Association analysis of the −308G > A promoter polymorphism of the tumor necrosis factor alpha (TNF-α) gene in Japanese patients with schizophrenia

Summary. Two research groups have thus far reported a significant association between schizophrenia and a promoter polymorphism (–308G > A) of the gene encoding tumor necrosis factor alpha (TNF-), while contradictive negative results have also been reported. We examined the possible association in a Japanese sample of 297 schizophrenia cases and 458 controls. Allele frequencies of both the patients and controls were very low (1.5% and 0.8%, respectively), and the difference was not statistically significant. We conclude that the effect of the –308G > A polymorphism on the development of schizophrenia is, if any, weak and the majority of Japanese schizophrenics are unrelated to the –308G > A polymorphism of the TNF- gene.     

Association between monoamine oxidase A gene promoter 30 bp repeat polymorphism and tardive dyskinesia in Chinese schizophrenics

INTRODUCTION Tardive dyskinesia (TD) is a disabling neurological side effect associ- ated with long-term treatment with typical antipsychotics[1]. It is characterized by excessive and involuntary movements predom- inantly in the orofacial region[2] and also in other body areas. It can be persistent, and cause difficulties in breathing, speech and mood[3]. Although the pathophysiology of TD is not yet fully understood [4], several hypotheses have been proposed, including dopamine re-cepto…     

Association between TNF-α promoter -308A/G polymorphism and tardive dyskinesiain Chinese Han patients with schizophrenia

Objective

Previous studies have indicated that the immune may be involved in the pathogenesis of tardive dyskinesia (TD). Some genetic polymorphisms in the human leukocyte antigen (HLA) I and II regions have been associated with TD, and the tumor necrosis factor-α (TNF-α) gene is located in the HLA III region. TNF-α levels in the striatum significantly increased in haloperidol-induced TD in rats. The TNF-α gene −308A/G single nucleotide polymorphism (SNP) has been shown to directly influence TNF-α expression. The genetic association between the TNF-α gene −308A/G SNP and TD is unclear. The present study investigated whether this variation is associated with clinical phenotypes and TD in schizophrenia in a genetically homogeneous northern Chinese Han population.

Methods

We genotyped the TNF-α gene −308A/G SNP in patients with schizophrenia with TD (n = 350) and without TD (n = 410). The Abnormal Involuntary Movement Scale (AIMS) and Positive and Negative Syndrome Scale (PANSS) were used to assess the severity of TD and psychopathology of schizophrenia, respectively.

Results

The allele and genotype frequencies did not significantly differ between patients with schizophrenia with and without TD (p > 0.05). No significant difference was found in the total AIMS score between the genotypes (p > 0.05). However, the PANSS negative symptom subscore was associated with risk for TD (p = 0.004), and a significant difference was found in total AIMS score between the genotypes in TD patients (p = 0.013).

Conclusion

The TNF-α gene −308A/G polymorphism does not appear to play a major role in the susceptibility to TD in patients with schizophrenia in a northern Chinese Han population. However this polymorphism may play a role in the TD severity.     

Association between interleukin-6 gene promoter −572C/G polymorphism and the risk of sporadic Alzheimer’s disease

Inflammation is a key component of Alzheimer’s disease (AD), and we have examined the effect of two polymorphisms (−174G/C and −572C/G) in the promoter of the inflammatory cytokine interleukin-6 (IL-6) gene on risk of AD in 318 AD patients. Significant differences in genotype and allele frequencies of −572C/G IL-6 promoter polymorphism were observed between AD patients and controls. The GG genotype was associated with a decreased risk of developing AD (OR 0.423, 95% CI 0.200–0.894). Similarly, logistic regression analysis revealed that G allele was a protective factor for AD (OR 0.732, 95% CI 0.567–0.945). For −174G/C variability, no C variability was found in all the subjects. The frequency of the IL-6 −174G/C promoter polymorphism is very low or no variability in Henan Han population. The −572C/G polymorphism of IL-6 gene promoter region is associated with AD, and G allele is an independent protective factor for AD.     

Polymorphism of the adrenergic receptor alpha 2a −1291C>G genetic variation and clozapine-induced weight gain

Summary. Weight gain, leading to further morbidity and poor treatment compliance, is a common consequence of treatment with clozapine. The substantial interindividual and interracial differences in drug-induced weight gain suggest that genetic factors may be important. Several studies showed that alpha-2, adrenoceptor may related to feeding behavior with rat or lipolytic activity of human adipocyte tissue, they are related to body weight change. In the study, we try to test the possible relation of clozapine-induced weight gain and adrenergic receptor alpha 2a −1291C>G genetic polymorphism in a long term follow up (14.0 ± 6.2 months). Our results show the genotype GG (8.45 ± 7.2 Kg) with higher mean body weight gain than genotype CC (2.79 ± 6.1 Kg) (p = 0.023). The finding identify a genetic factor associated with clozapine-induced weight gain in schizophrenic patients.     

Association between NMDA receptor subunit 2b gene polymorphism and Alzheimer’s disease in Chinese Han population in Shanghai

Objective

N-methyl-D-aspartate (NMDA) receptor has been indicated to be involved in the pathogenesis of Alzheimer’s disease (AD). The NMDA receptor subunit 2b (NR2B) has attracted more attention due to its characteristic distribution and selective reduction in AD brain. The present study aimed to explore the association between NMDA gene polymorphism and AD.

Methods

A total of 63 AD patients and 68 normal controls in Shanghai city were employed in this study. Genotype of C2664T variant (rs1806201) in the exon13 of GRIN2B gene was determined by gene sequencing.

Results

Among AD patients, 15 (23.6%) subjects were identified as C/C genotype, and 35 (55.6%) were identified as C/T genotype. The left 13 (20.6%) subjects were identified as T/T genotype. In normal controls, 15 (22.1%) subjects were identified as C/C genotype, 39 (57.4%) as C/T genotype and 14 (20.6%) as T/T genotype. The distribution frequency of neither GRIN2B C2664T genotype (P=0.895) nor allele (P=0.790) was significantly different between AD patients and normal controls, even when the subjects were stratified by gender and age of disease onset in AD patients.

Conclusion

The results suggest that there is no relation between GRIN2B C2664T polymorphism and AD in Chinese Han population of Shanghai City.

     

Association between essential hypertension and polymorphisms of beta 1 adrenergic receptor gene G1165C （Gly389Arg） in Chinese Mongolian population

INTRODUCTION Essential hypertension is a complex disease involves various genes and factors, and the prevalence of hypertension in Chinese adults is 27.2%[1]. The sympathetic nerve-catecholamine system acts as an important player in regulating the cardiac…     

Association studies of the adenosine A2a receptor (1976T > C) genetic polymorphism in Parkinson’s disease and schizophrenia

Summary. Given the implications with respect to the pathogenesis of dopaminergic dysfunction in schizophrenia and Parkinson’s disease (PD), as well as the reciprocal antagonistic interactions between adenosine A2a receptor (A2aAR) and the dopamine D2 receptors, A2aAR may be a candidate gene conferring susceptibility to PD or schizophrenia. In this study, we tested the hypothesis that the A2aAR 1976T > C genetic variant confers susceptibility to or is related to the onset age of schizophrenia or PD using a sample population consisting of 94 PD and 227 schizophrenic patients. We also tested whether the A2aAR 1976T > C relates to antipsychotic-induced tardive dyskinesia in the schizophrenic population. The results demonstrated that in comparing PD patients and controls the distribution of the A2aAR 1976T > C genotypes (P = 0.788) and alleles (P = 0.702) did not vary significantly. Furthermore, the PD onset age was not significantly different amongst the three A2aAR 1976T > C genotypic groups. In comparing schizophrenic patients and controls, the distribution of the A2aAR genotypes (P = 0.330) and alleles (P = 0.632) also did not differ significantly. The onset age of schizophrenia and tardive dyskinesia (evaluated with Abnormal Involuntary Movements Scale) were similar within the three A2aAR genotypic groups. Our findings suggest that it is unlikely that the A2aAR 1976T > C polymorphism plays a major role in the pathogenesis of PD, schizophrenia, or antipsychotic-induced tardive dyskinesia in the Chinese population.     

Effect of α2A-adrenoceptor C-1291G genotype and maltreatment on hyperactivity and inattention in adolescents

The C-1291G polymorphism (rs1800544) in the promoter region of the α_2A-adrenoceptor gene (ADRA2A) has been associated with attention deficit and hyperactivity in clinical samples. We have examined the effect of ADRA2A C-1291G on inattentive, hyperactive and aggressive behaviour in a population representative cohort of healthy schoolchildren, and possible interaction of genotype with family relations. Ratings on aggressiveness, motor restlessness and concentration difficulties were obtained from the class teachers by using the Hyperactivity Scale of af Klinteberg, and the teacher-report version of SNAP-IV. The relations in the family were reported by children. Symptom scores, self-reports and genotype data of 429 15-years old children (196 boys, 233 girls) were available for analysis. There was a significant interaction effect of maltreatment and the ADRA2A genotype on behavioural functioning in 15 years old boys. Boys with CC genotype and higher score of maltreatment demonstrated more overactive behaviour and concentration difficulties than boys with CC genotype and low maltreatment score. They also had more inattentive symptoms measured by SNAP-IV. Among boys with low maltreatment score, subjects with CC genotype demonstrated less overactivity than G allele carriers. In girls, the G allele carriers did not differ from the CC genotype, but in maltreated girls with GG genotype aggression and inattention symptoms were reduced, and the score of aggressive behaviour was also lower compared to maltreated girls with CC genotype. Our data suggest that family environmental factors may act together with the α_2A-adrenoceptor genotype to increase the expression of hyperactive and inattentive symptoms in adolescents.     

Genetic association between −93A/G polymorphism in the Fyn kinase gene and alcohol dependence in Spanish men

BackgroundFyn tyrosine kinase is a member of the Scr family that phosphorylates the NR2A and NR2B subunits of the NMDA receptors reducing the inhibitory effects of ethanol and therefore may regulate the individual sensitivity to ethanol.ObjectivesTo investigate whether there is any relationship between the polymorphism at position ?93 of the Fyn kinase gene and the susceptibility to develop alcoholism.MethodsWe studied the distribution of genotypes and alleles of the polymorphism ?93A/G (137346 T/C) in the 5′ UTR region of the fyn gene in 207 male heavy drinkers (119 with alcohol dependence and 88 with alcohol abuse) and 100 control subjects from Castilla y León (Spain).ResultsThe frequency of G allele carriers was higher in alcohol dependents than in alcohol abusers (47.9% vs 30.6%; p = 0.015; OR = 2.077; 95% CI 1.165–3.704).ConclusionOur results show that the ?93G allele of Fyn kinase gene is associated with higher risk to develop alcohol dependence in Spanish men.     

Association between the RAGE G82S polymorphism and Alzheimer’s disease

The receptor for advanced glycation end products (RAGE) is associated with several pathological states including Alzheimer’s disease (AD) pathology, while its soluble form (sRAGE) acts as a decoy receptor. We have tested for association of AD with a functional single-nucleotide polymorphism (SNP) in the RAGE gene (G82S; rs2070600), a SNP associated with increased ligand affinity of RAGE. Analysis of a Chinese cohort (276 cases; 254 controls) showed a higher prevalence of the RAGE 82S allele and GS + SS genotype in the patients [82S vs. 82G: P = 0.017, odds ratio (OR) = 1.431; GS + SS vs. GG: P = 0.025, OR = 1.490]. Further stratification analysis revealed that the association of the RAGE G82S polymorphism with AD was significant in early onset AD stratum. Moreover, plasma sRAGE levels were lower in AD than in normal elderly controls, and the presence of the risk allele was associated with further plasma sRAGE reduction and a fast cognitive deterioration. The present study provides preliminary evidence that the RAGE G82S variant is involved in genetic susceptibility to AD.     

Association between G2385R and R1628P polymorphism of LRRK2 gene and sporadic Parkinson’s disease in a Han-Chinese population in south-eastern China

The G2385R and R1628P polymorphisms of the leucine-rich repeat kinase 2 (LRRK2) gene have been reported to be associated with Parkinson’s disease (PD), but no data are available on Han-Chinese population of south-eastern China. This study aimed to investigate whether G2385R and R1628P variants are associated with sporadic PD in this population. Total 1,060 subjects were enrolled; including 550 unrelated healthy controls and 510 patients with sporadic PD. Genotyping of polymorphisms was performed by PCR–restriction fragment length polymorphism analysis. All variant samples were sequenced for further confirmation. The results showed that the A allele of the G2385R variant was significantly enriched in sporadic PD patient group (4.8 %) when compared with control group [1.1 %; odds ratio (OR) 4.58, 95 % confidence interval (CI) 2.42–8.65, P < 0.01]. However, no significant difference in the frequency of the C allele of R1628P polymorphism variant was observed between cases and controls (2.8 vs. 1.7 %, OR 1.67, 95 % CI 0.93–2.99, P = 0.08). In conclusion, this study provides the first evidence that G2385R polymorphism is a risk factor for sporadic PD in Han-Chinese population of south-eastern China.     

A role for the BDNF gene Val66Met polymorphism in schizophrenia? A comprehensive review

Schizophrenia is believed to arise from complex gene–environment interactions. Brain-derived neurotrophic factor (BDNF) is involved in neuronal development, differentiation and plasticity. A functional single nucleotide polymorphism that results in a valine (Val) to methionine (Met) substitution at codon 66 (Val66Met) results in the aberrant sorting and release of mature BDNF through the activity-dependent secretion pathway. The Val66Met polymorphism has been linked to impaired neurocognitive function in healthy adults, and identified as a locus of risk for a range of neuropsychiatric disorders including schizophrenia. Here we provide a comprehensive review of the relationship between the BDNF Val66Met polymorphism and schizophrenia, integrating evidence from the fields of genetic epidemiology, clinical psychiatry, behavioral neuroscience and neuroimaging. We argue that while the Val66Met polymorphism may not be a major risk-conferring agent for the development of schizophrenia per se, there is mounting evidence that the polymorphism modulates a range of clinical features of the illness, including age of onset, symptoms, therapeutic responsiveness, neurocognitive function and brain morphology.     

Adenosine A2A receptor gene disruption protects in an α-synuclein model of Parkinson's disease

To investigate the putative interaction between chronic exposure to adenosine receptor antagonist caffeine and genetic influences on Parkinson's disease (PD), we determined whether deletion of the adenosine A(2A) receptor in knockout (KO) mice protects against dopaminergic neuron degeneration induced by a mutant human α-synuclein (hm(2)-αSYN) transgene containing both A53T and A30P. The A(2A) KO completely prevented loss of dopamine and dopaminergic neurons caused by the mutant α-synuclein transgene without altering levels of its expression. The adenosine A(2A) receptor appears required for neurotoxicity in a mutant α-synuclein model of PD. Together with prior studies the present findings indirectly support the neuroprotective potential of caffeine and more specific A(2A) antagonists.     

Association between Sirtuin 2 gene rs10410544 polymorphism and depression in Alzheimer’s disease in two independent European samples

Among the several genes associated with late-onset Alzheimer’s disease (LOAD), recently, Sirtuin genes have roused a growing interest because of their involvement in metabolic homeostasis and in brain aging. Particularly SIRT2 gene has been associated with Alzheimer’s disease (AD) as well as with mood disorders. The aim of this study is to investigate the possible associations between Sirtuin 2 gene (SIRT2) rs10410544 polymorphism and AD as well as depression in AD. In addition, we performed some exploratory analyses to investigate possible associations between the rs10410544 genotype and clinical features. We investigated these associations in two independent samples: the first one was composed of 275 Greek inhabitants and 117 patients; the second sample counted 181 Italian people and 43 patients. All patients were affected by LOAD. We failed to find any association between rs10410544 genotype and AD in the two samples. On the other hand, we found an association between the single nucleotide polymorphism (SNP) and depressive symptomatology (in the total sample p = 0.002), which was modulated by the tumor necrosis factor (TNF) values. Particularly, TT genotype seems to be protective versus depression. Finally, in the exploratory analyses, we found that the TT genotype was associated with earlier AD onset and a longer duration of the illness. In conclusion, we confirmed the association between SIRT2 gene and mood disturbances, although in AD patients. Further, we provided evidence that the TT genotype may be protective versus depressive symptoms, allowing an easier and thus earlier diagnosis of AD. This awareness may lead to a more detailed approach to these patients concerning diagnosis and therapy.     

A functional polymorphism of the µ-opioid receptor gene is associated with completed suicides

Summary. A recent linkage study suggested that a putative locus for suicidal behavior independent of psychiatric disease phenotypes lies at 5′ upstream of the μ-opioid receptor (OPRM1) gene. We explored an association between suicide and genetic variations of the OPRM1 using a case-control study of 183 completed suicides and 374 control subjects. We genotyped four single nucleotide polymorphisms (SNPs) including a common A118G SNP. The genotypic and allelic distributions of the A118G SNP were significantly different between the completed suicide and control groups (P = 0.014 and 0.039, respectively). A dominant model analysis of the A118G SNP showed an enhanced association with suicide (P = 0.0041, Odds ratio 0.575) and this significant association was observed with a logistic regression analysis that takes sex and age factors into account (P = 0.021). Our results raise the possibility that the A118G SNP of the OPRM1 gene is associated with suicide. Correspondence: Akitoyo Hishimoto, Division of Psychiatry and Neurology, Department of Environmental Health and Safety, Faculty of Medical Sciences, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho Chuo-ku, Kobe 650-0017, Japan     

The –A162G polymorphism of the PON1 gene and the risk of sporadic amyotrophic lateral sclerosis

Background and purposeSporadic amyotrophic lateral sclerosis (sALS) is a devastating neurodegenerative disease, which results from complex genetic and environmental interactions. Recent studies have reported an association between several polymorphisms of the PON1 and PON2 genes and risk of sALS. The aim of the present study was to identify an association between the – A162G polymorphism of the promoter region of the human PON1 gene and the risk of sALS in a Polish population.Material and methodsWe included 259 patients with a diagnosis of definite or probable sALS (76 bulbar onset, 183 limb onset) and 694 healthy controls matched for age and sex. The diagnosis of ALS was established according to El Escorial criteria. The polymorphism was studied by Single Nucleotide Polymorphism Real-Time Polymerase Chain Reaction analysis.ResultsNo overall difference in the PONI – A162G genotype and allele distribution was seen between cases and controls (all p > 0.05). There was, however, a difference in the A allele frequency when the bulbar onset group was compared to the controls (p = 0.03), but this significance disappeared after the Bonferroni correction.ConclusionsThe results did not show that the – A162G polymorphism of the PON1 gene is a risk factor of sALS in a Polish population; it may affect, however, bulbar onset of the disease.