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Convincing evidence has shown that microRNAs (miRNAs) are involved in the pathogenesis of stroke. This study aimed to examine whether miRNA biogenesis genes polymorphisms are associated with risk of large artery atherosclerosis (LAA) stroke. Three polymorphisms (DROSHA rs10719 T>C, RAN rs3803012 A>G, and PIWIL1 rs10773771 C>T) were screened by certain criteria. A total of 1,785 (710 cases and 1,075 controls) study subjects were included in this study. We found that rs10773771 CC genotype was associated with a decreased risk of LAA stroke (CC vs. TT/CT: OR 0.63, 95% CI 0.46–0.86, P = 3 × 10–3). In silico analysis suggested that rs10773771 can change the mRNA secondary structure of PIWIL1 and affect the binding of the miRNAs and regulatory motifs to the 3′-UTR of PIWIL1. Expression quantitative trait loci analysis showed that rs10773771 could change the expression of PIWIL1 in human skin (P = 1.534 × 10–10) and thyroid tissues (P = 4.869 × 10–6). These findings suggested that PIWIL1 rs10773771 may be associated with a decreased risk of LAA stroke. [ABSTRACT FROM AUTHOR]

Background: In 2009, a genome-wide association study (GWAS) identified two variants (rs12425791 and rs11833579) nearNINJ2gene that confer susceptibility to stroke in Caucasian populations. Recently, a number of studies have been conducted to replicate this finding in Asian populations. However, the results are conflicting. Thus, we performed a quantitative analysis to summarize the evidence regarding the association between these two polymorphisms and ischemic stroke risk.Methods: Pertinent studies were identified by searching PubMed and Embase through September 2014. Studies that reported odds ratio (OR) with 95% confidence interval (CI) for the association between these two polymorphisms and stroke risk were included.Results: Eight independent publications, with 8626 cases and 8046 controls for rs12425791 and 9142 cases and 8657 controls for rs11833579, were included. Overall, significantly increased ischemic stroke risk was associated with rs12425791 A allele when all studies were pooled into the meta-analysis (AA/GA vs. GG: OR = 1.08, 95% CI: 1.01–1.14). However, rs11833579 was not associated with increased stroke risk in any genetic model.Conclusions: These findings indicate that rs12425791 G>A polymorphism may be a low-penetrance susceptibility marker of stroke in Asian populations and further studies are warranted to verify this association. [ABSTRACT FROM AUTHOR]

Recently, a genome-wide association study (GWAS) identified two common variants (rs12425791 and rs11833579) on Chromosome 12p13 that confer risk for stroke. The aim of this study was to evaluate whether these two variants are associated with risk of large artery atherosclerotic (LAA) stroke in a Chinese population. Rs12425791 and rs11833579 were genotyped using the improved multiple ligase detection reaction in 423 patients with LAA stroke and 423 healthy controls. We found a statistically significantly increased risk of LAA stroke associated with the rs12425791AA genotype (OR = 2.28, 95% CI = 1.15–4.51) and rs11833579 AA genotype (OR = 1.92, 95% CI = 1.16–3.15) compared with their GG genotype. When we evaluated these two polymorphisms together, we found that the combined genotypes with 3–4 variant alleles (rs12425791A and rs11833579A) were associated with an increased risk of LAA stroke (OR = 2.06, 95% CI = 1.26–3.36) compared to 0–2 variants. Moreover, genotype–phenotype correlation analysis showed that rs12425791AA and rs11833579AA carriers had significantly decreased NINJ2 mRNA expression levels in the Chinese population ( P = 0.003 for rs12425791 and P = 0.005 for rs11833579). These results suggested that the rs12425791 and rs11833579 polymorphisms on Chromosome 12p13 may be associated with the risk of LAA stroke and might be used as candidate biomarkers for LAA stroke susceptibility. [ABSTRACT FROM AUTHOR]

As the key point of function for aspirin to educe anti-platelet effects, cyclooxygenase-1 (COX-1) gene polymorphisms have long been suspected as a potential cause for aspirin nonresponsiveness. But this hypothesis has not been confirmed by large longitudinal studies. This study prospectively evaluated the impacts of COX-1 gene polymorphisms on stroke recurrence and other vascular events in a large cohort of Chinese patients with ischemic stroke and treated with aspirin. Between December 2009 and October 2012, consecutive patients with ischemic stroke and treated with aspirin were enrolled. Polymorphisms of four alleles (rs1330344, rs10306114, rs3842788 and rs5788) in COX-1 gene were determined at baseline. The primary endpoint was a composite of nonfatal ischemic stroke, myocardial infarction, and death from cardiovascular causes. Impacts of COX-1 gene polymorphisms on vascular outcomes were evaluated with multivariate analysis. A total of 859 patients were included in data analysis. The minor allele frequencies of rs1330344, rs10306114, rs3842788 and rs5788 were 38.53%, 0.12%, 6.64% and 5.53%, respectively. During 14.64 ± 7.44 months of follow-up, primary endpoint was observed in 67 (7.80%) patients. Incidence of primary endpoint was higher in patients with CC genotype of rs1330344 than in patients with CT or TT genotype (HR = 1.916, 95% CI: 1.126–3.260, P = 0.016). After being adjusted for potential confounding factors, rs1330344 CC genotype was still independently associated with incidence of primary endpoint (HR = 1.958, 95% CI: 1.151–3.332, P = 0.013). The impacts of other three tested polymorphisms on primary endpoint were unremarkable. In conclusion, in Chinese patients with ischemic stroke and treated with aspirin, CC genotype of rs1330344 may increase the risk of subsequent vascular events. [ABSTRACT FROM AUTHOR]

Abstract: Polymorphisms of PDGFRB, MMP-3, TIMP-2, RNF213, TGFB1, Raptor and eNOS genes have been associated with Moyamoya disease (MMD) separately in studies, but their interactions on MMD have never been evaluated in one study. This study enrolled 96 MMD patients and 96 controls to evaluate the contributions and interactions of these polymorphisms on MMD in Chinese Hans. After genotyping, five polymorphisms loci were deemed suitable for analysis, rs3828610 in PDGFRB, rs3025058 in MMP-3, rs8179090 in TIMP-2, rs112735431 and rs148731719 in RNF213. Interactions of different loci on MMD were evaluated by multifactor dimensionality reduction (MDR) method. Significantly higher frequencies of A allele and G/A genotype of rs112735431 in RNF213 were observed in MMD patients compared with controls (P=0.011; P=0.018, respectively). In the dominant model, G/A genotype of rs112735431 was associated with increased risk of MMD (P=0.018). A higher frequency of G allele and G/G genotype of rs148731719 in RNF213 gene in patient than control group (P<0.001; P<0.01, respectively) was also detected. No significant association between MMD and other three loci (P>0.05) was detected. MDR analysis failed to detect any significant interaction among these five loci in the occurrence of MMD (P>0.05), but the combination of three loci (rs112735431 in RNF213, rs3828610 in PDGFRB, rs3025058 in MMP-3) could have the maximum testing accuracy (57.29%) and cross-validation consistency (10/10). The results indicated that RNF213 rs112735431 and rs148731719 may exert a significant influence on MMD occurrence. Compared with this overwhelming effect, the influences of PDGFRB, MMP-3, and TIMP-2 on MMD may be unremarkable in Chinese Hans. There may be no prominent interaction among these five gene polymorphisms on the occurrence of MMD. [Copyright &y& Elsevier]

Background: P53 is a tumor suppressor gene and plays important role in the etiology of breast cancer. Intron 3 sixteen-bp duplication polymorphism of p53 has been reported to be associated with breast cancer risk. However, the reported results remain conflicting rather than conclusive. Methods: A meta-analysis including 19 case-control studies was performed to address this issue. Odds ratios (ORs) with 95% confidence intervals (CIs) were adopted to evaluate the association. Results: The overall results suggested that the variant genotypes were associated with a significantly increased breast cancer risk (Del/Ins vs Del/Del: OR = 1.18, 95% CI: 1.00–1.40; Ins/Ins vs Del/Del: OR = 1.42, 95% CI = 1.09–1.84; Ins/Ins+Del/Ins vs Del/Del: OR = 1.21, 95% CI = 1.03–1.41). When stratifying by sample size of studies, a significantly elevated risk was also observed among large sample studies (>500 subjects) but not among small sample studies (≤500 subjects). Conclusion: These results suggested that the 16-bp duplication polymorphism of p53 may contribute to susceptibility to breast cancer. Additional well-designed large studies were required to validate this association in different populations. [ABSTRACT FROM AUTHOR]

Genetic polymorphisms in the promoter regions of FAS, FASL and CASP8 involved in the apoptotic signaling pathway are thought to be associated with susceptibility to cancer. We hypothesized that these functional genetic variants might be associated with the risk of childhood acute lymphoblastic leukemia (ALL). A case-control study in a Chinese population with 361 cases of ALL and 519 controls was performed to evaluate the association between FAS, FASL and CASP8 variants and risk of childhood ALL. Individuals with FAS − 1377AG had an odds ratio (OR) of 0.72 for the risk of ALL compared to − 1377GG and the variant FASL − 844CC was associated with a statistically significantly decreased risk of childhood ALL (OR = 0.38). Furthermore, combined genotypes with 5-8 protective alleles were associated with a significantly decreased risk of childhood ALL compared with those with 0-4 variants, and this decreased risk was more pronounced among the subgroups of age < 6 years, female, parental never-drinking status and never house-painting. Our results provide evidence that FAS-FASL-CASP8 polymorphisms contributed to a reduced risk of childhood ALL in our population. Larger studies are warranted to validate our findings. [ABSTRACT FROM AUTHOR]

The Ser326Cys polymorphism in the human 8-oxogunaine DNA glycosylase (hOGG1) gene had been implicated in cancer susceptibility. Studies investigating the associations between the Ser326Cys polymorphism and cancer susceptibility showed conflicting results. To derive a more precise estimation of the relationship, a meta-analysis was performed. This meta-analysis was performed from 83 case–control studies, including 27 918 cases and 33 399 controls. The fixed and random effect models were used to estimate the odds ratios (ORs) and their 95% confidence interval (CI) for various contrasts of this polymorphism. The combined results based on all studies showed that the hOGG1 Ser326Cys polymorphism was associated with an increased cancer susceptibility in different genetic models. In the stratified analyses, the association was significantly in head and neck cancer (homozygote comparison: OR = 2.19, 95% CI: 1.20–4.01, Pheterogeneity = 0.002; heterozygote comparison: OR = 1.48, 95% CI: 1.11–1.99, Pheterogeneity = 0.004; dominant model comparison: OR = 1.58, 95% CI: 1.14–2.19, Pheterogeneity < 0.001; recessive model comparison: OR = 1.73, 95% CI: 1.02–2.94, Pheterogeneity = 0.002; and additive model comparison: OR = 1.43, 95% CI: 1.09–1.88, Pheterogeneity < 0.001) which remained for studies of the Asian populations and hospital-based of control sources. But it was not observed in other cancer types of the European population and population based of control sources. This meta-analysis suggested that the hOGG1 Ser326Cys polymorphism might contribute to an increased risk on cancer susceptibility. More studies based on larger sample size should be performed to confirm the findings. [ABSTRACT FROM PUBLISHER]

Background: MicroRNAs (miRNAs) are a family of endogenous, small and noncoding RNAs that negatively regulate gene expression by suppressing translation or degrading mRNAs. Recently, many studies investigated the association between hsa-miR-196a2 rs11614913 polymorphism and cancer risk, which showed inconclusive results. Methodology/Principal Findings: We conducted a meta-analysis of 15 studies that included 9,341 cancer cases and 10,569 case-free controls. We assessed the strength of the association, using odds ratios (ORs) with 95% confidence intervals (CIs). Overall, individuals with the TC/CC genotypes were associated with higher cancer risk than those with the TT genotype (OR = 1.18, 95% CI = 1.03-1.34, P<0.001 for heterogeneity test). In the stratified analyses, we observed that the CC genotype might modulate breast cancer risk (OR = 1.11, 95%CI = 1.01-1.23, Pheterogeneity = 0.210) and lung cancer risk (OR = 1.25, 95%CI = 1.06-1.46, Pheterogeneity = 0.958), comparing with the TC/TT genotype. Moreover, a significantly increased risk was found among Asian populations in a dominant model (TC/CC versus TT, OR = 1.24, 95% CI = 1.07-1.43, Pheterogeneity = 0.006). Conclusions: These findings supported that hsa-miR-196a2 rs11614913 polymorphism may contribute to the susceptibility of cancers. [ABSTRACT FROM AUTHOR]

Abstract: Objective: p53 is a tumor suppressor gene and is involved in the etiology of ovarian cancer. Studies investigating the associations between the p53 codon 72 polymorphism and ovarian cancer risk showed conflicting results. We performed this meta-analysis from eligible studies to evaluate this purported relationship. Methods: This meta-analysis was performed from 9 case-control studies, including 825 ovarian cases and 1073 controls. T he fixed and random effect models were used to estimate the odds ratios(ORs) for various contrasts of this polymorphism. Results: The combined results based on all studies showed that a significantly decreased risk was associated with the variant Pro/Pro genotype, compared with Arg/Pro+Arg/Arg genotypes(OR, 0.70; 95%CI, 0.51∼0.95). When stratifying the studies by ethnicity, we found that individuals with the variant genotype Pro/Pro had a significantly decreased risk of ovarian cancer compared with Arg/Arg genotype(OR, 0.43; 95%CI, 0.20∼0.89) and Arg/Pro+Arg/Arg genotypes(OR, 0.61; 95%CI, 0.37∼0.99) among Africans. Conclusion: This meta-analysis suggests that the p53 codon 72 polymorphism may contribute to genetic susceptibility to ovarian cancer. More studies based on larger sample size should be performed to confirm the findings. [Copyright &y& Elsevier]

Purpose Prostaglandin-Endoperoxide Synthase 1 (PTGS1) and smoking may play important roles in aspirin nonresponsiveness, but the effect of their interaction on stroke outcomes remains largely unknown. We examined the effects of PTGS1 polymorphisms, smoking status, and their interaction on functional outcomes in a cohort of Chinese Han patients with stroke during aspirin therapy. Methods A total of 617 ischemic stroke patients taking aspirin were enrolled. Three single nucleotide polymorphisms (SNPs) rs1330344, rs3842788, and rs5788 in PTGS1 were determined for genotyping. Poor functional outcomes were defined as a modified Rankin Scale (mRS) of 3–6 at 90-day follow-up. The influence of PTGS1 gene-smoking interaction on functional outcomes was examined. Results Poor functional outcomes occurred in 145 (23.5%) patients. When adjusting multiple factors by logistic regression, CC genotype of rs1330344 was associated with poor functional outcomes (risk ratio [RR] = 1.73; 95% confidence interval [CI]: 1.17–2.37). A similar connection was found in the CGC haplotype (RR = 1.40; 95% CI: 1.08–1.77). Furthermore, we found a significant interaction between rs1330344 and smoking status ( P interaction = 0.018); the interaction effect between the PTGS1 haplotype and smoking also showed statistical significance ( P interaction = 0.040). Conclusions In Chinese Han stroke patients with aspirin therapy, the adverse effect of PTGS1 polymorphisms on functional outcomes may be modulated by the smoking status. PTGS1 gene-smoking interaction might in part reflect the heterogeneity in the prognosis of patients treated with aspirin. [ABSTRACT FROM AUTHOR]

Background Despite clopidogrel has been widely applied to patients with ischemic stroke combined with aspirin, decreased metabolic activation of clopidogrel still occurs because of genetic variations in CYP2C19 . Methods Three hundred twenty-one patients completed a genetic test for CYP2C19 loss of function (LOF) alleles in hospital. Cox regression models were used to assess the relationship between CYP2C19 genotypes with the primary endpoint, which was a composite of nonfatal ischemic stroke, myocardial infarction, or vascular death. Functional outcome was measured by the modified Rankin Scale (mRS) at 3 months, 6 months and 12 months intervals. Binary logistic regression was used to analyze the correlation between poor functional outcome and CYP2C19 LOF alleles. Results The CYP2C19 LOF alleles were independently associated with the primary endpoint. There was no significant association between poor functional outcome and CYP2C19 LOF allele ( *2 and *3 ) in overall patients. After the participants were stratified by stent treatment into two groups, the polymorphisms of CYP2C19 had significant impact on poor prognosis at 3 months and 6 months but not at 12 months in patients without stent. No correlation was found in patients with stent. Conclusions The CYP2C19 LOF alleles may increase the recurrent risk of ischemic events. The polymorphisms of CYP2C19 may be predictors of poor functional outcome of patients without stent, and the effect may be weakened by time. [ABSTRACT FROM AUTHOR]

Abstract: Death receptor 4 (DR4) is an important mediator of apoptosis, and its dysfunction may be related to carcinogenesis and cancer development. We hypothesized that common variants in the DR4 gene are associated with risk of bladder cancer and test this hypothesis in a case–control study of 368 bladder cancer patients and 368 cancer-free controls. We genotyped six tagging single nucleotide polymorphisms (tagSNPs) in these subjects and found a significantly increased risk of bladder cancer associated with the SNP1−397GT/TT genotype (adjusted OR=1.55; 95% CI=1.15–2.09) compared with the GG genotype. This increased risk was more pronounced for superficial bladder cancer. A luciferase assay, performed in vitro, revealed that the −397T allele had a lower transcriptional activity than the −397G allele. Multifactor dimensionality reduction (MDR) analysis indicated that the two-factor model including −397G>T and pack-years of smoking was best for predicting bladder cancer risk. Moreover, a significant additive (but not multiplicative) interaction, was found between the −397G>T polymorphism and smoking on bladder cancer risk. In conclusion, genetic variants of the DR4 gene may be involved in the etiology of bladder cancer, and our findings need further validation by larger studies. [Copyright &y& Elsevier]