Zhiyi He

Association of PDE4D and IL-1 gene polymorphism with ischemic stroke in a Han Chinese population

BACKGROUND The single-nucleotide polymorphisms (SNPs) of the phosphodiesterase 4D (PDE4D) and interleukin-1 (IL-1) genes are associated with increased risk for the development of ischemic stroke (IS) in whites. However, little is known about whether this association could also occur in Han Chinese. METHOD A total of 371 patients with IS and unrelated healthy controls were recruited and the SNPs of the PDE4D (83T/C), (87T/C), IL-1 (-889C/T) and IL-1 (-511C/T) were characterized, respectively, by polymerase chain reactions-restriction fragment length polymorphism (PCR-RFLP). The genotype and allele frequencies of these SNPs in this population were statistically analyzed. RESULTS The genotype and allele frequencies of the PDE4D (87T/C) and IL-1 (-511C/T) were similar between IS patients and controls. In contrast, the frequencies of CC genotype and C allele of the PDE4D (83T/C) and the T allele frequency of IL-1 (-889C/T) in IS patients were significantly higher than that in healthy controls (p=0.001, p=0.003 and p=0.02, respectively), independent of the conventional risk factors. The values of odds ratio (OR) reached at OR=1.603; 95%CI=1.032-2.489; p=0.036 for the CC genotype of the PDE4D (83T/C) and OR=1.913; 95%CI=1.621-2.375; p=0.034 for the TT genotype of the IL-1 (-889C/T), respectively. CONCLUSIONS the SNPs of the PDE4D (83T/C) and IL-1 (-889C/T) were associated with increased risk for the development of IS in Northern Han Chinese.

Association of apolipoprotein M gene polymorphisms with ischemic stroke in a Han Chinese population.

The apolipoprotein M (ApoM) gene is critical in the formation of pre-β-high-density lipoprotein (HDL) and cholesterol efflux to HDL. In this case and control study, 314 ischemic stroke patients and 389 healthy controls were analyzed for three ApoM gene single-nucleotide polymorphisms (SNPs), i.e., C-1065A, T-855C, and T-778C, using a SNaPshot Multiplex sequencing assay. The genotype and allele frequencies of the T-855C were similar in both ischemic stroke patients and the controls. But the frequency of the TC genotype, the C allele of T-778C, and the A allele of the C-1065A SNPs in ischemic stroke patients was significantly higher than that of the healthy controls. After adjusting for confounding risk factors (such as hypertension, diabetes, tobacco smoking, and alcohol consumption), the ApoM gene TC genotype, C allele of T-778C, and A allele of C-1065A were associated with a risk of ischemic stroke. Moreover, plasma levels of total cholesterol were significantly higher in patients with CC or CT genotypes of T-778C than those with TT genotype in the controls. The current data demonstrated that ApoM T-778 C and C-1065A SNPs were associated with increased risk of ischemic stroke in this Han Chinese population.

Association of inflammatory response gene polymorphism with atherothrombotic stroke in Northern Han Chinese

Atherosclerosis is an important pathophysiological basis of atherothrombotic stroke (ATS), and inflammation plays a significant role in atherosclerosis formation. In this study, single-nucleotide polymorphisms (SNPs) in three key inflammation-related genes, 5-lipoxygenase activating protein (ALOX5AP), phosphodiesterase 4D (PDE4D), and interleukin-1α (IL-1α), were investigated to determine their association with ATS in Northern Han Chinese. Six-hundred and eighty-two ATS patients and 598 unrelated controls were recruited. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism and matrix-assisted laser desorption ionization time-of-flight mass spectrometry primer extension. The genotype and allele frequencies of each SNP were statistically analyzed. Risk of ATS was found for the ALOX5AP SG13S114A/T AA genotype (P = 0.040) and A allele (P = 0.033), PDE4D SNP83C/T TT genotype (P = 0.010) and T allele (P = 0.008) and SNP219A/G GG genotype (P = 0.025) and G allele (P = 0.022), and the IL-1α-889C/T T allele (P = 0.035). The differences still remained significant after adjustment. The ALOX5AP HapA haplotype was not correlated with ATS (P = 0.834), but GCGA represented an at-risk haplotype (P = 0.008). Furthermore, the PDE4D AA haplotype at SNP219-220 might be an at-risk haplotype (P = 0.013), while GA might be a protective haplotype (P = 0.005). The ALOX5AP (SG13S114A/T), PDE4D (SNP83C/T, 219A/G), and IL-1α (-889C/T) SNPs were associated with an increased risk of ATS in Northern Han Chinese.

ApoE gene polymorphism and vascular dementia in Chinese population: a meta-analysis

Vascular dementia is the second common cause of dementia, only second to Alzheimer’s disease in later life. The Apolipoprotein E (ApoE) gene polymorphism as a risk factor in vascular dementia has been suggested, but direct evidence from genetic association studies remains inconclusive even in Chinese population. Therefore, we performed this meta-analysis in order to evaluate the relationship between ApoE gene polymorphism and susceptibility to vascular dementia in Chinese population by pooling data from all relevant case–control studies published domestically and abroad from January 1990 to May 2011. 18 case–control studies were selected. Meta-analysis results showed that the pooled OR value of vascular dementia subjects in Chinese population with ε4 allele carriers was 2.07 [95% CI (1.69, 2.53)], and the pooled OR value of vascular dementia subjects with E4/E4 genotype was 3.34 [95% CI (1.89, 5.88)]. These results suggest that ApoE polymorphism is significantly associated with susceptibility to vascular dementia in Chinese population. The subject with at least one ε4 allele or E4/E4 genotype has higher risk suffering from vascular dementia than others.

Association of PLA2G7 gene polymorphisms with ischemic stroke in northern Chinese Han population.

OBJECTIVE Human lipoprotein-associated phospholipase A2 (Lp-PLA2), encoded by the PLA2G7 gene, plays an important role in the pathophysiology of inflammation. This study is aimed at evaluating the potential association of V279F and A379V in PLA2G7 gene with ischemic stroke where inflammatory process is involved. DESIGN AND METHODS A total of 386 patients with ischemic stroke and 386 healthy controls were included in the study. The single nucleotide polymorphisms, V279F and A379V, were analyzed by the polymerase chain reaction-ligation detection reaction method. RESULTS The frequencies of VV+AV genotype, AV genotype and V allele of A379V in the patients with ischemic stroke were significantly higher than those in the controls (P=0.02, P=0.03, P=0.02, respectively). These correlations still remained after adjusting for confounding risk factors of stroke. Furthermore, subgroup analysis showed that a significant association with A379V was found in large-artery atherosclerotic stroke subgroup. In addition, no significant association was observed between V279F and ischemic stroke. CONCLUSION The study indicated that the A379V variant in PLA2G7 gene might contribute to ischemic stroke susceptibility in northern Chinese Han population.

Genetic polymorphism in PDE4D gene and risk of ischemic stroke in Chinese population: a meta-analysis.

Background Stroke is the second most common cause of death and major cause of disability worldwide. The SNP 83 in PDE4D gene has been suggested as a risk factor in ischemic stroke, but direct evidence from genetic association studies remains inconclusive even in Chinese population. Methods Meta-analysis of case-control studies on the relationship between SNP 83 in PDE4D gene and susceptibility to ischemic stroke in Chinese population published domestically and abroad from January 2003 to September 2012. Results 9 case-control studies were selected. Meta-analysis results showed that the significant association between SNP 83 and ischemic stroke was found under the dominant model (OR = 1.34, 95% CI: 1.20–1.49) and recessive model (OR = 1.45, 95% CI: 1.19–1.76) in Chinese population. In subgroup meta-analysis, SNP 83 and atherothrombotic stroke, rather than lacunar stroke, showed the significant association under the dominant model (OR = 1.69, 95% CI: 1.41–2.01) and recessive model (OR = 1.47, 95% CI: 1.04–2.06). Conclusions The results suggest that SNP 83 in PDE4D gene is significantly associated with susceptibility to ischemic stroke in Chinese population.

Association of ALOX15 Gene Polymorphism with Ischemic Stroke in Northern Chinese Han Population

Arachidonate 12/15-lipoxygenase (12/15-LOX) is a member of the lipid peroxidizing enzyme family and plays a major role in atherosclerosis. The present study aimed to evaluate whether or not the ALOX15 gene polymorphism is involved in ischemic stroke in northern Chinese Han population. Participants in a case–control study included 396 patients (239 males, 157 females) with ischemic stroke and 360 healthy subjects (211 males, 149 females). The rs7217186 polymorphism of the ALOX15 gene was analyzed by polymerase chain reaction and restriction fragment length polymorphism, while the rs2619112 polymorphism of the ALOX15 gene was analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The frequencies of the CC genotype and the C allele of rs7217186 were higher in participants with ischemic stroke than in the control group [P = 0.014 in males, P = 0.007 in atherosclerosis ischemic stroke (ACI)]. The frequencies of the AA genotype and the A allele of rs2619112 were higher in participants with ischemic stroke than in the control group (P = 0.011 in males, P = 0.015 in ACI). Multiple logistic regression analysis revealed the significance of rs7217186 and rs2619112 in males and in ACI after adjustment for confounding factors. The rs7217186 and rs2619112 polymorphisms of the ALOX15 gene were associated with ischemic stroke in males and in patients with ACI in northern Chinese Han population.

Ursolic acid reduces the metalloprotease/anti-metalloprotease imbalance in cerebral ischemia and reperfusion injury

Background Activators of PPARs, particularly PPARγ, may be effective neuroprotective drugs against inflammatory responses in cerebral ischemia and reperfusion injury. Ursolic acid (UA) may act as a PPARγ agonist and serve as an anti-inflammatory agent. In this study, we used a rat middle cerebral artery occlusion and reperfusion model to examine how UA acts as a neuroprotective agent to modulate the metalloprotease/anti-metalloprotease balance. Methods The middle cerebral artery occlusion and reperfusion model (occlusion for 2 hours followed by reperfusion for 48 hours) was induced in male Sprague Dawley rats. UA was administered intragastrically 0.5, 24, and 47 hours after reperfusion. Bisphenol A diglycidyl ether (a PPARγ antagonist) was intraperitoneally administered 1, 24.5, and 47.5 hours after reperfusion. Forty-eight hours after reperfusion, neurological deficits and infarct volume were estimated. The PPARγ level and the metalloprotease/anti-metalloprotease balance were examined by Western blotting and immunohistochemistry. The activation of MAPK signaling pathways was also assessed. Results UA-treated (5, 10, or 20 mg/kg) rats showed significant improvement in neurological deficit score, infarct volume, and the number of intact neurons compared with control rats (P<0.01). Both the PPARγ protein level and the percentage of PPARγ-positive cells were increased in the UA-treated groups (P<0.01). Compared with the control group, the UA-treated groups exhibited reduced protein levels of MMP2, MMP9, and activated MAPKs (P<0.01) but an increased level of TIMP1 (P<0.01). UA exerted its protective effects in a dose-dependent manner. Co-treatment with UA and bisphenol A diglycidyl ether completely abolished the UA-induced changes in PPARγ expression; however UA continued to exert a significant but partial neuroprotective effect. Conclusion UA can act as a PPARγ agonist to improve the metalloprotease/anti-metalloprotease balance, possibly by inhibiting the activation of the MAPK signaling pathway, thereby attenuating cerebral ischemia and reperfusion injury. Therefore, UA may serve as a novel neuroprotective therapeutic agent.

Association of Altered Serum MicroRNAs with Perihematomal Edema after Acute Intracerebral Hemorrhage

Background and Purpose Perihematomal edema (PHE) contributes to secondary brain damage and aggravates patient outcomes after intracerebral hemorrhage (ICH). MicroRNAs (miRNAs) are stable in circulation, and their unique expression profiles have fundamental roles in modulating vascular disease. The objective of this study was to test the hypothesis that altered miRNA levels are associated with PHE in ICH patients. Methods Hematoma and PHE volumes of ICH patients were measured on admission and in follow-up computed tomography scans. Whole-genome miRNA profiles of ICH patients and healthy controls were determined using the Exiqon miRCURY LNA Array, and validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Bioinformatics analysis investigated dysregulated miRNA target genes and the signaling pathways involved. Results We identified 55 miRNAs that were differentially expressed in ICH patients compared with normal controls, of which 54 were down-regulated and one was up-regulated. qRT-PCR confirmation showed decreases in miR-126 (0.63-fold), miR-146a (0.64-fold), miR-let-7a (0.50-fold), and miR-26a (0.54-fold) in ICH patients relative to controls. Serum miR-126, but not miR-146a, miR-let-7a or miR-26a, levels were significantly correlated with relative PHE volume on days 3–4 (r = −0.714; P<0.001) in patients with ICH. Conclusions ICH patients appear to have a specific miRNA expression profile. Low expression of miR-126 was positively correlated with the extent of PHE, suggesting it may have a pathogenic role in the development of PHE after ICH.

The RANTES gene promoter polymorphisms are associated with the risk of atherothrombotic cerebral infarction in Northern Han Chinese

BACKGROUND Regulated upon activation, normal T-cell expressed and secreted (RANTES) plays an important role in the inflammatory process. This study is aimed at evaluating the potential association of the -403G/A (rs2107538) and -28C/G (rs2280788) polymorphisms of the RANTES gene promoter with the risk of atherothrombotic cerebral infarction (ACI) in Northern Han Chinese. METHOD A total of 314 patients with ACI and 389 unrelated aged-matched healthy controls were recruited. Their genotypes of the RANTES gene promoter -403G/A (rs2107538) and -28C/G (rs2280788) were analyzed by multiplex polymerase chain reaction (multiplex PCR) and multiplex SNaPshot analysis. The potential association of genotyping and allele frequencies with ACI in this population was assessed statistically. RESULTS The frequencies of -403AA genotype and A allele in ACI male patients were significantly higher than that in healthy controls (P=0.007, P=0.009, respectively). Female patients were not different. Multiple logistic regression analysis revealed that the -403AA genotype in males was significantly associated with an increased risk of ACI, even after adjusting for confounding factors (OR=4.344; 95% CI=1.969-9.582; P<0.001). Although there was no significant association of the -28C/G polymorphism with ACI, the A-(403)C-(28) haplotype was significantly associated with an increased risk of ACI in Han Chinese [OR=1.56, 95% CI=1.23-1.98, P<0.001]. CONCLUSIONS Our data suggest that the -403AA genotype and A allele of the RANTES promoter were associated with increased risk for the development of ACI in male Northern Han Chinese.