Investigation of the Possible Role of Macrophage Migration Inhibitory Factor Gene -173G/C Polymorphism ın Patients with Atherosclerosis

Abstract

Purpose: Atherosclerosis is defined as an inflammatory disease that results in the formation of atherosclerotic plaques caused by the deposition of cholesterol in the arterial intima. As a result of damage to the intima layer of the vessel, foam cell formation following cholesterol accumulation and plaque development due to smooth muscle cell increase are observed. In different stages of atherosclerosis, migration of leukocytes to the vessel wall is provided by functional type chemokines; ıt was aimed to investigate the possible role of MIF -173G/C polymorphism in atherosclerosis disease depending on this function, since it has the same functional properties as chemokines. Materials and Methods: Thirty patients with 70% occlusion detected by angiography and 30 healthy individuals were included in the study. DNA isolation was performed with DNA isolation kit from blood samples taken into EDTA tubes from individuals participating in the study. Analysis of MIF -173G/C polymorphism was performed on Real Time PCR (LC480, Roche). Statistical analyzes were performed with the program STATISTICA version 13.5.0.17 (TIBCO Software Inc. (2017)). Statistical significance level p≤ 0.05 was taken in all comparisons. Results: The frequency of GG, GC and CC genotypes in the MIF -173G/C polymorphism was 55.26%, 41.18% and 66.66% in the patient group, respectively, and 44.74%, 58.82% and 33.33% in the control group. When compared with the GG genotype, it was determined that those with the GC genotype had a 0.567-fold (p=0.3367) risk of developing the disease and those with the CC genotype had a 1.6190-fold (p= 0.7038) risk of developing the disease. Conclusion: It was determined that those with the C allele in the MIF-173 G/C polymorphism pose a risk for atherosclerosis disease.

Keywords

• MIF
• PCR
• ATEROSCLEROSIS

Aterosklerozlu Hastalarda Makrofaj Migrasyon İnhibitör Faktör Geni -173G/C Polimor-fizminin Olası Rolünün Araştırılması

Abstract

Amaç: Ateroskleroz, arteriyel intimada kolesterol birikiminin neden olduğu aterosklerotik plak oluşumu ile sonuçlanan enflamatuar bir hastalık olarak tanımlanmaktadır. Damarın intima tabakasındaki hasarlanma sonucunda kolesterol birikmesini takiben köpük hücre oluşumu ve düz kas hücre artışına bağlı olarak plak gelişimi görülmektedir. Aterosklerozun farklı aşamalarında, lökositlerin damar duvarına göçü fonksiyonel türdeki kemokinler ile sağlanmaktadır; kemokinlerle aynı fonksiyonel özelliklere sahip olduğu için MIF -173G/C polimorfizminin bu fonksiyona bağlı olarak ateroskleroz hastalığındaki olası rolünün araştırılması amaçlanmıştır. Araçlar ve Yöntem: Çalışmaya, anjiyografi ile %70 tıkanıklık tespit edilen 30 hasta ve 30 sağlıklı birey dahil edildi. Çalışmaya katılan bireylerden EDTA’lı tüplere alınan kan örneklerinden DNA izolasyon kiti ile DNA izolasyonu yapıldı. MIF -173G/C polimorfizminin analizi Real Time PCR (LC480, Roche) cihazında gerçekleştirildi. İstatistiksel analizler STATISTICA version 13.5.0.17 (TIBCO Software Inc. (2017)) programı ile yapıldı. Tüm karşılaştırmalarda istatistik önem seviyesi p≤ 0.05 alınmıştır. Bulgular: MIF -173G/C polimorfizminde, hasta grubunun GG, GC ve CC genotipi sıklığı sırasıyla %55.26 %41.18 ve %66.66 kontrol grubunda ise %44.74 %58.82 ve %33.33 olarak saptandı. GG genotipiyle karşılaştırıldığında, GC genotipine sahip olanlar 0.567 kat (p=0.3367), CC genotipine sahip olanlar 1.6190 kat (p=0.7038) hastalık geliştirme riskine sahip olduğu belirlendi. Sonuç: MIF -173 G/C polimorfizminde C aleline sahip olanların ateroskleroz hastalığı için risk oluşturduğu saptandı.

Keywords

• MIF
• PCR
• ATEROSKLEROZ

References

1. 1. Zengin H. Pathogenesis of atherosclerosis. J. Exp. Clin. Med. 2012;29:101-106.
2. 2. Merk M, Mitchell RA, Endres S, Bucala R. D-dopachrome tautomerase (D-DT or MIF-2): doubling the MIF cytokine family. Cytokine. 2012;59(1):10-17.
3. 3. Kim BS, Tilstam PV, Arnke K, Leng L et al. Differential regulation of macrophage activation by the MIF cytokine superfamily members MIF and MIF‐2 in adipose tissue during endotoxemia. FASEB J. 2020;34(3):4219-4233.
4. 4. Baugh J, Donnelly S. Macrophage migration inhibitory factor: a neuroendocrine modulator of chronic inflammation. J Endocrinol. 2003;179(1):15-23.
5. 5. Sumaiya K, Langford D, Natarajaseenivasan K, Shanmughapriya S. Macrophage migration inhibitory factor (MIF): a multifaceted cytokine regulated by genetic and physiological strategies. Pharmacol Ther. 2022;233:108024.
6. 6. Donn R, Ray D. Macrophage migration inhibitory factor: molecular, cellular and genetic aspects of a key neuroendocrine molecule. J Endocrinol 2004;182(1): 1-9.
7. 7. Xu L, Li Y, Sun H, et al. Current developments of macrophage migration inhibitory factor (MIF) inhibitors. Drug Discov Today. 2013;18(11):592-600.
8. 8. Pan J. H., Sukhova G. K., Yang J. T., et al. Macrophage migration inhibitory factor deficiency impairs atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation. 2004;109(25): 3149-3153.

9. 9. Burger-Kentischer A., Göbel H., Kleemann R., et al. Reduction of the aortic inflammatory response in spontaneous atherosclerosis by blockade of macrophage migration inhibitory factor (MIF). Atherosclerosis. 2006;184(1):28-38.
10. 10. Bernhagen J, Krohn R, Lue H, et al. MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med. 2007;13(5):587-596.
11. 11. Tillmann S, Bernhagen J, Noels H. Arrest functions of the MIF ligand/receptor axes in atherogenesis. Front Immunol. 2013;4:1-20.
12. 12. Calandra T, Roger T. Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol. 2003;3(10):791-800.
13. 13. Hertelendy J, Reumuth G, Simons D, et al. Macrophage migration inhibitory factor - a favorable marker in inflammatory diseases? Curr Med Chem. 2018;25(5):601-605.
14. 14. Morand EF, Leech M, Bernhagen J. MIF: a new cytokine link between rheumatoid arthritis and atherosclerosis. Nat Rev Drug Discov. 2006;5(5):399-410.
15. 15. Morrison MC, Kleemann R. Role of macrophage migration inhibitory factor in obesity, insulin resistance, type 2 diabetes, and associated hepatic co-morbidities: a comprehensive review of human and rodent studies. Front Immunol 2015;6:1-13.
16. 16. Sauler M, Bucala R, Lee PJ. Role of macrophage migration inhibitory factor in age-related lung disease. Am J Physiol Lung Cell Mol Physiol. 2015;309(1): L1–L10.
17. 17. O’Reilly C, Doroudian M, Mawhinney L, Donnelly SC. Targeting MIF in cancer: therapeutic strategies, current developments, and future opportunities. Med Res Rev. 2016;36(3):440-460.
18. 18. Conroy H, Mawhinney L, Donnelly SC. Inflammation and cancer: macrophage migration inhibitory factor (MIF)–the potential missing link. QJM. 2010;103(11):831-836.
19. 19. Chesney JA, Mitchell RA, Yaddanapudi K. Myeloid-derived suppressor cells-a new therapeutic target to overcome resistance to cancer immunotherapy. J Leukoc Biol. 2017;102(3):727-740.
20. 20. Chesney JA, Mitchell RA. 25 years on: a retrospective on migration inhibitory factor in tumor angiogenesis. Mol Med. 2015;21(1):19-24.
21. 21. Burger-Kentischer A, Goebel H, Seiler R, et al. Expression of MIF in different stages of human atherosclerosis. Circulation. 2002;105(13):1561-1566.
22. 22. Zernecke A, Bernhagen J, Weber C. Macrophage migration inhibitory factor in cardiovascular disease. Circulation. 2008;117(12):1594-1602.
23. 23. Tilstam PV, Qi D, Leng L, Young L, Bucala R. MIF family cytokines in cardiovascular diseases and prospects for precisionbased therapeutics. Expert Opin Ther Targets. 2017;21(07):671-683.
24. 24. Wirtz TH, Tillmann S, Strüßmann T, et al. Platelet-derived MIF: a novel platelet chemokine with distinct recruitment properties. Atherosclerosis. 2015;239(1): 1-10.
25. 25. Lin SG, Yu XY, Chen YX, et al. De novo expression of macrophage migration inhibitory factor in atherogenesis in rabbits. Circ Res. 2000;87(12):1202-1208.
26. 26. Burger-Kentischer A, Göbel H, Kleemann R, et al. Reduction of the aortic inflammatory response in spontaneous atherosclerosis by blockade of macrophage migration inhibitory factor (MIF). Atherosclerosis. 2006;184(1):28-38.
27. 27. Pan JH, Sukhova GK, Yang JT, et al. Macrophage migration inhibitory factor deficiency impairs atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation. 2004;109(25):3149-3153.
28. 28. Burger-Kenti1scher A, Goebel H, Seiler R, et al. Expression of macrophage migration inhibitory factor in different stages of human atherosclerosis. Circulation. 2002;105(13):1561-1566.
29. 29. Kong YZ, Huang XR, Ouyang X, et al. Evidence for vascular macrophage migration inhibitory factor in destabilization of human atherosclerotic plaques. Cardiovasc Res. 2005;65(1):272-282.
30. 30. Ross R. The pathogenesis of atherosclerosis: perspective for the 1990s. Nature. 1993;362(6423): 801-809.
31. 31. Cybulsky MI, Gimbrone MA Jr. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science. 1991;251(4995):788-791.
32. 32. Reape TJ, Groot PH. Chemokines and atherosclerosis. Atherosclerosis. 1999;147(2):213-225.
33. 33. Kleemann R, Kapurniotu A, Frank RW, et al. Disulfide analysis reveals a role for macrophage migration inhibitory factor (MIF) as a thiol-protein oxidoreductase. J Mol Biol. 1998;280(1):85-102.
34. 34. Rosengren E, Bucala R, Åman P, et al. The immunoregulatory mediator macrophage migration inhibitory factor (MIF) catalyzes a tautomerization reaction. Mol Med. 1996;2(1):143-149.
35. 35. Onodera S, Kaneda K, Mizue Y, et al. Macrophage migration inhibitory factor up-regulates expression of matrix metalloproteinases in synovial fibroblasts of rheumatoid arthritis. J Biol Chem. 2000;275(1):444-450.
36. 36. Tillmann S., Bernhagen J., Noels H. Arrest functions of the MIF ligand/receptor axes in atherogenesis. Front. Immunol. 2013;4:1-20.
37. 37. Benigni F, Atsumi T, Calandra T, et al. The proinflammatory mediator macrophage migration inhibitory factor induces glucose catabolism in muscle. J Clin Invest. 2000;106(10):1291-1300.
38. 38. Sheu WH, Chang TM, Lee WJ, et al. Effect of weight loss on proinflammatory state of mononuclear cells in obese women. Obesity. 2008;16(5):1033-1038.
39. 39. Stosic-Grujicic S, Stojanovic I, Maksimovic-Ivanic D, et al. Macrophage migration inhibitory factor (MIF) is necessary for progression of autoimmune diabetes mellitus. J Cell Physiol. 2008;215(3):665-675.