Nantarat Komanasin

Factor XIII Val34Leu polymorphism, factor XIII antigen levels and activity and the risk of deep venous thrombosis.

Summary. Varying results on the effect of factor XIII (FXIII) Val34Leu on venous thrombotic risk have been reported. The probability of a true association between this polymorphism and venous thrombotic risk would be enhanced by a laboratory phenotype associated with this polymorphism and with the thrombotic risk. The aim of this study was to assess the effect of FXIII Val34Leu, FXIII activity and subunit levels on venous thrombotic risk in a large case–control study, The Leiden Thrombophilia study (LETS). We found higher FXIII activity for 34Leu carriers (Leu/Leu: 158·0, Val/Val: 95·0). FXIII subunit levels were not associated with genotype. Higher FXIII activity was associated with a slightly decreased thrombotic risk [Odds ratio (OR): 0·8, 95% confidence intervals (CI):u20030·5–1·3]. This effect was not present for elevated FXIII subunit levels. Higher FXIII activity was also associated with a higher dissociation index (percentage A2B2 complex dissociated after activation by thrombin for a fixed time interval). This index was higher for FXIII 34Leu carriers. The risk of deep venous thrombosis was slightly decreased for carriers of the 34Leu allele [OR: 0·9 (95%CI:u20030·7–1·1)]. For homozygous 34Leu carriers the OR was 0·7 (95%CI:u20030·4–1·3). This finding, suggesting a weak protective effect, was completely restricted to men. An overall estimate of thrombotic risk was calculated by using earlier reports on the risk of FXIII Val34Leu. The overall risk estimate for homozygous 34Leu carriers was 0·8 (95%CI:u20030·6–1·0). In this study, a weak protective effect against venous thrombosis was found, of FXIII 34Leu as well as of increased FXIII activity.

A novel polymorphism in the factor XIII B-subunit (His95Arg) : relationship to subunit dissociation and venous thrombosis

Summary.u2002 Background:u2002Factor (F)XIII B‐subunit, which plays a carrier role for zymogen FXIIIA, is highly polymorphic, but the molecular basis for these polymorphisms and their relationship to disease remains unknown. Objectives: To screen the FXIIIB gene coding region for common variation and analyze possible functional effects. Methods and Results:u2002We examined the FXIIIB gene by PCR‐SSCP and identified three common single nucleotide polymorphisms: A8259G, C29470T and A30899G. A8259G results in substitution of His95Arg in the second Sushi domain. An FXIII tetramer ELISA was developed to analyze B‐subunit dissociation from A‐subunit (leading to access to the catalytic site of FXIII). Increased subunit dissociation, 0.51 vs. 0.45 (fraction of total tetramer), was found in plasma from subjects possessing the Arg‐allele. However, when the variants were purified to homogeneity and binding was analyzed by steady‐state kinetics, no difference was observed. The relationship between His95Arg and venous thrombosis was investigated in 214 patients and 291 controls from Leeds. His/Argu2003+u2003Arg/Arg genotypes were more frequent in patients than controls (22.4% vs. 15.1%). His95Arg was also investigated in the Leiden Thrombophilia Study, in which a similar difference was observed for 471 patients vs. 472 controls (18.5% vs. 14.0%), for a pooled odds ratio (OR) of 1.5 (CI95 1.1–2.0). Conclusions:u2002We have identified three FXIIIB polymorphisms, one of which codes for substitution of His95Arg. The Arg95 variant associates with a moderately increased risk for venous thrombosis, and with increased dissociation of the FXIII subunits in plasma, although in vitro steady‐state binding between purified subunits was not affected.

Antihypertensive and antioxidant effects of dietary black sesame meal in pre-hypertensive humans

BackgroundIt has been known that hypertension is an independent risk factor for cardiovascular disease (CVD). CVD is the major cause of morbidity and mortality in developed and developing countries. Elevation of blood pressure (BP) increases the adverse effect for cardiovascular outcomes. Prevention of increased BP plays a crucial role in a reduction of those outcomes, leading to a decrease in mortality. Therefore, the purpose of this study was to investigate the effects of dietary black sesame meal on BP and oxidative stress in individuals with prehypertension.MethodsTwenty-two women and eight men (aged 49.8 ± 6.6 years) with prehypertension were randomly divided into two groups, 15 subjects per group. They ingested 2.52 g black sesame meal capsules or placebo capsules each day for 4 weeks. Blood samples were obtained after overnight fasting for measurement of plasma lipid, malondialdehyde (MDA) and vitamin E levels. Anthropometry, body composition and BP were measured before and after 4-week administration of black sesame meal or a placebo.ResultsThe results showed that 4-week administration of black sesame meal significantly decreased systolic BP (129.3 ± 6.8 vs. 121.0 ± 9.0 mmHg, P < 0.05) and MDA level (1.8 ± 0.6 vs. 1.2 ± 0.6 μmol/L, P < 0.05), and increased vitamin E level (29.4 ± 6.0 vs. 38.2 ± 7.8 μmol/L, P < 0.01). In the black sesame meal group, the change in SBP tended to be positively related to the change in MDA (R = 0.50, P = 0.05), while the change in DBP was negatively related to the change in vitamin E (R = -0.55, P < 0.05). There were no correlations between changes in BP and oxidative stress in the control group.ConclusionsThese results suggest the possible antihypertensive effects of black sesame meal on improving antioxidant status and decreasing oxidant stress. These data may imply a beneficial effect of black sesame meal on prevention of CVD.

Association of arterial stiffness with single nucleotide polymorphism rs1333049 and metabolic risk factors

BackgroundIncreased arterial stiffness is a cardiovascular outcome of metabolic syndrome (MetS). The chromosome 9p21 locus has been identified as a major locus for risk of coronary artery disease (CAD). The single nucleotide polymorphism (SNP), rs1333049 on chromosome 9p21.3 has been strongly associated with CAD and myocardial infarction. Increased arterial stiffness could be the link between the 9p21 polymorphism and increased cardiovascular risk. Since the impact of a genetic polymorphism on arterial stiffness especially in Asian populations has not been well defined, we aimed to investigate the association of arterial stiffness with rs 1333049 variant on chromosome 9p21.3 in Thai subjects with and without MetS risk factors.MethodsA total of 208 Thai subjects, aged 35–75 years, 135 with and 73 without MetS, according to IDF and NCEP-ATPIII criteria, were included in this study. Aortic-femoral pulse wave velocity (afPWV), brachial-ankle pulse wave velocity (baPWV) and aortic ankle pulse wave velocity (aaPWV) were measured and used as markers of arterial stiffness. The chromosome 9p21.3 locus, represented by the rs 1333049 variant and blood biochemistry were evaluated.ResultsArterial stiffness was elevated in subjects with MetS when compared with nonMetS subjects. PWV, especially afPWV increased progressively with increasing number of MetS risk factors (r = 0.322, P <0.001). We also found that the frequency distribution of the rs1333049 genotypes is significantly associated with the afPWV (P <0.05). In multivariate analyses, there was an association between homozygous C allele and afPWV (Odds ratio (OR), 8.16; 95% confidence interval (CI), 1.91 to 34.90; P = 0.005), while the GC genotype was not related to afPWV (OR, 1.79; 95% CI, 0.84 to 3.77; P = 0.129) when compared with the GG genotype.ConclusionsOur findings demonstrate for the first time that arterial stiffness is associated with genetic polymorphism in 9p21 and metabolic risk factors in a Thai population.

Single nucleotide polymorphisms and haplotypes of protein C and protein S genes in the Thai population.

Protein C (PC) and protein S (PS) play key roles in an anticoagulant pathway in order to control the haemostatic system. We identified single nucleotide polymorphisms (SNPs) and/or haplotypes in the promotor and exons of the whole PC and PS genes and in the 3′-untranslated region of the PS gene in 55 Thai individuals. The PC gene revealed 10 haplotypes. One synonymous SNP at 2196 was found in the normal Thai population with a minor allele frequency of 4.90%. One homozygous mutation in exon 7, R147W, co-segregated with the synonymous SNP 2196 (homozygote) of the PC gene, resulting in decreased PC activity and antigenic levels. The PS gene revealed three haplotypes with two frequent dimorphisms in exon 15 and the 3′-untranslated region. The most frequent haplotype in the PS gene was H3 (wild type). There was no correlation between the haplotypes of PC and PS genes with functional and antigenic levels of PC and PS.

Characterization of the binding of a glycosylated serine protease from Euphorbia cf. lactea latex to human fibrinogen

In this study, the binding of a glycosylated serine protease (EuP‐82) with human fibrinogen was investigated by isothermal titration calorimetry (ITC). ITC analysis indicated that the binding of EuP‐82 to fibrinogen in the conditions with or without the activator (Ca2+) was an exothermic reaction (dominant negative enthalpy), which tended to be driven by hydrogen bonding and van der Waals interactions. In contrast, the binding of fibrinogen−EuP‐82 in the condition with the inhibitor (Zn2+) was an unfavorable endothermic reaction. EuP‐82 could not inhibit the platelet activity in citrated whole blood via the ADP–receptor pathways (mainly, P2Y1 and P2Y12), but it could enhance the platelet aggregation. The ITC together with whole blood platelet aggregation suggested that EuP‐82 provided multiple fibrinogen‐binding sites that were not related to the arginine‐glycine‐aspartate (RGD) and the dodecapeptide sequences of fibrinogen. In addition, EuP‐82 had neither thrombin‐like activity nor anticoagulant activity. The SR‐FTIR spectra revealed that EuP‐82 was a glycoprotein. Deglycosylation of EuP‐82 did not affect its proteolytic activity. Moreover, EuP‐82 did not exhibit any toxicity to the living cells (NIH‐3T3). This study supports that EuP‐82 may be useful for wound‐healing material through stabilizing the clot via the platelet induction for the first process.

Association of TAFI gene polymorphisms with severity of coronary stenosis in stable coronary artery disease

INTRODUCTIONnCoronary stenosis is a consequence of atherosclerotic plaque progression that is associated with impaired fibrinolysis. Thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor 1 (PAI-1) are fibrinolysis inhibitors whose levels are influenced by acquired conditions and by polymorphisms. This study therefore aimed to investigate the association of TAFI and PAI-1 gene polymorphisms with severity of coronary stenosis in subjects with stable coronary artery disease (CAD).nnnMATERIALS AND METHODSnA total of 327 subjects suspected with CAD who underwent a coronary angiogram were recruited. Gensini score was applied to stratify the severity of coronary stenosis. Based on the Gensini score, the subjects were categorized into low-medium (<20) or high (≥20) groups. The study polymorphisms included TAFI Ala147Thr (505G/A), Thr325Ile (1040C/T), +1542C/G, +1583T/A and PAI-1 -675 4G/5G. Most polymorphisms were genotyped by allele-specific polymerase chain reaction, except for TAFI Thr325Ile that was genotyped by polymerase chain reaction-restriction fragment length polymorphism.nnnRESULTSnA significant increase in the Gensini score was found in TAFI 505A and +1583A allele carriers. Binary regression analysis revealed the independent association of the TAFI 505G/A and +1583T/A polymorphisms with a high Gensini score [adjusted ORu202f=u202f1.67 (95% CI: 1.03, 2.73) and 1.69 (95% CI: 1.04, 2.76), respectively]. Neither the homozygous PAI-1 -675 4G/4G nor the heterozygous 4G/5G was associated with a high Gensini score.nnnCONCLUSIONSnThe results indicated the contribution of TAFI polymorphisms to atherosclerosis progression and severity of coronary stenosis in stable CAD.

Protective effect of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 haplotype on coronary artery disease.

&NA; Genetic variations of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) and von Willebrand factor (vWF) were related to ADAMTS13 levels. Reduction of ADAMTS13 activity may affect atherosclerotic progression. However, the associations of polymorphisms of these genes with coronary artery disease (CAD) are still unclear. This study, therefore, aimed to investigate the relationship of genetic variations and haplotypes of ADAMTS13 and vWF with CAD risk in Thais. A case–control study was performed in 197 CAD and 135 non-CAD patients. Genetic polymorphisms of ADAMTS13 (P475S, Q448E, rs2073932, P618A, A900V, S903L, rs652600, and rs4962153) and vWF (V1565L and Y1584C) along with ADAMTS13 activity, vWF antigen and vWF activity were examined in the patients. The vWF V1565L polymorphism was associated with increased ADAMTS13 activity, whereas none of ADAMTS13 polymorphisms or haplotypes was associated with its activity. Interestingly, haplotype analysis indicated that the QAGA or H4 haplotype of ADAMTS13 gene had a protective effect on CAD after adjustment for ABO blood group [odds ratio (OR)u200a=u200a0.3, 95% confidence interval (CI)u200a=u200a0.1, 0.6] and major CAD risk factors (ORu200a=u200a0.3, 95% CIu200a=u200a0.1, 0.7). However, the combination of H4 haplotype and the L allele of V1565L was not associated with increased ADAMTS13 activity when compared with the V allele. ADAMTS13 haplotype had an independent protective effect on CAD and genetic variation of vWF V1565L polymorphism modulates ADAMTS13 activity.

Association of combined genetic variations in PPARγ, PGC-1α, and LXRα with coronary artery disease and severity in Thai population

BACKGROUNDnAtherosclerosis is a major cause of coronary artery disease (CAD). Peroxisome proliferator-activated receptor-γ (PPARγ), liver X receptor-α (LXRα), and PPARγ co-activator-1α (PGC-1α) are nuclear factors that regulate lipid metabolism and inflammation implicated in atherosclerosis. Although association of genetic variations in these nuclear factors with CAD risk has been reported, it was based on individual gene with inconsistent results among different ethnicities. We investigated the association of combined gene-polymorphisms of these nuclear factors with the risk and severity of CAD in Thai population.nnnMETHODSnHospital-based subjects, 225 CADs and 162 non-CADs, were genotyped for PPARγ C1431T, PGC-1α G482S, and LXRαxa0-115G/A polymorphisms. Gene-polymorphisms were examined for their association with CAD risk and the severity of coronary atherosclerosis, assessed by both the number of main vessels with ≥50% stenosis and Gensini score.nnnRESULTSnThe minor allele frequencies were 21.6% (1431T), 44.8% (482S), and 10.7% (-115A). Initially, only 482S allele revealed association with CAD risk [ORxa0=xa01.64 (95%CI: 1.01-2.66), Pxa0=xa00.048] and severity [ORs for four-vessel diseasexa0=xa01.23 (95%CI: 1.01-1.48), Pxa0=xa00.036, and for severe atherosclerosis (score >32)xa0=xa01.76 (95%CI: 1.05-2.96), Pxa0=xa00.032]. Combined two risk-genotypes, 1431T/482S andxa0-115GG/482S, also predicted the risk of CAD [ORxa0=xa01.87 (95%CI: 1.09-3.21), Pxa0=xa00.023 and ORxa0=xa01.87 (95%CI: 1.15-3.03), Pxa0=xa00.012 respectively]. The combination of three risk-genotypes further increased the risk of both CAD [ORxa0=xa02.13 (95%CI: 1.12-4.06), Pxa0=xa00.022] and severe coronary atherosclerosis [ORxa0=xa02.09 (95%CI 1.09-4.02), Pxa0=xa00.027].nnnCONCLUSIONnThe combined PPARγ C1431T, PGC-1α G482S, and LXRαxa0-115G/A polymorphisms increased the risk of CAD and predicted the severity of coronary atherosclerosis in Thais.

Low diastolic blood pressure is associated with a high atherosclerotic burden in patients with obstructive coronary artery disease

BACKGROUNDnThe optimal blood pressure (BP) treatment target is still being debated, specifically di-astolic BP (DBP) in patients with obstructive coronary artery disease (CAD); a DBP which is too low could compromise myocardial perfusion and is associated with adverse outcomes.nnnMETHODSnThis study examined the relationship between DBP levels and the severity and atheroscle-rotic burden of CAD in 231 consecutive stable patients with evidence of obstructive CAD as detected by elective coronary angiography. The SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) Score and SYNTAX Score II were used to quantify the atherosclerotic burden.nnnRESULTSnThe patients were male (71%), median age 62, interquartile range [IQR] of 57 to 67, and 84% had hypertension. The median DBP was 71.0 mmHg (IQR: 61 to 80) and the median SYNTAX Score was 16.0 (IQR 9.0-23.0). DBP levels were inversely correlated with SYNTAX Score (r = -0.61) and SYNTAX Score II (r = -0.73). Adjusting for traditional risk factors, unprotected left main CAD, systolic BP, renal function, and medications, DBP levels remained independently inversely associated with a higher tertile of SYNTAX Score (adjusted odds ratio [OR] 0.89; 95% confidence interval [CI] 0.85-0.92, p < 0.001) and SYNTAX Score II (adjusted OR 0.75; 95% CI 0.69-0.80, p < 0.001). The frequency of high athero-sclerotic burden identified by the presence of intermediate or high SYNTAX Score and SYNTAX Score II was significantly higher among patients with a DBP < 60 mmHg.nnnCONCLUSIONSnLow DBP levels are independently associated with high SYNTAX Score and SYNTAX Score II in stable patients with obstructive CAD.