Yıl: 2020 Cilt: 48 Sayı: 5 Sayfa Aralığı: 484 - 493 Metin Dili: İngilizce DOI: 10.5543/tkda.2020.15686 İndeks Tarihi: 24-10-2020

The effects of genetic polymorphisms and diabetes mellitus on the development of peripheral artery disease

Öz:
Objective: Peripheral artery disease (PAD) is a conditioncaused by the narrowing of limb arteries due to atherosclerosis. In recent years, polymorphisms in a number of geneshave been shown to contribute to the risk of PAD development.However, whether the contribution of these inheritable factorsis independent of traditional cardiovascular risk factors remainsunclear. This study was an investigation of the effects of diabetes mellitus (DM) and genetic background, examined singlyand together, on the pathogenesis of PAD.Methods: The effects of the factor V Leiden (G1691A), factorV H1299R, prothrombin G20210A, factor XIII V34L, B-firinogen -455 G>A, PAI-1 4G/5G, HPA1, MTHFR C677T, MTHFRA1298C, ACE I/D, APO B R3500Q, and APOE polymorphismswere evaluated using a cardiovascular disease strip assay(CVD StripAssay). Two groups were created: 100 patients withPAD (50 with DM, 50 without DM) and 60 controls without PAD(30 with DM, 30 without DM).Results: There was a signifiantly greater presence of theMTHFR A1298C and PAI 4G/5G homozygous polymorphismsin the PAD patients compared with the control group (p=0.035,p=0.004, respectively). There were no signifiant associationsbetween the other genotypes and polymorphism frequencies.In the presence of DM, the PAI-1 4G/5G homozygous polymorphism was linked to the formation of PAD (p=0.021). Regression analysis indicated that the PAI-1 4G/5G gene homozygous polymorphism demonstrated a 17.1 times greater risk forDM with PAD [95% confience interval (CI): 2.113-138.660;p=0.008] and the MTHFR A1298C homozygous polymorphismdemonstrated a 316.6 times greater risk (95% CI: 10.763-9315.342; p<0.001) for the possibility of DM with PAD.Conclusion: The MTHFR A1298C and PAI 4G/5G homozygouspolymorphisms may be associated with the development of PAD.The presence of the PAI 4G/5G homozygous polymorphism withDM was a powerful predictor for the development of PAD
Anahtar Kelime:

Periferik arter hastalığı oluşumunda genetik polimorfimin ve diabetes mellitusun etkisi

Öz:
Amaç: Periferik arter hastalığı (PAD), ateroskleroz nedeniyle ekstremite arterlerinin daralmasından kaynaklanan bir durumdur. Geçtiğimiz yıllarda, birkaç gende polimorfimin PAD geliş- me riskine katkıda bulunduğu gösterilmiştir, ancak geleneksel kardiyovasküler risk faktörlerinden bağımsız olan bu kalıtımsal faktörlerin katkısı hala belirsizliğini korumaktadır. Bu çalışmada, diabetes mellitus (DM) ve genetik arkaplanın PAD patogenezinde sadece ve birlikte etkilerini araştırdık. Yöntemler: Çalışmamızda faktör V Leiden (G1691A), Faktör V H1299R, Protrombin G20210A, Faktör XIII V34L, B-Fibrinojen-455 G> A, PAI-1 4G/5G, HPA1, MTHFR C677T, MTHFR A1298C, ACE I/D, APO B R3500Q ve APOE polimorfiminin kardiyovasküler hastalık Strip panel kullanılarak etkilerini değerlendirmeyi planladık. Hastalar iki gruba ayrıldı: PAD’lı 100 hasta (50 DM+, 50 DM-), PAD olmayan 60 kontrol hasta (30 DM+, 30 DM-). Bulgular: MTHFR A1298C ve PAI 4G/5G homozigot polimorfimi, PAD hastalarında kontrol grubuna göre anlamlı derecede yüksek bulundu (sırasıyla, p=0.035, p=0.004). Diğer genotipler ve polimorfim sıklıkları arasında anlamlı bir ilişki bulunamamıştır. Ayrıca DM varlığında PAI 4G/5G homozigot polimorfimi PAD oluşumunu etkili olduğu belirlendi (p=0.021). Regresyon analizinde PAD oluşumunda DM+ hastalarda PAI-1 4G/5G gen homozigot polimorfimi 17.1 kat daha riskli, (p=0.008) Gü- ven Aralığı (GA) %95 (2.113–138.660), MTHFR A1298C homozigos polimorfimi 316.6 kat daha riskli (p<0.001) GA %95 (10.763–9315.342) olduğu görüldü. Sonuç: MTHFR A1298C ve PAI 4G/5G homozigoz polimorfimi, PAD oluşumu ile ilişkili olabilir. PAİ 4G/5G homozigot polimorfimi, DM varlığında PAD oluşumunda güçlü bir belirleyicidir.
Anahtar Kelime:

Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık
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  • 1. Leeper NJ, Kullo IJ, Cooke JP. Genetics of peripheral artery disease. Circulation 2012;125:3220–8.
  • 2. Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, et al. ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic InterSociety Consensus; and Vascular Disease Foundation. Circulation 2006;113:e463–654.
  • 3. Criqui MH. Peripheral arterial disease--epidemiological aspects. Vasc Med 2001;6:3–7.
  • 4. Conte SM, Vale PR. Peripheral Arterial Disease. Heart Lung Circ 2018;27:427–32.
  • 5. Balkau B, Vray M, Eschwege E. Epidemiology of peripheral arterial disease. J Cardiovasc Pharmacol 1994;23:S8–S16.
  • 6. Belkin N, Damrauer SM. Peripheral Arterial Disease Genetics: Progress to Date and Challenges Ahead. Curr Cardiol Rep 2017;19:131.
  • 7. Meijer WT, Grobbee DE, Hunink MG, Hofman A, Hoes AW. Determinants of peripheral arterial disease in the elderly: the Rotterdam study. Arch Intern Med 2000;160:2934–8.
  • 8. Vogt MT, Wolfson SK, Kuller LH. Lower extremity arterial disease and the aging process: a review. J Clin Epidemiol 1992;45:529–42.
  • 9. Elhadd TA, Robb R, Jung RT, Stonebridge PA, Belch JJF. Pilot study of prevalence of asymptomatic peripheral arterial occlusive disease in patients with diabetes attending a hospital clinic. Pract Diabetes Int 1999;16:163–6.
  • 10. Mizuguchi T, Matsumoto N. Recent progress in genetics of Marfan syndrome and Marfan-associated disorders. J Hum Genet 2007;52:1–12.
  • 11. Knowles JW, Assimes TL, Li J, Quertermous T, Cooke JP. Genetic susceptibility to peripheral arterial disease: a dark corner in vascular biology. Arterioscler Thromb Vasc Biol 2007;27:2068–78.
  • 12. Kwon JM, Goate AM. The candidate gene approach. Alcohol Res Health 2000;24:164–8.
  • 13. Sing CF, Stengård JH, Kardia SL. Genes, environment, and cardiovascular disease. Arterioscler Thromb Vasc Biol 2003;23:1190–6.
  • 14. Wilhelmsen L, Svärdsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med 1984;311:501–5.
  • 15. Newman PJ, Derbes RS, Aster RH. The human platelet alloantigens, PlA1 and PlA2, are associated with a leucine33/ proline33 amino acid polymorphism in membrane glycoprotein IIIa, and are distinguishable by DNA typing. J Clin Invest 1989;83:1778–81.
  • 16. Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64–7.
  • 17. Michelson A. Platelets. 3rd ed. San Diego, Calif, USA: Academic Press; 2013.
  • 18. Mehta R, Shapiro AD. Plasminogen activator inhibitor type 1 defiiency. Haemophilia 2008;14:1255–60.
  • 19. Aso Y. Plasminogen activator inhibitor (PAI)-1 in vascular inflmmation and thrombosis. Front Biosci 2007;12:2957–66.
  • 20. Schillinger M, Exner M, Mlekusch W, Amighi J, Sabeti S, Muellner M, et al. Statin therapy improves cardiovascular outcome of patients with peripheral artery disease. Eur Heart J 2004;25:742–8.
  • 21. Lahoz C, Garcia-Fernandez T, Barrionuevo M, Vicente I, Gonzalez-Alegre T, Mostaza JM. Differences in the anklebrachial index in the general population after 4 years of follow-up. Vasa 2013;42:112–9.
  • 22. Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, et al. Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identifiation. Nat Genet 1994;7:195–200.
  • 23. Parpugga TK, Tatarunas V, Skipskis V, Kupstyte N, Zaliaduonyte-Peksiene D, Lesauskaite V. The Effect of PAI- 1 4G/5G Polymorphism and Clinical Factors on Coronary Artery Occlusion in Myocardial Infarction. Dis Markers 2015;2015:260101.
  • 24. Dawson SJ, 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-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem 1993;268:10739–45.
  • 25. Goyette P, Pai A, Milos R, Frosst P, Tran P, Chen Z, et al. Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR). Mamm Genome 1998;9:652-6.
  • 26. Weisberg I, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 1998;64:169–72.
  • 27. Sabino A, Fernandes AP, Lima LM, Ribeiro DD, Sousa MO, de Castro Santos ME, et al. Polymorphism in the methylenetetrahydrofolate reductase (C677T) gene and homocysteine levels: a comparison in Brazilian patients with coronary arterial disease, ischemic stroke and peripheral arterial obstructive disease. J Thromb Thrombolysis 2009;27:82–7.
  • 28. Sof F, Lari B, Rogolino A, Marcucci R, Pratesi G, Dorigo W, et al. Thrombophilic risk factors for symptomatic peripheral arterial disease. J Vasc Surg 2005;41:255–60.
  • 29. Todesco L, Angst C, Litynski P, Loehrer F, Fowler B, Haefeli WE. Methylenetetrahydrofolate reductase polymorphism, plasma homocysteine and age. Eur J Clin Invest 1999;29:1003–9.
  • 30. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88:3698–703.
  • 31. Hiatt WR, Hoag S, Hamman RF. Effect of diagnostic criteria on the prevalence of peripheral arterial disease. The San Luis Valley Diabetes Study. Circulation 1995;91:1472–9.
  • 32. Gürgey A, Hicsönmez G, Parlak H, Balta G, Celiker A. Prothrombin gene 20210 G-A mutation in Turkish patients with thrombosis. Am J Hematol 1998;59:179–80.
  • 33. Nowak-Göttl U, Sträter R, Heinecke A, Junker R, Koch HG, Schuierer G, et al. Lipoprotein (a) and genetic polymorphisms of clotting factor V, prothrombin, and methylenetetrahydrofolate reductase are risk factors of spontaneous ischemic stroke in childhood. Blood 1999;94:3678–82.
  • 34. Margaglione M, D’Andrea G, Giuliani N, Brancaccio V, De Lucia D, Grandone E, et al. Inherited prothrombotic conditions and premature ischemic stroke: sex difference in the association with factor V Leiden. Arterioscler Thromb Vasc Biol 1999;19:1751–6.
  • 35. Mueller T, Marschon R, Dieplinger B, Haidinger D, Gegenhuber A, Poelz W, et al. Factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations are not associated with chronic limb ischemia: the Linz Peripheral Arterial Disease (LIPAD) study. J Vasc Surg 2005;41:808–15.
  • 36. Voetsch B, Loscalzo J. Genetic determinants of arterial thrombosis. Arterioscler Thromb Vasc Biol 2004;24:216–29.
  • 37. Bennet AM, Di Angelantonio E, Ye Z, Wensley F, Dahlin A, Ahlbom A, et al. Association of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA 2007;298:1300–11.
  • 38. Mahfouz RA, Sabbagh AS, Zahed LF, Mahfoud ZR, Kalmoni RF, Otrock ZK, et al. Apolipoprotein E gene polymorphism and allele frequencies in the Lebanese population. Mol Biol Rep 2006;33:145–9.
  • 39. Utermann G, Hees M, Steinmetz A. Polymorphism of apolipoprotein E and occurrence of dysbetalipoproteinaemia in man. Nature 1977;269:604–7.
APA YALIM Z, Tutgun Onrat S, YALIM S, ALDEMİR M, Avsar A, DOĞAN İ, Onrat E (2020). The effects of genetic polymorphisms and diabetes mellitus on the development of peripheral artery disease. , 484 - 493. 10.5543/tkda.2020.15686
Chicago YALIM Zafer,Tutgun Onrat Serap,YALIM Sümeyra Alan,ALDEMİR Mustafa Tayfun,Avsar Alaettin,DOĞAN İsmet,Onrat Ersel The effects of genetic polymorphisms and diabetes mellitus on the development of peripheral artery disease. (2020): 484 - 493. 10.5543/tkda.2020.15686
MLA YALIM Zafer,Tutgun Onrat Serap,YALIM Sümeyra Alan,ALDEMİR Mustafa Tayfun,Avsar Alaettin,DOĞAN İsmet,Onrat Ersel The effects of genetic polymorphisms and diabetes mellitus on the development of peripheral artery disease. , 2020, ss.484 - 493. 10.5543/tkda.2020.15686
AMA YALIM Z,Tutgun Onrat S,YALIM S,ALDEMİR M,Avsar A,DOĞAN İ,Onrat E The effects of genetic polymorphisms and diabetes mellitus on the development of peripheral artery disease. . 2020; 484 - 493. 10.5543/tkda.2020.15686
Vancouver YALIM Z,Tutgun Onrat S,YALIM S,ALDEMİR M,Avsar A,DOĞAN İ,Onrat E The effects of genetic polymorphisms and diabetes mellitus on the development of peripheral artery disease. . 2020; 484 - 493. 10.5543/tkda.2020.15686
IEEE YALIM Z,Tutgun Onrat S,YALIM S,ALDEMİR M,Avsar A,DOĞAN İ,Onrat E "The effects of genetic polymorphisms and diabetes mellitus on the development of peripheral artery disease." , ss.484 - 493, 2020. 10.5543/tkda.2020.15686
ISNAD YALIM, Zafer vd. "The effects of genetic polymorphisms and diabetes mellitus on the development of peripheral artery disease". (2020), 484-493. https://doi.org/10.5543/tkda.2020.15686
APA YALIM Z, Tutgun Onrat S, YALIM S, ALDEMİR M, Avsar A, DOĞAN İ, Onrat E (2020). The effects of genetic polymorphisms and diabetes mellitus on the development of peripheral artery disease. Türk Kardiyoloji Derneği Arşivi, 48(5), 484 - 493. 10.5543/tkda.2020.15686
Chicago YALIM Zafer,Tutgun Onrat Serap,YALIM Sümeyra Alan,ALDEMİR Mustafa Tayfun,Avsar Alaettin,DOĞAN İsmet,Onrat Ersel The effects of genetic polymorphisms and diabetes mellitus on the development of peripheral artery disease. Türk Kardiyoloji Derneği Arşivi 48, no.5 (2020): 484 - 493. 10.5543/tkda.2020.15686
MLA YALIM Zafer,Tutgun Onrat Serap,YALIM Sümeyra Alan,ALDEMİR Mustafa Tayfun,Avsar Alaettin,DOĞAN İsmet,Onrat Ersel The effects of genetic polymorphisms and diabetes mellitus on the development of peripheral artery disease. Türk Kardiyoloji Derneği Arşivi, vol.48, no.5, 2020, ss.484 - 493. 10.5543/tkda.2020.15686
AMA YALIM Z,Tutgun Onrat S,YALIM S,ALDEMİR M,Avsar A,DOĞAN İ,Onrat E The effects of genetic polymorphisms and diabetes mellitus on the development of peripheral artery disease. Türk Kardiyoloji Derneği Arşivi. 2020; 48(5): 484 - 493. 10.5543/tkda.2020.15686
Vancouver YALIM Z,Tutgun Onrat S,YALIM S,ALDEMİR M,Avsar A,DOĞAN İ,Onrat E The effects of genetic polymorphisms and diabetes mellitus on the development of peripheral artery disease. Türk Kardiyoloji Derneği Arşivi. 2020; 48(5): 484 - 493. 10.5543/tkda.2020.15686
IEEE YALIM Z,Tutgun Onrat S,YALIM S,ALDEMİR M,Avsar A,DOĞAN İ,Onrat E "The effects of genetic polymorphisms and diabetes mellitus on the development of peripheral artery disease." Türk Kardiyoloji Derneği Arşivi, 48, ss.484 - 493, 2020. 10.5543/tkda.2020.15686
ISNAD YALIM, Zafer vd. "The effects of genetic polymorphisms and diabetes mellitus on the development of peripheral artery disease". Türk Kardiyoloji Derneği Arşivi 48/5 (2020), 484-493. https://doi.org/10.5543/tkda.2020.15686