variability might be due to genetic or environmental factors. In the present analysis we searched for relationships between dopamine D2 receptor gene (DRD2) polymorphisms and striatal dopamine D2 receptor density in vivo, as measured by positron emission tomography and [11C]raclopride in 56 healthy subjects. There was a significant association between presence of a putative functional DRD2 promoter allele (-141C Del) and high striatal dopamine receptor density (t= 2.32, P= 0.02). In agreement with some previous studies the presence of the DRD2 TaqIA1 allele was associated with measures of low dopamine receptor density (t=2.58, P=0.01). Also the DRD2 TaqIB1 allele was associated with low dopamine receptor density (t= 2.58, P= 0.01) wheras there was no significant relationship between another common silent intronic DRD2 short tandem repeat polymorphism (STRP) and striatal dopamine D2 receptor density. The results suggest that DRD2 genotypes may participate differentially in the regulation of striatal dopamine D2 receptor density in healthy human subjects. The results should be interpreted with caution because of the limited sample size.     

Association of specific haplotypes of D2 dopamine receptor gene with vulnerability to heroin dependence in 2 distinct populations

CONTEXT: Dopamine receptor-mediated pathways play critical roles in the mechanism of addiction. However, associations of the D(2) dopamine receptor gene (DRD2) with substance abuse are controversial. OBJECTIVE: To determine whether susceptibility sites resided at DRD2. DESIGN: Haplotype-based case-control analysis of 2 distinct populations using 10 single nucleotide polymorphisms (SNPs) with heroin dependence. SETTING: Universities of Mainz and Bonn, Germany, and 3 local hospitals in southwestern China.Patients Cases and control subjects recruited from China (486 cases, 313 controls) and Germany (471 cases, 192 controls). INTERVENTIONS: Genotyping for 10 SNPs by 5'-exonuclease fluorescence assays. The D' value of linkage disequilibrium and haplotypes were generated by the expectation-maximization algorithm. MAIN OUTCOME MEASURES: Genotype, allele, and haplotype frequencies were compared between cases and controls by chi(2) tests constructed for each population. An additional 32 SNPs randomly distributed in the genome were genotyped for detecting population admixture in the 2 populations. RESULTS: A haplotype block of 25.8 kilobases (kb) was defined by 8 SNPs extending from SNP3 (TaqIB) at the 5' end to SNP10 site (TaqIA) located 10 kb distal to the 3' end of the gene. Within this block, specific haplotype cluster A (carrying TaqIB1 allele) was associated with a high risk of heroin dependence in Chinese patients (P = 1.425 x 10(-22); odds ratio, 52.80; 95% confidence interval, 7.290-382.5 for 8-SNP analysis). A putative recombination "hot spot" was found near SNP6 (intron 6 ins/del G), creating 2 new daughter haplotypes that were associated with a lower risk of heroin dependence in Germans (P = 1.94 x 10(-11) for 8-SNP analysis). There was no evidence of population stratification in either population. CONCLUSIONS: These results strongly support a role of DRD2 as a susceptibility gene with heroin dependence in Chinese patients and was associated with low risk of heroin dependence in Germans.     

Allelic association between the DRD2 TaqI A polymorphism and Parkinson's disease.

Genes encoding proteins involved in dopaminergic transmission have been of special interest during the evaluation of candidate genes for Parkinson's disease (PD). The dopamine D2 receptor gene (DRD2) is located on chromosome 11 q22-q23, and several polymorphisms of the gene have been described. The DRD2 gene has a TaqI A restriction fragment length polymorphism that is located in the untranslated region, approximately 10 kilobases from the 3' end of the gene. This polymorphism creates the two alleles A1 (variant) and A2. In this study, we investigated the hypothesis that a TaqI repeat fragment length polymorphism in the dopamine D2 receptor gene may be associated with PD. DNA from 72 patients with PD, classified as definite, probable, or atypical PD, and from 81 controls was genotyped by polymerase chain reaction and gel electrophoresis for the presence of the TaqI A1 polymorphism. The controls were matched for age, race, and geographic origin. There were significant differences in allelic distribution between the overall PD group and control groups (chi2 = 5.009, p = 0.025). When only patients with definite PD were considered an even more significant association was found (chi2 = 8.2121, p = 0.004). Among the overall PD group, the odds ratio for having the variant allele A1 was found to be 2.2 (95% confidence interval, [1.1; 4.4]), whereas it was calculated to be 3.0 (95% confidence interval, [1.4; 6.4]) when only patients with definite PD were considered. The current study showed that there is a statistically significant association between the DRD2 variant allele A1 and PD. This association is most pronounced in patients with definite PD and becomes nonsignificant when the clinical picture is classified as atypical PD.     

Association study of three polymorphisms in the dopamine D2 receptor gene and schizophrenia in the Russian population

Polymorphisms in the dopamine D2 receptor gene (DRD2) have repeatedly been associated with schizophrenia. Recently, the C957T polymorphism (rs6277), which alters mRNA stability and dopamine-induced upregulation of DRD2 expression in cell cultures and DRD2 mRNA translation in vitro, was tested for an association with the disease. Frequency of the C allele, corresponding to a normal wild-type level of expression, was higher in patients compared to controls, and that of the T allele was lower. To replicate and extend previous findings, we conducted an association study of the C957T polymorphism and two additional SNPs (C939T and TaqIA) in 311 patients with a DSM-IV diagnosis of schizophrenia and 364 mentally healthy people from the Russian population as controls. The results of our study confirmed the association between the C957T polymorphism and schizophrenia. Consistent with previous findings, frequency of the C allele and the CC genotype were higher in patients compared to the control group (p = 0.002). Meta-analysis of total 5 samples also suggests significant allelic association. The distribution of C939T genotypes in the case sample was significantly different from that of the controls: in the case sample, the TT genotype frequency was higher compared to the combined frequency of CT and CC genotypes (p = 0.002). Though no association was found between the TaqIA polymorphism and schizophrenia, a haplotype-wise analysis revealed a lower frequency of the T–C (C957T–TaqIA) haplotype in patients (p = 0.02). In conclusion, our findings provide additional evidence for an association between the C957T polymorphism and schizophrenia.     

Lack of allelic association of dopamine D4 receptor gene polymorphisms with Parkinson's disease in a Chinese population.

Parkinson's disease (PD) is a neurodegenerative disease caused by a multitude of environmental, neurochemical, and genetic factors. The gene for human dopamine D4 receptor (DRD4) has been considered as a plausible candidate for the pathogenesis of PD. Different dopamine D4 receptor allelic forms have variable affinity toward certain neuroleptics such as clozapine, suggesting a role for dopamine D4 receptors in neurologic disorders. To test the hypothesis that the DRD4 polymorphism is associated with the susceptibility to Parkinson's disease, we have examined differences in allele frequencies of different DRD4 polymorphisms in 101 Chinese patients with PD and in 105 age-matched control subjects in Hong Kong. The DRD4 gene was analyzed by a non-radioactive polymerase chain reaction-based Southern hybridization with chemiluminescence detection. The number of polymorphic 48 base pair tandem repeats in exon 3 was identified in each study subject. The DRD4 alleles with high frequencies in the control subjects are 4-repeat allele (72.4%), 2-repeat allele (21.4%), and 7-repeat allele (3.8%) which accounted for over 97% of the total alleles in the elderly Chinese population. The most prevalent genotype in the control subjects is the 4/4 (47.6%), followed by 4/2 (38.6), 4/7 (7.6%), and 2/2 (3.0%). None of the variable number tandem repeat polymorphism showed evidence for genetic association with Parkinson's disease.     

多巴胺2受体基因TaqIA多态性与美沙酮维持治疗海洛因依赖患者心理症状相关性研究

目的研究昆明市美沙酮维持治疗A门诊接受美沙酮维持治疗的汉族海洛因依赖者多巴胺D2受体基因TaqIA多态性与接受美沙酮维持治疗海洛因依赖患者心理症状的相关性,探讨影响病人治疗效果的遗传因素。方法对81例接受美沙酮维持治疗的海洛因依赖者实施SCL-90测试,应用聚合酶链式反应-限制性片段长度多态性（PCR-RFLP）技术,检测多巴胺D2受体基因TaqIA基因多态,比较不同基因型与SCL-90各因子的关系。结果 A1＋组（A1/A1,A1/A2）与A1-组（A2/A2）SCL-90各因子分无显著性差异。结论D2受体基因TaqIA多态性与美沙酮维持治疗海洛因依赖患者心理症状可能不存在相关性。     

Polymorphism of dopamine D2 receptor (TaqIA, TaqIB, and-141C Ins/Del) and dopamine degradation enzyme (COMT G158A, A-278G) genes and extrapyramidal symptoms in patients with schizophrenia and bipolar disorders

OBJECTIVE: The relationship is examined of the dopamine D2 receptor (DRD2) polymorphism (TaqIA, TaqIB, -141 C Ins/Del) and the catechol-O-methyltransferase (COMT) polymorphism (A-278G, G158A) to the risk of antipsychotic-induced extrapyramidal symptoms (EPS) in schizophrenia and bipolar disorders. Participants comprised 80 cases presenting with EPS (Simpson-Angus Scale score >3) and 188 controls presenting without EPS (Simpson-Angus Scale score 相似文献   

Variations in the monoamine oxidase B (MAOB) gene are associated with Parkinson's disease.

The monoamine oxidase B gene (MAOB; Xp15.21-4) is a candidate gene for Parkinson's disease (PD) given its role in dopamine metabolism and its possible role in the activation of neurotoxins. The association of MAOB polymorphisms (a [GT] repeat allelic variation in intron 2 and an A-G transition in intron 13) with Parkinson's disease (PD) was studied in an Australian cohort of 204 (male:female ratio 1.60) people with PD and 285 (male:female ratio 1.64) age- and gender-matched control subjects. Genomic DNA was extracted from venous blood and polymerase chain reaction was used to amplify the appropriate regions of the MAOB gene. The length of each (GT) repeat sequence was determined by 5% polyacrylamide denaturing gel electrophoresis and a DNA fragment analyzer, while the G-A genotype was determined using 2% agarose gel electrophoresis. The G-A polymorphism showed no association with PD (odds ratio [OR] = 0.80; p = 0.51; 95% confidence interval [CI] = 0.42-1.53). There was a significant difference in allele frequencies of the (GT) repeat allelic variation between patients and control subjects (chi2 = 20.09; p<0.01). After statistical adjustment for potential confounders using a logistic regression analysis, the (GT) repeat alleles > or =188 base pairs in the intron 2 marker of the MAOB gene were significantly associated with PD (OR = 4.60; p<0.00005; 95% CI = 1.97-10.77). The 186 base pair allele was also significantly associated with PD (OR = 1.85; p = 0.048; 95% CI = 1.01-3.42). The GT repeat in intron 2 of the MAOB gene is a powerful marker for PD in this large Australian cohort.     

Dopamine D2 receptor gene polymorphism and the risk of levodopa-induced dyskinesias in PD.

OBJECTIVE: To investigate whether polymorphisms in the genes for dopamine receptors D1 and D2 are associated with the risk of developing peak-dose dyskinesias in PD. BACKGROUND: Peak-dose dyskinesias are the most common side effects of levodopa therapy for PD. The identified predictors may only partially account for the risk of developing peak-dose dyskinesias because a substantial proportion of patients never develop peak-dose dyskinesias. Genetic factors could play a role in determining the occurrence of peak-dose dyskinesias. METHODS: A case-control study of 136 subjects with sporadic PD and 224 population control subjects. We studied three polymorphisms involving the dopamine receptor D1 gene and one intronic short tandem repeat polymorphism of the dopamine receptor D2 gene. RESULTS: The polymorphisms of the dopamine receptor D1 gene were not associated with the risk of developing PD or peak-dose dyskinesias. The 15 allele of the polymorphism of the dopamine receptor D2 gene was more frequent in parkinsonian subjects than in control subjects. More important, the frequency of both the 13 allele and the 14 allele of the dopamine receptor D2 gene polymorphism was higher in nondyskinetic than in the dyskinetic PD subjects. The risk reduction of developing peak-dose dyskinesias for PD subjects carrying at least 1 of the 13 or 14 alleles was 72% with respect to the PD subjects who did not carry these alleles. CONCLUSIONS: Certain alleles of the short tandem repeat polymorphism of the dopamine receptor D2 gene reduce the risk of developing peak-dose dyskinesias and could contribute to varying susceptibility to develop peak-dose dyskinesias during levodopa therapy.     

The TaqIA polymorphism linked to the DRD2 gene is related to lower attention and less inhibitory control in alcoholic patients.

The TaqIA polymorphism linked to the DRD2 gene has been associated with alcoholism. The aim of this work is to study attention and inhibitory control as per the continuous performance test and the stop task in a sample of 50 Spanish male alcoholic patients split into two groups according to the presence of the TaqIA1 allele in their genotype. Our results show that alcoholics carrying the TaqIA1 allele present lower sustained attention and less inhibitory control than those patients without such allele.     

Effects of DRD2/ANKK1 gene variations and clinical factors on aripiprazole efficacy in schizophrenic patients

OBJECTIVES: Aripiprazole, a novel antipsychotic agent, acts as a partial agonist at dopamine D2 receptors (DRD2). We investigate whether its efficacy is predictable by DRD2/ANKK1 gene polymorphisms and clinical factors in Han Chinese hospitalized patients with acutely exacerbated schizophrenia. METHOD: After hospitalization, the patients (n=128) were given aripiprazole for up to 4 weeks. They were genotyped for four functional DRD2/ANKK1 polymorphisms: -141 Ins/Del, Ser311Cys, C957T, and TaqIA. Clinical factors such as gender, age, illness duration, education level, diagnostic subtype, and medication dosage were also recorded. Psychopathology was measured biweekly with the positive and negative syndrome scale (PANSS). The effects of genetic and clinical factors on PANSS performance upon aripiprazole treatment were analyzed by a mixed modeling approach (SAS Proc MIXED). RESULTS: Compared to the patients with TaqI A2/A2 genotype, A1 carriers are associated with superior therapeutic response on positive symptoms after 4-week aripiprazole treatment. Regarding the C957T polymorphism, patients with C/C genotype were associated with poor aripiprazole response for excitement symptoms when compared with T/T patients. The other two polymorphisms, -141 Ins/Del, and Ser311Cys, have no significant effects on PANSS performance. The clinical factors including medication dosage, illness duration, and diagnostic subtype could influence PANSS performance upon aripiprazole treatment. CONCLUSION: This study suggests that DRD2/ANKK1 gene variations and some clinical factors may predict individual response to aripiprazole.     

Association analysis between dopamine receptor genes and bipolar affective disorder.

We have performed a case-control analysis of dopamine D2-like receptor (DRD2, DRD3 and DRD4) gene polymorphisms in 118 Han Chinese cases with bipolar affective disorder and 196 control subjects, and replication analysis in 157 English cases and 143 control subjects. We found association between a functional DRD2 promoter variant (P = 0.03 by allele) and the DRD2 taq1A polymorphism (P = 0.001 by allele) in Chinese bipolar disorder patients. However, this finding was not replicated in the Caucasian subjects, indicating that the significant association we observed in the Chinese population is a false positive finding. An alternative explanation is that these polymorphisms are risk factors in Chinese but not Caucasian populations, a hypothesis which seems unlikely in view of the similarity of the clinical characteristics of bipolar disorder in the two populations. We also report a novel, rare one-repeat variant of the DRD4 exon 3 VNTR repeat in Chinese populations, which appears to be absent in Caucasians and is not associated with disease.     

Variability and validity of polymorphism association studies in Parkinson's disease

BACKGROUND: In recent years, interest in gene-environment interactions has spurred a great number of association studies on polymorphism of different genes. OBJECTIVE: To review case-control studies of genetic polymorphisms in PD, and perform meta-analysis of individual gene polymorphism. METHODS: The authors searched the Medline database (PubMed) for publications (English language) from January 1966 to November 1999 for association studies in PD. The key words used were "PD" and "polymorphism." The authors supplemented the search with relevant references quoted in these published articles. Those with four or more independent studies of a specific gene polymorphism were subjected to meta-analysis, with the exception of cytochrome-P450 enzyme polymorphisms, for which meta-analyses results were already available in the literature. RESULTS: The authors identified 84 studies on 14 genes, including dopamine receptors (DRD2 and DRD4), dopamine transporter (DAT), monoamine oxidase (MAOA and MAOB), catechol-O-methyltransferase (COMT), N-acetyltransferase 2 (NAT2), APOE, glutathione transferase (GSTT1, GSTM1, GSTP1, and GSTZ1), and mitochondrial genes (tRNAGlu and ND2). Four polymorphisms showed significant association with PD: slow acetylator genotypes of NAT2 (PD:control OR = 1.36), allele >188bp of the MAOB (GT)n polymorphism (OR = 2.58), the deletion allele of GSTT1 (OR = 1.34), and A4336G of tRNAGlu (OR = 3.0). No significant differences were found for the other genes. CONCLUSION: Significant associations with PD were found in polymorphisms of NAT2, MAOB, GSTT1, and tRNAGlu. Although significant association does not imply a causal relationship between the presence of the polymorphisms and PD pathogenesis, their pathophysiologic significance should be studied further.     

Association in Japanese patients between neuroleptic malignant syndrome and functional polymorphisms of the dopamine D(2) receptor gene

A genetic predisposition to the development of neuroleptic malignant syndrome (NMS) has been suggested by clinical studies. Although the molecular basis of NMS is unclear, a dopaminergic blockade mechanism has been considered the main cause. We therefore investigated the association between NMS and three functional polymorphisms of the dopamine D(2) receptor (DRD(2)) gene: TaqI A, -141C Ins/Del, and Ser311Cys. Subjects included 32 Japanese patients, previously diagnosed with NMS, and 132 schizophrenic patients treated with neuroleptics without occurrence of NMS. Polymerase chain reaction and restriction fragment length polymorphism analyses were performed to determine each genotype. We found significant differences in genotypic and allelic frequencies of the -141C Ins/Del polymorphism between patients with and without NMS. The -141C Del allele was significantly more frequent in the NMS group (23.4 vs 11.7%, P=0.026). Similarly, the proportion of -141C Del allele carriers was significantly higher in the NMS group (40.6 vs 20.5%, P=0.022). No significant differences between the two groups were seen for allelic and genotypic frequencies of the TaqI A and Ser311Cys polymorphisms. This result suggests that the -141C Ins/Del polymorphism is likely to predispose toward the development of NMS, probably together with other unidentified factors.     

No association between D2 dopamine receptor (DRD2) "A" system alleles, or DRD2 haplotypes, and posttraumatic stress disorder.

BACKGROUND: Association studies between marker alleles at the D2 dopamine receptor gene (DRD2) and various psychiatric illnesses have produced conflicting results. Reports of allelic associations were originally made with alcoholism, but were then extended to other psychiatric disorders, including posttraumatic stress disorder (PTSD). METHODS: We studied allele frequency of the DRD2 TaqI "A," "B," and "D" system markers in 52 European-American subjects with diagnoses of PTSD (based on structured interviews). RESULTS: Frequency of the A1 allele in this sample was .15, not significantly different from the .19 allele frequency seen in 87 control subjects. We were thus unable to replicate the previous reports of allelic association between the DRD2 TaqI "A1" allele and PTSD. There were also no significant differences in allele frequency for the "B" or "D" systems. We then computed three marker (TaqI "A," "B," and "D" system) haplotypes for the sample; DRD2 haplotype frequencies also did not differ between control subjects and subjects with PTSD. CONCLUSIONS: We conclude that DRD2 alleles are not associated with PTSD in this sample, and that genetic variation at the DRD2 locus is not likely to be an important contributor to risk for this disorder.     

The paraoxonase gene polymorphism in stroke patients and lipid profile

Objectives –  The paraoxonase (PON) gene can reduce the risk of developing atherosclerosis. We investigated the associations between PON polymorphisms and ischemic stroke. We also investigated the associations between PON polymorphisms and lipid profile in stroke patients.
Methods –  A total of 350 patients with ischemic stroke and 242 control subjects in Korean population were genotyped for the PON1M55 L, PON1Q192R, PON2A148 G and PON2S311C polymorphisms using melting point analysis with LightCycler real-time polymerase chain reaction (PCR) technology.
Results –  There were no significant differences in genotype and allele distribution of the PON polymorphisms between the ischemic stroke patients and control subjects. The concentration of total homocysteine was significantly different in the PON1M55 L polymorphism ( P  = 0.047), and the apolipoprotein (Apo)B concentration was significantly different in the PON1Q192R polymorphism ( P  = 0.02) in stroke patients. The concentrations of low-density lipoprotein (LDL) cholesterol and ApoB were significantly different between the PON2A148 G ( P  = 0.011, P  = 0.000, respectively) and PON2S311C polymorphisms ( P  = 0.046, P  = 0.003, respectively) in stroke patients.
Conclusions –  This study did not provide association between PON gene polymorphisms and ischemic stroke. However, it confirmed that the PON1L55 L allele is associated with plasma concentration of total homocysteine and that the PON2G148 G and PON2S311S allele is associated with plasma concentrations of LDL cholesterol and ApoB.     

An association study between the Cys311 variant of dopamine D2 receptor gene and schizophrenia in the Okinawan population

Abstract  Neuroleptic drugs have a high affinity for the dopamine D₂ receptor (DRD2); therefore DRD2 is thought to be a candidate gene for schizophrenia. Arinami et al . have reported a positive association between schizophrenia and the Cys311 variant of the DRD2 gene. We determined the allele frequency of this polymorphism in 78 Okinawan schizophrenic patients and 112 control subjects. The patients and controls did not differ significantly in allele frequencies of Cys311.