Chi-Jen Chang

The Gln–Arg 191 polymorphism of the human paraoxonase gene is not associated with the risk of coronary artery disease among Chinese in Taiwan

Paraoxonase (PON1) is a high density lipoprotein-associated enzyme capable of hydrolyzing lipid peroxides, and thus, might protect lipoproteins from oxidation. A common polymorphism due to an amino acid substitution (Gln-Arg) at codon 191 is considered to be a major determinant of variation in serum PON1 activity. Recent studies have suggested that the PON1-191 polymorphism is an independent risk factor for coronary atherosclerosis in patients with or without diabetes mellitus. The association of PON1-191 polymorphism genotypes and coronary artery disease (CAD) among Chinese subjects in Taiwan was examined. The genotype of 218 angiographically documented CAD patients and the same number of age- and sex-matched control subjects was determined. Genotypes AA, AB and BB were present in 25 (11%), 102 (47%) and 91 (42%) of control subjects, respectively, and in 30 (14%), 96 (44%) and 92 (42%) of CAD patients, respectively (chi2 = 0.57, P = 0.75 between groups). The frequency of the A allele was 0.36 for the control group and 0.35 for CAD patients (P = 0.94). No significant differences in the PON1-191 genotype frequencies could be found between groups when multivariate logistic regression analysis was performed, or different subgroups of age, sex or risk factors were analyzed. Among control subjects, there was also no significant difference between genotypes of the PON1-191 polymorphism and various clinical and lipid variables. In conclusion, our data suggest that there is no association between the Gln-Arg 191 polymorphism of the human PON1 gene and CAD among Chinese subjects in Taiwan.

The C677T mutation of the methylenetetrahydrofolate reductase gene is not associated with the risk of coronary artery disease or venous thrombosis among Chinese in Taiwan.

Objectives: We sought to investigate the association between the methylenetetrahydrofolate reductase (MTHFR) gene C677T mutation and the risk of coronary artery disease (CAD), myocardial infarction (MI) and venous thrombosis (VT) in a Chinese population in Taiwan. Methods: The subjects included 218 CAD patients, 107 VT patients, and their age- and sex-matched controls. DNA was extracted from the blood and genotypes were determined by polymerase chain reaction, restriction mapping with HinfI and gel electrophoresis. Results: The distribution of MTHFR genotypes was similar in the CAD cases and controls; the genotype TT was present in 6.0% of CAD patients, as compared to 6.9% of CAD control subjects (p = 0.165; odds ratio = 0.86; 95% confidence interval = 0.40–1.85). The frequency of the T allele was also similar in CAD cases and controls (25.5% vs. 24.8%; p = 0.788). There was no significant association between TT homozygosity and the risk of MI. The genotype distributions and the frequency of the T allele were also similar in VT cases and controls. Conclusions: Our data suggest that there is no association between the C677T mutation of the human MTHFR gene and the risk of CAD or VT among Chinese in Taiwan.

Importance of hyperhomocysteinemia as a risk factor for venous thromboembolism in a Taiwanese population. A case-control study.

OBJECTIVE To determine the current status of hyperhomocysteinemia, which is a known risk for venous thrombosis (DVT), in Taiwan. SUBJECTS 101 unselected patients with a minimum of one episode of deep leg DVT, either initial inpatients or current compliant outpatients in a teaching hospital. METHODS Various thrombophilic risks, gene polymorphism and clinical predisposition were evaluated. RESULTS AND CONCLUSIONS Patients presented higher fast total plasma homocysteine (hcy) levels than age- and sex-matched controls did (14.1 vs. 9.94 microM). Based on the 95th percentile of control values, hyperhomocysteinemia had a four- to nine-fold risk for DVT, irrespective of clinical predisposition, as well as other thrombophilic risks surveyed. Polymorphism of a metabolizing enzyme, methylenetetrahydrofolate reductase (MTHFR), was not associated with DVT, although homozygous thermolabile mutation tended to have higher plasma hcy levels. Factor V Leiden was absent in analysis of 80 patients. In complete evaluation (hcy, antithrombin (AT), protein S (PS), protein C (PC), lupus anticoagulant (LA), anticardiolipin antibody) of a subset of 83 patients hyperhomocysteinemia was the most prevalent risk (33.7%), with PC or PS deficiencies following (22.9%). Thus, hyperhomocysteinemia is a prominent risk for DVT in Taiwan.

Apolipoprotein A5 gene -1131T/C polymorphism is associated with the risk of metabolic syndrome in ethnic Chinese in Taiwan

Abstract Background: The –1131T>C polymorphism in the apolipoprotein gene A5 (APOA5) was found to be associated with increased levels of plasma triglyceride and decreased levels of high-density lipoprotein cholesterol (HDL-C), which are characteristic dyslipidemic components of metabolic syndrome. This study aimed to identify a link between this polymorphism and the risk of metabolic syndrome. Methods: The sample population comprised 615 unrelated subjects, 18.7% of whom had metabolic syndrome. Genotypes were determined via polymerase chain reaction, restriction mapping with MseI, and gel electrophoresis. Results: A significantly higher level of triglycerides and a lower level of HDL-C were noted in carriers of the –1131C allele than in the non-carriers (p<0.001 and p=0.044, respectively). The frequency of the –1131C allele in the metabolic syndrome-affected subjects was significantly higher than that of the group of unaffected subjects (37.4% vs. 27.7%, p=0.004). Even after adjusting for age, gender, smoking, regular exercise, and waist-to-hip ratio, the APOA5 –1131C allele carriers remained significantly associated with an increased risk of metabolic syndrome (OR=1.77, 95% CI, 1.13–2.77; p=0.012). Conclusions: These results indicate that the association of APOA5 –1131T>C polymorphism with dyslipidemia can also contribute to an increased susceptibility to metabolic syndrome in the Chinese, as a result of its effect on triglyceride metabolism. Clin Chem Lab Med 2008;46:1714–9.

The G1691A mutation of the coagulation factor V gene (factor V Leiden) is rare in Chinese: an analysis of 618 individuals

Abstract To understand the allele frequency of the G1691A mutation of the coagulation factor V gene (factor V Leiden) in Chinese, 618 Chinese individuals, including 54 cases with venous thrombosis, were analyzed. Only one case in the control group was heterozygous for the 1691G allele and the 1691A allele. Our data suggest that the factor V Leiden is rare in Chinese.

Thrombin regulates matrix metalloproteinase-9 expression in human monocytes

We investigated whether thrombin, the final activator of coagulation cascade, regulates expression of matrix metalloproteinases (MMP)-9 in human monocytes. We show that thrombin stimulation induced MMP-9 secretion of monocytes dose- and time-dependently as revealed by gelatin zymography. Real-time RT-PCR and Western blot analysis demonstrated that thrombin up-regulated mRNA and protein levels of MMP-9. Pre-incubation with anti-protease-activated receptor (PAR)-1 or anti-PAR-3 antibody partially inhibited the thrombin-induced MMP-9 secretion. Simultaneous incubation with both showed synergistic effect, indicating the involvement of both receptors in this thrombin effect. BAPTA, a Ca(2+) chelator, abolished the thrombin-induced MMP-9 secretion, indicating the requirement of Ca(2+) mobilization in this process. Inhibition of thrombin-induced MMP-9 secretion by either MEK inhibitor or p38 kinase inhibitor revealed that the thrombin effect was mediated by both ERK1/2 and p38 pathways. The activation of NFkappaB by thrombin as demonstrated by electromobility shift assay was also shown to be critical to the thrombin-induced MMP-9 up-regulation.

Recoordination Rather than Resynchronization Predicts Reverse Remodeling after Cardiac Resynchronization Therapy

BACKGROUND Mechanical discoordination as studied by magnetic resonance imaging has been shown to be a better predictor of left ventricular (LV) reverse remodeling after cardiac resynchronization therapy (CRT) compared with mechanical dyssynchrony. MATERIALS AND METHODS This study assessed the value of acute recoordination derived from speckle-tracking echocardiography for predicting response to CRT compared with acute resynchronization. Thirty patients with heart failure scheduled for CRT were studied at baseline, immediately after CRT, and after 6 months of CRT. Acute recoordination after CRT was indexed by an acute reduction in radial discoordination index (RDI), defined as the ratio of average myocardial thinning to thickening during the ejection phase. RESULTS CRT responders were defined as those patients whose LV end-systolic volume decreased by >or= 15% at the 6-month follow-up. Immediately after CRT, the responders (n = 18) demonstrated a significant reduction in RDI (P < .001), which was sustained at the 6-month follow-up (P < .001). The nonresponders, however, did not show a significant change in RDI after CRT. LV reverse remodeling at the 6-month follow-up was significantly correlated with acute recoordination (r = 0.75, P < .001) but weakly correlated with acute resynchronization (r = 0.43; P = .02). CONCLUSIONS Receiver operating characteristic analysis revealed that acute recoordination provided the best separation for prediction of CRT responders compared with acute resynchronization, baseline dyssynchrony, or baseline discoordination. LV recoordination after CRT is an acute phenomenon and predicts response to CRT at 6-month follow-up better than resynchronization.

The PCSK9 gene E670G polymorphism affects low-density lipoprotein cholesterol levels but is not a risk factor for coronary artery disease in ethnic Chinese in Taiwan.

Abstract Background: An E670G polymorphism of the exon 12 of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene was recently found to be associated with increased plasma low-density lipoprotein cholesterol (LDL-C) levels and severity of coronary atherosclerosis. This case-control study tested for a possible link between this PCSK9 polymorphism and the risk of coronary artery disease (CAD) in an ethnic Chinese population in Taiwan. Methods: The subjects included 202 CAD patients and 614 unrelated controls. Genotypes were determined via polymerase chain reaction, restriction mapping with MboII, and gel electrophoresis. Results: Contradictory to the results of a previous report, a significantly lower level of LDL-C was noted in 670G carriers than in non-carriers (2.78±0.82 mmol/L vs. 3.02±0.85 mmol/L; p=0.029) among controls, after adjusting for age, gender, smoking, hypertension, diabetes mellitus, body mass index, and use of lipid-lowering agents. The 670G carrier was identified less frequently in patients with CAD than in controls (9.9% vs. 11.9%), but the difference was not significant in a multivariable logistic regression analysis (odds ratio=0.73; 95% CI=0.24–2.22; p=0.575). The G allele also occurred at similar frequencies in the two groups (5.0% vs. 6.0%; p=0.421). Conclusions: These results indicate that the E670G polymorphism of the PCSK9 gene modulates plasma LDL-C levels, but that it is not a risk variant for CAD in ethnic Chinese in Taiwan. Clin Chem Lab Med 2009;47:154–8.

Association of soluble intercellular adhesion molecule–1 with insulin resistance and metabolic syndrome in Taiwanese

Circulating concentrations of soluble cell adhesive molecules are useful predictors for the risk of development and progression of atherosclerosis. This study was initiated to investigate the association between soluble intercellular adhesive molecule-1 (sICAM-1) levels and traditional and emerging cardiovascular risk factors, as well as insulin resistance and metabolic syndrome, in a Taiwanese population. Six hundred nine unrelated individuals recruited during routine health examinations were enrolled for the analysis. In age- and sex-adjusted regression models, sICAM-1 levels were negatively associated with high-density lipoprotein cholesterol levels and positively associated with systolic, mean, and diastolic blood pressure; body mass index; waist circumference; waist-hip ratio; the homeostasis model assessment index; fasting serum insulin; triglyceride; and C-reactive protein levels. The sICAM-1 levels were also higher in subjects with current smoking (P = .001), diabetes mellitus (P = .004), insulin resistance (P < .001), and metabolic syndrome (P < .001). The sICAM-1 levels increased in a stepwise fashion with increasing Framingham risk score quartiles (P = .001) and with increasing number of metabolic syndrome components (P < .001). In subjects with metabolic syndrome, increased C-reactive protein levels were associated with increased sICAM-1 levels (P = .003). In stepwise linear regression models, sICAM-1 levels remained associated with current smoking, insulin resistance, and metabolic syndrome. In conclusion, our data revealed that insulin resistance and metabolic syndrome were associated with sICAM-1 levels in Taiwanese. These data provide further evidence of the mechanisms of sICAM-1 as a molecular marker for atherosclerosis.

Functional polymorphisms of FGA, encoding α fibrinogen, are associated with susceptibility to venous thromboembolism in a Taiwanese population

To determine the genetic risk factors for venous thromboembolism (VTE), this study examined 14 genetic variants from 10 hemostatic genes in 186 Taiwanese VTE patients and the same number of matched controls, which demonstrated FGA (encoding α fibrinogen) Thr312Ala polymorphism was the only variant significantly associated with VTE. Nine genetic polymorphisms on the fibrinogen cluster region of chromosome 4q28 were further studied, in which four FGA polymorphisms were found in strong linkage disequilibrium and were significantly associated with VTE by genotype and allele frequency analyses. Haplotype analysis showed significantly different FGA haplotype frequencies between VTE patients and controls with the haplotype F1, containing -1051G, -3A, 312Ala and TaqI duplication alleles, significantly associated with susceptibility to VTE (P=0.001). Haplotype-pair analysis results also indicated a strong association of the haplotype-pair F1F1 with VTE in various VTE patient subgroups. In vitro functional analysis indicated that FGA -1051G, -3A and TaqI duplication alleles enhanced significantly the transcription level of FGA; however, control subjects with FGA genotypes containing these alleles had no elevated plasma fibrinogen levels. In conclusion, our experimental data indicated that functional genetic variants in FGA are risk factors for VTE in Taiwanese populations. Determination of FGA genotypes will likely contribute to primary prevention of this condition.