About relationship of polymorphisms of the VEGFA 634C>G and MMP9 8202A>G genes with endothelial dysfunction markers and state of the microvasculature in diabetes mellitus

Introduction. Diabetes mellitus is one of the most common diseases in the world. In 4–25 % of patients with this pathology, diabetic foot syndrome develops, leading to a large number of amputations accompanied by postoperative mortality. Aim. To assess the relationship of polymorphisms of the VEGFA 634 C˃G and MMP9 8202 A˃G genes with markers of endothelial dysfunction and state of the microvasculature in diabetes mellitus. Materials and methods. In 198 people with uncomplicated diabetes mellitus and 199 people with diabetic feet, polymorphisms 634 C˃G of the VEGFA gene and 8202 A˃G of the MMP9 gene were studied by polymerase chain reaction. The content of endothelin 1, NO₂ and NO₂^– /NO₃^–, MMP 9 and state of microcirculation at three points were studied by laser Doppler flowmetry in 30 people from each group, comparable in frequency of the indicated gene polymorphisms. Results. The frequency of polymorphisms of genes VEGFA 634 C˃G, MMP9 8202 A>G did not differ in the groups of patients. In diabetic feet, a decrease in the total perfusion index by 1.4, 1.8 and 1.5 times was recorded at three points. At a point on the forearm with a diabetic foot, a 1.6-fold decrease in the temporal variability of perfusion was revealed; at the dorsum and first toe of the foot, a decrease in the coefficient of variation by 1.7 and 1.5 times was revealed. In patients with different variants of the course of diabetes mellitus, there were no differences in the levels of endothelin-1, NO₂ and NO₂^– / NO₃^–, MMP 9. Conclusion. Polymorphisms of the VEGFA 634 C˃G, MMP9 8202 A˃G genes in different variants of the course of3 – diabetes mellitus correlate with indicators of general state of the microvasculature. The parallelism of changes in the content of endothelin 1, MMP 9 and polymorphic variants of the MMP9 8202 A˃G gene indicates a deep remodeling of the vasculature, which may be an important link in the pathogenesis of the development of complications of diabetes mellitus.

diabetes mellitus, diabetic foot, gene polymorphism, microvasculature, laser Doppler flowmetry, markers of endothelial dysfunction

1. International Diabetes Federation. Diabetes Atlas. 7th Edition. 2015:144.

2. Standards of Medical Care in Diabetes-2017: Summary of Revisions. Diabetes Care. 2017;40(1):4–5. Doi: 10.2337/dc17-S003.

3. Amin N, Doupis J. Diabetic foot disease: From the evaluation of the “foot at risk” to the novel diabetic ulcer treatment modalities. World J. Diabetes. 2016;7(7):153–164. Doi: 10.4239/wjd.v7.i7.153.

4. Veves A, Giurini JM, Guzman RJ. The Diabetic Foot. Medical and Surgical Management Fourth Edition. Humana Press, 2018:514. Doi: 10.1007/978-3-319-89869-8.

5. Serebrennikov RV, Grishina IF, Lyagaeva AG. Vascular wall remodeling and endothelial function in patients with arterial hypertension and weight loss. Ural’skiy meditsinskiy zhurnal. 2016;11(144):67–73. (In Russ.).

6. Baranov VS. A genetic passport is the basis of individual and predictive medicine. SPb., Izd-vo N-L, 2009:528. (In Russ.).

7. Sellami N, Lamine LB, Turki A, Sarray S, Jailani M, Al-Ansari AK, Ghorbel M, Mahjoub T, Almawi WY. Association of VEGFA variants with altered VEGF secretion and type 2 diabetes: A case-control study. Cytokine. 2018;106:29–34. Doi: 10.1016/j.cyto.2018.03.003.

8. Singh K, Agrawal NK, Gupta SK, Singh KA. Functional single nucleotide polymorphism -1562C>T in the matrix metalloproteinase-9 promoter is associated with type 2 diabetes and diabetic foot ulcers. Int. J. Low. Extrem. Wounds. 2013;12(3):199–204. Doi: 10.1177/1534734613493289.

9. Dedov II, Shestakova MV, Galstyan GR, Grigoryan OR, Esayan RM, Kalashnikov VYu, Kuraeva TL, Lipatov DV, Mayorov AYu, Peterkova VA, Smirnova OM, Starostina EG, Surkova EV, Sukhareva OYu, Tokmakova AYu, Shamkhalova MSh, Yarek-Martynova IR. Algorithms for specialized medical care for patients with diabetes mellitus. Edited by Dedov II, Shestakova MV (7th edition). Sakharnyy diabet. 2015;1S:1–112. (In Russ.). Doi: 10.14341/DM20151S1-112.

10. Dedov II, Shestakova MV, Mayorov AYu, Vikulova OK, Galstyan GR, Kuraeva TL, Peterkova VA, Smirnova OM, Starostika EG, Surkova EV, Sukhareva OYu, Tokmakova AYu, Shamkhalova MSh, Yarek-Martynova IR, Beshlieva DD, Bondarenko ON, Volevodz NN, Grigoryan OR, Esayan RM, Ibragimova LI, Kalashnikov VYu, Lipatov DV, Shestakova EA. Algorithms for specialized medical care for patients with diabetes mellitus. Sakharnyy diabet. 2017;1S:1–121. (In Russ.). Doi: 10.14341/DM20151S1-112.

11. Orlova AYu, Artyushkova EB, Sukovatykh BS, Bushueva OYu, Polonikov AV, Gordov MYu. Polymorphism + 936C> T of the gene for vascular endothelial growth factor as a marker of predisposition to arteriosclerosis obliterans of lower limb arteries. Klinicheskaya meditsina. 2018;3:234–239. (In Russ.). Doi: 10.18821/0023-2149-2018-96-3-234-239.

12. Rusanov AV, Chumachenko YaD, Dubovik EI, Garbuzova VYu, Ataman AV. Analysis of the relationship of the C936T polymorphic site of the VEGFA gene with the development of diabetic foot syndrome in the Ukrainian population. Nauchnye rezul’taty biomeditsinskikh issledovaniy. 2019;2:34–42. (In Russ.). Doi: 10.18413/2658-6533-2019-5-2-0-4.

13. Gavrilyuk ND, Irtyuga OB, Druzhkova TA, Uspenskiy VE, Malashicheva AB, Kostartseva AA, Moiseeva OM. Matrix metalloproteinase 2 and 9 gene polymorphisms in patients with aneurysm of the ascending aorta. Rossiyskiy kardiologicheskiy zhurnal. 2015;10(20):65–69. (In Russ.). Doi: 10.15829/15604071-2015-10-65-69.

14. Beletskaya IS, Astakhov SYu. The role of matrix metalloproteinases in the pathogenesis of glaucoma. Oftal’mologicheskie vedomosti. 2015;3:28–43. (In Russ.).

15. Moskalenko MI. Associations of combinations of matrix metalloproteinase polymorphisms with the development of essential hypertension. Vestnik novykh meditsinskikh tekhnologiy. Elektronnoe izdanie. 2017;2:212–216. (In Russ.). Doi: 10.12737/article_5922bb446cd2b0.14691350.

16. Chuyan EN, Tribrat NS, Ravaeva MYu, Ananchenko MN. Tissue microhemodynamics: the influence of low-intensity electromagnetic radiation of the millimeter range: monograph. Simferopol’, IT «ARIAL, 2017:422. (In Russ.).

17. Kouadio AA, Jordana F, Koffi NJ, Le Bars P, Soueidan A. The use of laser Doppler flowmetry to evaluate oral soft tissue blood flow in humans: a review. Arch. Oral. Biol. 2018;86:58–71. Doi: 10.1016/j.archoralbio.2017.11.009.

18. Krupatkin AI, Sidorov VV. Functional diagnostics of the state of microcirculatory-tissue systems: oscillations, information, nonlinearity. A guide for doctors. Moscow, LIBROKOM, 2014:498. (In Russ.).

19. Radaykina OG, Vlasov AP, Myshkina NA. The role of endothelial dysfunction in the pathology of the cardiovascular system. Ul’yanovskiy mediko-biologicheskiy zhurnal. 2018;4:8–17. Doi: 10.23648/UMBJ.2018.32.22685. (In Russ.).

20. Afonas’eva TM. Endothelial dysfunction. Opportunities for early diagnosis. Zdorov’e i obrazovanie v XXI veke. 2016;11:103–104. (In Russ.).

21. Belushkina NN, Chemezov AS, Pal’tsev MA. Genetic studies of multifactorial diseases in the concept of personalized medicine. Profilakticheskaya meditsina. 2019;3:26–30. (In Russ.). Doi: 10.17116/profmed20192203126.

22. Ishakova AG. The role of genetic risk factors in the development of diabetic retinopathy. Vestnik meditsinskogo instituta «Reaviz»: reabilitatsiya, vrach i zdorov’e. 2018;5(35):41–49. (In Russ.).

23. Gudz’ AS, Zyablitsev SV, Zakharevich GE. The influence of the rs2010963 and rs699947 polymorphisms of the VEGFA gene on clinical and laboratory parameters in diabetic retinopathy in patients with type 2 diabetes mellitus. Mezhdunarodnyy endokrinologicheskiy zhurnal. 2017;7(13):471–477. (In Russ.). Doi: 10.22141/2224-0721.13.7.2017.115745.

24. Amoli M, Hasani-Ranjbar S, Roohipour N, Sayahpour FA, Amiri P, Zahedi P, Mehrab-Mohseni M, Heshmat R, Larijani B, Tavakkoly-Bazzar J. VEGF gene polymorphism association with diabetic foot ulcer. Diabetes. Res. Clin. Pract. 2011;93(2):215–219. Doi: 10.1016/j.diabres.2011.04.016.

25. Li X, Lu Y, Wei P. Association between VEGF genetic variants and diabetic foot ulcer in Chinese Han population. Medicine (Baltimore). 2018;97(20):e10672. Doi: 10.1097/MD.0000000000010672.

26. Li X. The association between MCP-1, VEGF polymorphisms and their serum levels in patients with diabetic foot ulcer. Medicine (Baltimore). 2018;97(24):e10959. Doi: 10.1097/MD.0000000000010959.

27. Solov’eva NI. Matrix metalloproteinases and their biological functions. Bioorganicheskaja himija. 1998;4(24):245–255. (In Russ.).

28. Singh K, Goyal P, Singh M, Deshmukh S, Upadhyay D, Kant S, Agrawal N, Gupta SK, Singh K. Association of functional SNP-1562C>T in MMP9 promoter with proliferative diabetic retinopathy in north Indian type 2 diabetes mellitus patients. Diabetes Complications. 2017;31(12):1648–1651. Doi: 10.1016/j.jdiacomp.2017.08.010.

29. Wang Y, Su Y, Xu Y, Pan S-H, Liu G-D. Genetic polymorphism c.1562C>T of the MMP-9 is associated with macroangiopathy in type 2 diabetes mellitus. Biochem. Biophys. Res. Commun. 2010;1:391(1);113–117. Doi: 10.1016/j.bbrc.2009.11.012.