The Vtn Plau And Plaur, Gene Functional Polymorphism And Myocardial Infarction Associated With Research

BackgroundMyocardial infarction, a complex and heterogeneous disease with a heritability exceeding 50%, is one of the leading causes of morbidity and mortality both in China and in western society. After decades of research, it is still a big challenge for medical society to elucidate the pathogenesis and to identify the subjects at risk. In addition to the 246 previous mentioned factors, molecules associated with abnormal coagulation and reduced fibrinolysis, with cardiovascular remodeling and/or inflammation, homocysteine, cell adhesion molecules (such as vitronectin), and markers of infection have been recently suggested to be associated with coronary atherosclerotic disease (including MI). Individual susceptibility to MI depends on multiple genetic and environmental factors that influence pathogenesis of atherosclerosis, coronary artery lesion morphology, metabolism, stabilization of atherosclerotic plaque, coagulation-fibrinolysis balance, formation of thrombin and therefore clinical presentation. Identification of genetic variants predisposing to MI is essential to improve our knowledge of the mechanisms underlying MI and, on a broader level, to ameliorate cardiovascular disease prevention and pharmacological treatment. Vitronectin, a multifunctional glycoprotein widespread in plasma and extracellular matrix, has been identified as a modulator of atherogenesis and thrombosis which are important processes during myocardial infarction development. We presumed that VTN gene variation might contribute to the risk of myocardial infarcton.ObjectivesIn the present study, we investigated whether genetic variants in vitronectin gene contributed to the risk of myocardial infarction. MethodsVariant rs2227728 was selected to study its association with myocardial infarction. We genotyped rs2227728 in one population including 778 patients with myocardial infarction and 456 control subjects, and then the results from first population was replicated in another two independent populations. The function of linked variant rs2227720 (-148T>C) and rs2227721 (-78G＞T) were studied by using luciferase reporter assays and Electrophoretic mobility shift assay (EMSA).ResultsWe found that rs2227728 C allele was significantly associated with increased risk of myocardial infarction. Under dominant model, the crude odds ratios [ORs] in 3 studies were 1.54 (95% confidence interval [CI] 1.21 to 1.97, P=0.001),1.56 (95%CI 1.19 to 2.04, P=0.001) and 1.49 (95%CI 1.17 to 1.89, P=0.001), respectively. Under additive model, the ORs were 1.42 (95%CI 1.16 to 1.74,P=0.001),1.47 95%CI (95%CI 1.17 to 1.84, P=0.001) and 1.35 (95%CI 1.11 to 1.64, P=0.003), respectively. After adjustment for conventional risk factors, the association remained. Under dominant model, the adjusted ORs in 3 studies were 1.57 (95%CI 1.18 to 2.08, P=0.002),1.47 (95%CI 1.03 to 2.1, P=0.034) and 1.52 (95%CI 1.06 to 2.18, P=0.022), respectively. Under additive model, the ORs were 1.45 (95%CI 1.14 to 1.83, P=0.002),1.37 (95%CI 95%CI 1.02 to 1.83, P=0.036) and 1.38 (95%CI 1.04 to 1.84,P=0.027), respectively. The linked variant rs2227720 (-148T>C) and rs2227721 (-78G＞T) in VTN gene promoter resulted in 44% higher transcriptional activity (P=1.46×10-7) and altered binding of specific transcription factor complexes.ConclusionsThe present results indicate that VTN gene variation is a genetic factor contributing to interindividual differences in MI risk in Chinese Han population. BackgroundMyocardial infarction, a complex and heterogeneous disease with a heritability exceeding 50%, is one of the leading causes of morbidity and mortality both in China and in western society. After decades of research, it is still a big challenge for medical society to elucidate the pathogenesis and to identify the subjects at risk. In addition to the 246 previous mentioneded factors, molecules associated with abnormal coagulation and reduced fibrinolysis, with cardiovascular remodeling and/or inflammation, homocysteine, cell adhesion molecules, and markers of infection have more recently been suggested to be associated with coronary atherosclerotic disease (including myocardial infarction). Individual susceptibility to myocardial infarction depends on multiple genetic and environmental factors that influence pathogenesis of atherosclerosis, coronary artery lesion morphology, metabolism, stabilization of atherosclerotic plaque, coagulation-fibrinolysis balance, formation of thrombin and therefore clinical presentation. Identification of genetic variants predisposing to myocardial infarction is essential to improve our knowledge of the mechanisms underlying myocardial infarction and, on a broader level, to ameliorate cardiovascular disease prevention and pharmacological treatment. The urokinase-plasminogen activator (uPA) and its receptor (uPAR) have been implicated in a broad spectrum of pathophysiological processes including fibrinolysis, proteolysis, inflammation, atherogenesis and plaque destabilization, all of which are involved in the pathogenesis of myocardial infarction. We hypothesized that putative functional genetic variation in these two genes might influence the susceptibility to myocardial infarction. ObjectivesIn the present study, we investigated whether variants in PLAU和PLAUR gene contributed to the risk of myocardial infarction.MethodsWe genotyped rs4065 (3'-untranslated region [UTR]*141C＞T) and rs2227564 (Pro141Leu) in PLAU gene as well as rs344781 (-516T>C) in 633 myocardial infarction patients and 1237 gender and age matched control subjects and then replicated the study in another independent case-control study including 545 myocardial infarction patients and 597 control subjects.ResultsOur results showed that the T allele of rs4065 was significantly associated with increased risk of myocardial infarction. Without adjustment of conventional risk factors, the crude odds ratios [ORs] in the first studies were 1.4 (95% confidence interval [CI]:1.12 to 1.74, P=0.003) under dominant model,1.42 (95%CI:1.17 to 1.72, P=0.0004) under additive model and 2.62 (95%CI:1.36 to 5.05,P=0.004) under recessive model. In the second population, the crude ORs were 1.33 (95%CI:1.02 to 1.74, P=0.034) under dominant model,1.32 (95%CI:1.03 to 1.68, P=0.026) under additive model and 1.74 (95%CI:0.67 to 4.51, P=0.257) under recessive model. After adjustment of conventional risk factors, the adjusted ORs in the first population were 1.38 (95%CI:1.07 to 1.78, P=0.012) under dominant model and 1.4 (95%CI:1.12 to 1.751.03, P=0.003) and 2.5 (95%CI:1.15 to 5.41, P=0.02). In the second population, the adjusted ORs were 1.4 (95%CI:1.05 to 1.86, P=0.022) under dominant model,1.4 (95% CI:1.08 to 1.83, P=0.01) under additive model and 2.5 (95%CI:0.93 to 6.7,P=0.067) under recessive model.ConclusionsThe present results indicate that variations in the genes PLAU and PLAUR are genetic risk factors contributing to interindividual differences in myocardial infarction risk in Chinese Han population.