Lung-An Hsu

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.

Association Between a Novel 11–Base Pair Deletion Mutation in the Promoter Region of the Scavenger Receptor Class B Type I Gene and Plasma HDL Cholesterol Levels in Taiwanese Chinese

Objective—Scavenger receptor class B type I (SR-BI) is a multiligand cell-surface receptor that mediates the selective uptake of lipid from HDL cholesterol (HDL-C) into cells. This study hypothesized an association between functional variants in the promoter region of SR-BI gene and HDL-C levels. Methods and Results—We identified 2 novel mutations in the SR-BI gene promoter region by using single-strand conformation polymorphism. One mutation was an 11-bp CCCCGCCCC GT deletion mutation from positions −140 to −150 relative to the transcription start site, corresponding to an Sp1 binding site; the other was a C →T substitution at position −142. Twenty-six of 690 unrelated subjects were heterozygous for the −140 to −150 deletion mutation, and the allele frequency in this population was 0.02. This study showed that the deletion variant prevented binding of Sp1 to this region of the SR-BI promoter and effectively reduced transcriptional activities in HepG2 cells. Notably, the −140 to −150 deletion mutation was significantly associated with increased HDL-C levels and explained ≈0.5% of the variation in HDL-C levels in this population. Conclusions—A genetic variant at the SR-BI gene promoter region might explain a significant proportion of individual differences in HDL-C levels among Taiwanese Chinese. Our results require further replication in an independent population.

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.

Association between C-reactive protein gene haplotypes and C-reactive protein levels in Taiwanese: Interaction with obesity

OBJECTIVE The level of C-reactive protein (CRP), an inflammatory marker that predicts future cardiovascular events, is a heritable trait. Our aim was to test the statistical associations between variations in the CRP gene and serum CRP levels in a Taiwanese population with interaction analysis. METHODS A sample population of 617 Taiwanese subjects was enrolled. Five CRP single nucleotide polymorphisms (SNPs) previously reported to be associated with CRP level and with reasonable coverage of the CRP gene region were analyzed using polymerase chain reaction and restriction enzyme digestion or by TaqMan SNP Genotyping Assays. RESULTS After adjusting for clinical covariates, minor alleles of 3 of the 5 SNPs were associated with change in CRP level: rs3091244 and rs1205 were associated with increased CRP level (P=0.001 and P<0.001, respectively) and rs1800947 with decreased CRP level (P=0.003). Two haplotypes inferred from 5 SNPs (GCGCG and AAGCG) were associated with increased CRP level (P=0.017 and P<0.0001, respectively). Interaction analysis revealed interaction of obesity with CRP genotypes associated with high CRP level (interaction P=0.034 and 0.020 for SNPs rs2794521 and rs1800947, respectively). An effect of obesity on CRP level was also noted in haplotype interaction analysis with the association occurring predominantly in obese subjects (P=0.034). CONCLUSION CRP polymorphisms are independently associated with increased or decreased CRP level in Taiwanese. Further, CRP genotypes/haplotypes interact with obesity to set CRP level. These findings have implications for the prediction of atherosclerotic disease.

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.

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.

Insulin resistance is associated with C-reactive protein independent of abdominal obesity in nondiabetic Taiwanese.

Insulin resistance, which plays a fundamental role in the pathogenesis of metabolic syndrome and type 2 diabetes mellitus, is associated with serum levels of inflammatory markers and abdominal obesity. Whether insulin resistance is caused by inflammation or is an epiphenomenon of obesity remains unresolved. We therefore conducted a cross-sectional study to investigate whether the association between insulin resistance and C-reactive protein (CRP) levels is independent of abdominal obesity in a nondiabetic Taiwanese population. The study included 574 Taiwanese participants (300 men and 274 women) who were nondiabetic persons with CRP levels not exceeding 10 mg/L and who did not have a history of cardiovascular disease or were taking medication for dyslipidemia. All participants were of Han-Chinese origin. The degree of insulin resistance was determined using the homeostasis model assessment of insulin resistance (HOMA-IR). The CRP levels were categorized into quartiles from the lowest to the highest concentrations (Q1-Q4). Blood pressure, fasting glucose level, triglycerides level, waist circumference, and HOMA-IR were all found to be significantly higher in Q3 and Q4 than in Q1 and Q2. Stratified analysis by sex and abdominal obesity showed that HOMA-IR was significantly associated with CRP levels in both sexes in either obese or nonobese populations. Multiple linear regression analysis adjusting for age, smoking, components of metabolic syndrome, and waist circumference showed that the association between HOMA-IR and CRP levels remained significant in both men and women (P = .029 for men and P < .001 for women). These findings confirm that insulin resistance is strongly associated with CRP levels independent of abdominal obesity in nondiabetic Taiwanese. Factors other than abdominal obesity, such as polymorphisms in the CRP gene, may influence the association of insulin resistance with CRP levels in different ethnic populations.