Association of Combined TCF7L2 and KCNQ1 Gene Polymorphisms with Diabetic Micro- and Macrovascular Complications in Type 2 Diabetes Mellitus.

BACKGROUND: Vascular complications are the major morbid consequences of type 2 diabetes mellitus (T2DM). The transcription factor 7-like 2 (TCF7L2), potassium voltage-gated channel subfamily Q member 1 (KCNQ1), and inwardly-rectifying potassium channel, subfamily J, member 11 gene (KCNJ11) are common T2DM susceptibility genes in various populations. However, the associations between polymorphisms in these genes and diabetic complications are controversial. This study aimed to investigate the effects of combined gene-polymorphisms within TCF7L2, KCNQ1, and KCNJ11 on vascular complications in Thai subjects with T2DM. METHODS: We conducted a case-control study comprising 960 T2DM patients and 740 non-diabetes controls. Single nucleotide polymorphisms in TCF7L2, KCNQ1, and KCNJ11 were genotyped and evaluated for their association with diabetic vascular complications. RESULTS: The gene variants TCF7L2 rs290487-T, KCNQ1 rs2237892-C, and KCNQ1 rs2237897-C were associated with increased risk of T2DM. TCF7L2 rs7903146-C, TCF7L2 rs290487-C, KCNQ1 rs2237892-T, and KCNQ1 rs2237897-T revealed an association with hypertension. The specific combination of risk-alleles that have effects on T2DM and hypertension, TCF7L2 rs7903146-C, KCNQ1 rs2237892-C, and KCNQ1 rs2237897-T, as genetic risk score (GRS), pronounced significant association with coronary artery disease (CAD), cumulative nephropathy and CAD, and cumulative microvascular and macrovascular complications (respective odds ratios [ORs] with 95% confidence interval [95% CI], comparing between GRS 2-3 and GRS 5-6, were 7.31 [2.03 to 26.35], 3.92 [1.75 to 8.76], and 2.33 [1.13 to 4.79]). CONCLUSION: This study demonstrated, for the first time, the effect conferred by specific combined genetic variants in TCF7L2 and KCNQ1 on diabetic vascular complications, predominantly with nephropathy and CAD. Such a specific pattern of gene variant combination may implicate in the progression of T2DM and life-threatening vascular complications.

Association of combined genetic variations in SOD3, GPX3, PON1, and GSTT1 with hypertension and severity of coronary artery disease.

Oxidative stress plays a critical role in the pathophysiology of hypertension (HT) and the progression of atherosclerotic coronary artery disease (CAD). Genetic variations in superoxide dismutase (SOD), glutathione peroxidase 3 (GPX3), paraoxonase 1 (PON1) and glutathione S-transferase theta 1 (GSTT1) may modulate their gene functions, affecting protein functions. These changes could have an impact on the pathogenesis of HT and progression of CAD. The present study investigated the associations of individual and combined antioxidant-related gene polymorphisms with the incidence of HT and severity of CAD. Two study populations were enrolled. The HT-associated study comprised 735 control and 735 hypertensive subjects (mean age 59.3 ± 9.0 years), matched for age and sex. The CAD study, hospital-based subjects (mean age 62.1 ± 9.5 years), included 279 CAD patients and 165 non-CAD subjects. Gene polymorphisms were identified in genomic DNA using polymerase chain reaction (PCR)-based technique. Genetic variations were assessed for their associations with HT and severity of CAD. Antioxidant gene variants, SOD3 rs2536512-GG, GPX3 rs3828599-GG, PON1 rs705379-TT, and GSTT1-/- and +/-, were independently associated with the incidence of HT. A combination of four HT-associated genotypes, as a genetic risk score (GRS), revealed an association of GRS 5 and GRS ≥ 6 with increased susceptibility to HT and CAD, and further with multivessel coronary atherosclerosis (multivessel CAD) compared with GRS 0-2 [respective ORs(95% CI) for GRS ≥ 6 = 2.37 (1.46-3.85), 3.26 (1.29-8.25), and 4.36 (1.36-14.0)]. Combined polymorphisms in these four antioxidant-related genes were associated with the incidences of HT and CAD, and with the severity of coronary atherosclerosis.

Association of Genetic Variations in NRF2, NQO1, HMOX1, and MT with Severity of Coronary Artery Disease and Related Risk Factors.

NRF2 is a transcription factor which, during oxidative stress, activates transcription of its target antioxidant genes. Polymorphisms in NRF2 and its target antioxidant genes: HMOX-1, NQO1, and MT, have been associated with cardiovascular diseases (CVDs) and diabetes in various ethnic groups, however, with variable results. The aim of this study was to investigate the association of NRF2, HMOX-1, NQO1, and MT gene polymorphisms with CVD risk factors in Thais. The study was conducted in two groups: group with high-risk for coronary artery disease (CAD) and health check-up group. Polymorphisms in NRF2 (rs6721961), NQO1 (rs1800566), MT1A (rs11640851), and HMOX-1 (rs2071746) were genotyped. Expressions of NRF2, HMOX-1, and NQO1 were also determined. In high-risk group, NRF2 rs6721961-TT was associated with CAD [OR (95% CI) 5.07 (1.42-18.10)] and severity of coronary atherosclerosis [Gensini score > 32, OR (95% CI) 4.31 (1.67-11.09)]; rs6721961 GT and TT revealed significant association with lower mRNA expression than GG (p = 0.021). NQO1 rs1800566 also revealed association with CAD, only in female. Combined effect of NQO1-rs1800566, HMOX1-rs2071746, and MT1A-rs11640851 was evaluated on the risks of DM and hypertension. With a combination of risk alleles as genetic risk score (GRS), the highest GRS (score 6) increased risk for hypertension, comparing with GRS 0-2 [OR (95% CI) 1.89 (1.02-3.49)]; group with score 5-6 revealed association with risk of DM [OR (95% CI) 1.481 (1.08-2.04)]. In conclusion, NRF2 rs6721961 associated with CAD and severity of coronary atherosclerosis. NQO1 rs1800566 also associated with CAD, only in female. Combined polymorphisms of three NRF2-regulated genes increased risk of DM and hypertension.

Association of genetic polymorphisms in SOD2, SOD3, GPX3, and GSTT1 with hypertriglyceridemia and low HDL-C level in subjects with high risk of coronary artery disease.

BACKGROUND: Oxidative stress modulates insulin resistant-related atherogenic dyslipidemia: hypertriglyceridemia (HTG) and low high-density lipoprotein cholesterol (HDL-C) level. Gene polymorphisms in superoxide dismutase (SOD2 and SOD3), glutathione peroxidase-3 (GPX3), and glutathione S-transferase theta-1 (GSTT1) may enable oxidative stress-related lipid abnormalities and severity of coronary atherosclerosis. The present study investigated the associations of antioxidant-related gene polymorphisms with atherogenic dyslipidemia and atherosclerotic severity in subjects with high risk of coronary artery disease (CAD). METHODS: Study population comprises of 396 subjects with high risk of CAD. Gene polymorphisms: SOD2 rs4880, SOD3 rs2536512 and rs2855262, GPX rs3828599, and GSTT1 (deletion) were evaluated the associations with HTG, low HDL-C, high TG/HDL-C ratio, and severity of coronary atherosclerosis. RESULTS: SOD2 rs4880-CC, SOD3 rs2536512-AA, rs2855262-CC, and GPX3 rs3828599-AA, but not GSTT1 -/- individually increased risk of HTG combined with low HDL-C level. With a combination of five risk-genotypes as a genetic risk score (GRS), GRS ≥ 6 increased risks of low HDL-C, high TG/HDL-C ratio, and HTG combined with low HDL-C, comparing with GRS 0-2 [respective adjusted ORs (95% CI) = 2.70 (1.24-5.85), 3.11 (1.55-6.23), and 5.73 (2.22-14.77)]. Gene polymorphisms, though, were not directly associated with severity of coronary atherosclerosis; high TG/HDL-C ratio was associated with coronary atherosclerotic severity [OR = 2.26 (95% CI [1.17-4.34])]. CONCLUSION: Combined polymorphisms in antioxidant-related genes increased the risk of dyslipidemia related to atherosclerotic severity, suggesting the combined antioxidant-related gene polymorphisms as predictor of atherogenic dyslipidemia.

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

INTRODUCTION: Coronary 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). MATERIALS AND METHODS: A 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. RESULTS: A 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 OR = 1.67 (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. CONCLUSIONS: The results indicated the contribution of TAFI polymorphisms to atherosclerosis progression and severity of coronary stenosis in stable CAD.

Association of a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13 polymorphisms with severity of coronary stenosis in type 2 diabetes mellitus.

BACKGROUND: The imbalance of von Willebrand factor (vWF) and a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13 (ADAMTS13) has been associated with atherosclerosis progression. A high level of vWF which regulates thrombus formation is associated with diabetes mellitus (DM), and some ADAMTS13 and vWF polymorphisms have effects on their levels. Therefore, this study aimed to evaluate the associations of ADAMTS13 and vWF polymorphisms and their levels with DM and severity of coronary stenosis. MATERIALS AND METHODS: Eighty-seven DM and 84 control individuals were recruited. vWF and ADAMTS13 activities as well as vWF antigen were measured by collagen-binding assay (CBA), residual-CBA, and in-house enzyme-linked immunosorbent assay, respectively. ADAMTS13 and vWF polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The E and G alleles and AA genotype of ADAMTS13 Q448E, rs2073932, and rs652600, respectively, were independently associated with DM (odds ratio [OR] [95% confidence interval (CI)] = 2.5 [1.1, 5.6], 2.3 [1.0, 5.2], and 4.7 [1.2, 18.6], respectively). Moreover, E allele and AA genotype of Q448E and rs652600 were also significantly associated with multi-vessel disease (OR [95% CI] = 2.2 [1.0, 4.8] and 3.2 [1.0, 10.0], respectively), while the E and G allele of Q448E and rs2073932 were associated with high Gensini score (OR [95% CI] = 2.3 [1.1, 4.9] and 2.3 [1.1, 5.1], respectively). CONCLUSION: Association of ADAMTS13 polymorphisms with DM, number of vessel stenosis, and Gensini score may indicate the possible contribution of ADAMTS13 polymorphisms to atherosclerosis progression and severity of coronary stenosis in DM.

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

BACKGROUND: The 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. METHODS: This 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. RESULTS: The 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. CONCLUSIONS: Low DBP levels are independently associated with high SYNTAX Score and SYNTAX Score II in stable patients with obstructive CAD.

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

: 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) = 0.3, 95% confidence interval (CI) = 0.1, 0.6] and major CAD risk factors (OR = 0.3, 95% CI = 0.1, 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.

BACKGROUND: Atherosclerosis 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. METHODS: Hospital-based subjects, 225 CADs and 162 non-CADs, were genotyped for PPARγ C1431T, PGC-1α G482S, and LXRα -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. RESULTS: The minor allele frequencies were 21.6% (1431T), 44.8% (482S), and 10.7% (-115A). Initially, only 482S allele revealed association with CAD risk [OR = 1.64 (95%CI: 1.01-2.66), P = 0.048] and severity [ORs for four-vessel disease = 1.23 (95%CI: 1.01-1.48), P = 0.036, and for severe atherosclerosis (score >32) = 1.76 (95%CI: 1.05-2.96), P = 0.032]. Combined two risk-genotypes, 1431T/482S and -115GG/482S, also predicted the risk of CAD [OR = 1.87 (95%CI: 1.09-3.21), P = 0.023 and OR = 1.87 (95%CI: 1.15-3.03), P = 0.012 respectively]. The combination of three risk-genotypes further increased the risk of both CAD [OR = 2.13 (95%CI: 1.12-4.06), P = 0.022] and severe coronary atherosclerosis [OR = 2.09 (95%CI 1.09-4.02), P = 0.027]. CONCLUSION: The combined PPARγ C1431T, PGC-1α G482S, and LXRα -115G/A polymorphisms increased the risk of CAD and predicted the severity of coronary atherosclerosis in Thais.

Relationship between aerobic capacity and cardiovascular disease risk factors in Thai men and women with normolipidemia and dyslipidemia.

[Purpose] This research aimed to investigate the relationship between aerobic capacity (VO2,peak) and cardiovascular risk factors in normolipidemic and dyslipidemic Thai men and women. [Subjects and Methods] We recruited 104 dyslipidemic and 100 healthy participants. Fasting blood samples were analyzed for lipid and blood glucose levels. Anthropometry, blood pressure, and body composition were measured before exercise. Each subject underwent exercise testing to determine VO2, peak. Heart rate (HR) was recorded throughout the exercise test. [Results] Dyslipidemic participants had a lower VO2, peak than normolipidemic participants (p<0.01). In normolipidemic male participants, VO2, peak was positively correlated with high density lipoprotein cholesterol (HDL-C) levels and negatively correlated with low density lipoprotein cholesterol (LDL-C) levels and triglycerides to HDL-cholesterol (TG/HDL-C) ratios; in females, VO2, peak was negatively correlated with age, total cholesterol, and LDL-C. In dyslipidemic males, VO2, peak was positively correlated with HDL-C levels and negatively correlated with age, LDL-C and TG levels, and percent body fat; in females, VO2, peak was positively correlated with resting HR and heart rate recovery and negatively correlated with age, TG/HDL-C, and waist circumference. [Conclusion] There was a relationship between aerobic capacity and cardiovascular disease risk factors in both normolipidemic and dyslipidemic participants. This relationship was affected by gender.

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

BACKGROUND: Increased 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. METHODS: A 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. RESULTS: Arterial 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. CONCLUSIONS: Our findings demonstrate for the first time that arterial stiffness is associated with genetic polymorphism in 9p21 and metabolic risk factors in a Thai population.

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

BACKGROUND: It 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. METHODS: Twenty-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. RESULTS: The 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. CONCLUSIONS: These 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.

Remodeling of apolipoprotein E-containing spherical reconstituted high density lipoproteins by phospholipid transfer protein.

Phospholipid transfer protein (PLTP) transfers phospholipids between HDL and other lipoproteins in plasma. It also remodels spherical, apolipoprotein A-I (apoA-I)-containing HDL into large and small particles in a process involving the dissociation of lipid-free/lipid-poor apoA-I. ApoE is another apolipoprotein that is mostly associated with large, spherical HDL that do not contain apoA-I. Three isoforms of apoE have been identified in human plasma: apoE2, apoE3, and apoE4. This study investigates the remodeling of spherical apoE-containing HDL by PLTP and the ability of PLTP to transfer phospholipids between apoE-containing HDL and phospholipid vesicles. Spherical reconstituted high density lipoproteins (rHDL) containing apoA-I [(A-I)rHDL], apoE2 [(E2)rHDL], apoE3 [(E3)rHDL], or apoE4 [(E4)rHDL] as the sole apolipoprotein were prepared by incubating discoidal rHDL with low density lipoproteins and lecithin:cholesterol acyltransferase. PLTP remodeled the spherical, apoE-containing rHDL into large and small particles without the dissociation of apoE. The PLTP-mediated remodeling of apoE-containing rHDL was more extensive than that of (A-I)rHDL. PLTP transferred phospholipids from small unilamellar vesicles to apoE-containing rHDL in an isoform-dependent manner, but at a rate slower than that for spherical (A-I)rHDL. It is concluded that apoE enhances the capacity of PLTP to remodel HDL but reduces the ability of HDL to participate in PLTP-mediated phospholipid transfers.