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��ࡱ�>��	��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������[�bjbj$$-�F|F|�~���������*****����>>>8v�"D>�a�ff|||W@�,��`�`�`�`�`�`�`e�!h��`*�WW���`**||��a{]{]{]�h8*|*|�`{]��`{]{]^_�_|���� ���p�>CV:v_v`�a0�a~_,i}Y i�_i*�_���{]������`�`�[�����a������������������������������������������������������������������������i�����������:Plasminogen Activator Inhibitor-1 (PAI-1) 4G/5G Allele Polymorphisms and NIDDM Risk Factor for Early Onset Myocardial Infarction
Serap Tutgun Onrat " �nder Akci  " Zafer S�ylemez  " Ersel Onrat  "Alaeddin Av_ar
Serap Tutgun Onrat� Zafer S�ylemez; Afyon Kocatepe University, Faculty of Medicine, Department of Medical Genetics, Afyonkarahisar, Turkey.
�nder Akc1� Ersel Onrat�Alaeddin Av_ar; Afyon Kocatepe University, Faculty of Medicine, Department of Cardiology, Afyonkarahisar, Turkey.
Correspondence to: Dr. Serap Tutgun Onrat
 Afyon Kocatepe �niversitesi T1p Fak�ltesi 
T1bbi Genetik ABD. Kocatepe T1p Binas1 
�zdilek yolu 03200 Afyonkarahisar-Turkiye
Phone: +902722463301-1007
Fax:+902722463300
Email:tutgunonrat@yahoo.com

�nder Akci:   HYPERLINK "mailto:akci003@hotmail.com" akci003@hotmail.com
Zafer S�ylemez:  HYPERLINK "mailto:zfrs@mynet.com" zfrs@mynet.com
Ersel Onrat :  HYPERLINK "mailto:eonrat@yahoo.com" eonrat@yahoo.com
Alaeddin Av_ar :   HYPERLINK "mailto:alavsar@hotmail.com" alavsar@hotmail.com

Running Title: PAI-1 Polymorphims in MI patients with NIDDM
There is no conflict of interest in any of the authors, all authors have read and agreed to the manuscript.



Abstract
The aim of this study was to further evaluate the role of this PAI-1 genes polymorphism on the risk of premature CAD in patients having early onset MI in the Turkish population. We tested with MI individuals for (PAI-1)-675 4G/5G polymorphisms using a ViennaLab CVD strip assay. Patients were placed into two groups: early onset MI (EOMI) age <50 years 66(43.32�3.9) and   without MI age<50years healthy control groups 34(39.26�7.3). The traditional risk factors [family history, smoking, diabetes mellitus (NIDDM-non-insulin dependent diabetes mellitus), hypertension, dyslipidemia] in both group were compared. According to the our results PAI-1 4G/5G deletions were most frequent genetic variants in risk groups for MI in patients with NIDDM (95% CI: 4,055.10-9-1,136.10-8), (OR)=1/2,146.10-8, p=0.000. In present study we found that PAI-1 4G/5G polymorphism may be a risk factor for early onset of myocardial infarction with diabetes mellitus patients. 

Key words: PAI-1 " myocardial infarction " polymorphism"cardiovascular diseases " diabetes mellitus














Introduction
The pathogenetic mechanism of MI is complex and involves the interaction                  of multiple environmental and genetic factors related to atherothrombosis [1]. In particular, MI at young ages is associated with less atheromatic burden in coronary arteries, lower prevalence of hypertension and diabetes mellitus and it has been proposed that thrombotic component plays a pivotal role in the pathogenesis of acute myocardial infarction (AMI) [2-5]. Plasminogen activator inhibitor-1 (PAI-1), a fast-acting Inhibitor of plasminogen activation, is a key regulator of the fibrinolysis cascade. High levels of PAI-1 lead to impaired fibrinolytic function and have been associated with a greater risk of cardiovascular disease [6-8]. PAI-1 levels are regulated by several factors including cytokines, growth factors and insulin [9-11]. Furthermore, PAI-1 levels are related to the PAI-1 promoter 4G/5G polymorphism [12]. PAI-1 gene is located on chromosome 7 and contains eight introns and nine exons [13]. A single guanosine insertion/deletion (4G/5G) polymorphism in the promoter region of PAI-1 gene at position �675 bp, may play an important role in the regulation of PAI-1 expression [14]. PAI-1 plays a central role in modulating intravascular thrombosis and thrombolysis  HYPERLINK "http://www.sciencedirect.com/science/article/pii/S0735109799004246" \l "BIB1" [15,16].  Impaired fibrinolytic function has been found to be associated with high levels of circulating PAI-1 levels in patient groups at risk for premature atherosclerosis, with documented coronary artery disease (CAD), and with a history of MI [17-22]. A link between PAI-1 activity and atherogenic metabolic derangements (i.e., obesity, hypertriglyceridemia, and insulin resistance) has also been suggested [23, 24]. Figure 1 shows that relationship between summary of coagulation cascade, PAI-1 genes and diabetes. Experimental induction of endothelial injury has been found to stimulate PAI-1 expression, facilitating thrombosis [25]. The possibility that genetically determined variability in PAI-1 expression might be a predisposing factor to coronary atherogenesis and thrombosis has been suggested  HYPERLINK "http://www.sciencedirect.com/science/article/pii/S0735109799004246" \l "BIB11" [26]. Recently, a common insertion/deletion polymorphism (designated 4G/5G) of the promoter region of the PAI-1 gene has received attention as a potential risk factor for CAD and MI  HYPERLINK "http://www.sciencedirect.com/science/article/pii/S0735109799004246" \l "BIB11" [27, 28].
Cardiovascular diseases are major causes of mortality and morbidity in diabetic populations and are frequently present even at the time of diagnosis. The insulin resistance syndrome that precedes the onset of overt diabetes is associated with metabolic alterations and abnormalities in hemostasis  HYPERLINK "http://www.sciencedirect.com/science/article/pii/S0735109799004246" \l "BIB11" [29, 30].  The cluster of cardiovascular risk factors in the prediabetic state may explain the high prevalence of cardiovascular diseases present at the diagnosis of overt disease. Impaired fibrinolysis increases the risk of cardiovascular diseases, particularly the risk of MI [31, 32]. Hypofibrinolysis favors the intravascular deposition of fibrin. Fibrinolysis is regulated through plasminogen activators, and especially inhibitors, primarily the plasminogen activator inhibitor-1 (PAI-1)  HYPERLINK "http://www.sciencedirect.com/science/article/pii/S0735109799004246" \l "BIB11" [33].  Several studies have found high PAI-1 levels in conditions associated with insulin resistance, such as hypertriglyceridemia [34, 35], obesity [36], type 2 diabetes [37], and coronary artery disease [38]. In all of these conditions, a significant correlation has been found between PAI-1 and plasma insulin levels. 
Diabetic patients have a high morbidity and mortality from AMI and ischemic heart disease [39]. Diabetes mellitus (DM) is an important risk factor for the development of atherosclerosis [40].Type II DM patients with 80% of small-vessel disease by up to evolving. In these patients, plasma insulin levels due to insulin resistance has increased and this is an important risk factor for atherosclerosis with diabetes.  Triglyceride elevation in patients with diabetes and high density lipoprotein (HDL) are thought to contribute to the development of atherosclerosis in impairment. Diabetic patients have a high mortality from AMI, with heart failure and cardiogenic shock, the most common causes of death [41-43].
Our results also indicate association between diabetes mellitus and PAI-1 gene 4G/5G polymorphism activity. There are also few and conflicting data regarding the role of 4G/5G polymorphism of the PAI-1 in patients with premature MI            [44-48]. Assuming that genetic factors associated with the thrombotic or fibrinolytic process are more likely to have a greater impact in patients with premature MI, we explored the role of 4G/5G polymorphism of the PAI-1 in NIDDM patients who sustained MI very early, i.e. <50 years of age.

Materials and Methods 
Patients 
This study case-control study included 100 patients who had early onset MI (EOMI) age <50 years (n=66, 43.32�3.9) and without MI age<50years healthy control groups (n=34, 39.26�7.3). They had been admitted to the Department of Cardiology, Afyon Kocatepe Universty Hospital. All patients were characterized on the basis of medical interview in respect of concomitant risk factors of atherosclerosis such as age, gender, hypertension, cigarette smoking, diabetes mellitus dyslipidemia or family history. Patients were living in the same areas during the time period of the study. Cardiovascular risk factors were recorded in all individuals. The following definitions were used: hypertension, blood pressure e"140/ 90 mmHg and/or antihypertensive treatment; hypercholesterolaemia, total cholesterol; 200 mg/dl (5.7 mmol/l) and/or lipid lowering agents; diabetes mellitus, fasting plasma glucose;126 mg/dl (6.94 mmol/l) and/or glucose lowering treatment. Smokers were defined participants who reported smoking currently and regularly (at least five cigarettes per day). This study was performed in the Medical Genetics Department, Afyon Kocatepe University Hospital, Afyonkarahisar, Turkey. The study was approved by the Ethics Committee of the Afyon Kocatepe University Hospital, and all individuals signed an informed consent form. DNA samples were aliquoted, who originated from Afyonkarahisar.

DNA isolation, PCR, and reverse hybridisation

Genomic DNA of the 97 samples was originally extracted from fresh blood anticoagulated with EDTA using either the CVD strip assay lysis solution and GENTRACT resin (ViennaLab, Vienna, Austria) or the QIAamp DNAblood Midi (Qiagen, Hilden, Germany) extraction kit, using a silica membrane-based DNA purification method that yields up to 60 mg of DNA from 2 ml initial blood volume following the manufacturer�s instructions. The CVD strip assay (ViennaLab) screens for PAI-1 gene mutations, which have already been mentioned based on a reverse hybridization principle. The different target gene sequences were concurrently amplified and biotin labeled in a single amplification reaction. The reaction consisted of 0.1 mg of DNA added to 15 mL already prepared PCR amplification mix, including primers that flank the target sequences and dNTPs in the presence of 1 U Taq polymerase. The PCR cycles were optimized as follows: 2 min at 94�C of initial denaturation followed by 35 cycles of amplification (15 s denaturation at 94� C, 30 s annealing at 58�C, and 30 s extension at 72�C), and a final extension of 3 min at 72�C. The amplification products were denatured and selectively hybridized to a test strip that contains allelespecific oligonucleotide probes (wild type and mutant) immobilized as an array of parallel lines. Bound biotinylated sequences were detected using streptavidin alkaline phosphatase and color substrates.

Statistical analysis

To assess the association between genotype and CVD, univariate and multivariate (by using logistic regression model) odds ratio (OR) with 95 % confidence interval (CI) were calculated. To assess the extent to which gene polymorphisms were associated with MI, odds ratios with 95 % CIs were estimated by multivariate logistic regression analysis. Adjustment for other variables (i.e., age, smoking, hypertension, diabetes mellitus) was performed by adding those covariates in a set of multiple logistic-regression models. Fisher�s exact test was used to compare demographic data between the control and study groups. Correlation between quantitative variables were assessed using Pearson�s  X2  test. Hardy�Weinberg equilibrium was tested for each genotype within groups by means of test X2. Statistical significance was defined by two tailed P<0.05. All statistical analysis was performed with SPSS for Windows (version 18.0, SPSS, Chicago, IL).

Results
Table 1 shows prevalence of cardiovascular risk factors and 4G/5G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) in young survivors of myocardial infarction and control subjects. In this study we had a myocardial infarction, divided into two groups: early onset MI (EOMI) age<50 years (n=66, 43.32�3.9) and without MI age<50years healthy control groups (n=34, 39.26�7.3). In this study we were obtained results of each of PAI-1 4G/5G gene polymorphism between the two groups. Between the two groups of cardiovascular risk factors such as hypertension, dyslipidemia, there was no difference between sex and gender (p=0.646> 0.05 and p=0.154> 0.05). According to the Pearson X2 test results; Diabetes mellitus was found to be 12.7 % in patients MI (EOMI) age <50 years, was found to be 2.9% in control groups (p=0.029 d"0.05). Cigarette smoking was 79.4% in patients early onset MI (EOMI) age <50 years, was found to be 26.5% in control groups, (p=0.001<0.05). Family history was 47.6% in patients MI (EOMI) age <50 years, was found to be 11.8 % in control groups (p=0.001<0.05).

Table 2  shows according to the Hardy�Weinberg equilibrium was tested for each genotype within groups by means of X2 test results; statistically significant differences were found between the results in patients MI (EOMI) age <50 years (X2=7.38, p=0.006<0.05), were found to be (X2=2.94, p=0.08>0.05)  in control groups.  The results of PAI-1 gene polymorphisms that may indicate an important role in pathogenesis of early onset myocardial infarction (EOMI) age <50 years.

We found difference in the genotype distribution between case group (p=0.006<0.05) 4G/4G; 10(14.30%), 4G/5G;44(67.70%), 5G/5G;12(19.0%) and and control group (p=0.08>0.05) 4G/4G;6(17.65%), 4G/5G;22(64.71%), 5G/5G;6(17.65%) (Table 3). The odds ratio for MI for 4G/5G genotype adjusted for family history, hypertension, diabetes mellitus, smoking and hyperlipidemia were calculated. Logistic regression analysis were calculated after adjustment for age, family history, hypertension, diabetes mellitus, smoking and dyslipidemia. The study had 95 % power to detect a 1/ 2.146.10-8 fold increase in risk of MI associated with the 4G/5G genotype in cases with diabetes mellitus (OR: 1/ 2.146E-8 , 95 % (CI) 4.055E-9� 1.136E-7, p = 0.000<0.05) (Table 4).

The results of PAI-1 gene 4G/5G polymorphisms that may indicate an important role in pathogenesis of early onset myocardial infarction  (EOMI) age <50 years in with NIDDM patients.

Discussion

The etiology of cardiovascular disease is multifactorial but strongly involves genetic and environmental factors. An increase in PAI-1 in vulnerable atherosclerotic plaques associated with an increased inflammatory response might provide the necessary conditions for an atherothrombotic event�such as STEMI(ST elevation myocardial infarction)�in young patients in whom initially non-obstructive lesions are expected. Some authors have reported an association between 4G/5G polymorphism in the promoter region of PAl-1 and the development of AMI [49, 50]. In this young study population, in which the degree of atherosclerosis might be relatively low, the predisposition to thrombosis might be a key determinant for the development of MI. Thus, the significance of the genotype of the PAI-I gene, a marker of fibrinolytic function, could be clearly detected in this population. Certainly, it is known that fibrinolytic activity is reduced in patients under 45 who suffer an acute AMI. PAI-1 is the main physiological inhibitor of the activity of the fibrinolytic system. It achieves this via the inhibition of tissue plasminogen activator (tPA) and via the inhibition of the inhibitor of the urokinase type activator (uPA). An increase in plasma concentration is therefore associated with thrombotic events  HYPERLINK "http://www.sciencedirect.com/science/article/pii/S0735109799004246" \l "BIB11" [7].  
In patients with CAD, especially with a history of MI or other ACS, fibrinolytic activity is impaired at rest and after exercise, and this impairment is associated with increases in circulating PAI-1 [51]. Moreover, PAI-1 activity is raised in diabetics and is particularly high in those with MI [52]. Also, PAI-1 activity correlates positively with very low density lipoprotein (VLDL) triglycerides and negatively with insulin sensitivity. In addition, PAI-1 has been proposed as a link among obesity, insulin resistance, and cardiovascular disease [53, 54]. High levels of PAI-1, as well as fibrinogen, are predictors of MI [55].
Previous studies have reported conflicting results regarding the association of 4G carrier status with the risk of MI. Our data support the concept that in some of them 4G/5G polymorphism of the PAI-1 was associated with an increased risk of MI [56].
There are also inconsistent and limited data regarding the association of 4G/5G polymorphism of the PAI-1 with the development of MI very early, our study was very similar to the reported data. Saely et al., (2006) described the cardiovascular risk conferred by the "675 4G/5G polymorphism in patients with NIDDM, this result similar to our study [57]. Few previous studies had cross-sectionally investigated the association between the "675 4G/5G polymorphism and CAD among diabetic patients, with conflicting results. Whereas Mansfield et al., (1995) and Nagi et al., (1997) described a significant association between CAD and the "675 4G/5G polymorphism, no such association was observed by Petrovic et al., (2003), and also another investigation found only a non-significant trend towards an association of the 4G4G genotype with CAD in diabetic patients from a French Caucasian cohort [52-59].

Further, our results from a population of patients undergoing coronary angiography for the evaluation of CAD are not necessarily applicable to the general population. However, the high-risk population we chose to investigate is of particular clinical importance, and because the relative importance of genetically determined risk factors varies strongly between populations the investigation of genetic polymorphisms in various populations is necessary. In particular, the impact of genotypes may vary strongly between different ethnical groups. From the background of our data it therefore appears very important to also address potential interactions between PAI-1 genotype and diabetes with respect to cardiovascular risk in cohorts of other ethnicity.  There is an interesting parallel between our present result on the PAI-1 "675 4G/5G polymorphism and our previous observation of a significant interaction between PAI-1 4G/5G polymorphism and NIDDM with regard to the incidence of vascular events: which is also largely genetically determined and involved in fibrinolysis, strongly predicts vascular events among non-diabetic subjects [60]. 
The PAI-1 4G/5G polymorphism is associated with plasma PAI-1 activity in NIDDM patients and healthy subjects  HYPERLINK "http://www.sciencedirect.com/science/article/pii/S0735109799004246" \l "BIB11" [61]. The importance of diabetes and obesity as CVD risk factors is increasing steadily; while cholesterol levels are decreasing due to targeted health programs and pharmaceutical use, in contrast to obesity and diabetes rates are constantly growing because of poor diet and physical inactivity  HYPERLINK "http://www.sciencedirect.com/science/article/pii/S0735109799004246" \l "BIB11" [62].
Our data support the idea that, while individual genetic susceptibility variants are of limited clinical use, the combined information from a number of these variants can permit the identification of groups of people at high and low risk of developing a complex trait such as MI.  The polygenic model used in our previously study we detected relationship PAI-1 4G/5G polymorphism and non insuline dependent diabetes mellitus,  this mean that considering the cumulative effect of hemostatic gene variants, was significantly associated to some in vitro measurements of thrombin generation  HYPERLINK "http://www.sciencedirect.com/science/article/pii/S0735109799004246" \l "BIB11" [63].
We detected relationship PAI-1 4G/5G polymorphism and non insuline dependent diabetes mellitus. In the specific context of advanced CAD, similar approaches may be useful as surrogate markers of the propensity to form blood clots leading to MI. In this study, we have concluded PAI-1 4G/5G polymorphism may increase the risk of MI with NIDDM in patients. Further studies on larger samples are needed to confirm this intriguing working-hypothesis, as well as to improve predictive modelling.
In summary, the present results show that the 4G/5G polymorphism of the PAI-I gene seems to be a useful marker of fibrinolytic activity, and is associated with the time course of the progression to acute coronary syndromes in subjects with coronary atherosclerosis.
Conflict of interest statement
None
Disclosure
No competing financial interests exist.DinleyiFonetik olarak okuyunS
Acknowledgments
The study was supported by grants from the Science Faculty of Afyon Kocatepe University Research Project Commission and the project number is 08.TIP.11.



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���� ������������������h�i���������/�0����������������������������������������������������������������������������������U(h�uyhH�CJOJPJQJaJnHtH(h�uyh�?�CJOJPJQJaJnHtHh�uyh�?�;�CJOJQJaJIThogersen AM, Jansson JH, Boman K, et al. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women. Circulation 1998;98:2241�7.
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&Fd��7$8$H$a$gdH�*$
&Fd��7$8$H$a$gd�?������L�X�d�x�z�������8�>�G�H�I�����������������:�;�<����͹��ܑ܏ܑܑ��~��m����YRhGF�h�?�'hGF�h�?�5�CJPJ^J
aJnHtH h�uyh�?�0J,CJOJQJaJ h�uyh�?�0J+CJOJQJaJU(h�uyhH�CJOJPJQJaJnHtH$h�uyhH�CJOJQJaJnHtH'h�uyhH�5�CJOJQJaJnHtHh�uyhH�CJOJQJaJ(h�uyh�?�CJOJPJQJaJnHtHh�uyh�?�CJOJQJaJnd vascular risk in coronary patients. Eur J Clin Invest 2006; 36:91�97.
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