Association between CYP2C9 and VKORC1 genetic polymorphisms and efficacy and safety of warfarin in Chinese patients.

OBJECTIVES: Genetic variation has been a major contributor to interindividual variability of warfarin dosage requirement. The specific genetic factors contributing to warfarin bleeding complications are largely unknown, particularly in Chinese patients. In this study, 896 Chinese patients were enrolled to explore the effect of CYP2C9 and VKORC1 genetic variations on both the efficacy and safety of warfarin therapy. METHODS AND RESULTS: Univariate analyses unveiled significant associations between two specific single nucleotide polymorphisms rs1057910 in CYP2C9 and rs9923231 in VKORC1 and stable warfarin dosage ( P  < 0.001). Further, employing multivariate logistic regression analysis adjusted for age, sex and height, the investigation revealed that patients harboring at least one variant allele in CYP2C9 exhibited a heightened risk of bleeding events compared to those with the wild-type genotype (odds ratio = 2.16, P  = 0.04). Moreover, a meta-analysis conducted to consolidate findings confirmed the associations of both CYP2C9 (rs1057910) and VKORC1 (rs9923231) with stable warfarin dosage. Notably, CYP2C9 variant genotypes were significantly linked to an increased risk of hemorrhagic complications ( P  < 0.00001), VKORC1 did not demonstrate a similar association. CONCLUSION: The associations found between specific genetic variants and both stable warfarin dosage and bleeding risk might be the potential significance of gene detection in optimizing warfarin therapy for improving patient efficacy and safety.

L-limonene reduces aortic artery atherosclerosis by inhibiting oxidative stress/inflammatory responses in diabetic rats fed high-fat diet.

Atherosclerosis, a leading cause of mortality worldwide, is driven by multiple risk factors such as diabetes. Oxidative stress and inflammation assist interrelated roles in diabetes-accelerated atherosclerosis. Thereby, treatment of diabetic atherosclerosis from an oxidative stress/inflammatory perspective seems to be a more effective modality to prevent and delay plaque formation and progression. This study aimed to evaluate the effects of l-limonene (LMN) on oxidative stress/inflammatory responses in the aortic artery of diabetic atherosclerosis-modeled rats. Male Wistar rats (n = 30, 250-280 g, 12 weeks old) were used to establish a diabetic atherosclerosis model (8 weeks) using high-fat diet/low-dose streptozotocin. LMN (200 mg/kg/day) was administered orally, starting on day 30th before tissue sampling. Plasma lipid profiles, aortic histopathological changes, atherogenic index, aortic artery levels of oxidative stress markers (manganese superoxide dismutase, glutathione, and 8-isoprostane), inflammatory markers (tumor necrosis factor-alpha, interleukin (IL)-6, and IL-10), and expression of phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK)/AMPK, Sirtuin 1 (SIRT1), and p-p65/p65 proteins were evaluated. The administration of LMN to diabetic rats improved lipid profiles, aortic histopathological morphology, and atherogenic index (P < 0.05 to P < 0.001). It also increased enzymatic antioxidant activities, decreased 8-isoprostane level, suppressed inflammatory response, upregulated p-AMPK and SIRT1 proteins, and downregulated p-p65 protein (P < 0.05 to P < 0.01). Inhibiting the AMPK through the administration of compound C significantly abolished or reversed the positive effects of LMN in diabetic rats (P < 0.05 to P < 0.01). LMN treatment had dual anti-oxidative and anti-inflammatory actions against atherosclerosis in the aortic artery of diabetic rats. Atheroprotection by LMN was mediated partly through modulation of AMPK/SIRT1/p65 nuclear factor kappa B signaling pathway. LMN appears to be a promising anti-atherosclerotic modality to improve the quality of life in diabetic patients.

Genetic Associations With Stable Warfarin Dose Requirements in Han Chinese Patients.

ABSTRACT: Warfarin is a commonly prescribed anticoagulant for valvular heart disease that plays an important role in clinical management to prevent thrombotic events. In this study, we aim to perform a comprehensive study to investigate the genetic biomarkers of stable warfarin dose in the Han Chinese population. We performed an integrative study on 211 Han Chinese patients with valvular heart disease. A total of 40 single nucleotide polymorphisms (SNPs) in 10 important genes (CYP2C9, VKORC1, ABCB1, CYP4F2, APOE, PROC, GGCX, EPHX1, CALU, and SETD1A) which are involved in the warfarin metabolic pathway and equilibrium of coagulation and anticoagulation were selected. We applied MassARRAY technology to genotype the 40 SNPs identified in these Han Chinese patients. Our results showed that 13 SNPs on 6 genes (CYP2C9, VKORC1, ABCB1, PROC, EPHX1, and SETD1A) were associated with the individual stable warfarin dose. Two VKORC1 SNPs (rs9934438 and rs2359612) were the strongest genetic factors determining warfarin dose requirements (P = 8 × 10-6 and 9 × 10-6, respectively). Rs4889599 in SETD1A was first reported to be associated with warfarin dose at a significant level of 0.001 in our study (Padjust = 0.040 after Bonferroni correction). We discovered that genetic variants in CYP2C9, VKORC1, ABCB1, PROC, EPHX1, and SETD1A may affect the stable warfarin dose requirement in Han Chinese patients with valvular disease. The discovery of these potential genetic markers will facilitate the development of advanced personalized anticoagulation therapy in Han Chinese patients.

Doping strategy, properties and application of heteroatom-doped ordered mesoporous carbon.

To date, tremendous achievements have been made to produce ordered mesoporous carbon (OMC) with well-designed and controllable porous structure for catalysis, energy storage and conversion. However, OMC as electrode material suffers from poor hydrophilicity and weak electrical conductivity. Numerous attempts and much research interest have been devoted to dope different heteroatoms in OMC as the structure defects to enhance its performance, such as nitrogen, phosphorus, sulphur, boron, and multi heteroatoms. Unfortunately, the "how-why-what" question for the heteroatom-doped OMC has not been summarized in any published reports. Therefore, this review focuses on the functionalization strategies of heteroatoms in OMC and the corresponding process characteristics, including in situ method, post treatment method, and chemical vapor deposition. The fundamentally influencing mechanisms of various heteroatoms in electrochemical property and porous structure are summarized in detail. Furthermore, this review provides an updated summary about the applications of different heteroatom-doped OMC in supercapacitor, electrocatalysis, and ion battery during the last decade. Finally, the future challenges and research strategies for heteroatom-doped OMC are also proposed.

Inhibition of TRAF3 expression alleviates cardiac ischemia reperfusion (IR) injury: A mechanism involving in apoptosis, inflammation and oxidative stress.

Ischemia reperfusion (IR) injury is known as a major issue in cardiac transplantation and various pathogenesis are involved in myocardial IR injury. Here, we show that tumor necrosis factor receptor-associated factor 3 (TRAF3) was increased in hearts of mice with cardiac IR injury and in cardiomyocytes incubated with lipopolysaccharide (LPS) and H2O2. Reducing TRAF3 expression in vivo markedly reduced the infacrted area, attenuated the histological changes, improved cardiac dysfunction and injury in mice subjected to IR injury. Functional study further indicated that TRAF3 knockdown inhibited apoptosis in murine hearts of mice with cardiac IR injury and in LPS and H2O2-cotreated cardiomyocytes, as evidenced by the decreased expression of cleaved Caspase-3 and poly (ADP-ribose) polymerases (PARP). In addition, inflammatory response and oxidative stress observed in hearts of mice with IR operation were significantly alleviated by TRAF3 knockdown through inhibiting nuclear factor-κB (NF-κB) and xanthine oxidase (XO) signaling pathways, and similar results were detected in LPS and H2O2-cotreated cardiomyocytes in vitro. Moreover, the loss of TRAF3 also restrained the phosphorylated c-Jun N-terminal protein kinase (JNK) activation following cardiac IR injury. Importantly, blocking JNK activation, as TRAF3 knockdown, greatly reduced apoptosis, inflammation and reactive oxygen species (ROS) production in LPS and H2O2-cotreated cardiomyocytes. In contrast, TRAF3 knockdown-reduced apoptosis, inflammatory response and oxidative stress were significantly rescued by promoting JNK activity in LPS and H2O2-cotreated cardiomyocytes. In summary, the results of our study indicated that repressing TRAF3 expression could be served as essential therapeutic target for protection against cardiac IR injury through restraining JNK-meditated apoptosis, inflammation and the production of ROS.

Study of the Association of PEAR1, P2Y12, and UGT2A1 Polymorphisms with Platelet Reactivity in Response to Dual Antiplatelet Therapy in Chinese Patients.

OBJECTIVES: Genetic variation is thought to contribute to considerable interindividual variability in platelet function, and there is a pressing need to identify genetic markers that can be used to predict the response to treatment. Our study investigated whether PEAR1, P2Y12, and UGT2A1 polymorphisms were associated with platelet reactivity in response to dual antiplatelet therapy in Chinese patients with acute coronary syndrome. METHODS: Patients with inhibition of platelet aggregation (IPA) < 30% after treatment were classified as the high platelet reactivity (HPR) group. Patients with IPA > 30% were classified as the normal platelet reactivity (NPR) group. ADP-induced platelet aggregation was measured by thromboelastography (TEG) platelet-mapping assay. Thirteen single nucleotide polymorphisms (SNPs) of PEAR1, P2Y12 and UGT2A1 were genotyped using the Mass-ARRAY platform. RESULTS: Seven SNPs were significantly associated with ADP-induced platelet aggregation by univariate analysis. Major allele G at rs12041331, minor allele G at rs2644592, minor allele C at rs11264580, and minor allele C at rs11249454 were significantly associated with HPR, whereas minor allele T at rs57731889, minor allele A at rs16863356, and minor allele T at rs7634096 were significantly associated with NPR. The mean IPA was significantly lower in patients suffering recurrent ischemic events than in patients without recurrent events in our study (p = 0.048). CONCLUSIONS: Our findings suggest that PEAR1, P2Y12, and UGT2A1 genetic variants may be potential biomarkers that can be used to guide clinical applications of clopidogrel and aspirin in Chinese patients.

Correlation between vascular endothelial growth factor and long-term prognosis in patients with acute myocardial infarction.

The aim of the present study was to investigate the correlation between plasma the levels of vascular endothelial growth factor (VEGF) and major adverse cardiovascular events (MACE) in patients with acute myocardial infarction (AMI). A total of 124 patients with AMI undergoing emergency percutaneous coronary intervention (PCI) were selected, and plasma VEGF levels were measured 7 days after the onset of AMI using an enzyme-linked immunosorbent assay. The patients were divided into the L (≤190 pg/ml VEGF) and H (>190 pg/ml VEGF) groups, and were followed up every 2 months for an average of 12 months. MACE were recorded during follow-up. On the basis of these results, the patients were further divided into the MACE and non-MACE (N-MACE) groups, and the serum VEGF concentration was compared between the two groups. At the 6-month follow-up, the incidence of MACE in the H group was found to be significantly reduced compared with the L group. The serum VEGF concentration in the N-MACE group was significantly higher compared with the MACE group. Multinomial logistic regression revealed that reduced VEGF levels (ß=1.243; 95% CI, 1.018-1.326; P=0.026) were independent risk factors for MACE. In conclusion, high plasma VEGF levels at 7 days after AMI onset facilitate the long-term prognosis in the same infarct zone in patients with AMI, while low plasma VEGF levels are independent risk factors for MACE.

Serum VEGF Predicts Worse Clinical Outcome of Patients with Coronary Heart Disease After Percutaneous Coronary Intervention Therapy.

BACKGROUND: Percutaneous coronary intervention (PCI) is an effective treatment for coronary heart disease (CHD) patients. However, patients after PCI treatment often have ischemic events that result in poor prognosis. Our study aimed to investigate the effects of vascular endothelial growth factor (VEGF) level on the prognosis of CHD patients. MATERIAL AND METHODS: We enrolled 114 CHD patients in the study. Serum VEGF level was measured by enzyme-linked immunosorbent assay (ELISA). Total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and Hs-CRP were also tested in patients. The patients were divided into 2 groups according to the level of VEGF. Kaplan-Meier curve was used to observe the differences in survival situation of patients of the 2 groups. Cox regression analysis was conducted to judge whether VEGF was an independent biomarker for prognosis in CHD. RESULTS: We included 104 patients for survival analysis. VEGF level in CHD patients was significantly lower than that of healthy individuals (P<0.05). In the analysis of basic information, we found differences in sex distribution and hypertension between groups (P<0.05 for both). Kaplan-Meier curve indicated that patients with low expression of VEGF presented with poor prognosis. The mortality rate of the low-expression group was 37.71%, higher than that of the high-expression group (14.3%). Cox analysis suggested that VEGF could serve as a biomarker for prognosis in CHD (HR: 3.014, P: 0.019). CONCLUSIONS: Low level of VEGF may predict poor clinical outcome of CHD patients after PCI treatment.

Association between VEGF polymorphisms (936c/t, -460t/c and -634g/c) with haplotypes and coronary heart disease susceptibility.

AIM: Our aim was to investigate the association between single nucleotide polymorphisms (SNPs) of vascular endothelial growth factor (VEGF) and coronary heart disease (CHD) susceptibility in Chinese Han population. METHODS: 144 CHD patients and 150 healthy individuals were enrolled in the study. Three SNPs (936C/T, -460T/C and -634G/C) of VEGF were chose and then were genotyped with Sequenom time-of-flight mass spectrometry (TOFMS). Odds ratio (OR) with 95% confidence interval (CI) were used to evaluate the association of genotypes and haplotypes and CHD susceptibility. RESULTS: The frequencies of -460T/C CC genotype (13.6%) was found higher in the case group than that of control group (6.7%), which indicated that CC genotype was a risk factor for CHD (OR=2.50, 95% CI=1.10-5.68). Correspondently, the C allele appeared to increase the risk of CHD (OR=1.54, 95% CI=1.07-2.22). For -634G/C polymorphism, the risk of the CC genotype carrier for CHD increased 2.24 fold compared to the wild genotype. Moreover, -634G/CC allele was significantly associated with CHD susceptibility (OR=1.65, 95% CI=1.15-2.36). In addition, +936C/T CT genotype and C allele appeared to be a genetic-susceptibility factors for CHD (OR=2.43, 95% CI=1.44-4.10; OR=1.95, 95% CI=1.26-3.02). The haplotype analysis showed that T-C-T, C-C-C and C-G-C haplotypes all could increase the risk for CHD (OR: 2.43, 2.77 and 2.33). CONCLUSION: we concluded VEGF polymorphisms were associated with CHD susceptibility. Moreover, the haplotypes of T-C-T, C-C-C and C-G-C all could increase the risk for CHD.

Association between phosphatase related gene variants and coronary artery disease: case-control study and meta-analysis.

Recent studies showed that the serum alkaline phosphatase is an independent predictor of the coronary artery disease (CAD). In this work, we aimed to summarize the association between three phosphatase related single nucleotide polymorphisms (rs12526453, rs11066301 and rs3828329) and the risk of CAD in Han Chinese. Our results showed that the rs3828329 of the ACP1 gene was closely related to the risk of CAD in Han Chinese (OR = 1.45, p = 0.0006). This significant association of rs3828329 with CAD was only found in the females (Additive model: OR = 1.80, p = 0.001; dominant model: OR = 1.69, p = 0.03; recessive model: OR = 1.96, p = 0.0008). Moreover, rs3828329 was likely to exert its effect in females aged 65 years and older (OR = 2.27, p = 0.001). Further meta-analyses showed that the rs12526453 of PHACTR11 gene (OR = 1.14, p < 0.0001, random-effect method) and the rs11066301 of PTPN11 gene (OR = 1.15, p < 0.0001, fixed-effects method) were associated with CAD risk in multiple populations. Our results showed that the polymorphisms rs12526453 and rs11066301 are significantly associated with the CAD risk in multiple populations. The rs3828329 of ACP1 gene is also a risk factor of CAD in Han Chinese females aged 65 years and older.

Quantitative assessment of the association between rs2046210 at 6q25.1 and breast cancer risk.

Genome-wide association studies (GWAS) have identified several genetic susceptibility loci for breast cancer (BC). One of them, conducted among Chinese women, found an association of rs2046210 at 6q25.1 with the risk of BC recently. Since then, numerous association studies have been carried out to investigate the relationship between this polymorphism and BC risk in various populations. However, these have yielded contradictory results. We therefore performed a meta-analysis to clarify this inconsistency. Overall, a total of 235003 subjects based on 13 studies were included in our study. Significantly increased BC risk was detected in the pooled analysis [allele contrast: OR = 1.13, 95%CI = 1.10-1.17, P(Z) <10(-5), P(Q) <10(-4); dominant model: OR = 1.21, 95%CI = 1.14-1.27, P(Z) <10(-5), P(Q) <10(-4); recessive model: OR = 1.18, 95%CI = 1.12-1.24, P(Z) <10(-5), P(Q) = 0.04]. In addition, our data revealed that rs2046210 conferred greater risk in estrogen receptor (ER)-negative tumors [OR = 1.27, 95%CI = 1.15-1.40, P(Z) <10(-5), P(Q) <10(-4)] than in ER-positive ones [OR = 1.18, 95%CI = 1.09-1.28, P(Z) <10(-4), P(Q) = 0.0003]. When stratified by ethnicity, significant associations were found in Caucasian and Asian populations, but not detected among Africans. There was evidence of heterogeneity (P<0.05), however, the heterogeneity largely disappeared after stratification by ethnicity. The present meta-analysis demonstrated that the rs2046210 polymorphism may be associated with increased BC susceptibility, but this association varies in different ethnicities.

Systematic functional characterization of cytochrome P450 2E1 promoter variants in the Chinese Han population.

CYP2E1 promoter polymorphisms can lead to significant interindividual differences in expression of CYP2E1. Using a database of CYP2E1 gene polymorphisms established in 2010, our study aimed to functionally characterize the single nucleotide polymorphisms (SNPs) of the promoter region and corresponding haplotypes in the Chinese Han population. Six novel SNPs and seven haplotypes with a frequency equal to or greater than 0.01 were constructed on a luciferase reporter system on the basis of site-directed mutagenesis. Dual luciferase reporter systems were used to analyze regulatory activity. The constructs including single novel SNP mutations exhibited insignificant change in luciferase activity, whereas, the activity produced by Haplo1(GTTGCTATAT), Haplo2 (CTTGCTATAT) and Haplo7 (GAGCTCACAT), containing a -333T>A polymorphism was significantly greater than for the wild type in Hep G2 cells (p<0.05), being 1.5-, 2.0- and 1.4- times greater respectively. These findings suggest the possibility of significant clinical prediction of adverse drug reaction and the facilitation of personalized medicine.

Genetic polymorphisms in CYP2E1: association with schizophrenia susceptibility and risperidone response in the Chinese Han population.

BACKGROUND: CYP2E1 is a member of the cytochrome P450 superfamily, which is involved in the metabolism and activation of both endobiotics and xenobiotics. The genetic polymorphisms of CYP2E1 gene (Chromosome 10q26.3, Accession Number NC_000010.10) are reported to be related to the development of several mental diseases and to be involved in the clinical efficacy of some psychiatric medications. We investigated the possible association of CYP2E1 polymorphisms with susceptibility to schizophrenia in the Chinese Han Population as well as the relationship with response to risperidone in schizophrenia patients. METHODS: In a case-control study, we identified 11 polymorphisms in the 5' flanking region of CYP2E1 in 228 schizophrenia patients and 384 healthy controls of Chinese Han origin. From among the cases, we chose 130 patients who had undergone 8 weeks of risperidone monotherapy to examine the relationship between their response to risperidone and CYP2E1 polymorphisms. Clinical efficacy was assessed using the Brief Psychiatric Rating Scale (BPRS). RESULTS: Statistically significant differences in allele or genotype frequencies were found between cases and controls at rs8192766 (genotype p = 0.0048, permutation p = 0.0483) and rs2070673 (allele: p = 0.0018, permutation p = 0.0199, OR = 1.4528 95%CI = 1.1487-1.8374; genotype: p = 0.0020, permutation p = 0.0225). In addition, a GTCAC haplotype containing 5 SNPs (rs3813867, rs2031920, rs2031921, rs3813870 and rs2031922) was observed to be significantly associated with schizophrenia (p = 7.47E-12, permutation p<0.0001). However, no association was found between CYP2E1 polymorphisms/haplotypes and risperidone response. CONCLUSIONS: Our results suggest that CYP2E1 may be a potential risk gene for schizophrenia in the Chinese Han population. However, polymorphisms of the CYP2E1 gene may not contribute significantly to individual differences in the therapeutic efficacy of risperidone. Further studies in larger groups are warranted to confirm our results.

Quantitative assessment of the effect of LRRK2 exonic variants on the risk of Parkinson's disease: a meta-analysis.

Leucine-rich repeat kinase 2 (LRRK2, PARK8) gene has attracted considerable attention since the variants in this gene are recognized as the most common cause of Parkinson's disease (PD) so far. A number of association studies concerning variants of LRRK2 gene and PD susceptibility have been conducted in various populations. However, some results were inconclusive. To derive a more precise estimation of the relationship between LRRK2 and genetic risk of PD, we performed a comprehensive meta-analysis which included 27,363 cases and 29,741 controls from 61 published case-control studies. Totally, the effect of five LRRK2 variants all within the coding regions, i.e. G2019S, G2385R, R1628P, P755L and A419V, were evaluated in the meta-analysis using fixed effect model or random effects model if heterogeneity existed. There were genetic associations between four variants (G2019S, G2385R, R1628P and A419V) and increased PD risk, while there was no evidence of statistically significant association between P755L and PD. Publication bias and heterogeneity were absent in most analyses. Within its limitations, this meta-analysis demonstrated that the G2019S, G2385R, R1628P and A419V variations are risk factors associated with increased PD susceptibility. However, these associations vary in different ethnicities.