Shuyan Zhang

PICALM Gene rs3851179 Polymorphism Contributes to Alzheimer’s Disease in an Asian Population

PICALM gene rs3851179 polymorphism was reported to an Alzheimer’s disease (AD) susceptibility locus in a Caucasian population. However, recent studies reported consistent and inconsistent results in an Asian population. Four studies indicated no association between rs3851179 and AD in a Chinese population and one study reported weak association in a Japanese population. We consider that the failure to replicate the significant association between rs3851179 and AD may be caused by at least two reasons. The first reason may be the genetic heterogeneity in AD among different populations, and the second may be the relatively small sample size compared with large-scale GWAS in Caucasian ancestry. In order to confirm this view, in this research, we first evaluated the genetic heterogeneity of rs3851179 polymorphism in Caucasian and Asian populations. We then investigated rs3851179 polymorphism in an Asian population by a pooled analysis method and a meta-analysis method. We did not observe significant genetic heterogeneity of rs3851179 in the Caucasian and Asian populations. Our results indicate that rs3851179 polymorphism is significantly associated with AD in the Asian population by both pooled analysis and meta-analysis methods. We believe that our findings will be very useful for future genetic studies in AD.

BIN1 gene rs744373 polymorphism contributes to Alzheimer's disease in East Asian population

Large-scale genome-wide association studies (GWAS) identified BIN1 gene rs744373 polymorphism to be significantly associated with Alzheimers disease (AD) in Caucasian ancestry. Recently, this polymorphism was also investigated in East Asian population. However, no study reported significant association. We consider that the failure to replicate significant association between rs744373 polymorphism and AD may be caused by the relatively small sample size. In this research, we evaluated this association using pooled samples from previous studies (n=4982, 1437 AD cases and 3545 controls). Two methods including pooled analysis and meta-analysis were used to investigate the association. Using the pooled analysis, we observed significant association between rs744373 polymorphism and AD by both genotype test (P=3.94E-03, 4.59E-03 and 1.04E-02) and allele test (P=1.12E-03, OR=1.16, 95% CI 1.06-1.28). Interestingly, the meta-analysis confirmed this association with P=8.00E-03 (OR=1.14, 95% CI 1.03-1.25) and P=2.00E-02 (OR=1.16, 95% CI 1.02-1.32). We also evaluated the effect of rs744373 polymorphism on AD risk in different ethnic backgrounds and found that rs744373 polymorphism contributed to AD with similar genetic risk in East Asian and Caucasian populations. To our knowledge, this is the first study to show significant association between rs744373 polymorphism and AD in East Asian population.

Cell adhesion molecule pathway genes are regulated by cis-regulatory SNPs and show significantly altered expression in Alzheimer's disease brains.

We previously identified the cell adhesion molecule (CAM) pathway as a consistent signal in 2 Alzheimers disease (AD) genome-wide association studies (GWAS). However, the genetic mechanisms of the CAM pathway in AD are unclear. Here, we conducted pathway analysis using (1) Kyoto Encyclopedia of Genes and Genomes and Gene Ontology pathways; (2) 4 brain expression GWAS datasets; and (3) 2 whole-genome AD case-control expression datasets. Using the 4 brain expression GWAS datasets, we identified that genes regulated by cis-regulatory single-nucleotide polymorphisms (SNPs) were significantly enriched in the CAM pathway (p = 2.05E-06, p = 6.10E-07, p = 2.05E-06, and p = 1.47E-07 for each dataset). Interestingly, CAM is a significantly enriched pathway using down-regulated genes (raw p = 0.0235 and adjusted p = 0.0305) and all differentially expressed genes (raw p = 0.0105 and adjusted p = 0.0156) in dataset 5, and all differentially expressed genes (raw p = 0.0041 and adjusted p = 0.0062) in dataset 6. Collectively, our results show that CAM pathway genes are regulated by cis-regulatory SNPs and show significantly altered expression in AD. We believe that our results advance the understanding of AD mechanisms and will be useful for future genetic studies of AD.

Harmine mediated neuroprotection via evaluation of glutamate transporter 1 in a rat model of global cerebral ischemia

Global cerebral ischemia (GCI) causes energy deficiency results in excessive release of glutamate from neurons. Astrocytic glutamate transporters play a predominant role in keeping extracellular glutamate concentrations below excitotoxic levels. Glutamate transporter 1 (GLT-1) may account for more than 90% of glutamate uptake in adult forebrain. Preclinical findings implicate that Harmine present neuroprotection effects in a rat model of amyotrophic lateral sclerosis disease, and the beneficial effects were specifically due to up-regulation of GLT-1. However, no experiments have explored the potential of Harmine to provide neuroprotection in the setting of GCI. The current study was designed to determine whether Harmine could attenuate cerebral infarction as well as improve neuronal survival after GCI. Furthermore, to test whether the mechanisms were associated with up-regulating of GLT-1, we used a GLT-1 specific inhibitor dihydrokainate (DHK) and analysis the expression of GLT-1 mRNA and protein in cortex of brain. We also examined whether Harmine treatment affected astrocytes activation via immunofluorescence. Our results showed that post-GCI administration of Harmine could attenuate cerebral infarct volume and decrease neurons death. It also caused significantly elevation of GLT-1 mRNA and protein and remarkably attenuation of astrocyte activation. We provide novel clues in understanding the mechanisms of which Harmine exerts its neuroprotective activity in neurological disorders.

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.

Polymorphisms in the receptor for advanced glycation end products gene are associated with susceptibility to drug-resistant epilepsy.

Increasing evidence has demonstrated that inflammation plays an important role in epilepsy (EP). As a cell-surface molecule of the immunoglobulin superfamily, the receptor for advanced glycation end products (RAGE) is involved in inflammation-related disease. Functional polymorphisms in the regulatory elements and/or ligand-binding regions of RAGE may alter the expression and function of RAGE, thus affecting EP susceptibility. Here, we have identified a novel association between genetic variants in the RAGE G82S locus and EP (p=0.033) using a case-control study in a Chinese population. Further analyses showed that the 82S+ genotype and S allele were more common in patients with drug-resistant epilepsy (DRE) than in those with drug-responsive EP compared with controls. The loci -374T/A and -429T/C did not demonstrate any association with EP, but the haplotype T-A-A exhibited significantly different frequencies between DRE patients and controls (OR=1.696, 95% CI: 1.188-2.420, P=0.003). Our study provides preliminary evidence that the G82S polymorphism in RAGE is associated with increased DRE risk and that the GS genotype of the G82S locus is a risk factor for DRE in the Chinese population.

Association of Tag SNPs and Rare CNVs of the MIR155HG/miR-155 Gene with Epilepsy in the Chinese Han Population.

Background. miR-155 likely acts as an important modulator in the inflammatory mechanism of epilepsy, and this study investigated its association with epilepsy from the perspective of molecular genetics. Methods. This study enrolled 249 epileptic patients and 289 healthy individuals of the Chinese Han population; 4 tag single-nucleotide polymorphisms (SNPs: rs969885, rs12483428, rs987195, and rs4817027) of the MIR155HG/miR-155 gene were selected, and their association with epilepsy was investigated. Additionally, this study determined the copy numbers of the MIR155HG/miR-155 gene. Results. The TCA haplotype (rs12483428-rs987195-rs4817027) and the AA genotype at rs4817027 conferred higher vulnerability to epilepsy in males. Stratification by age of onset revealed that the CC haplotype (rs969885-rs987195) was a genetic susceptibility factor for early-onset epilepsy. Further stratification by drug-resistant status indicated the CC haplotype (rs969885-rs987195) and the AA genotype at rs4817027 were genetic susceptibility factors for drug-resistant epilepsy (DRE) but the CG haplotype (rs987195-rs969885) was a genetically protective factor against DRE. Besides, 3 epileptic patients with copy number variants of the MIR155HG/miR-155 gene were observed. Conclusions. This study first demonstrates the association of MIR155HG/miR-155 tag SNPs with epilepsy and shows that rare CNVs were found exclusively in epileptic patients, clarifying the genetic role of miR-155 in epilepsy.