Haihong Zhou

Association of a miRNA-137 Polymorphism with Schizophrenia in a Southern Chinese Han Population

Both genome wide association study (GWAS) and biochemical studies of Caucasian populations indicate a robust association between the miR-137 genetic variant rs1625579 and schizophrenia, but inconsistent results have been reported. To assay the association between this variant and schizophrenia, we genotyped 611 schizophrenic patients from Southern Chinese Han population for the risk single nucleotide polymorphism (SNP) rs1625579 using the SNaPshot technique and compared the clinical profiles of different genotypes. Additionally, a meta-analysis was performed using the combined sample groups from five case-control publications and the present study. Both the genotype and allele distributions of the rs1625579 SNP were significantly different between patients and controls (P = 0.036 and 0.026, SNP). TT genotype carriers showed slightly lower Brief Assessment of Cognition in Schizophrenia- (BACS-) derived working memory performance than G carriers (15.58 ± 9.56 versus 19.71 ± 8.18, P = 0.045). In the meta-analysis, we observed a significant association between rs1625579 and schizophrenia under different genetic models (all P < 0.05). The results of our study and meta-analysis provide convincing evidence that rs1625579 is significantly associated with schizophrenia. Furthermore, the miR-137 polymorphism influences the working memory performance of schizophrenic patients in a Chinese Han population.

Genetic Association of MiR-146a with Multiple Sclerosis Susceptibility in the Chinese Population

Background: miR-146a polymorphisms have been involved in susceptibility to multiple diseases. The aim of the present study was to analyze the potential association between two functional miR-146a polymorphisms (rs2910164 and rs57095329) and multiple sclerosis (MS) in the Han Chinese population. Methods: A cohort of 525 patients and 568 healthy controls were genotyped to detect the two polymorphisms by SNaPshot. Results: No significant differences were detected in the distribution of the two miR-146a polymorphisms between the patients and controls (P > 0.05). However, stratification by gender showed a statistically significant difference in the frequency of the genotype rs2910164 between MS patients and control females (P=0.009). Further stratification analysis by subgroup revealed that the miR-146a rs2910164 C allele conferred a higher risk of developing relapsing-remitting MS (RRMS) (P=0.018). In addition, the rs2910164 C allele was significantly associated with increased expression of miR-146a in patients with RRMS (P=0.025). Moreover, patients with the rs2910164 C allele released more TNF-α and IFN-γ, but not IL-1β, compared with individuals carrying the homozygous GG genotype (P < 0.05). Conclusions: Our results provide evidence that rs2910164 may play a role in MS susceptibility in females. The rs2910164 G>C variation may affect the expression of miR-146a and the release of proinflammatory cytokines.

A functional polymorphism of the microRNA-146a gene is associated with susceptibility to drug-resistant epilepsy and seizures frequency.

PURPOSE Epilepsy is the third most common chronic brain disorder and is characterized by an enduring predisposition for seizures. Recently, a growing body of evidence has suggested that microRNA-146a (miR-146a) is upregulated in the brains of epilepsy patients and of mouse models; furthermore, miR-146a may be involved in the development and progression of seizures through the regulation of inflammation and immune responses. In this report, we performed a case-control study to analyze the relationship between the two potentially functional single nucleotide polymorphisms (SNPs) of the miR-146a gene (rs2910464 and rs57095329) and the risk of epilepsy in a Chinese population comprising 249 cases and 249 healthy controls. METHOD Our study comprised 249 epilepsy patients and 249 healthy controls in two regions of China. The DNA was genotyped using the ABI PRISM SNapShot method. The statistical analysis was estimated using the chi-square test or Fishers exact test. RESULTS Our results indicated a significant association between the rs57095329 SNP of the miR-146a gene and the risk of drug resistant epilepsy (DRE) (genotypes, p = 0.0258 and alleles, p = 0.0108). Moreover, the rs57095329 A allele was found to be associated with a reduced risk of seizures frequency in DRE patients (all p < 0.001). However, the rs2910164 variant was not associated with epilepsy. CONCLUSION Our data indicate that the rs57095329 polymorphism in the promoter region of miR-146a is involved in the genetic susceptibility to DRE and the seizures frequency.

An Association Study on ADAM10 Promoter Polymorphisms and Atherosclerotic Cerebral Infarction in a Chinese Population

Dysregulation of the activity of the disintegrin/metalloproteinase ADAM10 could contribute to the development of atherosclerosis. Although a number of genetic studies have focused on the association of ADAM10 gene polymorphisms with susceptibility to diseases, no genetic association studies of ADAM10 gene variability with atherosclerotic cerebral infarction (ACI) have been conducted. The aim of this study was to analyze the potential association between ADAM10 promoter polymorphisms and ACI.

Intranasal Delivery of miR-146a Mimics Delayed Seizure Onset in the Lithium-Pilocarpine Mouse Model

Unveiling the key mechanism of temporal lobe epilepsy (TLE) for the development of novel treatments is of increasing interest, and anti-inflammatory miR-146a is now considered a promising molecular target for TLE. In the current study, a C57BL/6 TLE mouse model was established using the lithium-pilocarpine protocol. The seizure degree was evaluated according to the Racine scale, and level 5 was considered the threshold for generalized convulsions. Animals were sacrificed to analyze the hippocampus at three time points (2 h and 4 and 8 weeks after pilocarpine administration to evaluate the acute, latent, and chronic phases, resp.). After intranasal delivery of miR-146a mimics (30 min before pilocarpine injection), the percent of animals with no induced seizures increased by 6.7%, the latency to generalized convulsions was extended, and seizure severity was reduced. Additionally, hippocampal damage was alleviated. While the relative miR-146a levels significantly increased, the expression of its target mRNAs (IRAK-1 and TRAF-6) and typical inflammatory modulators (NF-κB, TNF-α, IL-1β, and IL-6) decreased, supporting an anti-inflammatory role of miR-146a via the TLR pathway. This study is the first to demonstrate that intranasal delivery of miR-146a mimics can improve seizure onset and hippocampal damage in the acute phase of lithium-pilocarpine-induced seizures, which provides inflammation-based clues for the development of novel TLE treatments.

Basic Fibroblast Growth Factor Protects C17.2 Cells from Radiation-Induced Injury through ERK1/2

To establish a radiation‐induced neural injury model using C17.2 neural stem cells (NSCs) and to investigate whether basic fibroblast growth factor (bFGF) can protect the radiation‐induced injury of C17.2 NSCs. Furthermore, we aim to identify the possible mechanisms involved in this model.

Role of glyoxalase I gene polymorphisms in late-onset epilepsy and drug-resistant epilepsy.

BACKGROUND Recent studies indicate that increased expression of glyoxalase I (GLO1) could result in epileptic seizures; thus, this study further explored the association of GLO1 with epilepsy from the perspective of molecular genetics. MATERIAL AND METHODS GLO1 single nucleotide polymorphisms (SNPs; rs1130534, rs4746 and rs1049346) were investigated in cohort I (the initial samples: 249 cases and 289 controls). A replication study designed to confirm the positive findings in cohort I was performed in cohorts II (the additional samples: 130 cases and 191 controls) and I+II. RESULTS In cohorts I, II and I+II, the CC genotype at rs1049346 T>C exerts a protective effect against both late-onset epilepsy (odds ratio [OR]=2.437, p=0.013; OR=2.844, p=0.008; OR=2.645, p=0.000, q=0.003, respectively) and drug-resistant epilepsy (DRE) (OR=2.985, p=0.020; OR=2.943, p=0.014; OR=3.049, p=0.001, q=0.006, respectively). Further analyses in cohort I+II indicate that the presence of the TAC/AAT haplotypes (rs1130534-rs4746-rs1049346) may be used as a marker of predisposition to/protection against DRE (p=0.002, q=0.010; p=0.000, q=0.002, respectively). CONCLUSIONS This study is the first to demonstrate that the GLO1 SNPs are significantly associated with epilepsy. In particular, the rs1049346 T>C SNPs are potentially useful for risk assessment of late-onset epilepsy and DRE.

Association of KEAP1 and NFE2L2 polymorphisms with temporal lobe epilepsy and drug resistant epilepsy.

BACKGROUND AND AIMS Temporal lobe epilepsy (TLE) is a prevalent form of epilepsy. TLE contributes to the majority of drug resistant epilepsy (DRE) cases and is associated with genetic factors. Kelch-like ECH-associated protein 1 (KEAP1)/Nuclear erythroid 2-related factor 2 (known as NFE2L2 or Nrf2) association has been implicated in neuroprotection due to induction of antioxidant enzymes. The association of one single KEAP1 gene nucleotide polymorphism (SNP) and nine NFE2L2 gene SNPs with TLE and DRE were examined to determine whether these SNPs influenced the risk of TLE and DRE in a Han population. SUBJECTS AND METHODS A total of 184 TLE patients (including 72 DRE patients) and 183 controls were included in this analysis. The SNaPshot Multiplex kit was used to assess the genotypes. RESULTS A NFE2L2 gene haplotype was identified as a risk factor for TLE (OR=7.11, 95% CI 1.53-32.98). Additionally, rs2706110 G>A in the NFE2L2 gene and rs1048290 C>G in the KEAP1 gene showed a significant risk for and a protective effect against DRE, respectively. CONCLUSION Our findings suggest that variations in NFE2L2 gene increase the risk of TLE and DRE but that variations in KEAP1 gene play a protective role for DRE.

Promoter Variants of the ADAM10 Gene and Their Roles in Temporal Lobe Epilepsy

Previous evidence has indicated that downregulated ADAM10 gives rise to epileptic seizures in Alzheimer’s disease, and this study investigated the association of ADAM10 with temporal lobe epilepsy (TLE) from a genetic perspective. A total of 496 TLE patients and 528 healthy individuals were enrolled and genotyped for ADAM10 promoter variants (rs653765 G > A and rs514049 A > C). The alleles, genotypes, and haplotypes were then compared with clarify the association of these variants with TLE and their impacts upon age at onset, initial seizure types before treatments, and responses to drug treatments. In cohorts I, II, and I + II, the frequencies of the A allele and AA genotype at rs514049 were consistently increased in the cases compared with the controls (p = 0.020 and p = 0.009; p = 0.008 and p = 0.009; p = 0.000 and p = 0.000; q = 0.003 and q = 0.002, respectively). In contrast, the frequency of the AC haplotype (rs653765–rs514049) decreased in cohorts I + II (p = 0.013). Further analyses of the TLE patients indicated that the AA genotype functioned as a predisposing factor to drug-resistant TLE and the AC haplotype as a protective factor against generalized tonic–clonic seizures (GTCS) and drug-resistant TLE. This study is the first to demonstrate an association of the ADAM10 promoter variants with TLE. In particular, the AA genotype and AC haplotype showed their effects upon GTCS and drug-resistant TLE.

Angiographic Correlation and Synergistic Effect of Coronary Artery Stenosis and Cerebral Artery Stenosis: A Retrospective Study

Background Comorbidity of coronary artery stenosis (CoAS) and cerebral artery stenosis (CeAS) is relatively common, but little is known about their angiographic correlation and synergistic effect. Material/Methods A total of 66 patients with CoAS were divided into 2 groups: 30 patients with mild CoAS in group A and 36 patients with severe CoAS in group B. Patients were subdivided further into 4 groups: 20 patients with multiple CeAS in group B1, 16 patients with non-multiple CeAS in group B2, 22 patients with multiple CeAS in group A1, and 8 patients with non-multiple CeAS in group A2. Then, the morbidity rates for myocardial infarction and ischemic stroke before angiography were analyzed. Results Overall, the incidence and extent of CoAS were positively related to those of CeAS (p=0.004 and p=0.008, respectively). After stratification, the incidences of stenotic vessels in the intracranial arteries (EA) and carotid artery system (CAS) in group B were significantly higher than those in group A (p=0.011 and p=0.007, respectively). Additionally, the morbidity rates for ischemic stroke in groups B1 and A1 showed a weak trend toward a significant difference (p=0.060). Conclusions This study indicates, for the first time, that severe CoAS might be a predictive marker for stenotic vessels of the EA and CAS and for severe CeAS. Furthermore, this study is the first to report that the synergistic effect of CoAS and CeAS might increase the risk of ischemic stroke, which must be confirmed in a large-scale prospective study.