Ming-Sheng Teng

Angiotensinogen and angiotensin-I converting enzyme gene polymorphisms and the risk of coronary artery disease in Chinese

Abstract The homozygous deletion allele (DD) of the angiotensin-I converting enzyme (ACE) gene and the T235 homozygote of the angiotensinogen (AGT) gene have been reported to be correlated with an increased prevalence of coronary artery disease (CAD) and myocardial infarction (MI). The importance of the DD genotype and T235 homozygote as genetic risk factors for CAD in Chinese remains uncertain. This study included 426 patients who underwent coronary angiography and 180 healthy subjects without clinical evidence of CAD. Coronary angiography identified 268 patients with CAD (CAD group) and 158 patients without CAD. The healthy subjects and patients without angiographic evidence of CAD constituted the control group. Three polymorphisms were studied: an insertion/deletion (I/D) polymorphism of the ACE gene and the T174 M and M235T polymorphisms of the AGT gene. No association was found between any of the three studied polymorphisms and the risk of CAD or MI in Chinese using univariate or multivariate analysis. In multivariate analysis, the relative risks were 1.20 (95% confidence interval = 0.91–1.61, P = 0.20) for the DD genotype, 1.05 (95% CI = 0.82–1.35, P = 0.69) for the T174 homozygote, and 1.19 (95% CI = 0.91–1.55, P = 0.20) for the T235 homozygote. Similarly, no significant difference was found in the frequencies of the DD genotype and the T174 and T235 homozygotes between the control group, the CAD group, the non-MI group, and the MI group when analyzed according to sex, age, or degree of risk. Our data suggest that neither the DD genotype of the ACE I/D polymorphism nor the T174 and T235 homozygotes of the AGT gene confer significant risk for CAD or MI in Chinese.

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.

Interaction between obesity and genetic polymorphisms in the apolipoprotein CIII gene and lipoprotein lipase gene on the risk of hypertriglyceridemia in Chinese

Abstract To understand the effects of the interaction between genetic polymorphisms and obesity on the risk of hypertriglyceridemia (HTG), two polymorphisms, an SstI polymorphism on the apolipoprotein CIII gene and a HindIII polymorphism on the lipoprotein lipase gene, were analyzed in 339 Chinese subjects with (82 cases in the HTG group) or without HTG (257 cases in the control group). Our data revealed that the frequencies of obesity, the SstI minor allele (S2), and the HindIII major allele (H+) in the HTG group were significantly higher than in the control group. Subgroup analysis revealed that the association between these two polymorphisms and HTG occurred predominantly in nonobese subjects and in subjects with the less hypertriglyceridemic genotype of another polymorphism. Multivariate logistic regression analysis showed that all three risk factors (obesity, S2-containing chromosome, and H+ homozygosity) were associated with HTG, and an interaction was found between obesity and H+ homozygosity for the occurrence of HTG. The risk of HTG increased significantly with combinations of risk factors. Subjects can be divided into low or high risk groups for HTG using such combinations. These results provide evidence of interaction between obesity and the HindIII polymorphism of the lipoprotein lipase gene on the risk of HTG.

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.

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 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.

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.

Effect of obesity on the association between common variations in the HNF1A gene region and C-reactive protein level in Taiwanese.

BACKGROUND The level of C-reactive protein (CRP), an inflammatory biomarker that predicts future cardiovascular events, is a heritable trait that has been associated with variants of CRP and hepatic nuclear factor-1α (HNF1A) genes. Our aim was to test the statistical association between HNF1A genotypes/haplotypes and serum CRP level in Taiwanese. METHODS A sample population of 617 Taiwanese subjects (all Han-Chinese origin) was enrolled. Five HNF1A single nucleotide polymorphisms (SNPs) rs1920792, rs1169288, rs7310409, rs2464196, rs1169310 were genotyped and analyzed. RESULTS After adjusting for clinical covariates, minor alleles of all the 5 study SNPs were associated with decreased CRP level (P=0.0078, P=0.0107, P=0.0006, P=0.0004 and P=0.0003, respectively). A common haplotype (TGATA) tagged by the minor alleles of study SNPs was associated with significantly decreased CRP level (P=0.0112). Subgroup analysis revealed that the association between HNF1A genotypes and CRP level occurred only in non-obese subjects. CONCLUSIONS HNF1A polymorphisms are independently associated with CRP level in Taiwanese. Further, HNF1A genotypes interact with obesity to set CRP level, revealing that genetic determinants for CRP level may be different between obese and non-obese individuals.