Lack of association between polymorphisms of the dopamine D4 receptor gene and personality

Recent studies have suggested a role of two polymorphisms of the dopamine D(4) receptor gene (DRD4 exon III and -521C/T) in the modulation of personality traits such as "novelty seeking" or "extraversion", which are supposed to be modulated by individual differences in dopaminergic function. However, several replication studies have not provided positive findings. The present study was performed to further investigate whether DRD4 exon III and -521C/T are associated with individual differences in personality. One hundred and fifteen healthy German volunteers completed the NEO-Five-Factor Inventory (NEO-FFI) and were genotyped for the two DRD4 polymorphisms. We found no association between DRD4 exon III and -521C/T, respectively, and estimated novelty seeking, NEO-FFI extraversion or other personality factors. Our findings are in line with several earlier studies which have failed to replicate the initial association results. Hence, our data do not provide evidence for a role of DRD4 exon III and the -521C/T polymorphism in the modulation of novelty seeking and extraversion.     

Interactions between four gene polymorphisms and their association with patients with Parkinson's disease in a Chinese Han population

The four previously reported Parkinson's disease (PD)-related single-nucleotide polymorphisms (SNPs) – rs1775143, rs823114, rs2071746 and rs62063857 – have rarely been studied in Chinese Han populations. To examine the association between these SNPs and PD, we conducted a case-control study of 158 patients with PD and 210 controls. All participants were Chinese Han from Northern China. With covariate adjustment for clinical characteristics, logistic regression analysis revealed no differences in genotype or allele frequencies for the four SNPs. Stratified by age of disease onset, sex, smoking status, duration of disease, baseline UPDRS, Hoehn–Yahr Stage, PD subtypes, scores of Hamilton anxiety scale, Hamilton depression scale and activity of daily living, all of the p values did not remain significant after Bonferroni correction. However, the haplotype rs1775143T-rs823114G-rs2071746T-rs62063857A was associated with increased risk of developing PD (p = 0.003, OR = 456.88, 95% CI: 27.40–7619.75) in our case-control sample set. The haplotype rs1775143T-rs823114G-rs2071746T was also associated with increased risk of developing PD (p = 0.003, OR = 338.43, 95% CI: 20.68–5538.27). Although the haplotype rs1775143T-rs823114G-rs62063857A was associated with increased risk of PD (p = 0.03), the 95% CI was 0.993–22.469. Our data demonstrate that although specific SNPs were not related with PD patients, certain haplotypes were associated with increased risk for PD in the Chinese Han population. These results provide further evidence that the etiology of PD is multifactorial, although the underling mechanism needs further study.     

The dopamine D2 receptor gene is a susceptibility locus for Parkinson's disease.

The dopamine D2 receptor (DRD2) gene has been proposed as a candidate gene underlying several psychiatric and neurologic disorders. The aim of the present study was to examine if selected polymorphisms in the DRD2 gene are associated with Parkinson's disease (PD). We determined the allelic frequencies for four polymorphisms located in the DRD2 gene in a sample of 135 patients with PD and 202 normal control subjects. No significant difference was observed in the allelic frequencies between patients with PD and control subjects with regard to the -141C Ins/Del and the Ser311/Cys311 variants. On the contrary, the A1 allele of the TaqIA polymorphism and the B1 allele of the TaqIB polymorphism were more frequent in patients with PD than in control subjects (control subjects: TaqIA A1 = 14.6%, TaqIB B1 = 10.6%; patients with PD: TaqIA A1 = 20.7%, TaqIB B1 = 17.4%). Patients carrying the A1 allele or the B allele had an increased risk of developing PD (TaqIA, odds ratio: 1.71, 95% confidence intervals: 1.08-2.73; TaqIB, odds ratio: 1.83, 95% confidence intervals: 1.12-3.02). The TaqIA and TaqIB polymorphisms were in strong linkage disequilibrium, suggesting that these two polymorphisms convey the same information about the risk of presenting with PD. Genetic variation in the DRD2 gene may influence the risk of developing PD, thus confirming that the DRD2 gene is a susceptibility locus for PD.     

Lack of association between schizophrenia and alleles in the dopamine D3 receptor gene

Dopamine receptor dysfunction has been implicated in the pathophysiology of schizophrenia. Schizophrenic patients (n= 76) and control subjects (n= 53) were examined for allele frequencies in a 2-allele BalI polymorphism, causing a serine → glycine amino acid substitution in the coding sequence of the dopamine D₃ receptor gene. No statistical significant differences of allele frequencies or genotype frequencies could be found between the two groups. Neither were there any significant relationships between allele frequencies and a number of clinical variables within the schizophrenic subsample. However, if not corrected for multiple testing, an association was found between homozygosity and positive response to neuroleptic drugs. The present study does not provide evidence that the BalI polymorphism in the dopamine D₃ receptor gene is involved in the pathophysiology of schizophrenia. Further investigations with an increased number and variety of patients concerning response to neuroleptic drugs and expression of the receptor in human brain should be performed to definitively exclude this hypothesis.     

Lack of association between CYP1A1 polymorphism and Parkinson's disease in a Chinese population

Summary. Apart from very few families who have a direct cause from genetic mutation, causes of most Parkinson's disease (PD) remain unclear. Many allelic association studies on polymorphism of different candidate genes have been studied. Although these association studies do not imply a causal relationship, it does warrant further studies to elucidate the pathophysiologic significance. CYP1A1 polymorphisms have been reported to be associated with PD in a Japanese population sample. Since CYP1A1 transforms aromatic hydrocarbons into products that may be neurotoxic and perhaps lead to PD, we therefore undertook a study to look at the possible association of CYP1A1 polymorphism and PD in a Chinese population. Contrary to the Japanese result, we did not find any statistically significant difference between the PD group and the control group in our study with a bigger sample size. Received April 30, 2001; accepted September 4, 2001     

Lack of association between an estrogen receptor 1 gene polymorphism and Parkinson's disease with dementia

OBJECTIVE: To test for an association between an estrogen receptor 1 (ESR1) gene polymorphism and Parkinson's disease with dementia (PDD) in Finnish subjects. SUBJECTS AND METHODS: Forty-one clinically demented and pathologically confirmed PDD patients and 59 cognitively intact aged individuals with normal neuropathology were genotyped for the ESR1 PvuII polymorphism. RESULTS: We found no significant differences in the genotype or allele frequencies when the PDD patients were compared with the controls. Nor were there any significant differences in these frequencies when the PDD patients with coexisting Alzheimer's disease pathology were compared with the control group. CONCLUSION: We failed to demonstrate an association between dementia-associated PD and the ESR1 PvuII polymorphism in Finnish subjects.     

Lack of association of trinucleotide repeat polymorphisms in the very-low-density lipoprotein receptor gene with Alzhelner's disease

Inheritance of the apolipoprotein E ε 4 allele is a risk factor for Alzheimer's disease (AD). A recent report studying Japanese patients suggested that a polymorphism of a trinucleotide repeat in the 5' untranslated region of an apolipoprotein E receptor, the very-low-density lipoprotein receptor, is genetically associated with AD, with overrepresentation of the allele containing five copies of the repeat. We determined the allele frequencies of the very-low-density lipoprotein receptor in 3 white populations totaling 469 individuals. In contrast to the previous report, we found no differences in allele frequencies between case patients and control subjects. The discrepancy could be due to differences in Japanese and white populations. Nonetheless, these data weaken the likelihood that this polymorphism in the very-low-density lipoprotein receptor gene is strongly associated with AD.     

Lack of association of CR1, PICALM and CLU gene polymorphisms with Alzheimer disease in a Polish population

Background and purposeRecent genome-wide association studies have indicated 3 new susceptibility loci for Alzheimer disease (AD): complement receptor 1 (CR1), clusterin (CLU), and the phosphatidylinositol-binding clathrin assembly protein (PICALM). We investigated the influence of the rs6656401 single nucleotide polymorphisms (SNP) of the CR1 gene, the rs3851179 SNP of the PICALM gene, and the rs11136000 SNP of the CLU gene on risk of AD in a Polish population.Material and methodsIn 253 Caucasian AD patients and 240 controls, analyses identifying the rs6656401, rs3851179 and rs11136000 SNPs and APOE common polymorphisms were performed.ResultsNo significant differences were observed in the distribution of the rs6656401 of CR1, rs3851179 of PICALM and rs11136000 of CLU SNPs between AD patients and controls. The APOE ?4 common polymorphism was strongly related to the risk of AD.ConclusionOur results suggest that investigated SNPs are not associated with AD in a Polish population.     

Case-control study of estrogen receptor gene polymorphisms in Parkinson's disease.

We investigated the association of Parkinson's disease (PD) with two estrogen receptor gene polymorphisms. In a sample of 319 unrelated PD cases and 196 control subjects including both men and women, we observed no association of PD with the estrogen receptor genotypes derived from XbaI and PvuII digests. Analyses restricted to women or to cases and controls of European origin yielded similar findings. Further analyses stratified by age at examination or by family history did not show associations. While exogenous and endogenous estrogen may modify the risk of PD in women, the two estrogen receptor gene polymorphisms considered here do not seem to contribute to PD susceptibility.     

Lack of association of the interleukin-1beta gene polymorphism with Alzheimer's disease in a Chinese population

Over the past few years, a number of genetic risk factors for Alzheimer's disease (AD) have been proposed. IL-1beta gene polymorphism such as IL-1beta-511 and IL-1beta+3953 have been reported to be associated with the risk of AD in a number of studies in a Caucasian population. However, conflicting results have been reported recently which showed that IL-1beta was not universally associated with the risk of AD in other populations. In order to validate these associations, we investigated the IL-1beta polymorphisms (IL-1beta-31, IL-1beta-511 and IL-1beta+3953) in a Chinese population, which has not been studied before. In our study, the allelic frequencies of IL-1beta-31C, IL-1beta-511T and IL-1beta+3953T for the AD group were 0.49, 0.57 and 0.03, respectively. The allelic frequencies of IL-1beta-31C, IL-1beta-511T and IL-1beta+3953T for the control group were 0.53, 0.61 and 0.03, respectively. No significant difference was detected in the genotypic or allelic frequencies (p > 0.25). We conclude that IL-1beta polymorphism is unlikely to be a significant risk factor for AD in the Chinese Population.     

Multiple alpha-synuclein gene polymorphisms are associated with Parkinson's disease in a Norwegian population

Objectives – Previous studies have found associations between Parkinson’s disease (PD) and polymorphisms located within both the alpha‐synuclein gene (SNCA) promoter and other gene regions. Our aim was to study SNCA gene markers in a closely matched Norwegian PD population to examine the genetic relationship between different polymorphisms associated with the disease. Methods – We genotyped seven single nucleotide polymorphisms (SNPs) located in the SNCA promoter and two SNPs in the 3′ gene region and seven microsatellite markers located across the gene in a closely matched series of 236 PD patients and 236 controls. Linkage disequilibrium (LD) structure was examined, and association of single markers and gene haplotypes analyzed. Results – Several markers located across the SNCA gene were associated with PD, including marker alleles associated with disease in previous studies (Rep1 263‐bp allele, rs356165 and rs356219). Conclusion – LD between associated marker alleles located across the SNCA gene suggests that a single genetic effect might explain the previous reported association in the promoter and 3′ regions.     

Association between dopamine D3 receptor gene polymorphisms and schizophrenia in an isolate population

There are several lines of evidence implicating the dopamine D3 receptor in the pathophysiology of schizophrenia. The Ser9Gly polymorphism of the dopamine D3 receptor gene (DRD3) has been the most extensively investigated DRD3 variant in connection with the disease but results have been inconclusive. Recent reports indicate that the Ser9Gly polymorphism is in linkage disequilibrium with other markers, but association studies between DRD3 haplotypes and schizophrenia have had mixed results. Genetic heterogeneity may be one of the causes of contradicting results. In order to clarify the role of DRD3 alterations in the aetiology of disease, we have investigated three D3 genetic variants (Ser9Gly, -205-G/A, -7685-G/C) in a sample of patients with schizophrenia or schizoaffective disorder (N=118) and controls (N=162) recruited from a human isolate from Navarra (Northern Spain) of Basque origin. Although no association was found between the Ser9Gly or the -205-A/G polymorphisms and disease, an excess of allele -7685-C was observed in patients (p=0.002 after correction for multiple analyses). Haplotype analysis shows the three markers to be in strong linkage disequilibrium (p<0.0001) and strongly associated with disease (p<1x 10(-5)). These results may suggest that these polymorphisms exert a combined or synergistic effect on susceptibility to schizophrenia, or are in linkage with an unknown causative factor. However, further replication in independent samples is required.     

Lack of association between an RFLP near the D2 dopamine receptor gene and severe alcoholism.

Blum et al (1990) have recently examined a restriction fragment length polymorphism (RFLP) detected by TaqI RFLP to the dopamine D2 receptor gene (DRD2) in deceased alcoholics and nonalcoholics, and reported an association between alcoholism and the A1 allele. Subsequent studies, however, by other investigators have failed to confirm this. We have examined the DRD2 TaqI RFLP in 47 living Caucasian males with severe alcoholism. All alcoholic subjects were thoroughly characterized by a structured interview, and met DSM-III-R criteria for alcohol dependence. Only 9/47 (19%) (1990) of these alcoholics had the AI allele compared to 14/22 (64%) reported by Blum et al. This rate was not significantly different from the rates reported in control populations by Blum et al (1990), CEPH, or Bolos et al (1990), and differed only slightly from those reported by Grandy et al (1990). Alcoholics selected for severe medical complications also displayed a similar rate. Our data do not support an association between alcoholism and the D2 dopamine receptor gene in this population.     

Lack of association between polymorphisms of the toll-like receptor 4 gene and cerebral ischemia

Abstract. Toll-like receptor-4 (TLR4), an important mediator of the innate immune response, is expressed in atherosclerotic lesions. The common single nucleotide exchange (Asp299Gly) of the TLR4 gene has been previously reported to impair TLR4 function and to be associated with a decreased risk of carotid atherosclerosis. Therefore, we aimed to detect the potential impact of TLR4 genotypes on the risk of cerebral ischemia.We studied the prevalence of two common polymorphisms of the TLR4 gene (Asp299Gly and Thr399Ile) in 3 independent study populations: (1.) in a cross-sectional study including 769 patients either with type 1 or type 2 diabetes mellitus, of whom 56 (7.2%) had a history of cerebral ischemia (study 1), (2.) a case-control study (study 2) including 128 consecutive patients with cerebral ischemia, mean age 60 ± 10.9 years and 139 control subjects, and (3.) a case-control study (study 3) including 171 young adults aged < 50 years with cerebral ischemia and 204 control individuals. In all subjects, Asp299Gly and Thr399Ile were detected by restriction length analysis.The prevalence of the TLR4 genotypes was essentially the same between patients with cerebral ischemia and control subjects in all 3 study populations. Furthermore, there was also no association with the subgroup of atherosclerotic stroke in both case-control studies populations.Although TLR4 polymorphisms are associated with a decreased risk of carotid atherosclerotic lesions, our findings indicate that they do not influence the prevalence of cerebral ischemia. This implies that the Asp299Gly TLR4-allele might have a protective role in carotid atherosclerosis, but not in cerebral ischemia.* both authors contributed equally to this work