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
Supakanya Lasom1, Nantarat Komanasin2, Nongnuch Settasatian3, Chatri Settasatian4, Upa Kukongviriyapan5, Pongsak Intharapetch6
1 Biomedical Science Program, Graduate School; Cardiovascular Research Group, Khon Kaen University, Khon Kaen, Thailand
2 Cardiovascular Research Group; Department of Clinical Microscopy, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
3 Cardiovascular Research Group; Department of Clinical Chemistry, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
4 Cardiovascular Research Group; Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
5 Cardiovascular Research Group; Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
6 Cardiovascular Research Group; Queen Sirikit Heart Center of the Northeast, Khon Kaen University, Khon Kaen, Thailand
|Date of Submission||21-Jun-2017|
|Date of Decision||21-Nov-2017|
|Date of Acceptance||18-Mar-2018|
|Date of Web Publication||26-Jul-2018|
Dr. Nantarat Komanasin
Department of Clinical Microscopy, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002
Source of Support: None, Conflict of Interest: None
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. ADAMTS1 3 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.
Keywords: A disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13, coronary stenosis, diabetes mellitus, polymorphism
|How to cite this article:|
Lasom S, Komanasin N, Settasatian N, Settasatian C, Kukongviriyapan U, Intharapetch P. 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. J Res Med Sci 2018;23:59
|How to cite this URL:|
Lasom S, Komanasin N, Settasatian N, Settasatian C, Kukongviriyapan U, Intharapetch P. 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. J Res Med Sci [serial online] 2018 [cited 2021 Jul 25];23:59. Available from: https://www.jmsjournal.net/text.asp?2018/23/1/59/237596
| Introduction|| |
Diabetes mellitus (DM) is a major risk factor for coronary artery disease (CAD). It has been known that cardiovascular disease (CVD) is the most important complication and approximately 75% of type 2 diabetic patients die from CVD. This observation can be explained by several mechanisms including concomitant risk factors such as hypertension, dyslipidemia, hyperglycemia, obesity, and metabolic syndrome which are responsible for endothelial dysfunction. Recently, many studies have suggested that proteins or factors relating to endothelial dysfunction were considered to be associated with DM. von Willebrand factor (vWF) is an important biomarker of endothelial dysfunction. It plays a crucial role in primary hemostasis and thrombus formation by mediating platelet adhesion and aggregation. Upon released from endothelial cells, ultralarge vWF multimers which are the most thrombogenic are cleaved into the less active forms by a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13 (ADAMTS13). Reduction in ADAMTS13 activity and elevated vWF antigen are associated with thrombotic thrombocytopenic purpura  and other thrombotic diseases such as ischemic stroke, acute myocardial infarction, and CAD.
High-circulating vWF concentrations are known to be associated with DM,, which mainly caused by endothelial dysfunction. It has been found to be a link to the development of microvascular and macrovascular diseases , and a risk marker for death in diabetic patients. On the other hand, there are few studies reporting ADAMTS13 levels in DM and the results were inconsistent. Skeppholm et al. have suggested that ADAMTS13 activity was significantly lower in diabetic patients and a decrease in ADAMTS13 activity was also associated with an increased risk of cardiovascular events and renal disease in type 2 DM patients. In contrast, the recent study has demonstrated that ADAMTS13 activity was elevated in type 1 DM patients with retinopathy. Although vWF is released from endothelial cells, increased circulating vWF may not only due to elevated endothelial secretion or endothelial damage but may also partly be related to a reduction of ADAMTS13 function. Many ADAMTS13 and vWF polymorphisms have been reported to be associated with impaired ADAMTS13 activity as well as increased vWF antigen and activity.,, Thus, vWF and ADAMTS13 genes may have an important role in genetic susceptibility to the thrombotic development or vascular complication in DM.
So far, there is no study investigating the possible relationship of known ADAMTS13 and vWF polymorphisms with DM and the progression of the plaque in coronary artery of the patients with macrovascular complication. In addition, the association between ADAMTS13 and DM is controversy. Therefore, those associations were explored in this study. Genetic variations of ADAMTS13 and vWF associated with impaired ADAMTS13 activity and increased levels of vWF antigen and activity were selected as the candidate polymorphisms. The polymorphisms were investigated in type 2 DM patients with CAD complication. This genetic association study could possibly provide the new insights into the role of ADAMTS13 and vWF polymorphisms in thrombus formation and vascular complication of DM in Thai population.
| Materials and Methods|| |
A total of 171 participants who attended to the Cardiac Catheterization Unit, Queen Sirikit Heart Center of the Northeast Hospital, Khon Kaen University, for cardiovascular checkup (2008–2010) were recruited in this study. Patients with acute coronary syndrome, left ventricular hypertrophy, heart failure, cardiomyopathy, valvular heart disease, deep vein thrombosis, liver disease, renal disease, and inflammatory disease were excluded. Type 2 DM was diagnosed according to the criteria of the World Health Organization. According to the coronary angiographic results, the DM participants (n = 87) were diagnosed as CAD if the angiographic results of coronary arteries showing ≥50% stenosis (single-vessel disease or multi-vessel disease). The individuals without DM and presenting none or < 50% stenosis were classified as control group (n = 84). The severity of coronary stenosis was determined using the numbers of main vessel stenosis ≥50% together with Gensini score, which was calculated from the degree of luminal narrowing and its geographic importance of coronary artery. Patients with Gensini score ≥20 were classified as high score, while those presenting the score < 20 were defined as low–medium score. Other clinical variables including age, sex, CAD risk factors, and use of medicines were obtained from medical records. Individuals presenting one or more of the following parameters: total cholesterol (TC) ≥6.2 mmol/L, triglyceride ≥2.3 mmol/L, high-density lipoprotein-cholesterol (HDL-C) <1.0 mmol/L, and low-density lipoprotein-cholesterol (LDL-C) ≥4.1 mmol/L or use of lipid-lowering drugs were diagnosed as dyslipidemia. Individuals whom had blood pressure ≥140/90 mmHg and/or used anti-hypertensive drugs were defined as hypertension. Individuals with body mass index (BMI) ≥25 kg/m2 were classified as obesity. Metabolic syndrome was considered if any three in five risk factors were presented: (i) waist circumference >90 cm in male and >80 cm in female, (ii) TG >1.7 mmol/L or on lipid-lowering drug treatment, (iii) HDL-C <1.0 mmol/L in male and <1.3 mmol/L in female, (iv) blood pressure >130/85 mmHg or use of anti-hypertensive medications, and (v) fasting blood glucose (FBG) >5.6 mmol/L or use of glucose-lowering drugs. The study was approved by the Khon Kaen University Ethics Committee for Human Research (HE510414). Signed consent form was obtained from each participant after explanation of the study.
Blood samples were obtained after 12 h of fasting before undergoing coronary angiography. Four milliliters of blood samples was collected in 3.2% tri-sodium citrate and immediately placed on ice. Platelet poor plasma was further separated within 30 min by centrifugation at 1500 g at 4°C for 15 min. All plasma samples were stored in small aliquots at −80°C until use. vWF antigen and activity were measured by an in-house sandwich enzyme-linked immunosorbent assay and collagen-binding assay (CBA), respectively, while ADAMTS13 activity was determined by residual CBA as previously described. The other blood chemical analysis serum high-sensitivity C-reactive protein (hs-CRP) concentration was examined by immunonephelometry using BN ProSpec® System (Siemens Healthcare Diagnostics Products GmbH, Germany).
Genotyping of ADAMTS13 and vWF polymorphisms including ADAMTS13 Q448E (rs2301612), rs2073932, rs652600, rs4962153, and vWF V1565 L (rs1800385) was performed by polymerase chain reaction-restriction fragment length polymorphism technique as described in the previous study.
Statistical analysis was performed using the SPSS version 17.0 (SPSS Inc., IL, USA). Kolmogorov–Smirnov was applied to test whether data were normally distributed. The continuous values were expressed as mean ± standard deviation (SD). If the values were not normal distribution, they were transformed to logarithm before comparison and presented as geometric mean ± SD. Independent sample t-test and one-way analysis of variance were used to compare continuous values between two or more than two groups, respectively. The χ2-test was performed for comparison of categorical variables such as CAD risk factors and genotype frequencies. The Hardy–Weinberg equilibrium was evaluated by χ2-test, and all genotype distributions observed in this study were compatible with Hardy–Weinberg equilibrium. Jonckheere–Terpstra test was used to analyze the probability of trend for a continuous variable across an ordinal group. Multivariate logistic regression analysis was performed to evaluate the association of genotypes with DM and severity of coronary stenosis. Statistical significance was considered when P < 0.05.
| Results|| |
Individuals in DM group presented higher proportions of hypertension, metabolic syndrome, as well as Gensini score, systolic blood pressure, triglyceride, FBG, insulin levels, homeostasis model assessment of insulin resistance (HOMA-IR), and white blood cell count as compared to controls. No significant differences between both groups were observed for BMI, TC, LDL-C, hs-CRP levels, and number of white blood cells [Table 1]. vWF antigen was likely to increase in DM compared to control group (94.5 ± 40.4 [n = 87] vs. 83.1 ± 39.6 IU/dL [n = 84], P for trend = 0.032). However, no significant differences of ADAMTS13 activity (72.3 ± 18.1 [n = 87] vs. 73.1 ± 17.9% [n = 84], P = 0.775), vWF activity (99.6 ± 28.8 [n = 87] vs. 94.7 ± 25.7 IU/dL [n = 84], P = 0.249), and vWF antigen/ADAMTS13 activity ratio (1.2 ± 1.0 [n = 87] vs. 1.0 ± 0.6 [n = 84], P = 0.113) were observed between both groups.
Frequencies of QE genotype and E allele carrier of ADAMTS13 Q448E, AG genotype and G allele carrier of ADAMTS13 rs2073932, as well as AA genotype of ADAMTS13 rs652600 were significantly higher in DM individuals than those in control group (P< 0.05) [Table 2]. To evaluate the association of genetic variations with DM, multivariate logistic regression analysis was performed. The results demonstrated that presences of QE genotype and E allele carrier of the Q448E, AG genotype and G allele carrier of the rs2073932, as well as AA genotypes of the rs652600 were found to be independently associated with DM after adjustment for gender, age, hypertension, and metabolic syndrome [Table 2].
|Table 2: Prevalence of a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13 and von Willebrand factor polymorphisms and their associations with diabetes mellitus|
Click here to view
To classify the severity of coronary stenosis in DM individuals with CAD, the number of stenotic vessels and Gensini score were considered. The significant differences were found in frequencies of E and G alleles of the Q448E and rs2073932 in DM with multi-vessel disease and high Gensini score when compared to controls (P< 0.05). However, there were no significant differences of other genotypes in those with single-vessel disease when compared to controls [Table 3]. Furthermore, multivariate logistic regression analysis was performed to investigate the relationship between ADAMTS13 and vWF polymorphisms with severity of coronary stenosis. The results demonstrated that after adjustment for sex and age, the E allele carrier of the Q448E and the AA genotype of the rs652600 were significantly associated with an increased risk of multi-vessel disease (odds ratio [OR] [95% confidence interval (CI)] = 2.2 [1.0, 4.8], P = 0.047 and 3.2 [1.0, 10.0], P = 0.043, respectively) [Figure 1]a. In addition, this study also revealed the significant association between the minor allele carrier of the Q448E and rs2073932 with high Gensini score when compared to the control group (OR [95% CI] = 2.3 [1.1, 4.9], P = 0.035 and 2.3 [1.1, 5.1], P = 0.033, respectively) [Figure 1]b.
|Table 3: Prevalence of a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13 and von Willebrand factor polymorphisms in diabetes mellitus patients with coronary artery disease according to number of stenotic vessels and Gensini score|
Click here to view
|Figure 1: Adjusted odds ratio for predicting severity of coronary stenosis in diabetes mellitus with each genotype of the polymorphisms. Odds ratios represent risk of coronary stenosis according to number of vessel stenosis (a) and Gensini score (b) in diabetes mellitus individuals with coronary artery disease compared to controls. The vertical bars represent 95% confident interval. The horizontal dashed line indicates the reference value (odds ratios = 1.0). *P < 0.05|
Click here to view
vWF activity was significantly increased in the EE and GG genotypes of ADAMTS13 Q448E and rs2073932 when compared to heterozygous and wild type (P< 0.05 and P < 0.01, respectively) as shown in [Table 4]. However, no association was found between ADAMTS13 polymorphisms with ADAMTS13 activity, except vWF V1565L (P< 0.01) [Table 4]. According to the association of ADAMTS13 polymorphisms and DM risk, additional assessment of the relationship between those polymorphisms and other biochemical parameters such as FBG, insulin, and HOMA-IR was performed. The results demonstrated that patients carrying the E, G, and A alleles of the Q448E, rs2073932, and rs652600 had significantly elevated FBS and HOMA-IR [Table 4], when compared to individuals carrying wild-type genotype. Furthermore, the result also showed a negative correlation between ADAMTS13 activity and FBG in individuals carrying the EE and GG genotype of the Q448E and rs2073932 (r = −0.567, P = 0.022 and r = −0.712, P = 0.001, respectively).
|Table 4: Association of genetic variations with von Willebrand factor activity and antigen, a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13 activity, and von Willebrand factor antigen/a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13 ratio|
Click here to view
| Discussion|| |
The present study evaluated whether ADAMTS13 and vWF levels were associated with type 2 DM and severity of coronary stenosis through the determination of ADAMTS13 activity, vWF antigen, and activity along with their polymorphisms in DM and control individuals. The results demonstrated that vWF antigen was likely to increase in DM when compared to the controls which was consistent with the previous studies., Moreover, this is the first investigation of the relationship between ADAMTS13 polymorphisms and type 2 DM in Thai population. The results showed that minor E and G alleles of ADAMTS13 Q448E and rs2073932 and the AA genotype of rs652600 polymorphisms were independently associated with type 2 DM in this population. However, the mechanism that links genetic variations of ADAMTS13 to risk of DM is remained unclear. To date, many genome-wide association studies have investigated the novel genetic susceptibility to type 2 DM. Previous studies found that the rs10811661of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) gene was associated with impaired insulin secretion and type 2 DM. As CDKN2A/B gene (9p21.3) is located near ADAMTS13 gene (9q34), it is possible that ADAMTS13 polymorphisms may be in linkage disequilibrium with this polymorphism. Other explanations may be explored from the results of this study showing the association of the minor alleles of ADAMTS13 Q448E, rs2073932, and rs652600 with increase in FBG and HOMA-IR, which may indicate the hyperglycemic condition, and the negative correlation of ADAMTS13 activity with FBG in individuals possessing the minor alleles of those polymorphisms. Taking this into account, this may in part contribute to the association of ADAMTS13 polymorphisms with DM.
An elevated vWF antigen in diabetic patients is associated with increased risk of thrombosis and cardiovascular events. In addition, the imbalance between vWF and ADAMTS13 levels was associated with promoting the atherosclerosis progression by increasing leukocyte rolling and adhesion. Therefore, alterations of ADAMTS13 and vWF levels by ADAMTS13 polymorphisms may partly contribute to atherosclerosis in type 2 DM. So far, however, no study has examined the possible role of the ADAMTS13 polymorphisms with atherosclerotic lesion progression in type 2 DM. This present study demonstrated that individuals carrying the minor E and G alleles of Q448E and rs2073932 as well as the AA genotype of rs652600 were associated with increased risk of multi-vessel disease and high Gensini score. These results suggested that ADAMTS13 polymorphisms may affect the occurrence and progression of vascular lesion in type 2 DM. Based on this finding, they may reduce ADAMTS13 activity or increase vWF antigen and/or activity. This study revealed the relationship of homozygous variants of Q448E and rs2073932 with increased vWF activity which was consistent with our previous study. To date, some studies have shown that vWF was positively correlated with Gensini score  and vascular endothelial growth factor, which associated with increased atherosclerosis progression. Therefore, the association between ADAMTS13 polymorphisms and vWF activity may in turn support their roles in promoting atherosclerosis progression in type 2 DM individuals. However, it should be noted that the sample size in this study was relatively small especially in each subgroup which may reduce the statistical power of tests. Thus, further investigation with a larger sample size is needed to elucidate the exact mechanism and association of ADAMTS13 polymorphisms with type 2 DM.
| Conclusion|| |
The present study has demonstrated the association of ADAMTS13 polymorphisms with type 2 DM and severity of coronary stenosis. These relationships suggested the importance of genetic variations of ADAMTS13 which may eventually be used as the atherosclerotic risk assessment in diabetic individuals.
This study and Lasom S. were supported by the grant from the National Research University, Office of the Higher Education Commission, Ministry of Education Thailand, the National Research Council of Thailand, and the Cardiovascular Research Group, Khon Kean University.
Financial support and sponsorship
This manuscript and Lasom S. were supported by the grant from the National Research University, Office of the Higher Education Commission, Ministry of Education Thailand, the National Research Council of Thailand, and the Cardiovascular Research Group, Khon Kean University.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bonow RO, Gheorghiade M. The diabetes epidemic: A national and global crisis. Am J Med 2004;116 Suppl 5A:2S-10S.
Rydén L, Standl E, Bartnik M, Van den Berghe G, Betteridge J, de Boer MJ, et al.
Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: Executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J 2007;28:88-136.
Jin C, Lu L, Zhang RY, Zhang Q, Ding FH, Chen QJ, et al.
Association of serum glycated albumin, C-reactive protein and ICAM-1 levels with diffuse coronary artery disease in patients with type 2 diabetes mellitus. Clin Chim Acta 2009;408:45-9.
Sadler JE. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood 2008;112:11-8.
Sonneveld MA, de Maat MP, Portegies ML, Kavousi M, Hofman A, Turecek PL, et al.
Low ADAMTS13 activity is associated with an increased risk of ischemic stroke. Blood 2015;126:2739-46.
Matsukawa M, Kaikita K, Soejima K, Fuchigami S, Nakamura Y, Honda T, et al.
Serial changes in von Willebrand factor-cleaving protease (ADAMTS13) and prognosis after acute myocardial infarction. Am J Cardiol 2007;100:758-63.
Miura M, Kaikita K, Matsukawa M, Soejima K, Fuchigami S, Miyazaki Y, et al.
Prognostic value of plasma von willebrand factor-cleaving protease (ADAMTS13) antigen levels in patients with coronary artery disease. Thromb Haemost 2010;103:623-9.
Skeppholm M, Kallner A, Kalani M, Jörneskog G, Blombäck M, Wallén HN, et al.
ADAMTS13 and von willebrand factor concentrations in patients with diabetes mellitus. Blood Coagul Fibrinolysis 2009;20:619-26.
Verkleij CJ, Bruijn RE, Meesters EW, Gerdes VE, Meijers JC, Marx PF, et al.
The hemostatic system in patients with type 2 diabetes with and without cardiovascular disease. Clin Appl Thromb Hemost 2011;17:E57-63.
Domingueti CP, Fuzatto JA, Fóscolo RB, Reis JS, Dusse LM, Carvalho MD, et al.
Association between von willebrand factor, disintegrin and metalloproteinase with thrombospondin type 1 motif member 13, d-dimer and cystatin C levels with retinopathy in type 1 diabetes mellitus. Clin Chim Acta 2016;459:1-4.
Stehouwer CD, Gall MA, Twisk JW, Knudsen E, Emeis JJ, Parving HH, et al.
Increased urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in type 2 diabetes: Progressive, interrelated, and independently associated with risk of death. Diabetes 2002;51:1157-65.
Rurali E, Noris M, Chianca A, Donadelli R, Banterla F, Galbusera M, et al.
ADAMTS13 predicts renal and cardiovascular events in type 2 diabetic patients and response to therapy. Diabetes 2013;62:3599-609.
Plaimauer B, Fuhrmann J, Mohr G, Wernhart W, Bruno K, Ferrari S, et al.
Modulation of ADAMTS13 secretion and specific activity by a combination of common amino acid polymorphisms and a missense mutation. Blood 2006;107:118-25.
Lasom S, Komanasin N, Settasatian N, Settasatian C, Kukongviriyapan U, Intharapetch P, et al.
Protective effect of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 haplotype on coronary artery disease. Blood Coagul Fibrinolysis 2017;28:286-94.
Kraisin S, Palasuwan A, Popruk S, Nantakomol D. Reduced ADAMTS13 activity is associated with an ADAMTS13 SNP, fever and microparticles in a malaria-like model. Malar J 2014;13:3.
World Health Organization. Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycemia: Report of a WHO/IDF Consulation. Geneva: The WHO Document Production Services; 2006.
Gensini GG. A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol 1983;51:606.
Chen ZW, Chen YH, Qian JY, Ma JY, Ge JB. Validation of a novel clinical prediction score for severe coronary artery diseases before elective coronary angiography. PLoS One 2014;9:e94493.
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult treatment panel III) final report. Circulation 2002;106:3143-421.
Whitworth JA; World Health Organization, International Society of Hypertension Writing Group. 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003;21:1983-92.
World Health Organization. Refining Obesity and its Treatment. The Asia-Pacific Perspective. Sydney: Health Communications Australia; 2000.
Suriyaprom K, Phonrat B, Tungtrongchitr R. Association of adiponectin gene -11377C>G polymorphism with adiponectin levels and the metabolic syndrome in Thais. Asia Pac J Clin Nutr 2014;23:167-73.
Wen J, Rönn T, Olsson A, Yang Z, Lu B, Du Y, et al.
Investigation of type 2 diabetes risk alleles support CDKN2A/B, CDKAL1, and TCF7L2 as susceptibility genes in a han Chinese cohort. PLoS One 2010;5:e9153.
Gandhi C, Khan MM, Lentz SR, Chauhan AK. ADAMTS13 reduces vascular inflammation and the development of early atherosclerosis in mice. Blood 2012;119:2385-91.
Li Q, Zhang Z, Du R, Hu X, Yan Y, Gao Q, et al.
Association analysis between endothelial function related factors and coronary artery stenosis degree in coronary heart disease patients with type 2 diabetes mellitus. J Pediatr Endocrinol Metab 2012;25:711-6.
Shao Y, Lv C, Yuan Q, Wang Q. Levels of serum 25(OH) VD3, HIF-1, VEGF, vWf, and IGF-1 and their correlation in type 2 diabetes patients with different urine albumin creatinine ratio. J Diabetes Res 2016;2016:1925424.
Heinonen SE, Kivelä AM, Huusko J, Dijkstra MH, Gurzeler E, Mäkinen PI, et al.
The effects of VEGF-A on atherosclerosis, lipoprotein profile, and lipoprotein lipase in hyperlipidaemic mouse models. Cardiovasc Res 2013;99:716-23.
[Table 1], [Table 2], [Table 3], [Table 4]