Download PDF
Thromb Haemost 2008; 99(02): 352-356
DOI: 10.1160/TH07-06-0395
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

PAI-1 gene 4G/5G polymorphism, cytokine levels and their relations with metabolic parameters in obese children

Sibel Tulgar Kinik   *
1   Pediatric Endocrinology
,
Namik Özbek   *
2   Pediatric Hematology
,
Muammer Yuce
3   Department of Biochemistry
,
Ayse Canan Yazici
4   Department of Biostatistics
,
Hasibe Verdi
5   Medical Biology and Genetics, Başkent University Faculty of Medicine, Ankara, Turkey
,
F. Belgin Ataç
5   Medical Biology and Genetics, Başkent University Faculty of Medicine, Ankara, Turkey
› Author Affiliations Financial support: This study was supported by a grant from Baskent University Research Fund (Grant no: KA04/158).
Further Information

Publication History

Received: 11 June 2007

Accepted after major revision: 12 January 2007

Publication Date:
24 November 2017 (online)

    Permissions and Reprints

Summary

Obesity is associated with the changes of plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor-alpha (TNFα) and transforming growth factor beta (TGFβ) levels. However, the precise effect of the 4G allele on obesity is still contradictory. Here, we aimed to elucidate the role of the 4G/5G polymorphism of the PAI-1 gene on the PAI-1 level and determine the associations between cytokines, glucose and lipid metabolism parameters in obese children. Thirty-nine obese children (mean age 11.4 ± 3.3 years) and 38 age-matched healthy control group (mean age 10.3 ± 3.5 years) were included in the study. In all cases, serum levels of glucose, lipid and insulin were measured, homeostasis model assessment of insulin resistance (HOMAIR) was calculated, and 4G/5G polymorphism of PAI-1 gene, plasma PAI-1 level and serum TNFα and TGFβ levels were studied. The mean relative body mass index (BMI) and HOMA-IR score, VLDL,TG, insulin, PAI-1,TNFα levels were higher, and HDL and TGFβ levels were lower in the obese group. The frequency of the 4G/4G genotype was considerably higher in obese children than in controls. Also, a positive correlation was found between PAI-1 and TNFα levels, and relative BMI, HOMA-IR score, insulin,TG, HDL levels. TGFβ was inversely correlated only with relative BMI. There was no correlation among three cytokines. In conclusion, childhood obesity contributes to higher PAI-1 andTNFα and lowerTGFβ levels. Especially PAI-1 andTNFα accompany insulin resistance and dyslipidemia.

Keywords

Childhood obesity - PAI-1 gene 4G/5G polymorphism - cytokines

* S. T. Kinik and N. Ozbek equally contributed to the study.


 

  • References

  • 1 Winkler UH. Obesity and haemostasis. Arch Gynecol and Obstet 1997; 261: 25-29.
    PubMedGoogle Scholar
  • 2 Albisetti M, Chan AKC, McCrindle BW. et al. Impaired fibrinolytic activity is present in children with dyslipidemias. Pediatr Res 2004; 55: 576-580.
    CrossrefPubMedGoogle Scholar
  • 3 Pittas AG, Joseph NA, Greenberg AS. Adipocytokines and insulin resistance. J Clin Endocrinol Metab 2004; 89: 447-452.
    CrossrefPubMedGoogle Scholar
  • 4 Guerre-Millo M. Adipose tissue and adipokines: for better or worse. Diabetes Metab 2004; 30: 13-19.
    CrossrefPubMedGoogle Scholar
  • 5 Estelles A, Dalmau J, Falco C. et al. Plasma PAI-1 levels in obese children—effect of weight loss and influence of PAI-1 promoter 4G/5G genotype. Thromb Haemost 2001; 86: 647-652.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Valle M, Gascon F, Martos R. et al. Relationship between high plasma leptin concentrations and metabolic syndrome in obese pre-pubertal children. Int J Obes 2003; 27: 13-18.
    CrossrefPubMedGoogle Scholar
  • 7 Glowinska B, Urban M, Koput A. Cardiovascular risk factors in children with obesity, hypertension, and diabetes: lipoprotein(a) levels and body mass index correlate with family history of cardiovascular disease. Eur J Pediatr 2002; 161: 511-518.
    CrossrefPubMedGoogle Scholar
  • 8 Vairaktaris E, Yiannopoulos A, Vylliotis A. et al. Strong association of interleukin-6 –174 G>C promoter polymorphism with increased risk of oral cancer. Int J Biol Markers 2006; 21: 246-250.
    CrossrefPubMedGoogle Scholar
  • 9 Sartori MT, Vettor R, De Pergola G. et al. Role of the 4G/5G polymorphism of PAI-1 gene promoter on PAI-1 levels in obese patients: influence of fat distribution and insulin-resistance. Thromb Haemost 2001; 86: 1161-1169.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Eriksson P, Kallin B, Van't Hooft FM. et al. Allelespecific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA 1995; 92: 1851-1855.
    CrossrefPubMedGoogle Scholar
  • 11 Hoffstedt J, Andersson LL, Persson L. et al. The common –675 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene is strongly associated with obesity. Diabetologia 2002; 45: 584-587.
    CrossrefPubMedGoogle Scholar
  • 12 Asselbergs FW, Williams SM, Hebert PR. et al. The gender-spesific role of polymorphisms from the fibrinolytic, renin-angiotensin, and bradykinin systems in determining plasma t-PA and PAI-1 levels. Thromb Haemost 2006; 96: 471-477.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Doggen CJM, Bertina RM, Cats VM. et al. The 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene is not associated with myocardial infarction. Thromb Haemost 1999; 82: 115-120.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Voros G, Maquoi E, Collen D. et al. Differential expression of plasminogen activator inhibitor-1, tumor necrosis factor-α, TNF-α coverting enzyme and ADAMTS family members in murine fat territories. Biochim Biophys Acta 2003; 1625: 36-42.
    CrossrefPubMedGoogle Scholar
  • 15 Samad F, Uysal TK, Wiesbrock SM. et al. Tumor necrosis factor α is a key component in the obesitylinked elevation of plasminogen activator inhibitor 1. Proc Natl Acad Sci USA 1999; 96: 6902-6907.
    CrossrefPubMedGoogle Scholar
  • 16 Crandall DL, Quinet EM, Morgan GA. et al. Synthesis and secretion of plasminogen activator inhibitor-1 by human preadipocytes. J Clin Endocrinol Metab 1999; 84: 3222-3227.
    CrossrefPubMedGoogle Scholar
  • 17 Alessi MC, Bastelica D, Morange P. et al. Plasminogen activator inhibitor-1, transforming growth factor-β1, and BMI are closely associated in human adipose tissue during morbid obesity. Diabetes 2000; 49: 1374-1380.
    CrossrefPubMedGoogle Scholar
  • 18 Bundak R, Furman A, Gunoz H. et al. Body mass index references for Turkish chidren. Acta Paediatr 2006; 95: 194-198.
    CrossrefPubMedGoogle Scholar
  • 19 Matthews DR, Hosker JP, Rudenski AS. et al. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-419.
    CrossrefPubMedGoogle Scholar
  • 20 Bonora E, Targher G, Alberiche M. et al. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care 2000; 23: 57-63.
    CrossrefPubMedGoogle Scholar
  • 21 Margaglione M, Granda E, Vecchione G. et al. Plasminogen activator inhibitor –1 (PAI-1) antigen plasma levels in subjects attending a metabolic ward: Relation to polymorphisms of PAI-1 and angiotensin converting enzyme (ACE) genes. Arterioscler Thromb Vasc Biol 1997; 17: 2082-2087.
    CrossrefPubMedGoogle Scholar
  • 22 Morange PE, Lijnen HR, Alessi MC. et al. Influence of PAI-1 on adipose tissue growth and metabolic parameters in a murine model of diet induced obesity. Arteroscler Thromb Vasc Biol 2000; 20: 1150-1154.
    CrossrefPubMedGoogle Scholar
  • 23 Kinik ST, Atac FB, Verdi H. et al. The effect of plasminogen activator inhibitor-1 gene 4G/5G polymorphism on glucose and lipid metabolisms in Turkish obese children. Clin Endocrinol 2005; 62: 607-610.
    CrossrefPubMedGoogle Scholar
  • 24 Akar N, Akar E, Yilmaz E. et al. Plaminogen-activator inhibitor-1 4G/5G polymorphism in Turkish children with cerebral infarct and effect on factor V 1691 A mutation. J Child Neurol 2001; 16: 294-295.
    CrossrefPubMedGoogle Scholar
  • 25 Balta G, Altay Ç, Gurgey A. PAI-1 gene 4G/5G genotype: A risk factor for thrombosis in vessels of internal organs. Am J Hematol 2002; 71: 89-93.
    CrossrefPubMedGoogle Scholar
  • 26 Berberoğlu M, Evliyaoğlu O, Adiyaman P. et al. Plasminogen activator inhibitor-1 (PAI-I) gene polymorphism (-675 4G/5G) associated with obesity and vascular risk in children. J Pediatr Endocrinol Metab 2006; 19: 741-748.
    PubMedGoogle Scholar
  • 27 Epstein FH. Plaminogen-activator inhibitor type 1 and coronary artery disease. N Engl J Med 2000; 34: 1792-1801.
    PubMedGoogle Scholar
  • 28 Asplund Carlson A, Hamsten A, Wiman B. et al. Relationship between plasminogen activator inhibitor-1 activity and VLDL triglyceride concentration, inslin levels and insulin sensitivity:studies in randomly selected normo-and hypertriglyceridaemic men. Diabetologia 1993; 36: 817-825.
    CrossrefPubMedGoogle Scholar
  • 29 Giltay EJ, Elbers JMH, Gooren LJG. et al. Visceral fat accumulation is an important determinant of PAI-1 levels in young, nonobese men and women. Modulation by cross-sex hormone administration. Arterioscler Thromb Vasc Biol 1998; 18: 1716-1722.
    CrossrefPubMedGoogle Scholar
  • 30 Ferguson MA, Gutin B, Owens C. et al. Fat disribution and haemostatic measures in obese children. Am J Clin Nutr 1998; 67: 1136-1140.
    CrossrefPubMedGoogle Scholar
  • 31 Mutch NJ, Wilson HM, Booth NA. Plasminogen activator inhibitor-1 and haemostasis in obesity. Proc Nutr Soc 2001; 60: 341-347.
    CrossrefPubMedGoogle Scholar
  • 32 Bastelica D, Mavri A, Verdier M. et al. Relationship between fibrinolytic and inflammatory parameters in human adipose tissue: Strong contribution of TNF a receptors to PAI-1 levels. Thromb Haemost 2002; 88: 481-487.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Skurk T, van Harmelen V, Lee YM. et al. Relationship between IL-6, leptin and adiponectin and variables of fibrinolysis in overweight and obese hypertensive patients. Horm Metab Res 2002; 34: 659-663.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Morange PE, Alessi MC, Verdier M. et al. PAI-1 produced ex vivo by human adipose tissue is relevant to PAI-1 blood level. Arterioscler Thromb Vasc Biol 1999; 19: 1361-1365.
    CrossrefPubMedGoogle Scholar
  • 35 Fain JN, Tichansky DS, Atul KM. Transforming growth factor β1 release by human adipose tissue is enhanced in obesity. Metab Clin Exp 2005; 54: 1546-1551.
    CrossrefPubMedGoogle Scholar
  • 36 Corica F, Allegra A, Buemi M. et al. Reduced plasma concentrations of transforming growth factor β1 (TGF-β1) in obese women. Int J Obes 1997; 21: 704-707.
    CrossrefPubMedGoogle Scholar
  • 37 Byrne CD, Wareham NJ, Martensz ND. et al. Increased PAI-1 level and PAI-1 antigen occurring with an oral fat load: associations with PAI-1 genotype and plasma active TGF-β levels. Atherosclerosis 1998; 140: 45-53.
    CrossrefPubMedGoogle Scholar