Mingqing Xu

Brain-derived neurotrophic factor gene C-270T and Val66Met functional polymorphisms and risk of schizophrenia: A moderate-scale population-based study and meta-analysis

BACKGROUND Lines of evidence have suggested that the brain-derived neurotrophic factor (BDNF) gene may be involved in the pathogenesis of schizophrenia. Two common functional polymorphisms C-270T and Val66Met within the BDNF gene were first reported by Kunugi et al. [Kunugi, H., Nanko, S., Hirasawa, H., Kato, N., Nabika, T., Kobayashi, S., 2003. Brain-derived neurotrophic factor gene and schizophrenia: polymorphism screening and association analysis. Schizophr. Res. 62, 281-283.] and pls expand this too: Hong et al. (2003) to be significantly associated with schizophrenia. However, subsequently several studies obtained conflicting results. METHODS We compared the allele/genotype frequencies of the C-270T and Val66Met polymorphisms and the haplotype frequencies at the two polymorphisms in a moderate independent patient-control sample from the Han Chinese population. Two systematic meta-analyses were performed to assess the collective evidence for association across studies for each of the two polymorphisms. RESULTS No statistically significant differences were found in allele or genotype or haplotype frequencies between patient and normal control subjects for either of the two polymorphisms. On the other hand, the meta-analysis of all published population-based association studies showed statistically significant evidence for heterogeneity among each of the two polymorphisms. Stratification of the studies by ethnicity of the samples yielded no significant evidence for an association with the polymorphisms in the Caucasian population (for C-270T polymorphism: pooled OR(Caucasian)=0.736, 95% CI=0.476-1.139, p=0.169; for Val66Met polymorphism: pooled OR(Caucasian)=1.027, 95% CI=0.796-1.325, p=0.835), nor in the Asian population (for C-270T polymorphism: pooled OR(Asian)=0.445, 95% CI=0.144-1.373, p=0.159; for Val66Met polymorphism: pooled OR(Asian)=0.962, 95% CI=0.820-1.128, p=0.635). CONCLUSIONS Our population-based study and meta-analysis demonstrate that the BDNF C-270T and Val66Met polymorphisms do not play major roles in the susceptibility to schizophrenia in either Caucasian or Asian populations. But we can not rule out the possibility that other polymorphisms with the BDNF gene are involved in the pathophysiology of schizophrenia.

Polymorphisms of the ABCB1 gene are associated with the therapeutic response to risperidone in Chinese schizophrenia patients

P-glycoprotein, a product of the ATP-binding cassette B1 (ABCB1) gene, plays an important role in absorption and distribution of drugs. The brain entry of risperidone and 9-OH-risperidone is greatly limited by P-glycoprotein, which implies that the functional polymorphisms of ABCB1 in humans may be a factor contributing to the variability in response to risperidone. The present study was therefore designed to examine whether polymorphisms of the ABCB1 gene are related to therapeutic response. For this purpose, 130 Chinese schizophrenia patients undergoing risperidone treatment were recruited. Plasma drug concentrations were monitored and clinical symptoms were evaluated using the Brief Psychiatric Rating Scale (BPRS) before and 8 weeks after the treatment. Association tests between genotypes and percentage improvement in total BPRS scores were performed using analyses of variance. Our results show that genotyping C1236T may help to predict the efficacy of risperidone treatment on the basis that patients with the TT genotype showed greater improvement than those with other genotypes on the overall BPRS (F = 3.967, p = 0.021), while other polymorphisms, including rs13233308, G2677T/A and C3435T polymorphism, did not show any association with the response to risperidone. These results showed suggestive evidence that genetic variation in the ABCB1 gene may influence the individual response to risperidone.

The relationship between the therapeutic response to risperidone and the dopamine D2 receptor polymorphism in Chinese schizophrenia patients

Antipsychotic drugs exert both therapeutic and adverse effects through dopamine D2 receptor (DRD2) antagonism. Genetic variants of this receptor may be responsible for individual variations in neuroleptic response and may therefore be useful in predicting response. In this study we evaluated the role of six polymorphisms of the DRD2 gene in 125 risperidone-treated Chinese schizophrenia patients following the hypothesis that variation in the DRD2 gene could affect drug response. Response was categorized as a change of >40% on the Brief Psychiatric Rating Scale (BPRS). Our results show that genotyping A-241G may help to predict the efficacy of risperidone treatment on the basis that patients with the A allele showed greater improvement than those with the G allele on the overall BPRS (chi2=7.19, p=0.007, p=0.031 after correction by the program SNPSpD), while other polymorphisms, including -141C Ins/Del, TaqIB, rs1076562, T939C and TaqIA, did not show any association with the response to risperidone. These data suggest that the DRD2 A-241G polymorphism or, alternatively, another genetic variation that is in linkage disequilibrium, may influence response to risperidone in schizophrenia patients.

Convergent Evidence Shows a Positive Association of Interleukin-1 Gene Complex Locus with Susceptibility to Schizophrenia in the Caucasian population

Recent genetic studies have revealed that the Interleukin-1 (IL1) gene complex (IL1 alpha, IL1 beta and IL1 receptor antagonist) is associated with schizophrenia, but contradictory findings have also been reported. We investigated the association of the IL1 gene complex locus and schizophrenia using meta-analytic techniques, covering all published data up to January 2010, to restrict to the most commonly reported 4 single nucleotide polymorphisms (SNP). We also explored potential sources of heterogeneity and to investigate whether ancestry and study design moderated any association. The combined allele-wise odds ratio (OR) for schizophrenia of the rs16944 (IL1B gene; T-511C) polymorphism was 0.86 (95% CI: 0.77to 0.96).When applying stratified analysis to this polymorphism, the pooled allele-wise OR was 0.88 (95% CI, 0.79 to 0.97) in 10 population-based studies and 0.85 (95% CI: 0.73 to 0.99) in Caucasian samples. In a stratified analysis of the rs1143634 (IL1B gene; T3953C) polymorphism, the pooled genotype-wise results in a dominant model were also statistically significant both in a population-based study subgroup with summary OR of 0.64 (95% CI: 0.41 to 0.99) and a Caucasian population subgroup with summary OR of 0.62 (95% CI: 0.40 to 0.97). Neither combined nor stratified analyses found any association of the rs1800587 (IL1A gene; T-889C) or rs1794068 (IL1RA Gene; IL1RN_86 bp; T/C) with schizophrenia susceptibility. Our study suggests the IL1B gene or the IL1 gene complex may play a moderate role in the etiology of schizophrenia in the Caucasian population.

BDNF gene is a genetic risk factor for schizophrenia and is related to the chlorpromazine-induced extrapyramidal syndrome in the Chinese population

Background Brain-derived neurotrophic factor (BDNF) belongs to a family of the neurotrophin, which plays important roles in the neurodevelopment of dopaminergic-related systems and interacts with meso-limbic dopaminergic systems involved in the therapeutic response to antipsychotics. Functional experiments have suggested that BDNF may be involved in the etiology of schizophrenia. Methods and results In this study, we genotyped two important functional polymorphisms in the BDNF gene using a sample of Han Chinese patients consisting of 340 schizophrenic patients and 343 healthy controls. We found a statistical difference in the 232-bp allele distribution of the BDNF gene (GT)n dinucleotide repeat polymorphism between the schizophrenic patients and controls. In early onset patients, the 234-bp allele had a risk role. For the chlorpromazine-induced extrapyramidal syndrome, the 230-bp allele and the 234-bp allele acted in opposite directions, that is, patients with the 230-bp allele of the (GT)n polymorphism exhibited a lower degree of induced extrapyramidal syndrome. Haplotype-based analysis also revealed a very important risk haplotype (P=0.0000226546). Conclusion These findings suggest that BDNF plays an important role in the susceptibility to schizophrenia and that the (GT)n repeat polymorphism of the BDNF gene may be an independent contributor to the chlorpromazine treatment-sensitive form of schizophrenia.

Response of risperidone treatment may be associated with polymorphisms of HTT gene in Chinese schizophrenia patients.

Serotonin transporter (5-HTT) is a key component of the serotonergic neurotransmitter system. Few studies have focused on polymorphisms of the serotonin transporter and antipsychotic response and, in particular, there have so far been no published studies on the association between the serotonin transporter and response to risperidone. This study examined the relationship between two polymorphisms of the serotonin transporter and the efficacy of risperidone treatment in 129 patients with schizophrenia. Our results revealed that patients with l allele of HTTRLP showed a greater improvement than those without l allele on the overall brief psychiatric rating scale (BPRS) (P=0.025). But no such relationship was found for the HTTVNTR. In haplotype analysis, the frequency of L-12 haplotype showed a significant difference between the responder group and the non-responder group (P=0.005). Our study has, for the first time, produced evidence that the potential for therapy in patients with schizophrenia is related to the HTTRLP polymorphism in the HTT gene and haplotype L-12 may help to predict risperidone treatment efficiency.

Intra-ethnic differences in genetic variants of the UGT-glucuronosyltransferase 1A1 gene in Chinese populations.

Variants within the human UGT1A1 gene are associated with irinotecan induced severely adverse reactions and hyperbilirubinemia. Intra-ethnic differences in the genetic variation and haplotypes of UGT1A1 gene have been analyzed in the present study. Relationship between the concentrations of total serum bilirubin (T-bil) and haplotype structure of UGT1A1 in healthy people were also evaluated. We genotyped five functional polymorphisms including −3279T>G and −3156G>A in the enhancer region, (TA)6>7 in the TATA box, and 211G>A (G71R), 686C>A (P229Q) in the exon1 region of UGT1A1 in three groups of healthy Chinese ethnic populations, consisting of 264 subjects of She origin, 539 of Han origin and 273 of Dong origin. The distribution of −3279T>G, (TA)6>7, 211G>A of UGT1A1 differed greatly as between the three ethnic groups. All of six haplotypes differed considerably between at least two of the three groups, which highlighted the need to analyze clinically irinotecan toxicity relevant SNPs and haplotypes in a variety of different racial groups within the Chinese population. Total bilirubin concentration in homozygous carriers of the −3279G and (TA)7 allele were significantly higher than those in heterozygous carriers or homozygous carriers of wild-type alleles. Carriers of the variant haplotypes (−3279G; −3156A; (TA)7; 211G; 686C) had higher serum T-Bil concentrations compared with the other groups. Our results indicate that heterogeneity among different ethnic populations is possibly the result of microevolution and is relevant to studies into the effect of tailored drug treatment.

Genetic variants in the BDNF gene and therapeutic response to risperidone in schizophrenia patients: a pharmacogenetic study

Risperidone is a widely used atypical antipsychotic agent that produces considerable interindividual differences in patient response. We investigated the pharmacogenetic relationship between the brain-derived neurotrophic factor (BDNF) gene and response to risperidone in 127 Han Chinese schizophrenic patients. Three functional polymorphisms, (GT)n dinucleotide repeat polymorphism, C-270T, and the rs6265G/A single-nucleotide polymorphism (SNP), were genotyped and analyzed for association, with reduction of Brief Psychiatric Rating Scale (BPRS) scores following an 8-week period of risperidone monotherapy. For individual polymorphic analysis, we found that the frequency of the 230-bp allele of the (GT)n polymorphism was much higher in responders (47.95%) than in nonresponders (32.41%) and the difference was statistically significant even after Bonferronis adjustment (for the 230-bp allele: adjusted P=0.039). For haplotype-based analyses of the three polymorphisms, no positive finding was observed in the global test, but in specific haplotype tests, two haplotypes were also significantly related to response to risperidone (for haplotype 230-bp/C-270/rs6265G: P=0.0009; for haplotype 234-bp/C-270/rs6265A: P=0.043), indicating that patients with the 230-bp allele of the (GT)n polymorphism or the 230-bp/C-270/rs6265G haplotype responded better to risperidone than those with other alleles or haplotypes, and that the positive effect of the individual haplotype 230-bp/C-270/rs6265G was mainly driven by the 230-bp allele. These findings demonstrate that the individual and combinatorial genetic variants in the BDNF gene might have a role in the therapeutic response to risperidone in the Han Chinese population.

Meta-analysis of association between ApoE ε4 allele and schizophrenia

Several case-control studies have reported an association between schizophrenia and the epsilon4 allele of Apolipoprotein E gene. The results have been equivocal. This meta-analysis has evaluated the collective evidence for an association between the epsilon4 allele of Apolipoprotein E gene and schizophrenia. We analyzed published data sequentially first considering epsilon4 allele itself, and then epsilon4 carrier status as risk factors for schizophrenia using a sample of 17 population-based case-control studies, of which 6 were from Asian and 11 from Caucasian populations. The pooled odds ratios from the Caucasian populations showed a modest association with risk of schizophrenia for epsilon4 allele and epsilon4 carrier genotype. No other alleles or genotypes were significant in either Asian or Caucasian populations when analysed separately or combined, although the sample size had over 80% power to detect a significant odds ratio of 1.9 in Asian-population studies and 1.6 in Caucasian-population studies. After allowing for sensitivity analysis of the studies and assessment of publication bias, we conclude that the epsilon4 allele of Apolipoprotein E does not play a major role in risk of schizophrenia in Caucasian populations. Since significant heterogeneity was present among the 6 Asian populations reported to date, further studies using larger sample sizes are required.

Testing for genetic association between the ZDHHC8 gene locus and susceptibility to schizophrenia: An integrated analysis of multiple datasets

A number of studies have reported an association between the ZDHHC8 gene locus and schizophrenia but have produced some divergent findings and their interpretation is not straightforward. We investigated the association of the ZDHHC8 gene locus with schizophrenia using meta‐analytic techniques, combining all published data up to May 2009 and focusing on 10 independent studies from six published references covering 2,894 cases, 2,932 controls and 1,225 parent‐offspring trios. We restricted the analysis to studies investigating rs175174, the most frequently studied single nucleotide polymorphism (SNP). Stratified meta‐analysis was conducted to investigate whether ancestry, study design, or gender moderated any association. Analyses of linkage disequilibrium (LD) and haplotype structure of this gene locus were also performed based on the hapmap project genotype data to determine whether there were other independent polymorphic markers which might contribute to susceptibility to schizophrenia in particular ethnic populations. We found no allelic‐ or genotype‐wise evidence for an association of the rs175174 SNP with schizophrenia in our overall analysis. After applying stratified analyses, there was only a weak nominal genotype‐wise association of this SNP with schizophrenia in the dominant genetic model in East Asian populations (P = 0.049), which might be caused by significant between‐study heterogeneity (P = 0.042). No significant publication bias was detected. Other polymorphic markers within this gene genotyped in the hapmap project across different ethnic populations were in strong LD with rs175174. Consistently negative associations were found in the rs175174 polymorphism. LD structure further suggested that the ZDHHC8 locus might not play an important role in the etiology of schizophrenia.