| Hypertension is a complex disorder that involves multiple genetic and environmental factors interacting to produce the characteristic phenotype. The pathogenesis of arterial thrombotic disease is very complex and involves multiple genetic and environmental factors related to atherosclerosis and thrombosis, as well as their interaction. Classically, acute thrombosis at the site of a ruptured, lipid-rich atherosclerotic plaque is understood as the precipitating event in the transition from stable or subclinical atherosclerotic disease to acute myocardial infarction (MI), ischemic stroke (IS), or peripheral arterial occlusion. To date, the prevention of arterial thrombotic disease has consisted of the modification of traditional cardiovascular risk factors that are largely environmental; however, approximately half of all thrombotic events occur in patients without such risk factors, and epidemiologic studies increasingly demonstrate that these are insufficient to explain completely the variations in incidence and risk.Some studies have shown that inherited risk factors contribute significantly to the development of coronary artery disease (CAD). Thus, in the current era of elucidation of the human genome, investigators have focused on the molecular genetics of thrombosis and atherosclerosis to improve their understanding of the pathobiology of arterial thrombosis.Increasing clinical and laboratory evidence suggests that hypertension per se may confer a prothrombotic or hypercoagulable state. Several genetic mutations affecting coagulation proteins have been suggested as prothrombotic risk factors. Among these genetic mutations, the thrombomodulin gene , transforming growth factor-beta-1 gene and interleukin 10 gene are an important potential candidate. This study aimed to estimate the proportion of incidence cardiovascular disease (CVD) among hypertensives that may be attributable to these gene polymorphisms.1. Thrombomodulin (TM) geneSoluble thrombomodulin (sTM) as abnormalities of levels of specific plasma markers of endothelial damage or dysfunction may be related to the complications of hypertension and the determination of blood pressure itself. We performed a case-control study, including 286 patients with essential hypertension(EH), 113 hypertensives with coronary arteries disease (CAD) and 213 age- and sex-matched controls. The TM -33G>A polymorphism was determined by polymerase chain reaction and restriction fragment length polymorphism (PCR–RFLP) analysis. TM on monocytes was measured by flow cytometry and sTM was determined with ELISA . Results We found that hypertensives have lower thrombomodulin on monocytes especially in patients with CVD. But we did not find significant difference in the sTM and the frequency of the A allele between hypertensives with CVD (14.2%) and controls (11%, P=0.616;OR 1.106, CI 0.746～1.640), or hypertensives (12.1%) and controls ( P=0.244, OR 1.330, CI 0.877～7.153). Similarly, the difference of the genotypic distributions could be neglected across the groups: GG :(GA/AA) was 81.2%:18.8% in controls, 79.7%:20.3% in hypertensives with CVD, and 77%:23% in hypertensives, respectively (vs. controls, all P>0.05). The lack of association also persisted after adjusting for other conventional risk factors. Conclusions Our results suggested that lower TM on monocytes associated with CVD risk in hypertensives, but no association of sTM with blood pressure. It also seemed not to support a significant association of the TM -33G>A polymorphism with CVD and EH in Chinese Han population. TM gene mutation may have a mildly affects on TM expression that might be balanced out by other factors during the progress of hypertention.2.Transforming growth factor-β1 (TGF-β1) geneEpidemiologic, clinical, and experimental evidence has suggested that upregulation of transforming growth factor-β1 (TGF-β1) may play a role in hypertensive disease. TGF-β1 is a multifunctional cytokine that regulates cell growth and differentiation, modulation of extracellular matrix and repair, which in turn regulate inflammatory and immune responses and can be involved in vascular remodelling. Transforming growth factor-β1 has been implicated in the pathogenesis of the vascular and target organ complications of hypertension. TGF-β1 may also regulate blood pressure via stimulation of endothelin-1 and/or renin secretion. Herein we explored the hypothesis that circulating levels of TGF-β1 protein are correlates of blood pressure levels. And study the relationship of the allele frequencies and genotype distribution of TGF-β1 gene polymorphism in patients with essential hypertension and coronary artery disease, and to analyze a association of the serum levels and genotype of TGF-β1 with essential hypertension and coronary artery disease. Methods The polymorphisms of TGF-β1 gene , including polymorphisms of TGF-β1 gene +869T/C and +915G/C, were analyzed by sequence specific primers-polymerase chain reaction ( PCR-SSP) methods in 286 patients with essential hypertension ,113 coronary artery disease and 213 healthy controls, and the serum level of TGF-β1 was determined by enzyme-linked immunosorbent assay( ELISA). Results The patients with coronary artery disease group showed significantly higher serum levels of TGF-β1 than essential hypertensives and control group. And essential hypertensives group showed significantly higher serum levels of TGF-β1 than control group (all P<0.05) the distributions of TGF-β1 gene +915G/C polymorphism did not show significant differences among patients with coronary artery disease, essential hypertensives and control group (P>0.05), but the TGF-β1 gene +869T/C polymorphism was significantly different between coronary artery disease group and control group(P<0.05). The relative risk of suffering from coronary artery disease in carriers of the C allele was 1.681 times than carriers of the T allele (OR =1.681, 95% CI: 1.213～2.328). the serum level of TGF-β1 C allele carriers was significantly higher than nocarriers. the serum level of TGF-β1 CC genotype was higher than TC genotype, and the serum level of TGF-β1 TC genotype was higher than TT genotype(CC:TC:TT was 7.06±0.69: 6.84±0.75: 6.12±0.58. It is suggested that the C allele may affect the TGF-β1 expression,even only one changed C allele of TGF-β1 gene +869 may influence the serum level of TGF-β1 expression. Conclusions TGF-β1 gene +869T/C polymorphism was associated with coronary artery disease, and C allele may be a risk factor for coronary artery disease in which the TGF-β1 C allele may be a increased risk factor by enhancing the TGF-β1 expression in the pathogenesis of essential hypertension with coronary artery disease. But it seemed not to support a significant association of the TGF-β1 gene +915 G/C polymorphism with coronary artery disease.3.Interleukin-10 geneInterleukin-10 (IL-10) is a cytokine produced by macrophages, T cells and B cells. It exerts an anti-inflammatory activity by inhibiting the production of pro-inflammatory cytokines and by activating B cells. IL-10 is expressed in both early and advanced human atherosclerotic plaques and inhibits many cellular processes involved in plaque progression, rupture, or thrombosis. The basic pathology mechanisms of coronary heart disease is atherosclerotic plaques and thrombosis. Interleukin 10 (IL10) is a major immunoregulatory cytokine . About 75% of the variability in IL10 secretion is determined by genetic differences. Therefore IL-10 gene seems to be implicated in both atherosclerosis and its acute complications. the IL-10 gene appears to be a good candidate for coronary heart disease studies. So our study aimed to investigate the relationship between interleukin-10 gene–627 polymorphisms and Serum interleukin-10 production and earlier coronary heart disease (CHD). Methods The genotype and allele frequency of interleukin-10 -627 gene site was assayed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). DNA samples were obtained from 163 patients with CHD and 112 controls. Serum IL-10 production was detected by ELISA method.Results No significant difference was found in the distribution of IL-10 genotype and allele frequency between healthy controls and patients with CHD.χ2 values were 1.9324 , 1.5703 respectively. P>0.05.Stratification analyses based on deferent sex, no significant difference was found in both male groups and female groups.χ2 values in male groups were 1.2708, 0.8595 and in female groups were 0.8254, 0.7127, respectively. P>0.05. Serum IL-10 production showed significant differences among AA genotype, AC genotype and CC genotype. But no significant difference was found between healthy controls and patients with CHD. Conclusions Our results suggest that IL-10–627 A/C polymorphisms are not associated with an increased risk of CHD, but it might have a role on IL-10 gene expression.
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