Advertisement

Clinical and Experimental Medicine

, Volume 16, Issue 3, pp 463–470 | Cite as

HFE p.C282Y gene variant is associated with varicose veins in Russian population

  • Ekaterina A. Sokolova
  • Alexandra S. Shadrina
  • Kseniya S. Sevost’ianova
  • Andrey I. Shevela
  • Evgenii Yu. Soldatsky
  • Evgenii I. Seliverstov
  • Marina Yu. Demekhova
  • Oleg A. Shonov
  • Evgenii A. Ilyukhin
  • Mariya A. Smetanina
  • Elena N. Voronina
  • Igor A. Zolotukhin
  • Maxim L. Filipenko
Original Article

Abstract

Recently, the association of polymorphism rs1800562 (p.C282Y) in the hemochromatosis (HFE) gene with the increased risk of venous ulceration was shown. We hypothesized that HFE gene polymorphism might be involved not only in ulceration process, but also in susceptibility to primary varicose veins. We genotyped HFE p.C282Y (rs1800562) and p.H63D (rs1799945) variants in patients with primary varicose veins (n = 463) and in the control group (n = 754). In our study, p.282Y variant (rs1800562 A allele) was significantly associated with the risk of varicose veins (OR 1.79, 95 % CI = 1.11–2.89, P = 0.02). A borderline significant reverse association of p.63D variant (rs1799945 G allele) with venous leg ulcer development was revealed in Russians (OR 0.25, 95 % CI = 0.06–1.00, P = 0.05), but not in the meta-analysis (P = 0.56). We conclude that the HFE gene polymorphism can affect the risk of developing primary varicose veins.

Keywords

Primary varicose veins Hemochromatosis gene 

Notes

Acknowledgments

This work was supported by Russian Science Fund [Project 14-15-00734 « Searching of genes involved in varicose vein disease pathology »].

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

References

  1. 1.
    Maurins U, Hoffmann BH, Lösch C, et al. Distribution and prevalence of reflux in the superficial and deep venous system in the general population–results from the Bonn Vein Study, Germany. J Vasc Surg. 2008;48:680–7. doi: 10.1016/j.jvs.2008.04.029.CrossRefPubMedGoogle Scholar
  2. 2.
    Abramson JH, Hopp C, Epstein LM. The epidemiology of varicose veins. A survey in western Jerusalem. J Epidemiol Community Health. 1981;35:213–7.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Fowkes FG, Evans CJ, Lee AJ. Prevalence and risk factors of chronic venous insufficiency. Angiology. 2001;52(Suppl 1):S5–15.CrossRefPubMedGoogle Scholar
  4. 4.
    Ruckley CV, Evans CJ, Allan PL, et al. Chronic venous insufficiency: clinical and duplex correlations. The Edinburgh Vein Study of venous disorders in the general population. J Vasc Surg. 2002;36:520–5.CrossRefPubMedGoogle Scholar
  5. 5.
    Savel’ev VS, Kirienko AI, Zolotukhin IA,SeliverstovEI (2012) Prospektivnoe observatsionnoe issledovanie SPEKTR: registr patsientov c khronicheskimi zabolevaniyami ven nizhnikh konechnostey (The prospective observational study SPEKTR: the registry of the patients presenting with chronic venous diseases of the lower). Flebologiya 6: 4–9.Google Scholar
  6. 6.
    Arnoldi CC. The heredity of venous insufficiency. Dan Med Bull. 1958;5:169–76.PubMedGoogle Scholar
  7. 7.
    Mayall RC. Varicose disease considered as hereditary clinical disease. Resen Clin Cient. 1968;37:28–9.PubMedGoogle Scholar
  8. 8.
    Chatard H. Should the topography of hereditary varices be considered from the genetic angle? Phlebologie. 1968;21(3):303.PubMedGoogle Scholar
  9. 9.
    Gundersen J, Hauge M. Hereditary factors in venous insufficiency. Angiology. 1969;20:346–55.CrossRefPubMedGoogle Scholar
  10. 10.
    Cornu-Thenard A, Boivin P, Baud JM, et al. Importance of the familial factor in varicose disease. Clinical study of 134 families. J Dermatol Surg Oncol. 1994;20:318–26.CrossRefPubMedGoogle Scholar
  11. 11.
    Pistorius MA. Chronic venous insufficiency: the genetic influence. Angiology. 2003;54(Suppl 1):S5–12.CrossRefPubMedGoogle Scholar
  12. 12.
    Coon WW. Willis PW3rd, Keller JB. Venous thromboembolism and other venous disease in the Tecumseh community health study. Circulation. 1973;48:839–46.CrossRefPubMedGoogle Scholar
  13. 13.
    Guberan E, Widmer LK, Glaus L, et al. Causative factors of varicose veins: myths and facts. An epidemiological study of 610 women. Vasa. 1973;2:115–20.PubMedGoogle Scholar
  14. 14.
    Da Silva A, Widmer LK, Martin H, et al. Varicose veins and chronic venous insufficiency. Vasa. 1974;3:118–25.PubMedGoogle Scholar
  15. 15.
    Brand FN, Dannenberg AL, Abbott RD, Kannel WB. The epidemiology of varicose veins: the Framingham Study. Am J Prev Med. 1988;4:96–101.PubMedGoogle Scholar
  16. 16.
    Nelzen O, Bergqvist D, Lindhagen A. The prevalence of chronic lower-limb ulceration has been underestimated: results of a validated population questionnaire. Br J Surg. 1996;83:255–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Jin Y, Xu G, Huang J, et al. Analysis of the association between an insertion/deletion polymorphism within the 3′ untranslated region of COL1A2 and chronic venous insufficiency. Ann Vasc Surg. 2013;27:959–63. doi: 10.1016/j.avsg.2013.04.001.CrossRefPubMedGoogle Scholar
  18. 18.
    Görmüş U, Kahraman ÖT, İsbir S, et al. MMP2 gene polymorphisms and MMP2 mRNA levels in patients with superficial varices of lower extremities. Vivo. 2011;25(3):387–91.Google Scholar
  19. 19.
    Katrancioglu N, Manduz S, Ozen F, et al. Type I plasminogen activator inhibitor 4G allele frequency is associated with chronic venous insufficiency. J Int Med Res. 2010;38:1513–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Sverdlova AM, Bubnova NA, Baranovskaya SS, et al. Prevalence of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation in patients with varicose veins of lower limbs. Mol Genet Metab. 1998;63:35–6.CrossRefPubMedGoogle Scholar
  21. 21.
    Xu H, Zhao Y, Zhang X, et al. Polymorphisms in MMP-9 and TIMP-2 in Chinese patients with varicose veins. J Surg Res. 2011;168:e143–8. doi: 10.1016/j.jss.2010.11.002.CrossRefPubMedGoogle Scholar
  22. 22.
    Nagy N, Szolnoky G, Szabad G, et al. Single nucleotide polymorphisms of the fibroblast growth factor receptor 2 gene in patients with chronic venous insufficiency with leg ulcer. J Invest Dermatol. 2005;124:1085–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Hafner J, Kühne A, Schär B, et al. Factor V Leiden mutation in postthrombotic and non-postthrombotic venous ulcers. Arch Dermatol. 2001;137:599–603.PubMedGoogle Scholar
  24. 24.
    Gaber Y, Siemens HJ, Schmeller W. Resistance to activated protein C due to factor V Leiden mutation: high prevalence in patients with post-thrombotic leg ulcers. Br J Dermatol. 2001;144:546–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Maessen-Visch MB, Hamulyak K, Tazelaar DJ, et al. The prevalence of factor V Leiden mutation in patients with leg ulcers and venous insufficiency. Arch Dermatol. 1999;135:41–4.CrossRefPubMedGoogle Scholar
  26. 26.
    Peus D, Heit JA, Pittelkow MR. Activated protein C resistance caused by factor V gene mutation: common coagulation defect in chronic venous leg ulcers? J Am Acad Dermatol. 1997;36:616–20.CrossRefPubMedGoogle Scholar
  27. 27.
    Tan JH, Price P, Gut I, et al. Characterization of tumor necrosis factor-α block haplotypes associated with susceptibility to chronic venous leg ulcers in Caucasian patients. Hum Immunol. 2010;71:1214–9. doi: 10.1016/j.humimm.2010.09.001.CrossRefPubMedGoogle Scholar
  28. 28.
    Gemmati D, Federici F, Catozzi L, et al. DNA-array of gene variants in venous leg ulcers: detection of prognostic indicators. J Vasc Surg. 2009;50:1444–51. doi: 10.1016/j.jvs.2009.07.103.CrossRefPubMedGoogle Scholar
  29. 29.
    Zamboni P, Tognazzo S, Izzo M, et al. Hemochromatosis C282Y gene mutation increases the risk of venous leg ulceration. J Vasc Surg. 2005;42:309–14.CrossRefPubMedGoogle Scholar
  30. 30.
    Yeoh-Ellerton S, Stacey M. Iron and 8-Isoprostane levels in acute and chronic wounds. J Invest Dermatol. 2003;121(4):918–25.CrossRefPubMedGoogle Scholar
  31. 31.
    Brissot P, Ropert M, Le Lan C, Loréal O. Non-transferrin bound iron: a key role in iron overload and iron toxicity. Biochim Biophys Acta. 2012;1820:403–10. doi: 10.1016/j.bbagen.2011.07.014.CrossRefPubMedGoogle Scholar
  32. 32.
    Kartikasari AE, Georgiou NA, Visseren FLJ, et al. Endothelial activation and induction of monocyte adhesion by nontransferrin-bound iron present in human sera. FASEB J. 2006;20:353–5.PubMedGoogle Scholar
  33. 33.
    Eklöf B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classification for chronic venous disorders: consensus statement. J Vasc Surg. 2004;40(6):1248–52.CrossRefPubMedGoogle Scholar
  34. 34.
    Kirienko AI, Bogachev VIu, Gavrilov SG, et al. Chronic diseases of lower extremity veins in industrial workers of Moscow (results of the epidemiological survey). Angiol Sosud Khir. 2004;10(1):77–85.PubMedGoogle Scholar
  35. 35.
    Saveliev VS, Kirienko AI, Zolotukhin IA, Seliverstov EI. Prospective observational study SPECTRUM: the registry of patients with chronic venous diseases. Flebologia. 2012;6(1):4–9.Google Scholar
  36. 36.
    Abbade LP, Lastória S. Venous ulcer: epidemiology, physiopathology, diagnosis and treatment. Int J Dermatol. 2005;44:449–56.CrossRefPubMedGoogle Scholar
  37. 37.
    Zamboni P, Izzo M, Tognazzo S, et al. The overlapping of local iron overload and HFE mutation in venous leg ulcer pathogenesis. Free Radic Biol Med. 2006;40:1869–73.CrossRefPubMedGoogle Scholar
  38. 38.
    Robertson L, Lee AJ, Gallagher K, et al. Risk factors for chronic ulceration in patients with varicose veins: a case control study. J Vasc Surg. 2009;49:1490–8. doi: 10.1016/j.jvs.2009.02.237.CrossRefPubMedGoogle Scholar
  39. 39.
    Milic DJ, Zivic SS, Bogdanovic DC, et al. Risk factors related to the failure of venous leg ulcers to heal with compression treatment. J Vasc Surg. 2009;49:1242–7. doi: 10.1016/j.jvs.2008.11.069.CrossRefPubMedGoogle Scholar
  40. 40.
    Kuo KL, Hung SC, Lee TS, Tarng DC. Iron sucrose accelerates early atherogenesis by increasing superoxide production and upregulating adhesion molecules in CKD. J Am Soc Nephrol. 2014;25:2596–606. doi: 10.1681/ASN.2013080838.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Schulz R, Murzabekova G, Egemnazarov B, et al. Arterial hypertension in a murine model of sleep apnea: role of NADPH oxidase 2. J Hypertens. 2014;32:300–5. doi: 10.1097/HJH.0000000000000016.CrossRefPubMedGoogle Scholar
  42. 42.
    Hirata Y, Yamamoto E, Tokitsu T, et al. Reactive oxygen metabolites are closely associated with the diagnosis and prognosis of coronary artery disease. J Am Heart Assoc. 2015;. doi: 10.1161/JAHA.114.001451.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Prasad K, Dhar I. Oxidative stress as a mechanism of added sugar-induced cardiovascular disease. Int J Angiol. 2014;23:217–26. doi: 10.1055/s-0034-1387169.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Budzyń M, Iskra M, Krasiński Z, et al. Serum iron concentration and plasma oxidant-antioxidant balance in patients with chronic venous insufficency. Med Sci Monit. 2011;17(12):CR719–27.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Zamboni P, Scapoli G, Lanzara V, et al. (2005) Serum iron and matrix metalloproteinase-9 variations in limbs affected by chronic venous disease and venous leg ulcers. Dermatol Surg. 31:644–9, discussion 649.Google Scholar
  46. 46.
    Ackerman Z, Seidenbaum M, Loewenthal E, Rubinow A. Overload of iron in the skin of patients with varicose ulcers. Possible contributing role of iron accumulation in progression of the disease. Arch Dermatol. 1988;124:1376–8.CrossRefPubMedGoogle Scholar
  47. 47.
    Morrison HI, Semenciw RM, Mao Y, Wigle DT. Serum iron and risk of fatal acute myocardial infarction. Epidemiology. 1994;5:243–6.CrossRefPubMedGoogle Scholar
  48. 48.
    De Valk B, Marx JJ. Iron, atherosclerosis, and ischemic heart disease. Arch Intern Med. 1999;159:1542–8.CrossRefPubMedGoogle Scholar
  49. 49.
    Basuli D, Stevens RG, Torti FM, Torti SV. Epidemiological associations between iron and cardiovascular disease and diabetes. Front Pharmacol. 2014;5:117. doi: 10.3389/fphar.2014.00117.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996;13:399–408.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Italia 2015

Authors and Affiliations

  • Ekaterina A. Sokolova
    • 1
    • 2
  • Alexandra S. Shadrina
    • 1
    • 2
  • Kseniya S. Sevost’ianova
    • 1
  • Andrey I. Shevela
    • 1
  • Evgenii Yu. Soldatsky
    • 3
  • Evgenii I. Seliverstov
    • 3
  • Marina Yu. Demekhova
    • 4
  • Oleg A. Shonov
    • 4
  • Evgenii A. Ilyukhin
    • 4
  • Mariya A. Smetanina
    • 1
  • Elena N. Voronina
    • 1
    • 2
  • Igor A. Zolotukhin
    • 3
  • Maxim L. Filipenko
    • 1
    • 2
  1. 1.Institute of Chemical Biology and Fundamental Medicine of the Siberian Branch of the Russian Academy of SciencesNovosibirskRussia
  2. 2.Novosibirsk State UniversityNovosibirskRussia
  3. 3.Pirogov Russian National Research Medical UniversityMoscowRussia
  4. 4.Private Surgery Center «Medalp»Saint PetersburgRussia

Personalised recommendations