Genetic factors determining thrombosis and fibrinolysis

Humphries, Steve E.; Green, Fiona R.; Temple, Anne; Dawson, Sally J.; Henney, Adriano; Kelleher, Cecily H.; Wilkes, H; Meade, T W; Wiman, Björn; Hamsten, Anders

doi:10.1016/1047-2797(92)90086-6

Cited by 22 publications

(10 citation statements)

References 58 publications

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“…Thrombosis including GMT has been considered a multifactorial or complex trait or disease (44, 45), the risk of which is determined by numerous factors including both genetic and nongenetic (e.g., environmental, clinical) elements (15, 16, 45). Complex diseases could be understood through analyzing the separate effect of each contributing variable and dissecting the complicated interactions between implicated factors (33, 46, 47).…”

Section: Discussionmentioning

confidence: 99%

“…Thrombosis has a multifactorial etiology involving both genetic and acquired factors (15). Recent studies suggest that hypofibrinolysis or hypercoagulation due to genetic variations in hemostasis factors, such as plasminogen activator inhibitor 1 (PAI‐1) and fibrinogen, is responsible, at least in part, for a variety of thrombotic diseases (16). PAI‐1 is a rapid inhibitor of tissue‐type plasminogen activator, the molecule that triggers the fibrinolysis pathway (17).…”

mentioning

confidence: 99%

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Epistatic effect of plasminogen activator inhibitor 1 and β‐Fibrinogen genes on risk of glomerular microthrombosis in lupus nephritis: Interaction with environmental/clinical factors

Gong¹,

Liu²,

Leishi³

2007

Arthritis & Rheumatism

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Objective. Glomerular microthrombosis (GMT) is not uncommon in lupus nephritis and has been associated with active renal injury and progressive kidney destruction. We undertook this study to determine whether genetic variations of hemostasis factors, such as plasminogen activator inhibitor 1 (PAI-1) and fibrinogen, affect the risk of GMT. Methods. A cross-sectional cohort of 101 lupus nephritis patients with or without GMT was genotyped for PAI-1 -675 4G/5G and ␤-fibrinogen (FGB) -455 G/A gene polymorphisms and analyzed.Results. PAI-1 4G/4G homozygotes and FGB A allele carriers were both at increased risk for GMT. When the data were stratified for both gene polymorphisms, an epistatic effect was detected. The PAI-1 4G/4G genotype was found to predispose to GMT not equally in all lupus nephritis patients, but only in FGB A allele carriers. Likewise, the association between the FGB A allele and GMT was restricted to lupus nephritis patients homozygous for the PAI-1 4G allele. This epistatic effect was revalidated by the multifactor dimensionality reduction (MDR) analysis and further assessed by incorporating a variety of environmental and clinical factors into the MDR analysis. The most parsimonious model that had a cross-validation consistency of 100% included joint effects of PAI-1 and FGB gene polymorphisms and anticardiolipin antibody (aCL) status and yielded the best prediction of GMT, with 66.6% accuracy.Conclusion. Our findings suggest that risk of GMT in lupus nephritis is attributable, at least in part, to an epistatic effect of PAI-1 and FGB genes, likely via an interaction with environmental/clinical factors, such as aCL.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Epistatic effect of plasminogen activator inhibitor 1 and β‐Fibrinogen genes on risk of glomerular microthrombosis in lupus nephritis: Interaction with environmental/clinical factors

Gong¹,

Liu²,

Leishi³

2007

Arthritis & Rheumatism

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“…Low apo B levels have been associated with a protection against thrombotic complications of cardiovascular diseases (Welty et al 1997). However, it is consistently found in diverse populations that Q353 allele was related with a lower risk of cardiovascular disease, and the lowest level and activity of factor VII (Green et al 1991;Lane et al 1992;Moor et al 1995;Mansfield et al 1996;Humphries et al 1992;Stengard et al 2001;Girelli et al 2000;Wu and Tsongalis 2001). In overweight and obese subjects, metabolic coagulation and fibrinolytic pathological changes are observed and may contribute to the pathogenesis of atherosclerosis vascular disease and to the higher rate of thromboembolic events among these subjects (Avellone et al 1994).…”

Section: Discussionmentioning

confidence: 99%

Effect of the factor VII R353Q missense mutation on plasma apolipoprotein B levels: impact of visceral obesity

Berthier¹,

Houde²,

Bergeron³

et al. 2003

J Hum Genet

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An atherogenic dyslipidemia, characterized by increased plasma triglyceride and apolipoprotein (apo) B levels, low HDL-cholesterol concentrations and the development of small, dense LDL particles has been associated with the presence of abdominal-visceral obesity. Visceral obesity is also associated with a hypercoagulate state and elevated concentrations of procoagulant factors such as factor VII. Moreover, it is known that some genetic variants in the gene encoding factor VII alter its activity and concentration, and consequently these variants may have an impact on atherosclerosis development. The objective of this study was to verify whether the factor VII R353Q polymorphism contributes to predict the risk of an atherogenic dyslipidemia in absence and in the presence of visceral obesity. A sample of 299 French-Canadian men, selected in order to cover a wide range of body fatness values, participated in this study. We observed that the R353 allele was more commonly observed among men characterized by apo B levels below 1.09 g/l than among men with apo B levels greater or above this threshold value (allele frequency of 92.1 vs 85.4%, v 2 =6.18, P=0.01). Multivariate analyses further showed that the genotype R353/R353 was associated with a lower risk to exhibit atherogenic concentrations of total-apo B ( ‡1.09 g/l) and LDL apo B ( ‡0.95 g/l) before (odds ratio:0.47, 95%CI=0.27-0.90, P=0.02; odds ratio: 0.46, 95%CI=0.25-0.85, P=0.01, respectively) and after adjustments for age and visceral AT (odds ratio:0.49, 95%CI=0.24-0.91, P=0.02; odds ratio:0.44, 95%CI=0.23-0.85, P=0.01, respectively). When the two genotype groups were further divided on the basis of visceral adipose tissue (AT) accumulation using a cutoff point of 130 cm 2 , we observed that R353/R353 homozygotes with low visceral AT were characterized by a more favorable lipoprotein-lipid profile, mainly lower total-cholesterol, total-apo B, and LDL-apo B levels compared with R353/R353 homozygotes with high levels of visceral AT. In contrast, irrespective of obesity, plasma lipid levels among carriers of the Q353 allele were similar to those of viscerally obese men homozygous for the R353 allele. In conclusion, results of the present study suggest that the factor VII R353 allele is associated with lower concentrations of plasma apo B levels. However, the presence of visceral obesity abolishes this effect. Further studies will be necessary to confirm this association and the mechanism involved.

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“…A 221 base‐pair fragment in the promoter region of the PAI‐1 gene with the 4G/5G polymorphism was amplified using polymerase chain reaction [8] followed by dot blot and hybridization with antigen‐specific oligonucleotides [9]. A subset of 129 samples (17%) was also genotyped using the method described by Margaglione with some modifications [10].…”

Section: Odds Ratios (95% Ci) For Cases (N = 285) Compared With Coronmentioning

confidence: 99%

The 4G‐allele of the PAI‐1 gene is not consistently associated with a higher prevalence of coronary stenosis

Bogt

Hoekstra

Roest

et al. 2004

Journal of Thrombosis and Haemostasis

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Genetic factors determining thrombosis and fibrinolysis

Cited by 22 publications

References 58 publications

Epistatic effect of plasminogen activator inhibitor 1 and β‐Fibrinogen genes on risk of glomerular microthrombosis in lupus nephritis: Interaction with environmental/clinical factors

Epistatic effect of plasminogen activator inhibitor 1 and β‐Fibrinogen genes on risk of glomerular microthrombosis in lupus nephritis: Interaction with environmental/clinical factors

Effect of the factor VII R353Q missense mutation on plasma apolipoprotein B levels: impact of visceral obesity

The 4G‐allele of the PAI‐1 gene is not consistently associated with a higher prevalence of coronary stenosis

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