Environmental and Genetic Factors in Relation to Elevated Circulating Levels of Plasminogen Activator Inhibitor-1 in Caucasian Patients with Non-Insulin-Dependent Diabetes Mellitus

Mansfield, Michael; Stickland, M. H.; Grant, Peter J.

doi:10.1055/s-0038-1649834

Cited by 151 publications

(139 citation statements)

References 38 publications

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“…28 In addition, environmentally influenced factors such as triglycerides have been reported to interact with the PAI-1 4G/5G polymorphism to regulate plasma PAI-1 levels. 29,30 Furthermore, a relationship between smoking habits and degree of insulin resistance as well as higher PAI-1 activity has been found. 31 As illustrated (Table 1), the incidence of diabetes mellitus, arterial hypertension, mean levels of triglycerides, and the percentage of current smokers were not different between the two groups.…”

Section: Discussionmentioning

confidence: 93%

The PAI-1 Gene Locus 4G/5G Polymorphism Is Associated With a Family History of Coronary Artery Disease

Margaglione

Cappucci

Colaizzo

et al. 1998

ATVB

123

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Abstract-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

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Section: Discussionmentioning

confidence: 93%

The PAI-1 Gene Locus 4G/5G Polymorphism Is Associated With a Family History of Coronary Artery Disease

Margaglione

Cappucci

Colaizzo

et al. 1998

ATVB

123

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“…An association of the 4G allele with higher PAI-1 levels/antigen has been shown in patients with coronary artery disease, 2,3 patients with diabetes mellitus, 7 healthy subjects, 4 and postmenopausal women, 5 whereas only a weak relation was found in healthy women but not men, 42 and no association was found in patients 6 or first-degree relatives of patients with type 2 diabetes, 43 in healthy men, 44 or in families with premature and severe coronary heart disease. 45 Differences in the study populations with regard to factors affecting PAI-1 levels or the relation of the 4G/5G genotype and PAI-1, such as gender, 42 various underlying disease conditions (coronary artery disease, diabetes mellitus, and insulin resistance), 46 and concomitant medications, such as estrogen replacement therapy 5 or drugs that affect the reninangiotensin-aldosterone system, 5,46 may account for these differences to some extent.…”

Section: Discussionmentioning

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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“…Previous studies have demonstrated that PAI-1 4G/5G genotype influences the relationship between serum triglycerides and PAI-1 antigen in diabetic patients, such that triglycerides and PAI-1 antigen correlate in individuals who are homozygous for the 4G allele but not in individuals who carry Ն1 copy of the 5G allele. 22 This genotype-specific effect of triglycerides has been attributed to the interaction of the PAI-1 4G/5G site and an adjacent VLDL triglyceridesensitive site in the promoter region of the PAI-1 gene. 45 In this study, we observed a similar genotype-specific effect of triglycerides on PAI-1 antigen in nondiabetic subjects with essential hypertension.…”

Section: Discussionmentioning

confidence: 99%

“…21 Studies in patients with insulin resistance suggest that PAI-1 4G/5G genotype influences the relationship between triglycerides and PAI-1 expression. 22 Furthermore, there is a concentration-response relationship between glucose and plasma PAI-1 in 4G/4G homozygotes. 22 The present study tests the hypothesis that the PAI-1 4G/5G polymorphism also modulates the effect of activation of the RAAS on PAI-1 expression in patients with essential hypertension.…”

mentioning

confidence: 99%

Interactive Effect of PAI-1 4G/5G Genotype and Salt Intake on PAI-1 Antigen

Brown

Murphey²,

Srikuma³

et al. 2001

ATVB

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Abstract-Activation of the renin-angiotensin-aldosterone system (RAAS) is associated with increased circulating PAI-1 antigen and increased risk of thrombotic cardiovascular events. A 4G/5G polymorphism located 675 bp upstream from the transcription start site of the PAI-1 gene affects PAI-1 antigen concentrations. To test the hypothesis that PAI-1 4G/5G genotype influences the effect of activation of the RAAS on PAI-1 expression, we measured morning PAI-1 antigen concentrations in 76 subjects with essential hypertension during low (10 mmol/d) and high (200 mmol/d) salt intake. Low salt intake was associated with activation of the RAAS as measured by plasma renin activity (2.3Ϯ0.2 versus 0.5Ϯ0.0 ng angiotensin I · mL Ϫ1 · h Ϫ1 , PϽ0.001) and aldosterone (529Ϯ40 versus 145Ϯ12 pmol/L). PAI-1 antigen concentrations were 17.9Ϯ2.7, 19.2Ϯ2.5, and 27.8Ϯ4.0 ng/mL during high salt intake and 19.2Ϯ2.7, 21.6Ϯ2.9, and 38.9Ϯ7.2 ng/mL during low salt intake in the 5G/5G (nϭ14), 4G/5G (nϭ40), and 4G/4G (nϭ22) groups, respectively. There was a significant effect of both salt intake (Fϭ6.0, Pϭ0.017) and PAI-1 4G/5G genotype (Fϭ7.6, Pϭ0.001) on PAI-1 antigen. More importantly, there was a significant interactive effect (Fϭ7.8, Pϭ0.001) of salt intake and PAI-1 4G/5G genotype on PAI-1 antigen. PAI-1 4G/5G genotype influenced the relationship between serum triglycerides and PAI-1 antigen such that the relationship was significant only in 4G homozygotes during either high (R 2 ϭ0.31, Pϭ0.014) or low (R 2 ϭ0.37, Pϭ0.006) salt intake. This study identifies an important gene-by-environment interaction that may influence cardiovascular morbidity and the response to pharmacological therapies that interrupt the RAAS. Key Words: thrombosis Ⅲ genetics Ⅲ fibrinolysis Ⅲ coagulation A ctivation of the renin-angiotensin-aldosterone (RAAS) system has been associated with an increased risk of myocardial infarction (MI) and stroke in patients with essential hypertension. 1,2 Conversely, interruption of the RAAS by ACE inhibition reduces the risk of MI in patients at risk for coronary artery disease. 3 Recent studies suggest that the effects of activation and interruption of the RAAS on cardiovascular morbidity and mortality derive in part from an interaction of the RAAS and fibrinolytic systems. 4,5 Endogenous fibrinolysis plays a critical role in limiting thrombosis and depends on the balance between plasminogen activators (primarily tissue plasminogen activator, tPA) and plasminogen activator inhibitors (PAI, predominantly PAI-1). 6,7 Both of these essential fibrinolytic components are synthesized locally in the vascular wall (in endothelial and smooth muscle cells), have short half-lives, and circulate in trace concentrations in the plasma. Increased PAI-1 expression has been demonstrated in atherosclerotic lesions. 8,9 Elevated PAI-1 concentrations are seen in youthful survivors of acute MI compared with age-matched control subjects, 10 and elevated levels of PAI-1 appear to be a risk factor for recurrent MI. 11 PAI-1 antigen and activity are ...

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Environmental and Genetic Factors in Relation to Elevated Circulating Levels of Plasminogen Activator Inhibitor-1 in Caucasian Patients with Non-Insulin-Dependent Diabetes Mellitus

Cited by 151 publications

References 38 publications

The PAI-1 Gene Locus 4G/5G Polymorphism Is Associated With a Family History of Coronary Artery Disease

The PAI-1 Gene Locus 4G/5G Polymorphism Is Associated With a Family History of Coronary Artery Disease

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

Interactive Effect of PAI-1 4G/5G Genotype and Salt Intake on PAI-1 Antigen

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