Plasminogen activator inhibitor-1 gene polymorphism as a risk factor for vascular complications in type 2 diabetes mellitus

Egyptian Journal of Medical Human Genetics - 2019
Fatma A. Khalaf1,2, Hatem R. Ibrahim3, Hanan M. Bedair3, Maha Allam3, Amr Aly Elshormilisy4, Samia Taher Ali5, Waseem M. Gaber6
1Dubai, United Arab Emirates
2Department of Clinical biochemistry, National Liver Institute-Menoufia University, Al Minufya, Egypt
3Department of Clinical Pathology, National Liver Institute-Menoufia University, Al Minufya, Egypt
4Internal Medicine, Faculty of Medicine, Helwan University, Helwan, Egypt
5Internal Medicine, Faculty of Medicine for girls, AL-Azhar University, Cairo, Egypt
6Cairo, Egypt

Tóm tắt

AbstractBackgroundDiabetes mellitus (DM) can lead to microvascular and macrovascular damages through hyperglycemia that is the main cause of diabetic complications. Other factors such as hypertension, obesity, and hyperlipidemia may worsen or accelerate the others. Several studies have revealed definitive genetic predispositions to the development of type 2 diabetes mellitus (T2DM) and development of vascular complications. This study aimed to address the association between plasminogen activator inhibitor-1 (PAI-1) gene polymorphism and T2DM, and if this gene polymorphism may have a possible role in the development of vascular complications in T2DM. This study is a case control; it included 200 patients with T2DM, 117 patients had no vascular complications, and 83 had previous vascular complications (VCs). One hundred eighty volunteer blood donors were selected as a healthy control group. All patients and controls were subjected to clinical examination, and laboratory investigations included lipid profile, fasting and 2 h blood glucose, complete blood cell count,d-dimer, PAI-1, thrombin activatable fibrinolysis inhibitor (TAFI), and detection of PAI-1 gene polymorphism by real-time polymerase chain reaction (PCR).ResultsThe most prevalent genotype of PAI-1 gene polymorphism in all studied groups, including controls, was 4G/5G with the highest allele frequency as 4G. The 4G/5G and 4G/4G genotypes were associated with increased risk of DM development as compared to 5G/5G genotype. The 4G/5G and 4G/4G genotypes also had a highly significant increased risk of VCs among diabetic patients, as compared to 5G/5G. The 4G allele also was highly associated with DM with VCs. Thed-dimer TAFI, PAI-1 showed the highest levels in 4G/5G genotype followed by 4G/4G genotype. The lowest level was expressed in 5G/5G genotype in diabetic patients with and without VCs. The univariable analysis showed that genotypes 4G/5G and 4G/4G were potentially risk factors for development of VCs with T2DM patients.ConclusionThis study concludes that the PAI-1 4G/5G polymorphism may be associated with T2DM and may be considered as a risk factor for development of thrombotic events. It may also help in selection and dosing of patients being treated with anticoagulant and fibrinolytic agents. Further large-scale studies are recommended to assess the possible role of environmental factors and gene interactions in the development of T2DM vascular risks.

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Tài liệu tham khảo

Stumvoll M, Goldstein BJ, van Haeften TW (2005) Type 2-diabetes: principles of pathogenesis and therapy. Lancet 9467:1333–1346. https://doi.org/10.1016/S0140-6736(05)61032-X

Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE (2014) Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res ClinPract 103:137–149. https://doi.org/10.1016/j.diabres.2013.11.002

Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R et al (2017) Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation 135:e146–e603. https://doi.org/10.1161/CIR.0000000000000485

Low Wang CC, Hess CN, Goldfine AB (2016) Clinical update: cardiovascular disease in diabetes mellitus: atherosclerotic cardiovascular disease and heart failure in type 2 diabetes mellitus – mechanisms, management, and clinical considerations. Circulation 133:24. https://doi.org/10.1161/CIRCULATIONAHA.116.022194

Johansson L, Jansson JH, Boman K, Nilsson TK, Stegmayr B, Hallmans G (2000) Tissue plasminogen activator, plasminogen activator inhibitor-1, andtissue plasminogen activator/plasminogen activator inhibitor-1 complexas risk factors for the development of a first stroke. Stroke 31:26–32

Rabieian R, Boshtam M, Zareei M, Kouhpayeh S, Masoudifar A, Mirzaei H (2018) Plasminogen Activator Inhibitor Type-1 as a Regulator of Fibrosis. J Cell Biochem 119:17–27

Crandall DL, Quinent EM, Morgan GA, Busler DE, Mchendry-Rinde B, Kral AG (1999) Synthesis and Secretion of Plasminogen Activator Inhibitor-1 by Human Preadipocytes. J Clin Endocrinol Metab 84(9):3222–3227

Chevilley A, Lesept F, Lenoir S, Ali C, Parcq J, Vivien D (2015) Impacts of tissue-type plasminogen activator (tPA) on neuronal survival. Front Cell Neurosci. 9:415

Eriksson P, Kallin B, van’t Hooft FM, Båvenholm P, Hamsten A (1995) Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci U S A 92:1851–1855

Nauck M, Wieland H, Marz M (1999) Rapid Homogeneous Genotyping of the 4G/5GPolymorphism in the Promoter Region of the PAI1Gene by Fluorescence Resonance Energy Transfer and Probe Melting Curves. Clinical Chemistry 45(8):1141–1147

Nordt TK, Lohrmann J, Bode C (2001) Regulation of PAI-1expression by genetic polymorphism. Impact on atherogenesis. Thromb Res 103(Suppl 1):S1–S5

Serrano Rios M (2007) The 4G/4G PAI-1 genotype is associated with elevated plasma PAI-1 levels regardless of variables of the metabolic syndrome and smoking status. A population-based study in Spanish population. Diab Obes Metab 9:134–136

Boeckoldt SM, Bijsterveld NR, Moon AH, Levi M, Buller HR, Peters RJ (2001) Genetic variation in coagulation and fibrinolyticprotein and their relation with acute myocardial infarction: asystematic review. Circulation 104:3064–3068

Kholer HP, Grant PJ (2000) Plasminogen-activator inhibitor type1 and coronary artery disease. N Engl J Med. 342:1792–1801

Hindorff LA, Schwartz SM, Siscovick DS, Psaty BM, Longstreth WT Jr, Reiner AP (2002) The association of PAI-1 promoter 4G/5Ginsertion/deletion polymorphism with myocardial infarction and stroke in young women. J Cardiovasc Risk 9:131–137

Vaughan DE, Rai R, Khan SS, Eren M, Ghosh AK (2017) Plasminogen Activator Inhibitor-1 Is a Marker and a Mediator of Senescence. Arterioscler Thromb Vasc Biol 37:1446–1452

Duggan E, O’Dwyer MJ, Caraher E, Diviney D, McGovern E, Kelleher D, McManus R and Ryan T (2007) Coagulopathy After Cardiac Surgery May Be Influenced by a Functional Plasminogen Activator Inhibitor Polymorphism. AnesthAnalg 104(6):1343–1347

Paneni F, Beckman JA, Creager MA, Cosentio F (2013) Diabetes and Vascular Disease Pathophysiology, Clinical Consequences, and Medical Therapy: Part I. Eur Hear J 30(31):2436–2443

Zhao L, Huang P (2013) Plasminogen activator inhibitor-1 4G/5G polymorphism is associated with type 2 diabetes risk. Int J ClinExp Med. 6(8):632–640

Liang XN, Xie L, Cheng JW, Tan Z, Yao J, Liu Q et al (2013) Association between PAI-1 4G/5GPolymorphisms and osteonecrosis of femoral head: a meta-analysis. Thromb Res. 132(2):158–163

Cesari M, Pahor M, Incalzi RA (2010) Plasminogen activator inhibitor-1 (PAI-1): A key factor linking fibrinolysis and age-related subclinical and clinical conditions. CardiovascTher. 28(5):e72–e79

Xie X, Shi X, Xun X, Rao L (2017) Endothelial nitric oxide synthase gene single nucleotide polymorphisms and the risk of hypertension: a meta-analysis involving 63,258 subjects. Clin Exp Hypertens 39(2):175–182

Nilsson JB, Boman K, Jansson JH, Nilsson T, Näslund U (2008) The influence of acute-phase levels of haemostatic factors on reperfusion and mortality in patients with acute myocardial infarction treated with streptokinase. J Thromb Thrombolysis 26:188–195

Wijesuriya MA, De-Arbew WK, Weerathunga A et al (2012) Association of chronic complications of type 2 diabetes with the biochemical and physical estimations in subjects attending single visit screening for complications. J Diabetol:1–3

Elnaggar AA, Fawzy MM, Nabawy EL, Kamal MM, Ibrahim NM (2017) The Association of Plasminogen Activator Inhibitor (PAI-1) Level and 4G/5G Gene Polymorphism with Diabetic Nephropathy in Type 2 Diabetes Mellitus. J Am Sci 13(11)

Rahimi M, HasanVand A, Rahimi Z et al (2010) Synergestic effects of MTHFR C677Tpolymorphisms on the increased risk of microand macro-albuminuria and progression ofdiabetic nephropathy among Iranians with type IIdiabetes mellitus. Clin Biochem 43:1333–1339

Mtiraoui N, Ezzidi I, Chaib M et al (2017) MTHFR C677T and A1298C gene polymorphism and hyperhomocysteinemia as a risk factor for diabetic nephropathy in diabetic patients. Diabet Res Clin Pract. 75:99–106

Eroglu Z, Erdogan M, Tetik A, Xilmaz C (2007) The relationship of MTHFR C677T gene polymorphism in Turkish type 2 diabetic patients with and without nephropathy. Diabet Metab Res Rev 23:621–624

Madan R, Gupta B, Saluja S et al (2010) Coagulation Profile in Diabetes and itsAssociation with Diabetic MicrovascularComplications. JAPI 58:481–484

Salas II, Miranda AL, Sainz IM, Maldonado RE, Sánchez GB (2009) Association of the Plasminogen Activator Inhibitor-1 Gene 4G/5G Polymorphism with ST Elevation Acute Myocardial Infarction in Young Patients. Rev Esp Cardiol 62 (4):365–372

Abdel Rasol HA, Attia FM, Ismail S, Abdel Azeem AA, Nowier SR, Aziz MA, Osman ZM (2012) Association between 4G/4G plasminogen activator inhibitor-1 polymorphism, PAI-1 activity, and diabetic retinopathy. Egypt J Haematol [serial online] [cited 2019 Apr 21] 37:81–87

Xu K, Xiaoyun L, Yang F, Cui D, Yun S, Chong S, Tang W, Yang T (2013) PAI-1 -675 4G/5G Polymorphism in association with diabetes and diabetic complications susceptibility: a meta-analysis study. PLoS One 8(11):e79150. https://doi.org/10.1371/journal.pone.0079150

Franco RF, Reitsma PH (2011) Gene polymorphisms of the haemostatic system and the risk of arterial thrombotic disease. Br J Haematol 115:491–506

Festa A, Williams K, Tracy RP, Wagenknecht LE, Haffner SM (2006) Progression of plasminogen activator inhibitor-1 and fibrinogen levels in relation to incident type 2 diabetes. Circulation 113:1753-1759

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Egyptian Journal of Medical Human Genetics

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