Plasminogen Activator Inhibitor Polymorphism and Coronary Disease

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Clin Chim Acta. 2004 Sep;347(1-2):209-16.
Association of plasminogen activator inhibitor-1 4G/5G gene polymorphism with variations in the LDL particle size in healthy Japanese men.
Kitamura Y, Okumura K, Imamura A, Mizuno T, Tsuzuki M, Numaguchi Y, Matsui H, Murohara T.
Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa, Nagoya 466-8550, Japan.

BACKGROUND: Several studies have supported the association between a predominance of small, dense low-density lipoprotein (LDL) and the risk of coronary artery disease. As another potentially atherogenic factor, impaired fibrinolytic activity due to increased plasminogen activator inhibitor-1 (PAI-1) concentrations has been shown. In addition, the 4G allele of the 4G/5G polymorphism in the promoter region of the PAI-1 gene is reported to be associated with the atherogenic lipid profile. We investigated the relation between the PAI-1 gene polymorphism and LDL particle size. METHODS: A total of 156 healthy Japanese male subjects were recruited. The diameter of LDL particles was determined at their peak size using polyacrylamide gels using fresh plasma samples. RESULTS: Fasting insulin and triglyceride concentrations were found to be significantly higher, and the LDL particle size was smaller in the homozygotes for the 5G allele than in the carriers of the 4G allele. An analysis of covariance (ANCOVA) adjusting for insulin and triglyceride concentrations showed a consistently significant difference in LDL particle size between the two groups. In the forward stepwise multiple regression analysis, triglycerides, insulin, and the PAI-1 5G/5G genotype remained in the model as independent and significant predictors capable of influencing the LDL particle size. CONCLUSIONS: Our findings suggest that the 4G/5G polymorphism of the PAI-1 gene might be associated with LDL particle size in healthy Japanese males.

J Thromb Thrombolysis. 2003 Dec;16(3):149-54.
4G/5G PAI-1 promoter polymorphism and acute-phase levels of PAI-1 following coronary bypass surgery: a prospective study.
Burzotta F, Iacoviello L, Di Castelnuovo A, Zamparelli R, D'Orazio A, Amore C, Schiavello R, Donati MB, Maseri A, Possati G, Andreotti F.
Department of Cardiovascular Medicine, Catholic University, Rome, Italy.

BACKGROUND AND OBJECTIVE: The 4G/5G plasminogen activator inhibitor-1 (PAI-1) promoter polymorphism has been associated with basal PAI-1 levels, with ischemic heart disease, and with adverse prognosis in critically ill patients. We hypothesized it might also influence the acute-phase levels of PAI-1 following coronary bypass surgery. METHODS: In 111 consecutive patients undergoing elective coronary bypass surgery, 4G/5G genotyping and serial plasma PAI-1 activity and antigen levels were prospectively measured before surgery, daily up to 72 h, and at discharge. The inflammatory reaction was additionally assessed by white cell count, fibrinogen, interleukin-6, and C-reactive protein levels. RESULTS: PAI-1 activity and antigen concentrations increased approximately two-fold after surgery, peaking at 48 hours. Carriers of the 4G-allele, compared with 5G/5G homozygotes, showed approximately 20% higher PAI-1 activity and antigen both preoperatively ( P = 0.007 and P = 0.035) and after surgery. White cell count, fibrinogen, interleukin-6, and C-reactive protein values did not differ significantly according to genotypic groups. In multivariate analysis, the 4G/5G genotype was the only significant modulator of postoperative PAI-1 activity (P = 0.003) and the main significant modulator of postoperative PAI-1 antigen (P = 0.013). No significant interaction was found between the effects of time and genotype on postoperative PAI-1. This indicates that the association between 4G/5G and acute-phase PAI-1 levels is secondary to the genotype-related difference of baseline PAI-1. CONCLUSIONS: Postoperative PAI-1 concentrations of patients undergoing elective coronary bypass surgery are higher in carriers of the 4G-allele than in 5G/5G homozygotes as a result of higher baseline values. Knowledge of 4G/5G status may be useful to predict acute-phase PAI-1 concentrations.

Am Heart J. 2003 Nov;146(5):855-61.
4G/5G polymorphism of the plasminogen activator inhibitor-1 gene and risk of restenosis after coronary artery stenting.
Bottiger C, Koch W, Lahn C, Mehilli J, von Beckerath N, Schomig A, Kastrati A.
Deutsches Herzzentrum Munchen and 1. Medizinische Klinik rechts der Isar, Technische Universitat Munchen, Munchen, Germany.

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) has been proposed as a candidate risk factor for restenosis after coronary artery stenting. Transcription, level, and activity of PAI-1 are influenced by the 4G/5G polymorphism in the promoter region of PAI-1 gene. The polymorphism may therefore affect wound-healing processes in injured blood vessels and influence restenosis. METHODS: In 1850 consecutive patients, angiographic measures of restenosis and the clinical outcome at 30 days and 1 year after stent implantation were evaluated. Angiographic restenosis was defined as > or =50% diameter stenosis determined at follow-up angiography, performed 6 months after stenting. The 4G/5G genotypes were determined with TaqMan technique. RESULTS: Among the patients, the frequency of the 4G allele was 0.55. Follow-up angiography was done in 84% of the patients. We observed restenosis in 32.5% of 4G/4G carriers, 32.2% of 4G/5G carriers, and 35.7% of 5G/5G carriers (P =.52). The occurrence of a major adverse event (death, myocardial infarction, or target vessel revascularization due to restenosis-induced ischemia) was 5.6% in 4G/4G carriers, 5.3% in 4G/5G carriers, and 4.6% in 5G/5G carriers at 30 days (P =.80), and 24.7% in 4G/4G carriers, 23.0% in 4G/5G carriers, and 26.2% in 5G/5G carriers at 1 year (P =.45). CONCLUSION: The 4G/5G polymorphism of the PAI-1 gene is not associated with an increased risk of thrombotic and restenotic events after coronary artery stenting.

Circulation. 2003 May 20;107(19):2422-7. Epub 2003 Apr 28.
Promoter (4G/5G) plasminogen activator inhibitor-1 genotype and plasminogen activator inhibitor-1 levels in blacks, Hispanics, and non-Hispanic whites: the Insulin Resistance Atherosclerosis Study.
Festa A, D'Agostino R Jr, Rich SS, Jenny NS, Tracy RP, Haffner SM.
Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78228-3900, USA.

BACKGROUND: The 4G/5G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) gene has been related to cardiovascular disease. METHODS AND RESULTS: Insulin resistance was measured with a frequently sampled intravenous glucose tolerance test in the Insulin Resistance Atherosclerosis Study (IRAS), and PAI-1 4G/5G promoter genotype was established by allele-specific polymerase chain reaction amplification of genomic DNA. There were 287 subjects with the 4G/4G genotype (18.4%), 691 heterozygote subjects (44.2%), and 586 carriers of the 5G/5G genotype (37.5%). The genotype distribution was different across the 3 ethnic groups (P=0.001). PAI-1 levels were lower in blacks than in non-Hispanic whites and Hispanics and lower in non-Hispanic whites than in Hispanics (all P=0.0001). Subjects homozygous for the 4G allele had the highest plasma PAI-1, heterozygote subjects were intermediate, and 5G homozygotes had the lowest levels of PAI-1. These patterns remained unaffected by adjustments for age, gender, clinical center, glucose tolerance status, body mass index, waist, triglycerides, and insulin resistance. Multiple linear regression analyses showed that the 4G/5G genotype explained very little of the variation in PAI-1 levels (0.63% in non-Hispanic whites, 0.99% in Hispanics, and 2.37% in blacks), and interaction analyses revealed no significant differences in the relation of circulating PAI-1 levels to the 4G/5G genotype by ethnicity (P=0.4). CONCLUSIONS: We have shown ethnic differences in the PAI-1 4G/5G polymorphism along with corresponding differences in circulating PAI-1 levels. The association of the genotype with PAI-1 levels was seen consistently among all 3 ethnic groups and was unaffected by metabolic covariates, including insulin resistance.

Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2002 Oct;19(5):393-6.
Association of plasminogen activator inhibitor-1 gene 4G/5G polymorphism and coronary heart disease in Chinese patients
Guan L, Ji X, Wang J, Zhang A, Zhang Y, Zhao L.
Weifang People's Hospital, Weifang, Shandong, 261041 P.R. China.

OBJECTIVE: To assess whether the plasminogen activator inhibitor-1 (PAI-1) gene 4G/5G polymorphism is associated with coronary heart disease (CHD) in Chinese patients. METHODS: PAI-1 gene 4G /5G polymorphism was analyzed in normal group (121 individuals) and CHD group (126 cases) by a combination of polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP). RESULTS: The 4G allele and 4G/4G genotype frequencies of PAI-1 gene (0.60 and 0.397) for CHD patients were higher than those (0.48 and 0.190) for healthy controls(chi-square=7.63 P<0.01; chi-square=12.67, P<0.01).The odds ratios(OR) for CHD in subjects with the 5G/5G (and 4G/5G) genotypes were 2.54 (95% CI 1.22-5.27, P<0.05) and 1.28(95% CI 1.45-2.38, P>0.05), respectively. CONCLUSION: These results suggest that the PAI-1 4G/4G genotype is associated with an increased risk for CHD in Chinese patients. The subjects with the 4G/4G genotype had a higher prevalence of CHD, compared to those with the 5G/5G PAI-1 genotype.

J Heart Lung Transplant. 2002 Jun;21(6):629-36.
Genetic variants of the hemostatic system and development of transplant coronary artery disease.
He JQ, Gaur LK, Stempien-Otero A, Nelson K, Levy WC, O'Brien KD, Bolgiano DC, Reiner AP.
Puget Sound Blood Center, Seattle, Washington, USA.

BACKGROUND: The occurrence of coronary artery disease (CAD) after heart transplantation may represent an accelerated inflammatory and thrombotic response to coronary vascular endothelial cell injury. Several common mutations involving hemostasis and cellular adhesion proteins have been associated with genetic susceptibility to native coronary heart disease. The clinical setting of heart transplantation provides a unique opportunity to examine the relative contribution of circulating (i.e., recipient) vs local vascular (i.e., donor) hemostatic components to the occurrence of CAD. METHODS: We performed genotyping for several common hemostatic polymorphisms among 53 cardiac transplant patients and their heart donors. Patients were observed for an average of 43 months, and the presence of transplant CAD was determined by coronary angiography. RESULTS: The development of transplant CAD did not relate to recipient hemostatic genotype, but 2 donor polymorphisms (PAI-1 4G/5G and alpha(2) integrin C807T) were important predictors of transplant CAD. The risk ratio (RR) of transplant CAD associated with donor PAI-1 4G/4G genotype was 2.6 (95% confidence interval [CI] 1.1-6.2) and was modified by recipient cytomegalovirus status, hyperlipidemia, diabetes, and recipient factor XIII Val34Leu genotype. The RR of transplant CAD associated with donor alpha(2) integrin 807 T/T genotype was 7.4 (95% CI, 2.5-22.0). CONCLUSIONS: Genetic and metabolic factors contributed by both donor and recipient may interact at the level of the coronary vessel wall in the development of transplant-associated CAD, and this finding may provide additional support for the importance of local thrombotic response to endothelial injury in the pathogenesis of this disorder.

Thromb Res. 2001 Jul 15;103(2):103-7.
PAI-I 4G/5G polymorphism and sudden cardiac death in patients with coronary artery disease.
Anvari A, Schuster E, Gottsauner-Wolf M, Wojta J, Huber K.
Department of Cardiology, University of Vienna, Wahringer Gurtel 18-20, A-1090 Vienna, Austria.

The 4G/5G polymorphism of the plasminogen activator inhibitor type I (PAI-I) gene is involved in coronary artery disease (CAD), with the highest risk in 4G/4G homozygotes. The role of PAI-I polymorphism in patients suffering from CAD and history of sudden cardiac death (SCD) has not been addressed yet. We studied the frequency distribution of the PAI-I gene to test the hypothesis that the 4G/4G genotype favors myocardial ischemia and, even in the absence of acute infarction, promotes SCD in patients with CAD. Methods: The PAI-I 4G/5G genotypes and PAI-I antigen plasma levels were determined in 97 patients with CAD and a history of SCD treated with an implantable cardioverter defibrillator (ICD) (defibrillator group) comparing to 113 patients with CAD but no history of SCD (control group). Results: The defibrillator group consisted of significantly more 4G/4G homozygotes and higher PAI-I levels than the control group (44% vs. 24%, 173+/-41 vs. 144+/-49 ng/ml; P<.01). The carriers of 4G allele had a significantly higher risk for SCD (odds ratio (OR) 1.9) with the highest risk in the 4G/4G genotype (OR 3.6, P<.01). Conclusion: These results suggest that the PAI-I 4G/4G genotype is associated with SCD in patients suffering from CAD.

J Mol Med. 2001 Jun;79(5-6):289-93.
The plasminogen activator inhibitor 1 4G/5G polymorphism is not associated with longevity: a study in octogenarians.
Lottermoser K, Dusing R, Ervens P, Koch B, Bruning T, Sachinidis A, Vetter H, Ko Y.
Medizinische Universitats-Poliklinik, Bonn, Germany.

Accumulating evidence suggests that plasma levels of the plasminogen activator inhibitor 1 (PAI-1) may modulate the risk of coronary artery disease. The regulation of PAI-1 levels underlies not only environmental but also genetic influences. The 4G/5G polymorphism of the PAI-1 gene has recently gained additional relevance as a possible cardiovascular risk factor, as the 4G allele may be associated with enhanced expression of the PAI-1 gene. This retrospective cohort study examined the effect of the PAI-1 4G/5G genotype on longevity among 205 subjects aged 80 years and older. Such studies in larger cohorts have recently become available along with new methods for the rapid and easy determination of gene polymorphisms. We utilized a light-cycler assisted method which is a fast and flexible method of analyzing the PAI-1 4G/5G polymorphism on the gene level. In these 205 persons the 4G/5G allele was found in 96 persons (47%), the 4G/4G variant in 62 (30%), and the 5G/5G allele in 47 (23%). These data are similar to the allele distribution described in other large cohorts not restricted to old age. Thus the results of this study are not suggestive of an important contribution of the PAI-1 genotype on total mortality.

J Am Coll Cardiol. 1999 Nov 15;34(6):1778-83.
Lack of association of a common polymorphism of the plasminogen activator inhibitor-1 gene with coronary artery disease and myocardial infarction.
Anderson JL, Muhlestein JB, Habashi J, Carlquist JF, Bair TL, Elmer SP, Davis BP.
Department of Medicine, University of Utah School of Medicine, Salt Lake City 84132, USA.

OBJECTIVES: The study was done to assess whether the common polymorphic allele (4G) of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with coronary artery disease (CAD) or myocardial infarction (MI). BACKGROUND: Impaired fibrinolytic function has been associated with CAD and MI. Plasminogen activator inhibitor-1 plays a central role in intravascular thrombosis and thrombolysis; the common insertion/deletion polymorphism (4G/5G) of PAI-1 has been correlated with altered PAI-1 levels and proposed as a coronary risk factor. METHODS: Blood was drawn and DNA extracted from 1,353 consenting patients undergoing coronary angiography. The 4G and 5G alleles of PAI-1 were amplified using specific primers. Amplified products were visualized by staining with ethidium bromide after electrophoresis in 1.5% agarose. RESULTS: Patient age averaged 63.5 (SD 11.7) years; 70% were men, 28% had a history of MI, 66% had severe CAD (>60% stenosis), and 23% had no CAD or MI. Overall, the frequency of the 4G allele was 54.2%, and 78% of patients were 4G carriers. Genotypic distributions were: 4G/4G = 30.1%, 4G/5G = 47.9%, and 5G/5G = 21.8%. Neither carriage of 4G (CAD odds ratio [OR] = 1.08 [0.80 to 1.46], MI OR = 1.11 [0.83 to 1.49]) nor 4G/4G homozygosity (CAD OR = 1.07, MI OR = 0.98) was associated with CAD or MI. In multivariate analyses, risk factors associated with CAD were (in order): gender, age, smoking, diabetes, cholesterol, and hypertension; for MI, they were gender, smoking, and cholesterol. CONCLUSIONS: A common PAI-1 polymorphism (4G) was not importantly associated with angiographic CAD or history of MI in a Caucasian population. Modest risk (i.e., OR <1.5), especially for MI, or risk in association with other factors, cannot be excluded.

Thromb Haemost. 1999 Apr;81(4):516-21.
Plasminogen activator inhibitor-1 (PAI-1) promoter 4G/5G genotype and increased PAI-1 circulating levels in postmenopausal women with coronary artery disease.
Grancha S, Estelles A, Tormo G, Falco C, Gilabert J, Espana F, Cano A, Segui R, Aznar J.
University Hospital La Fe, Valencia, Spain.

Increased circulating levels of type 1 plasminogen activator inhibitor (PAI-1) have been associated with coronary artery disease (CAD). However, genetic and environmental determinants of PAI-1 expression are only partially understood. The levels of PAI-1 have been found to relate to 4/5 guanosine (4G/5G) polymorphism in the promoter region of the PAI-1 gene. The 4G allele in this polymorphism has been associated with higher levels of plasma PAI-1 activity, but despite the strong correlation between PAI-1 activity and antigen, no association has been found between PAI-1 antigen levels and the PAI-1 promoter 4G/5G genotype. The aim of the present study was to analyze the influence of the PAI-1 promoter 4G/5G genotype on PAI-1 levels in post-menopause women with coronary disease in comparison with healthy women in pre and postmenopausal status, and the influence of this genotype on variations in PAI-1 levels after hormone replacement therapy (HRT). No differences between 4G/5G allele distribution in the groups studied were observed. The group of postmenopausal women with CAD showed significantly increased PAI-1 antigen and activity levels in comparison with the control groups, and the levels of PAI-1 correlated with the 4G/5G genotype. A multivariate analysis revealed that in the CAD group there was a high correlation between 4G allele dosage and PAI-1 antigen levels, which were also influenced by the triglyceride levels but not by estrogen or glucose levels. After hormone replacement therapy the decrease in PAI-1 levels was correlated with the 4G allele dosage. We conclude that in the group of postmenopausal women with CAD the influence of the PAI-1 promoter 4G/5G genotype on PAI-1 levels is more evident than in the control groups, and that the decrease in PAI-1 levels after HRT in CAD women correlates with the 4G allele dosage.

Arterioscler Thromb Vasc Biol. 1998 Feb;18(2):152-6.
The PAI-1 gene locus 4G/5G polymorphism is associated with a family history of coronary artery disease.
Margaglione M, Cappucci G, Colaizzo D, Giuliani N, Vecchione G, Grandone E, Pennelli O, Di Minno G.
Unita' di Aterosclerosi e Trombosi and Direzione Sanitaria, IRCCS Casa Sollievo della Sofferenza, S Giovanni Rotondo, Italy.

A family history of ischemic events is a major determinant of coronary artery disease (CAD). Plasma levels of plasminogen activator inhibitor 1 (PAI-1) modulate this risk. A deletion/insertion polymorphism within the PAI-1 locus (4G/5G) affects the expression of this gene. We investigated the relationship between the PAI-1 4G/5G polymorphism in 1179 healthy employees of our institution and the occurrence of CAD in their first-degree relatives. A family history of documented ischemic coronary disease was assessed by a modified WHO questionnaire. The PAI-1 4G/5G polymorphism was evaluated by polymerase chain reaction and endonuclease digestion. The group with a first-degree relative who had suffered from a coronary ischemic episode had a higher number of homozygotes for the deleted allele (4G/4G) of the PAI-1 gene compared with subjects without such a family history (odds ratio [OR] = 1.62, 95% confidence interval [CI]=1.17 to 2.25; P=.005). The frequency of the 4G allele was abnormally high as well (OR=1.29, 95% CI=1.04 to 1.60; P=.025). The individuals with a positive family history were older (P<.001) and exhibited a higher body mass index (P=.033) and total cholesterol levels (P<.001) than those without. In a multiple logistic regression analysis, age (P=.006) and PAI-1 4G/4G (P=.024) independently contributed to a family history of coronary heart disease, with 4G/4G carriers exhibiting a more frequent family history of CAD (OR=1.60). The PAI-1 4G/5G polymorphism to some extent thus accounts for the risk of CAD related to a family history for such an event. These findings support the hypothesis that the 4G variant is a transmissible coronary risk factor.

Thromb Haemost. 1995 Oct;74(4):1032-4.
Plasminogen activator inhibitor-1 (PAI-1) promoter polymorphism and coronary artery disease in non-insulin-dependent diabetes.
Mansfield MW, Stickland MH, Grant PJ.
Division of Medicine, Leeds General Infirmary, UK.

Elevated levels of PAI-1 are found in coronary artery disease (CAD) and non-insulin-dependent diabetes (NIDDM). PAI-1 may be involved in the pathogenesis of CAD through suppression of fibrinolysis, alternatively the high levels may result from vascular damage. There is evidence that PAI-1 levels are related to genotype at a PAI-1 promoter polymorphism. Genotype at this 4G/5G polymorphism was determined in 160 NIDDM (90 males and 70 females) patients with (n = 38) or without (n = 122) clinical evidence of CAD. Levels of cholesterol were higher (6.5 vs 5.9 mM, p < 0.01) and PAI-1 tended to be higher (PAI-1 activity 23.0 vs 20.4 U/ml) with CAD. The frequency of the 4G/4G genotype was increased and the 5G/5G genotype decreased, in the group CAD compared to those without (p < 0.05). These results suggest that possession of the 4G/4G PAI-1 promoter genotype is a risk factor for the development of CAD in subjects with NIDDM.

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