Association of CYP3A4*1G and CYP3A5*3 With the 1-year Outcome of Acute Ischemic Stroke in the Han Chinese Population.

BACKGROUND AND PURPOSE: Previous studies have shown that common variants within CYP3A4 and CYP3A5 are associated with statin pharmacokinetics and the risk of cardiovascular disease. However, the association of variants in CYP3A4 and CYP3A5 with the prognosis of ischemic stroke remains undetermined. Therefore, we investigated this herein. METHODS: Four hundred thirty-three consecutive patients with acute ischemic stroke were recruited. The outcome at the 1-year follow-up was assessed using the modified Rankin Scale (mRS). Two variants, CYP3A4*1G and CYP3A5*3, were genotyped by the improved Multiple Ligase Detection Reaction platform. RESULTS: Binary logistic regression analysis showed that the CYP3A4*1G/*1G homozygote was associated with poor outcome at 1 year (mRS score ≥2) after adjustment for conventional factors in the additive model (odds ratio [OR] = 2.92; 95% confidence interval, 1.07-7.98; P = .037) and recessive model (OR = 3.37; 95% confidence interval, 1.26-9.04; P = .016). Subgroup analysis indicated that the CYP3A4*1G/*1G homozygote was associated with poor prognosis at 1 year among patients with stable high-intensity atorvastatin therapy (40-80 mg/d) after adjustment for conventional factors in the additive model (OR = 8.16; 95% confidence interval, 1.50-44.44; P = .015) and recessive model (OR = 9.06; 95% confidence interval, 1.72-47.64; P = .009). No significant association was identified between CYP3A5*3 and the 1-year outcome of patients with ischemic stroke. CONCLUSIONS: Our study findings suggest that the CYP3A4*1G/CYP3A4*1G genotype may be associated with poor prognosis at 1 year after acute ischemic stroke in the Han Chinese population.

Association of FOXF2 gene polymorphisms with ischemic stroke in Chinese Han population.

Recently, a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with an increased risk of stroke in European populations was identified. However, whether polymorphisms in FOXF2 are also associated with the incidence of ischemic stroke in other populations remains unknown. In this case-control study, 803 Chinese Han patients with ischemic stroke and 803 matched control individuals were enrolled. Four tag SNPs and rs12204590 located in or near FOXF2 were selected, and the associations between genotypes/alleles and ischemic stroke were analyzed. In our study, we did not detect an association between the previously reported locus rs12204590 and ischemic stroke. By the genotype analysis, a novel SNP rs1711972, near FOXF2, was observed to be associated with an increased risk of ischemic stroke(CA genotype, adjusted OR = 1.35; 95% CI, 1.07 to 1.70), but not significantly after Bonferroni corrections for multiple tests. However, in the subgroup analysis, we discovered that rs1711972 was associated with an increased risk of large-artery atherosclerotic stroke in the additive model (P = 0.020; CA genotype, adjusted OR = 1.50; 95%CI, 1.09 to 2.07) and dominant model (P = 0.010; OR = 1.47; 95%CI, 1.09 to 1.99). Collectively, these results indicate that a novel SNP near FOXF2 may influence the risk of large-artery atherosclerotic stroke in Chinese Han population.

Association of GWAS-Reported Variant rs11196288 near HABP2 with Ischemic Stroke in Chinese Han Population.

A recent genome-wide association analysis identified a novel single nucleotide polymorphism locus on chromosome 10q25.3 (rs11196288, near HABP2) associated with the risk of early-onset ischemic stroke (IS) in European population, but not with late-onset IS. However, the role of this genome-wide association study (GWAS)-reported variant in ischemic stroke in Chinese Han population remained unknown. In our study, 389 adult ischemic stroke patients with an age of onset <60 years and 389 matched healthy controls were enrolled to investigate association of rs11196288 genotypes with early-onset ischemic stroke and its subtypes; the association was further examined in another independent population consisting of 349 ischemic stroke patients with an age of onset ≧60 years and 349 matched healthy individuals. Logistic regression analysis showed no significant association between rs11196288 and early-onset ischemic stroke (IS), large artery atherosclerotic (LAA) stroke, or small vessel disease (SVD) stroke (all P > 0.050). Nevertheless, in subgroup analysis of the older population, rs11196288 presented significant effect on late-onset SVD stroke susceptibility in the dominant model (GG/GA vs AA, OR 1.70; 95%CI 1.02 to 2.85; P = 0.042). The results indicated that the role of rs11196288 polymorphism in ischemic stroke susceptibility in Chinese Han population may be different from that in European. Larger studies with diverse populations are warranted to confirm and extend our findings.

Nerve growth factor for the treatment of spinocerebellar ataxia type 3: an open-label study.

BACKGROUND: Spinocerebellar ataxia type 3 (SCA3) is the most common subtype of SCA worldwide, and runs a slowly progressive and unremitting disease course. There is currently no curable treatment available. Growing evidence has suggested that nerve growth factor (NGF) may have therapeutic effects in neurodegenerative diseases, and possibly also in SCA3. The objective of this study was to test the efficacy of NGF in SCA3 patients. METHODS: We performed an open-label prospective study in genetically confirmed adult (>18 years old) SCA3 patients. NGF was administered by intramuscular injection (18 µg once daily) for 28 days consecutively. All the patients were evaluated at baseline and 2 and 4 weeks after treatment using the Chinese version of the scale for assessment and rating of ataxia (SARA). RESULTS: Twenty-one SCA3 patients (10 men and 11 women, mean age 39.14 ± 7.81 years, mean disease duration 4.14 ± 1.90 years, mean CAG repeats number 77.57 ± 2.27) were enrolled. After 28 days of NGF treatment, the mean total SARA score decreased significantly from a baseline of 8.48 ± 2.40 to 6.30 ± 1.87 (P < 0.001). Subsections SARA scores also showed significant improvements in stance (P = 0.003), speech (P = 0.023), finger chase (P = 0.015), fast alternating hand movements (P = 0.009), and heel-shin slide (P = 0.001). CONCLUSIONS: Our preliminary data suggest that NGF may be effective in treating patients with SCA3.

[Construction of the HSV-1 strain HF amplicon and study on its unversal function between different HSV serotypes].

The study aimed to construct the amplicon vector of HSV-1 strain HF and explore its universal package function between different serotypes of HSV. OriS and pac elements were obtained by enzyme digestion from the Plasmid BAC-HSV-1 strain HF and sequenced. With red fluorescence (DsRed) as a reporter gene, the amplicon vector of HSV-1 strain HF was constructed based on pSilencer2.0-U6. The amplicon vector was transfected into Vero cells by lipofectamine 2000, then packaged by HSV-1 strain HF and HSV-2 strain HG52 as helper virus separately. The supernatant was collected after cytopathic effect. Red fluorescence was observed in Vero cells reinfected by the supernatant. In this study,the amplicon vector of HSV-1 strain HF was successfully constructed and it could be packaged by HSV-1 strain HF and HSV-2 strainHG52.

[Construction of a recombinant BAC-HSV-1 strain HF with a GFP reporter gene and characterization of its infectious progeny virus].

To construct the plasmid of BAC-HSV-1 with GFP reporter gene and research the biological property of its infectious progeny virus. We constructed the plasmid C223-UL43-left-arms-UL47-right-arms which carried the homologous sequences of HSV-1. Liposome embedding method was used to transfect HSV-1 genome and the plasmid C223-UL43-left-arms-UL47-right-arms linearized by Mlu I digestion into Vero cells. After the successful homologous recombination in the eukaryotic cells, the recombinant BAC-HSV-1 with GFP reporter gene was generated. Then, the positive CPE were taken by plaque purification and by hirt extraction during the moment of the circularization of HSV-1 DNA, and the plasmid of BAC -HSV-1 was acquired. Electroporation was used to transfect the BAC -HSV-1 into DH10B, and then the single colonies of interest were confirmed both by MluI digestion and PCR. Experimental group and the control group cells were given BAC-HSV-1 plasmid and HSV-1 genomic DNA respectively to produce the BAC-HSV-1 and HSV-1 progeny virions. Vero cells were inoculated with the progeny virions at MOI = 0.1 and then a TCID50 assay was performed to determine the titers of virons in the two groups at 48 hours post inoculation. The plasmid BAC-HSV-1 was successfully constructed by the restriction enzyme analysis and the PCR. The titers of progeny virions were calculated by the TCID50 assay. No significant difference in the titers of virions between two groups was observed (P > 0.05). The infectious BAC-HSV-1 shuttle virus/plasmid between eukaryotic and prokaryotic cells was successfully constructed.