Plasminogen Activator Inhibitor-1 (PAI-1) 4G/5G Promoter Polymorphism and Levels in Subjects with Cerebrovascular Disease

Aj, Catto; Carter, Anthony Michael; Stickland, M. H.; Jm, Bamford; Ja, Davies; Grant, P. J.

doi:10.1055/s-0038-1656042

Cited by 106 publications

(80 citation statements)

References 21 publications

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“…Furthermore, the point estimate of the IRR for the heterozygote individuals was exactly between the IRR estimate for the homozygotes and 1. Together with findings of previous studies, 21 this clearly calls for additional research.…”

Section: Discussionsupporting

confidence: 64%

“…4,20 The only study on PAI-1 genotype and cerebrovascular disease was suggestive of a reduced risk of stroke incidence for the PAI-1 4G allele compared with the PAI-1 5G allele, although this did not reach statistical significance. 21 Other large studies on PAI-1 4G/5G genotype and stroke have not yet been reported. Additional support for the validity of our findings is provided by the relationship between plasma tPA levels and increased risk of myocardial infarction and stroke, which was consistently found in 4 large studies.…”

Section: Discussionmentioning

confidence: 99%

“…4,20 In contrast, PAI-1 4G genotype may be inversely associated with morbidity of stroke. 21 We had the opportunity to study the relationship between PAI-1 4G/5G genotype and both myocardial infarction and stroke mortality in a cohort study of 12 239 women initially aged 52 to 67 years who were followed up with regard to mortality for 16 to 18 years. 22 …”

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confidence: 99%

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Plasminogen Activator Inhibitor 4G Polymorphism Is Associated With Decreased Risk of Cerebrovascular Mortality in Older Women

et al. 2000

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Background-A common 4G allele of a 4G/5G polymorphism in the promoter region of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with increased transcription of the PAI-1 protein, which may lead to decreased fibrinolysis. It has therefore been proposed as a candidate risk factor for myocardial infarction or stroke. Methods and Results-We studied the relationship between PAI-1 4G/5G genotype and the risk of cardiovascular mortality in a prospective cohort study among 12 239 women initially aged between 52 and 67 years, with a maximum follow-up time of 18 years (153 732 follow-up years). PAI-1 4G/5G genotype was measured in DNA obtained from urine samples, which were collected at baseline, of 498 women who died of a cardiovascular disease and a random sample of 512 women from the same cohort who did not die of cardiovascular disease. The PAI-1 4G/5G genotype was not associated with risk of myocardial infarction or other cardiovascular mortality. However, PAI-1 4G4G homozygotes had a markedly reduced risk of cerebrovascular mortality compared with PAI-1 5G5G homozygotes: the relative risk was 0.4, with a 95% CI of 0.2 to 0.7, whereas the relative risk of cerebrovascular mortality in PAI-1 4G5G heterozygotes compared with PAI-1 5G5G homozygotes was 0.7, with a 95% CI of 0.4 to 1.1. Conclusions-These

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

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Plasminogen Activator Inhibitor 4G Polymorphism Is Associated With Decreased Risk of Cerebrovascular Mortality in Older Women

et al. 2000

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“…1 Moreover, a comparable but nonsignificant reduced stroke incidence in relation to the plasminogen activator inhibitor (PAI-1) 4G polymorphism was reported previously by Catto et al 2 In a pooled analysis of the results of all published studies on the relationship between PAI-1 4G5G genotype and stroke, the genotype distribution in stroke incidence cases is as follows: 4G4G, 296 (26.1%); 4G5G, 559 (49.3%); and 5G5G, 278 (24.5%). The distribution in controls is as follows: 4G4G, 344 (30.1%); 4G5G, 587 (51.3%); and 5G5G, 213 (18.6%).…”

Section: Responsesupporting

confidence: 54%

“…2 The distributions of genotypes in cases were as follows: 4G/4G, 27.1%; 4G/5G, 48.4%; and 5G/5G, 24.5%. The distribution in controls was as follows: 4G/4G, 28.0%; 4G/5G, 53.1%; and 5G/5G, 18.9%.…”

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confidence: 93%

Plasminogen Activator Inhibitor Genotype and Brain Infarction

2001

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Roest et al 1 reported a nested case-control study that assessed the relation between 4G/5G polymorphism in the plasminogen activator inhibitor (PAI-1) gene and cardiovascular and cerebrovascular mortality in women. The authors found that 4G/4G homozygotes had a decreased risk of dying from stroke compared with 5G/5G homozygotes (relative risk, 0.4; 95% confidence interval [CI], 0.2 to 0.7); the relative risk was 0.7 (95% CI, 0.4 to 1.1) for 4G/5G heterozygotes.The authors raised 2 important issues. First, because the diagnosis was not always confirmed by CT scan or MRI, they could not distinguish brain infarcts (BIs) from hemorrhages, which are very different from a pathophysiological perspective. Thus, the possibility that misclassification may have introduced some bias cannot be discarded. The authors think that this is unlikely because the incidence of brain hemorrhages was lower than that of BIs; however, it is also true that the case fatality of hemorrhages was higher than that of BIs. Because it is likely that any gene associated with stroke will have small effects, it is difficult to draw any conclusions about the impact of misclassification. Second, these findings are somewhat unexpected because the 4G allele is associated with increased PAI-1 transcription. They concluded that PAI-1 may contribute to cerebrovascular disease via pathways other than fibrinolysis, and that additional studies are needed.We studied the relationship between 4G/5G polymorphism and BI in the Etude du profil Génétique de l'Infarctus Cérébral (GÉNIC) case-control study, which examined 461 cases with MRI-proven BI and 461 matched hospital controls (61.6% men; median age, 69 years; range, 20 to 85 years). 2 The distributions of genotypes in cases were as follows: 4G/4G, 27.1%; 4G/5G, 48.4%; and 5G/5G, 24.5%. The distribution in controls was as follows: 4G/4G, 28.0%; 4G/5G, 53.1%; and 5G/5G, 18.9%. When considering 5G/5G homozygotes as the reference group, the odds ratios (ORs) were 0.7 (95% CI, 0.5 to 1.0) for 4G/4G homozygotes and 0.7 (95% CI, 0.5 to 1.0) for 4G/5G heterozygotes. Carrying at least one 4G allele was associated with an OR of 0.7 (95% CI, 0.5 to 1.0); adjustment for hypertension, diabetes, smoking, and cholesterol did not modify these findings. This association was not modified by sex (Pϭ0.25), although it was stronger in men (OR, 0.6; 95% CI, 0.4 to 0.9) than women (OR, 0.9; 95% CI, 0.5 to 1.4). After stratification by median age, the relation was stronger for younger subjects (OR, 0.5; 95% CI, 0.3 to 0.8) than for older subjects (OR, 0.9; 95% CI, 0.6 to 1.4; interaction, Pϭ0.05).Only patients with ischemic cerebrovascular disease were studied in the GÉNIC study, and we also found that 4G carriers were at decreased risk of BI (lethal or nonlethal). These results are similar to those reported by Roest et al, 1 and this association remains to be understood. ResponseThe findings by Elbaz et al confirm our observations. 1 Moreover, a comparable but nonsignificant reduced stroke incidence in relation to the plasminogen...

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Fibrinolytic measurements in Type 2 diabetic patients with acute cerebral infarction

et al. 1998

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The aim of this study was to investigate disturbances in fibrinolytic components in Type 2 diabetes patients with acute ischaemic stroke. Levels of plasminogen activator inhibitor-1 (PAI-1) activity and tissue PA (t-PA) antigen were measured in Type 2 diabetes subjects with (n=40) and without (r=80) acute stroke compared to non-diabetic subjects with (n=80) and without (n=80) acute ischaemic stroke. Diabetes was defined by WHO criteria and absence of diabetes by blood glucose <7.8 mmol(-1) and HbA(IC) <6% (reference range for assay 4.5-6.5%). Levels of t-PA antigen were lower in healthy controls (9.2 ng ml(-1) than in either stroke group (non-diabetic stroke patient: 12.6 ng ml(-1); diabetic patient with stroke: 13.5 ng ml(-1)(each at p<0.05)) and intermediate in diabetic patients without stroke (11.1 ng ml(-1), ns). In a regression model levels of t-PA were related to stroke, BMI and age but not to diabetes or sex. Diabetic subjects without stroke had higher PAI-1 activity levels than either non-diabetic group (17.7 U ml(-1) vs 12.1 U ml(-1) and 9.2 U ml(-1) (each at p<0.05)). Levels were intermediate in diabetic subjects with stroke (12.8 U ml(-1), ns). In a regression model levels of PAI-1 were related to Type 2 diabetes, female sex, and body mass index but not stroke or age. These data suggest that further suppression of fibrinolysis does not occur with ischaemic stroke in Type 2 diabetes. The findings contrast with the importance of impaired fibrinolysis in coronary artery disease previously reported in both Type 2 diabetic patients and non-diabetic subjects.

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Plasminogen Activator Inhibitor-1 (PAI-1) 4G/5G Promoter Polymorphism and Levels in Subjects with Cerebrovascular Disease

Cited by 106 publications

References 21 publications

Plasminogen Activator Inhibitor 4G Polymorphism Is Associated With Decreased Risk of Cerebrovascular Mortality in Older Women

Plasminogen Activator Inhibitor 4G Polymorphism Is Associated With Decreased Risk of Cerebrovascular Mortality in Older Women

Plasminogen Activator Inhibitor Genotype and Brain Infarction

Fibrinolytic measurements in Type 2 diabetic patients with acute cerebral infarction

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