Chuan-Qin Fang

Association between apolipoprotein E gene polymorphism and the risk of vascular dementia: A meta-analysis

It remains controversial regarding the association between Apolipoprotein E (ApoE) gene polymorphism and the risk of vascular dementia (VaD). The present meta-analysis was performed to derive a more precise estimation of the relationship. The meta-analysis was performed by searching PubMed, Embase and Web of Science databases. A total of 29 studies included 1763 VaD cases and 4534 controls were identified. The results showed evidence for significant association between ApoE ɛ4 mutation and VaD risk (for ɛ3/ɛ4 vs. ɛ3/ɛ3: OR=1.65, 95% CI=1.40-1.94, p-value<0.00001; for ɛ4/ɛ4 vs. ɛ3/ɛ3: OR=3.17, 95% CI=2.09-4.80, p-value<0.00001; for ɛ4 allele vs. ɛ3 allele: OR=1.72, 95% CI=1.40-2.12, p-value<0.00001). The similar results were obtained in the subgroup analysis based on ethnicity. In summary, the present meta-analysis suggests an association between ApoE ɛ4 mutation and increased risk of VaD. However, due to the small sample size in most of the included studies and the selection bias existed in some studies, the results should be interpreted with caution.

PPARγ attenuates intimal hyperplasia by inhibiting TLR4-mediated inflammation in vascular smooth muscle cells

AIMS Peroxisome proliferator-activated receptor γ (PPARγ) has been reported to attenuate intimal hyperplasia. This study aimed to test the hypothesis that PPARγ inhibits intimal hyperplasia through suppressing Toll-like receptor 4 (TLR4)-mediated inflammation in vascular smooth muscle cells. METHODS AND RESULTS TLR4(-/-) mice on a C57BL/6J background were used. Increased TLR4 and pro-inflammatory cytokines were observed in wire-injury-induced carotid neointima and in platelet-derived growth factor (PDGF)-activated vascular smooth muscle cells. The TLR4 deficiency protected the injured carotid from neointimal formation and impaired the cellular proliferation and migration in response to lipopolysaccharide and PDGF. Rosiglitazone attenuated intimal hyperplasia. Overexpression of PPARγ suppressed PDGF-induced proliferation and migration and inhibited TLR4-mediated inflammation in vascular smooth muscle cells, while PPARγ silencing exerted the opposite effect. Lipopolysaccharide counteracted the inhibitory effect of PPARγ on PDGF-induced proliferation and migration. Eritoran suppressed the proliferation and migration induced by PDGF and PPARγ silencing. Vascular smooth muscle cells derived from TLR4(-/-) mice showed impaired proliferation and migration upon PDGF activation and displayed no response to PPARγ manipulation. CONCLUSION PPARγ inhibits vascular smooth muscle cell proliferation and migration by suppressing TLR4-mediated inflammation and ultimately attenuates intimal hyperplasia after carotid injury.

Impaired Peroxisome Proliferator-activated Receptor-γ Contributes to Phenotypic Modulation of Vascular Smooth Muscle Cells during Hypertension

The phenotypic modulation of vascular smooth muscle cells (VSMCs) plays a pivotal role in hypertension-induced vascular changes including vascular remodeling. The precise mechanisms underlying VSMC phenotypic modulation remain elusive. Here we test the role of peroxisome proliferator-activated receptor (PPAR)-γ in the VSMC phenotypic modulation during hypertension. Both spontaneously hypertensive rat (SHR) aortas and SHR-derived VSMCs exhibited reduced PPAR-γ expression and excessive VSMC phenotypic modulation identified by reduced contractile proteins, α-smooth muscle actin (α-SMA) and smooth muscle 22α (SM22α), and enhanced proliferation and migration. PPAR-γ overexpression rescued the expression of α-SMA and SM22α, and inhibited the proliferation and migration in SHR-derived VSMCs. In contrast, PPAR-γ silencing exerted the opposite effect. Activating PPAR-γ using rosiglitazone in vivo up-regulated aortic α-SMA and SM22α expression and attenuated aortic remodeling in SHRs. Increased activation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling was observed in SHR-derived VSMCs. PI3K inhibitor LY294002 rescued the impaired expression of contractile proteins, and inhibited proliferation and migration in VSMCs from SHRs, whereas constitutively active PI3K mutant had the opposite effect. Overexpression or silencing of PPAR-γ inhibited or excited PI3K/Akt activity, respectively. LY294002 counteracted the PPAR-γ silencing induced proliferation and migration in SHR-derived VSMCs, whereas active PI3K mutant had the opposite effect. In contrast, reduced proliferation and migration by PPAR-γ overexpression were reversed by the active PI3K mutant, and further inhibited by LY294002. We conclude that PPAR-γ inhibits VSMC phenotypic modulation through inhibiting PI3K/Akt signaling. Impaired PPAR-γ expression is responsible for VSMC phenotypic modulation during hypertension. These findings highlight an attractive therapeutic target for hypertension-related vascular disorders.

Association between NADPH Oxidase p22phox C242T Polymorphism and Ischemic Cerebrovascular Disease: A Meta-Analysis

Background Epidemiological studies have evaluated the association between nicotinamide adenine dinucleotide phosphate (NADPH) oxidase p22phox C242T polymorphism and risk of ischemic cerebrovascular disease (ICVD), but the results remain inconclusive. This meta-analysis was therefore designed to clarify these controversies. Methodology/Principal Findings Systematic searches of electronic databases Embase, PubMed and Web of Science, as well as hand searching of the references of identified articles and the meeting abstracts were performed. Statistical analyses were performed using software Review Manager (Version 5.1.7) and Stata (Version 11.0). The pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were performed. Fixed or random effects model was separately used depending on the heterogeneity between studies. Publication bias was tested by Beggs funnel plot and Eggers regression test. A total of 6 studies including 1,948 cases and 2,357 controls were combined showing no statistical evidence of association between NADPH oxidase p22phox C242T polymorphism and overall ICVD (allelic model: OR = 1.08, 95%CI = 0.93–1.26; additive model: OR = 1.33, 95%CI = 0.81–2.17; dominant model: OR = 1.00, 95%CI = 0.86–1.15; recessive model: OR = 1.06, 95%CI = 0.77–1.45). Significant association was found in large-artery atherosclerotic stroke subgroup (allelic model: OR = 1.12, 95%CI = 0.88–1.41; additive model: OR = 1.36, 95%CI = 0.60–3.09; dominant model: OR = 1.25, 95%CI = 0.74–2.11; recessive model: OR = 2.17, 95%CI = 1.11–4.23). No statistical evidence of significant association was observed for small-vessel occlusive stroke, as well as Asian subgroup and Caucasian subgroup. Statistical powers on the combined sample size (total and subgroup) were all lower than 80%. Conclusions/Significance This meta-analysis indicates that NADPH oxidase p22phox C242T polymorphism is more associated with large-artery atherosclerotic stroke than small-vessel occlusive stroke. However, this conclusion should be interpreted with caution due to the small sample size. Larger sample-size studies with homogeneous ICVD patients and well-matched controls are required.

Vascular Risk Aggravates the Progression of Alzheimer's Disease in a Chinese Cohort

To investigate whether vascular risk affects the progression of Alzheimers disease (AD), 415 AD patients aged 65 years old and over without cerebrovascular diseases were enrolled and administered with a structured interview to assess demography, vascular risk factors, and cognitive and functional status at baseline, and 324 AD patients were followed up annually for 5 years. A mixed random effects regression model was used to identify the association between vascular risk, individual vascular risk factors, and the progression of AD. After adjusting for confounding factors, AD patients with vascular risk had faster cognitive and functional decline rates than the subjects without such risk factors. Individual vascular risk factors including hypertension and diabetes mellitus, transient ischemic attack and cerebrovascular accident during the follow-up were independently associated with the progression of AD. Our findings suggest that vascular risk aggravates the progression of AD and may be involved in the etiologic process of AD. As such, control of vascular risk may slow down the progression of AD.

Association between apolipoprotein E gene polymorphism and the risk of multiple sclerosis: A meta-analysis of 6977 subjects

Epidemiological studies have evaluated the association between apolipoprotein E (ApoE) gene polymorphism and multiple sclerosis (MS) risk. However, the results remain conflicting. Therefore, in order to derive a more precise association of ApoE gene polymorphism with MS risk, we performed this meta-analysis. Systematic searches of electronic databases PubMed, Embase and Web of Science, as well as hand searching of the references of identified articles were performed. Twenty studies were identified, covering a total of 4080 MS cases and 2897 controls. The results showed evidence for significant association between ApoE ε2 mutation and MS risk (for ε2/ε4 versus ε3/ε3: OR=1.74, 95% CI=1.12-2.71, p=0.01; for ε2 allele versus ε3 allele: OR=1.16, 95% CI=1.01-1.35, p=0.04). In the subgroup analysis by ethnicity, the similar results were obtained among Europeans (for ε2/ε4 versus ε3/ε3: OR=1.81, 95% CI=1.14-2.87, p=0.01; for ε2 allele versus ε3 allele: OR=1.19, 95% CI=1.02-1.38, p=0.03). After excluding the outlier studies by observing Galbraith plot, marginal association was found between ApoE ε3/ε4 genotype and the protective factor for MS (for ε3/ε4 versus ε3/ε3: OR=0.86, 95% CI=0.75-0.99, p=0.04). In summary, the present meta-analysis provides evidence that ApoE ε2 mutation is associated with MS risk. In addition, ApoE ε3/ε4 genotype appears to be a protective factor for MS.

Apolipoprotein A5 gene promoter region-1131T/C polymorphism is associated with risk of ischemic stroke and elevated triglyceride levels: a meta-analysis.

Background: The association between polymorphism -1131T/C in the promoter region of apolipoprotein A5 (APOA5) and ischemic stroke and plasma triglyceride (TG) levels remains controversial. To better clarify the association between APOA5-1131T/C and risk of ischemic stroke and plasma TG levels, we performed a meta-analysis to examine the allele and genotype of APOA5-1131T/C polymorphism in ischemic stroke cases and controls. Methods: Based on the search of PubMed, Embase, MEDLINE, CNKI (National Knowledge Infrastructure) and CBM (Chinese BioMedical Literature Database) databases, we identified and abstracted outcome data from all articles to evaluate the association between APOA5 and ischemic stroke/plasma TG levels. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were performed in dominant model (CC + TC vs. TT), recessive model (CC vs. TC + TT), homozygote comparison (CC vs. TT) and heterozygote comparison (TC vs. TT). The association between dominant model (CC + TC vs. TT) and plasma TG/total cholesterol/high-density lipoprotein cholesterol levels was measured by a weighted mean difference (WMD) with its corresponding 95% CI. To evaluate the ethnicity-specific effects, subgroup analyses were performed by ethnic group. Results: A meta-analysis containing 2,294 ischemic stroke cases and 1,858 controls from 8 case-control studies was performed. The results showed that APOA5-1131T/C polymorphism was significantly associated with ischemic stroke in all comparison models (CC + TC vs. TT, OR = 1.70, 95% CI = 1.24–2.32; CC vs. TC + TT, OR = 1.36, 95% CI = 0.98–1.90; CC vs. TT, OR = 1.73, 95% CI = 1.34–2.23; TC vs. TT, OR = 1.67, 95% CI = 1.19–2.36). On subgroup analysis by ethnicity, similarly significant associations were found in both Asians and Europeans, and the Europeans possessed a higher risk of ischemic stroke, especially in CC versus TT model (OR = 4.47, 95% CI = 1.33–15.06). Significant association between the C allele and elevated TG levels was detected in both ischemic stroke cases and controls; the TG levels were higher in the ischemic stroke cases and controls carrying the APOA5-1131C allele than in the noncarriers (CC + TC vs. TT, cases WMD = 0.43, 95% CI = 0.27–0.59; controls WMD = 0.51, 95% CI = 0.35–0.66). Similar within-group comparison of the total cholesterol and high-density lipoprotein cholesterol levels did not show any difference. Conclusions: Our meta-analysis revealed that the APOA5-1131T/C polymorphism is associated with a significant risk of ischemic stroke and elevated TG levels. The CC genotype and C allele might be a genetic risk factor that increases susceptibility of ischemic stroke and elevates plasma TG levels, and might be a useful target for clinical therapeutic intervention.

Lack of an association between Paraoxonase 1 gene polymorphisms (Q192R, L55M) and Alzheimer's disease: A meta-analysis

The association between Paraoxonase 1 (PON1) gene polymorphisms (Q192R, L55M) and Alzheimers disease (AD) risk has been reported inconsistent results. To assess the association between PON1 polymorphisms and AD risk, a meta-analysis was performed. Based on comprehensive searches of the PubMed, Embase, Web of Science, Weipu, and CBM databases, a total of 10 studies including 3081 AD cases and 3054 controls were identified. The pooled odds ratio (OR) with 95% confidence interval (95% CI) were performed. There was no significant association between PON1 Q192R polymorphism and AD risk in all comparison models (R vs. Q, OR=0.89, 95% CI=0.82-0.96; RR vs. QQ, OR=0.83, 95% CI=0.68-1.01; RR+RQ vs. QQ, OR=0.86, 95% CI=0.75-0.97; and RR vs. QR+QQ, OR=0.94, 95% CI=0.81-1.11). For the PON1 L55M polymorphism, lack of an association was also found (L vs. M, OR=0.95, 95% CI=0.86-1.05; LL vs. MM, OR=0.67, 95% CI=0.51-0.88; LL vs. ML+MM, OR=0.82, 95% CI=0.69-0.98; and LL+ML vs. MM, OR=0.75, 95% CI=0.58-0.96). On subgroup analysis by ethnicity, similar results were found. Conclusively, the present meta-analysis revealed that PON1 gene polymorphisms (Q192R, L55M) were unlikely to contribute to AD susceptibility.

Association between 12p13 SNPs rs11833579/rs12425791 near NINJ2 gene and ischemic stroke in East Asian population: evidence from a meta-analysis.

BACKGROUND Meta-analysis in European population found no association between rs12425791/rs11833579 and ischemic stroke. Several studies focused on East Asians have evaluated the association between this two SNPs and risk of ischemic stroke, but the results have been inconsistent. The aim of this study was to perform a meta-analysis to investigate a more authentic association between rs12425791 and rs11833579 G>A mutation and ischemic stroke in East Asian population, as well as in Chinese Han population. METHODS Systematic searches of electronic databases Embase, PubMed, Web of Science, and CBM as well as hand searching of the references of identified articles and the meeting abstracts were performed. Study selection, data abstraction and study quality evaluation were independently conducted in duplicate. Statistical analyses were performed using software Stata 11.0. The pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were performed. Different effects models were used according to the difference in heterogeneity. Publication bias was tested by Beggs funnel plot and Eggers regression test. RESULTS A total of 4 publications including 7 studies were involved. For rs12425791, significant association was found in allelic model (OR=1.06, 95%CI=1.00-1.11) and dominant model (OR=1.10, 95%CI=1.03-1.18), whereas no evidence of association was found for additive model (OR=1.04, 95%CI=0.93-1.17) and for recessive model (OR=0.99, 95%CI=0.88-1.10). For rs11833579, no evidence of association was found for all genetic models. In the analysis of Chinese Han population, there is lack of evidence for association of ischemic stroke for both SNPs. CONCLUSIONS In summary, our meta-analysis suggests that rs12425791 is significantly associated with ischemic stroke in East Asian population but not Chinese Han population, of which A alleles increase the risk of ischemic stroke, whereas no evidence of association was found for rs11833579 in East Asian population as well as Chinese Han population.

Lack of evidence for association between factor XIII-A Val34Leu polymorphism and ischemic stroke: A meta-analysis of 8,800 subjects

INTRODUCTION Epidemiological studies have evaluated the association between factor XIII-A (FXIII-A) Val34Leu polymorphism and risk of ischemic stroke, but the results remain inconclusive. This meta-analysis was therefore designed to clarify these controversies. METHODS Systematic searches of electronic databases Embase, PubMed and Web of Science, as well as hand searching of the references of identified articles and the meeting abstracts were performed. Study selection, data abstraction and study quality evaluation (using the Newcastle-Ottawa Scale, NOS) were independently conducted in duplicate. Statistical analyses were performed using software Review Manager (Version 5.1.2) and Stata (Version 11.0). The pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were performed. Fixed or random effects model was separately used depending on the heterogeneity between studies. Publication bias was tested by funnel plot, Eggers regression test and Beggs test. Sensitivity analysis was conducted by limiting the meta-analysis to the high quality studies (NOS score≥8). RESULTS A total of 16 studies including 3,807 cases and 4,993 controls were combined showing no evidence of association between FXIII-A Val34Leu polymorphism and ischemic stroke (for Val/Leu vs. Val/Val : OR=0.95, 95%CI=0.77-1.16; for Leu/Leu vs. Val/Val: OR=0.90, 95%CI=0.73-1.11; for dominant model: OR=0.97, 95%CI=0.81-1.17; for recessive model: OR=0.95, 95%CI=0.77-1.17). In the subgroup analyses by study design, ethnicity and specific subtypes (small-vessel occlusive ischemic stroke and large-artery atherosclerotic ischemic stroke ), there was lack of evidence for the association. CONCLUSIONS This meta-analysis indicates that there is no evidence for association between factor XIII-A Val34Leu polymorphism and ischemic stroke.