Plasma PAI-1 Levels in Obese Children – Effect of Weight Loss and Influence of PAI-1 Promoter 4G/5G Genotype

Amparo Estellés; Jaime Dalmau; Cristina Falcó; Octavio Berbel; Remedios Castelló; Francisco España; Justo Aznar

doi:10.1055/s-0037-1616100

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2001; 86(02): 647-652
DOI: 10.1055/s-0037-1616100

Review Article

Schattauer GmbH

Plasma PAI-1 Levels in Obese Children – Effect of Weight Loss and Influence of PAI-1 Promoter 4G/5G Genotype

Amparo Estellés

¹Research Center

,

Jaime Dalmau

²Children Hospital

,

Cristina Falcó

¹Research Center

,

Octavio Berbel

²Children Hospital

,

Remedios Castelló

¹Research Center

,

Francisco España

¹Research Center

,

Justo Aznar

³Department of Clinical Pathology, “La Fe” University Hospital, Valencia, Spain

› Author Affiliations

Abstract

Summary

An association between an increase in plasminogen activator inhibitor type 1 (PAI-1) and obesity, and also between elevated levels of PAI-1 and the presence of PAI-1 promoter 4G allele has been described in adults and can contribute to increased risk of cardiovascular disease. It has also been suggested that in adults a decrease in adiposity has beneficial effects on the haemostatic system. However, less information is available regarding adiposity and fibrinolysis in children. The aim of the present study is to evaluate the effect of weight loss and the influence of the PAI-1 promoter 4G/5G genotype on the fibrinolytic system and lipid parameters in obese children. The clinical groups included 102 obese children and 105 controls of similar age and sex distribution. A significant decrease in fibrinolytic activity due to a significant increase in PAI-1 antigen and activity levels was observed in the obese children in comparison with the control group. In obese children, no significant differences in PAI-1 levels between the PAI-1 4G/5G genotypes were obtained. A significant correlation was observed between PAI-1 antigenic and functional levels and body mass index (BMI), as well as between PAI-1 levels and both triglyceride and insulin levels. No correlation between PAI-1 levels and either cholesterol or glucose levels was observed.

After a three-month period of treatment to reduce weight, an increase in fibrinolytic activity due to a decrease in PAI-1 levels was observed in the obese children who had reduced their BMI in comparison with the group of obese children who did not show a decrease in their BMI. No significant differences between the two groups with respect to the variations in tissue type plasminogen activator and fibrinogen levels were obtained after three months of intervention to reduce weight. A significant correlation was observed between variations in BMI and variations in PAI-1 levels, and a significant inverse correlation was also observed between previous PAI-1 levels and variation in PAI-1 levels. Therefore, the largest decrease in PAI-1 levels was observed in the obese children with the highest previous PAI-1 levels.

In conclusion, a decrease in BMI in obese children shows a favourable effect on the fibrinolytic system due to a decrease in PAI-1 levels. However, no influence of 4G/5G genotype on PAI-1 levels was observed.

Keywords

PAI-1 genotype - hypofibrinolysis - obese children

Full Text

References

References
1 Eckel RH, Kraus RM. American Heart association call to action: Obesity as a major risk factor for coronary heart disease. Circulation 1998; 97: 2099-100.
2 Vague P, Juhan-Vague I, Aillaud MF, Badier C, Viard R, Alessi MC. Correlation between blood fibrinolytic activity, plasminogen activator inhibitor level, plasma insulin level and relative body weight in normal and obese subjects. Metabolism 1986; 35: 250-3.
3 McGill JB, Schneider DJ, Arfken CL, Lucore CL, Sobel BE. Factors responsible for impaired fibrinolysis in obese subjects and NIDDM patients. Diabetes 1994; 43: 104-9.
4 Samad F, Yamamoto K, Loskutoff DJ. Distribution and regulation of plasminogen activator inhibitor-1 in murine adipose tissue in vivo: Induction by tumor necrosis factor-α and lipopolysaccharide. J Clin Inv 1996; 97: 37-46.
5 Alessi MC, Bastelica D, Morange P, Berthet B, Leduc I, Verdier M, Geel O, Juhan-Vague I. Plasminogen activator inhibitor 1, transforming growth factor-β₁ and BMI are closely associated in human adipose tissue during morbid obesity. Diabetes 2000; 49: 1374-80.
6 Van Harmelen V, Wahrenberg H, Eriksson P, Arner P. Role of gender and genetic variance in plasminogen activator inhibitor-1 secretion from human adipose tissue. Thromb Haemost 2000; 83: 304-8.
7 Loskutoff DJ. Regulation of PAI-1 gene expression. Fibrinolysis 1991; 5: 197-206.
8 van Meijer M, Pannekoek H. Structure of plasminogen activator inhibitor-1 (PAI-1) and its function in fibrinolysis: an update. Fibrinolysis 1995; 9: 263-76.
9 Alessi M, Juhan-Vague I, Kooistra T, Declerck PJ, Collen D. Insulin stimulates the synthesis of plasminogen activator inhibitor-1 by the human hepatocellular cell line HepG2. Thromb Haemost 1988; 60: 491-4.
10 Dawson S, Wiman B, Hamsten A, Green F, Humphries S, Henney AM. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor (PAI-1) gene respond differently to inter-leukin-1 in hepG2 cell. J Biol Chem 1993; 268: 10739-45.
11 Eriksson P, Kallin B, van’t Hooft FM, Bavenholm P, Hamsten A. Allele-specific increase in basal transcription of the plasminogenactivator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA 1995; 92: 1851-5.
12 Margaglione M, Cappucci G, Colaizzo D, Giulani N, Vecchione G, Gran-done E, Pennelli O, Di Minno G. The PAI1 gene locus 4G/5G polymorphism is associated with a family history of coronary artery disease. Arterioscler Thromb Vasc Biol 1998; 18: 152-6.
13 Ye S, Green FR, Scarabin PY, Nicaud V, Bara L, Dawson SJ, Humphries SE, Evans A, Luc G, Cambou JP, Arveiler D, Henney AM, Cambien F. The 4G/5G genetic polymorphism in the promoter of the plasminogen activator inhibitor1 (PAI1) gene is associated with differences in plasma PAI-1 activity but not with risk of myocardial infarction in the ECTIM study. Thromb Haemost 1995; 74: 837-41.
14 Stegnar M, Uhrin P, Peternel P, Mavri A, Salobir-Pajnic B, Stare J, Binder BR. The 4G/5G sequence polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene: Relationship to plasma PAI-1 levels in venous thromboembolism. Thromb Haemost 1998; 79: 975-9.
15 Sartori MT, Wiman B, Vettore S, Dazzi F, Girolami A, Patrassi GM. 4G/5G polymosphism of PAI-1 gene promoter and fibrinolytic capacity in patients with deep vein thrombosis. Thromb Haemost 1998; 80: 956-60.
16 Seguí R, Estellés A, Mira Y, España F, Villa P, Falcó C, Vayá A, Grancha S, Ferrando F, Aznar J. PAI-1 promoter 4G/5G genotype as an additional risk factor for venous thrombosis in subjects with genetic thrombophilic defects. Brit J Haematol 2000; 110: 1-8.
17 Mansfield MW, Stickland MH, Grant PJ. Environmental and genetic factors in relation to elevated circulating levels of plasminogen activator inhibitor-1 in Caucasian patients with non-insulin-dependent diabetes mellitus. Thromb Haemost 1995; 74: 842-7.
18 Burzotta F, DiCastelnuovo A, Amore C, D’Orazio A, Di Bitondo R, Donati MB, Iacoviello L. 4G/5G promoter PAI-1 gene polymorphism is associated with plasmatic PAI-1 activity in italians: a model of gene-environment interaction. Thromb Haemost 1998; 79: 354-8.
19 Legnani C, Maccaferri M, Tonini P, Cassio A, Cacciari E, Coccheri S. Reduced fibrinolytic response in obese children: association with high baseline activity of the fast acting plasminogen activator inhibitor (PAI-1). Fibrinolysis 1988; 2: 323-6.
20 Ferguson MA, Gutin B, Owens S, Litaker M, Tracy RP, Allison J. Fat distribution and hemostatic measures in obese children. Am J Clin Nutr 1998; 67: 1136-40.
21 Valle M, Gascón F, Martos R, Ruz FJ, Barmudo F, Ríos R, Cañete R. Infantile obesity: a situation of atherothrombotic risk?. Metabolism 2000; 49: 672-5.
22 Svendsen OL, Hassager C, Christiansen C, Nielsen JD, Winther K. Plasminogen activator inhibitor-1, tissue-type plasminogen activator, and fibrinogen: effect of dieting with or without exercise in overweight postmenopausal women. Arterioscle Thromb Vasc Biol 1996; 16: 381-5.
23 Mavri A, Stegnar M, Krebs M, Sentocnik JT, Geiger M, Binder BR. Impact of adipose tissue on plasma plasminogen inhibitor-1 in dieting obese women. Arterioscle Thromb Vasc Biol 1999; 19: 1582-7.
24 Ferguson MA, Gutin B, Owens S, Barbeau P, Tracy RP, Litaker M. Effects of physical training and its cessation on hemostatic system in obese children. Am J Clin Nutr 1999; 69: 1130-4.
25 Must A, Dallal GE, Dretz WH. Reference data for obesity: 85^th and 95^th percentiles of body mass index and triceps skinfold thickness. Am J Clin Nutr 1991; 53: 839-46.
26 Hernández M, Castellet J, García M, Narvaiza JL, Rincón JM, Ruiz J, Sánchez E, Sobradillo B, Surimendi A. Curvas y tablas de crecimiento. Instituto de Investigaciones sobre crecimiento y desarrollo. Fundación F Orbegozo. Garsi editorial. Madrid: 1988
27 Committe on Nutrition.. American Academy of Pediatrics. Obesity in children. In: Kleinman AE. (ed). Pediatric Nutrition Handbook. 4^th Edition. Elk Grove Village. Illinois; 1998: 423-58.
28 Aznar J, Estellés A, Bretó M, España F, Alós T. Euglobulin clot lysis induced by tissue-type plasminogen activator is reduced in subjects with increased levels of lipoprotein(a). Thromb Res 1992; 66: 569-82.
29 Estellés A, Gilabert J, Keeton M, Eguchi Y, Aznar J, Grancha S, España F, Loskutoff DJ, Schleef RR. Altered expression of plasminogen activator inhibitor type 1 in placentas from pregnant women with preeclampsia and/or intrauterine fetal growth retardation. Blood 1994; 84: 143-50.
30 Ross E, Mondronico P, Lombardi A, Prada L. Method for the determination of funtional (clottable) fibrinogen by the new family of ASL coagulo-meters. Thromb Res 1988; 52: 453-68.
31 Margaglione M, Grandone E, Cappucci G, Colaizzo D, Giulani N, Vecchione G, d’Addedda M, Di Minno G. An alternative method for PAI-1 promoter polymorphism (4G/5G) typing. Thromb Haemost 1997; 77: 600-9.
32 Grancha S, Estellés A, Tormo G, Falcó C, Gilabert J, España F, Cano A, Seguí R, Aznar J. Plasminogen activator inhibitor-1 (PAI-1) promoter 4G/5G genotype and increased PAI-1 circulating levels in postmenopausal women with coronary artery disease. Influence of hormone replacement therapy. Thromb Haemost 1999; 81: 516-2.
33 Mannucci PM, Mari D, Merati G, Peyvandi MF, Tagliabue L, Sacchi E, Taioli E, Sansoni P, Bertolini Franceschi C. Gene polymorphisms predicting high plasma levels of coagulation and fibrinolysis proteins. A study in centenarians. Arterioscler Thromb Vasc Biol 1997; 17: 755-9.
34 Henry M, Tregouët DA, Alessi MC, Aillaud MF, Visvikis S, Siest G, Tiret L, Juhan-Vague I. Metabolic determinants are much more important than genetic polymorphisms in determining the PAI-1 activity and antigen concentrations. A family study with part of the Stanislas cohort. Arterioscler Thromb Vasc Biol 1998; 18: 84-91.
35 Sudi KM, Gallistl S, Weinhandl G, Muntean W, Borkenstein MH. Relationship between plasminogen activator inhibitor-1 antigen, leptin, and fat mass in obese children and adolescents. Metabolism 2000; 49: 890-5.
36 Gallistl S, Sudi KM, Borkenstein M, Troebinger M, Weinhandl Muntean W. Determinants of haemostatic risk factors for coronary heart disease in obese children and adolescents. Int J Obes 2000; 24: 1459-64.
37 Meade TW, Ruddock V, Stirling Y, Chakrabani R, Miller GJ. Fibrinolytic activity, clotting factors, and longterm incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet 1993; 342: 1076-9.
38 Thögersen A, Jansson J, Boman K, Nilsson TK, Weinehall L, Huhtasaari F, Hallmans G. High plasminogen activator inhibitor and tissue plasminogen levels in plasma precede a first acute myocardial infarction in both men and women. Evidence for the fibrinolytic system as an independent primary risk factor. Circulation 1998; 98: 2241-7.
39 Aznar J, Estellés A, Tormo G, Sapena P, Tormo V, Blanch S, España F. Plasminogen activator inhibitor activity and other fibrinolytic variables in patients with coronary artery disease. Brit Heart J 1988; 59: 535-41.
40 Morange PE, Aubert J, Peiretti F, Lijnen H-R, Vague P, Verdier M, Negrel R, Juhan-Vague I, Alessi MC. Glucocorticods and insulin promote plasminogen activator inhibitor 1 production by human adipose tissue. Diabetes 1999; 48: 890-5.