Determinants of Plasma Levels of Plasminogen Activator Inhibitor-1

Cesari, Maurizio; Sartori, Maria Teresa; Patrassi, G; Vettore, Silvia; Rossi, Gian Paolo

doi:10.1161/01.atv.19.2.316

Cited by 34 publications

(26 citation statements)

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“…Other such factors include genetic factors and thinness at birth. Serum concentrations of PAI-1 are in part genetically determined, and several polymorphisms of the PAI-1 gene have been identified (35). Common genes may exist that confer the risk of developing both enhanced PAI-1 expression and type 2 diabetes.…”

Section: Discussionmentioning

confidence: 99%

Elevated Levels of Acute-Phase Proteins and Plasminogen Activator Inhibitor-1 Predict the Development of Type 2 Diabetes

et al. 2002

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Elevated serum levels of acute-phase proteins, indicating chronic subclinical inflammation, have been associated with cardiovascular disease as well as the insulin resistance syndrome. Chronic inflammation may also be a risk factor for developing type 2 diabetes. We studied the concentrations of C-reactive protein (CRP), fibrinogen, and plasminogen activator inhibitor-1 (PAI-1) in 1,047 nondiabetic subjects in relation to incident diabetes within 5 years in the Insulin Resistance Atherosclerosis Study. Subjects with diabetes at follow-up (n ‫؍‬ 144) had higher baseline levels of fibrinogen (mean ؎ SD; 287. ). It has been hypothesized that atherosclerotic cardiovascular disease and type 2 diabetes arise from a "common soil" (2,3), and chronic inflammation may be such a candidate (4,5). Inflammatory markers, such as high white cell count, high fibrinogen, or low albumin (6), and markers of hemostasis, such as factor VIII (7), have been related to the development of type 2 diabetes. Adipose body mass may be an important mediator to explain these relations (6,7), but pathophysiological mechanisms remain elusive, and no data on the role of insulin resistance are available. This is of particular interest because decreased insulin sensitivity has been linked to incident type 2 diabetes (8), as well as increased levels of inflammatory proteins (9,10) and markers of hemostasis (11,12) and fibrinolysis (11,13).In the present study, we investigated the relation of C-reactive protein (CRP), fibrinogen, and plasminogen activator inhibitor 1 (PAI-1) to incident type 2 diabetes during a 5-year period in the Insulin Resistance Atherosclerosis Study (IRAS). Furthermore, we sought to clarify the role of insulin resistance, as directly measured using a frequently sampled intravenous glucose tolerance test. RESEARCH DESIGN AND METHODSThe Insulin Resistance Atherosclerosis Study (IRAS) is a multicenter, epidemiological study aiming to explore relationships among insulin resistance, cardiovascular risk factors, and disease across different ethnic groups and varying states of glucose tolerance. A full description of the design and methods of the IRAS has been published previously (14). The IRAS protocol was approved by local institutional review committees, and all subjects gave informed consent.A total of 1,625 individuals participated in the IRAS. This report includes data on 1,047 subjects, who were nondiabetic at the baseline examination and in whom CRP, PAI-1, and fibrinogen were measured. Subjects were investigated twice following the same protocol. The mean follow-up duration was 5.2 years (range 4.5-6.6). Each of the two IRAS examinations required two visits. Patients were asked before each visit to fast for 12 h, to abstain from heavy exercise and alcohol for 24 h, and to refrain from smoking on the morning of the examination. Race and ethnicity were assessed by self-report. Family history of type 2 diabetes and physical activity were assessed using standard interviewing procedures. A positive family history of diabetes was d...

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Section: Discussionmentioning

confidence: 99%

Elevated Levels of Acute-Phase Proteins and Plasminogen Activator Inhibitor-1 Predict the Development of Type 2 Diabetes

et al. 2002

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“…38 More intriguingly, the impact of genetic factors appears to be reduced on progression through the coagulation cascade. The greatest influence is on individual hemostatic protein concentrations (44%-75%), [6][7][8][9] but this influence subsequently falls through thrombin generation (as measured by fragment 1 ϩ 2 and thrombinantithrombin complex levels) (40%-45%) 39 and fibrin clot formation (39%-46%), with environmental factors having a progressively greater effect.…”

Section: Discussionmentioning

confidence: 99%

“…[2][3][4][5] Variation in the genes coding for components of the coagulation and fibrinolytic system provides a potential mechanism to explain the heritable nature of interindividual susceptibility to atherothrombotic disease. However, although some genetic factors have been shown to have a major effect on the variance in plasma levels of a number of hemostatic cardiovascular risk factors, [6][7][8][9] the relationship between individual polymorphisms in coding genes and risk of CHD has been inconsistent. 10 Although the structure of the fibrin clot does not have a specific coding gene, because it is generated by the fluid phase of an activated coagulation cascade, the sum total of genetic and environmental influences on the component proteins will be integrated into those that affect fibrin structure/function.…”

Section: Introductionmentioning

confidence: 99%

“…The structure of the fibrin clot has been studied in vitro using a variety of techniques, 11 and it has been shown to be influenced by several factors including fibrinogen concentration 12 and common polymorphisms in genes encoding A␣-fibrinogen (Thr312Ala) 13 and the factor XIII (FXIII) A subunit (Val34Leu). 14 Although genetic factors have been shown to influence plasma concentrations of hemostatic proteins [6][7][8][9] and individual polymorphisms have been found to influence fibrin clot structure, no studies have assessed the overall influence of genetic factors on the fibrin clot. In this study, we used a sample of female twin pairs to apply quantitative genetic model fitting to estimate and contrast genetic and environmental effects on the structure of ex vivo fibrin clots.…”

Section: Introductionmentioning

confidence: 99%

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Genetics of fibrin clot structure: a twin study

Dunn

Ariëns

Lange

et al. 2004

Blood

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“…46,52 Also, ethnic differences seen in circulating PAI-1 levels are unlikely to be explained by these metabolic factors, and further environmental factors (not accounted for in the multivariate models or as yet unidentified) and genetic factors have to be considered. Specifically, additional polymorphisms within the PAI-1 gene could contribute to PAI-1 levels.…”

Section: Festa Et Al Pai-1 4g/5g Genotype In 3 Ethnic Groups 2425mentioning

confidence: 99%

Promoter (4G/5G) Plasminogen Activator Inhibitor-1 Genotype and Plasminogen Activator Inhibitor-1 Levels in Blacks, Hispanics, and Non-Hispanic Whites

et al. 2003

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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 allelespecific 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 (Pϭ0.001). PAI-1 levels were lower in blacks than in non-Hispanic whites and Hispanics and lower in non-Hispanic whites than in Hispanics (all Pϭ0.0001). 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 (Pϭ0.4). 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. (Circulation. 2003;107:2422-2427.)

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Determinants of Plasma Levels of Plasminogen Activator Inhibitor-1

Cited by 34 publications

References 35 publications

Elevated Levels of Acute-Phase Proteins and Plasminogen Activator Inhibitor-1 Predict the Development of Type 2 Diabetes

Elevated Levels of Acute-Phase Proteins and Plasminogen Activator Inhibitor-1 Predict the Development of Type 2 Diabetes

Genetics of fibrin clot structure: a twin study

Promoter (4G/5G) Plasminogen Activator Inhibitor-1 Genotype and Plasminogen Activator Inhibitor-1 Levels in Blacks, Hispanics, and Non-Hispanic Whites

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