Genetic risk factors of chronic venous leg ulceration: Can molecular screening aid in the prevention of chronic venous insufficiency complications?

Molecular Medicine Reports

Volumn 3, Issue 2, 2010, Pages 205-211

  Grzela, Tomasz ^a   Bialoszewska, Agata ^a  

^a MEDICAL UNIVERSITY OF WARSAW   (Poland)

Author keywords

Gene polymorphism; Venous leg ulcer; Wound healing

Indexed keywords

5,10 METHYLENETETRAHYDROFOLATE REDUCTASE (FADH2); ACTIVATED PROTEIN C; ASPARTIC ACID; BLOOD CLOTTING FACTOR 13A; BLOOD CLOTTING FACTOR 5 LEIDEN; CELL ADHESION MOLECULE; ESTROGEN RECEPTOR; FIBRIN; FIBRINOGEN; FIBROBLAST GROWTH FACTOR RECEPTOR 2; GELATINASE A; GELATINASE B; GENE PRODUCT; HISTIDINE; INTERLEUKIN 1; KERATINOCYTE GROWTH FACTOR RECEPTOR; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 1; MESSENGER RNA; STROMELYSIN; THROMBIN; TRANSFERRIN; TRANSFERRIN RECEPTOR; TUMOR NECROSIS FACTOR ALPHA; VASCULOTROPIN;

ALLELE; BLOOD CLOTTING; CHRONIC DISEASE; CHRONIC VEIN INSUFFICIENCY; CHRONIC VENOUS LEG ULCERATION; DEEP VEIN THROMBOSIS; DISEASE COURSE; DISEASE PREDISPOSITION; DNA POLYMORPHISM; ENZYME ACTIVITY; FIBRIN POLYMERIZATION; GENE EXPRESSION REGULATION; GENE FREQUENCY; GENE MUTATION; GENETIC ASSOCIATION; GENETIC CODE; GENETIC RISK; GENETIC SCREENING; GENETIC TRANSFECTION; GENETIC VARIABILITY; HEMOCHROMATOSIS; HEMOSTASIS; HETEROZYGOTE; HORMONE SUBSTITUTION; HUMAN; HYPERHOMOCYSTEINEMIA; IN VITRO STUDY; ISCHEMIA; LEG ULCER; OXYGENATION; PATHOPHYSIOLOGY; PREVALENCE; REPERFUSION; REVIEW; RISK FACTOR; SIGNAL TRANSDUCTION; SINGLE NUCLEOTIDE POLYMORPHISM; STRESS; THROMBOPHILIA; TISSUE INJURY; TISSUE PERFUSION; ULCER HEALING; WOUND;

EID: 77950826496     PISSN: 17912997     EISSN: 17913004     Source Type: Journal    
DOI: 10.3892/mmr_000000241     Document Type: Review

References (88)

1. Mekkes JR, Loots MAM, van der Wal AC and Box JD: Causes, investigation and a treatment of leg ulceration. Br J Dermatol 148: 388-401, 2003.
2. Labropoulos N, Manalo D, Patel NP, Tiongson J, Pryor L and Giannoukas AD: Uncommon leg ulcers in the lower extremity. J Vasc Surg 45: 568-573, 2007.
3. Etufugh CN and Phillips TJ: Venous ulcers. Clin Dermatol 25: 121-130, 2007.
4. Ruckley C: Socioeconomic impact of chronic venous insufficiency and leg ulcers. Angiology 46: 67-69, 1997.
5. Jawien A: The influence of environmental factors in chronic venous insufficiency. Angiology 54: S19-S31, 2003.
6. MacKenzie RK, Brown DA, Allan PL, Bradbury AW and Ruckley CV: A comparison of patients who developed venous leg ulceration before and after their 50th birthday. Eur J Vasc Endovasc Surg 26: 176-178, 2003.
7. Milic DJ, Zivic SS, Bogdanovic DC, Karanovic ND and Golubovic ZV: Risk factors related to the failure of venous leg ulcers to heal with compression treatment. J Vasc Surg 49: 1242-1247, 2009.
8. Hehenberger K, Kratz G, Hansson A and Brismar K: Fibroblasts derived from human chronic diabetic wounds have a decreased proliferation rate, which is recovered by the addition of heparin. J Dermatol Sci 16: 144-151, 1998.
9. Pistorius MA: Chronic venous insufficiency: the genetic influence. Angiology 54: S5-S12, 2003.
10. Bradbury AW, MacKenzie RK, Burns P and Fegan C: Thrombophilia and chronic venous ulceration. Eur J Vasc Endovasc Surg 24: 97-104, 2002.
11. Darvall KA, Sam RC, Adam DJ, Silverman SH, Fegan CD and Bradbury AW: Higher prevalence of thrombophilia in patients with varicose veins and venous ulcers than controls. J Vasc Surg 49: 1235-1241, 2009.
12. Bergan J: Molecular mechanisms in chronic venous insufficiency. Ann Vasc Surg 21: 260-266, 2007.
13. Mustoe TA, O'Shaughnessy K and Kloeters O: Chronic wound pathogenesis and current treatment strategies: a unifying hypothesis. Plast Reconstr Surg 117: S35-S41, 2006.
14. MacKenzie RK, Ludlam CA, Ruckley CV, Allan PL, Burns P and Bradbury AW: The prevalence of thrombophilia in patients with chronic venous leg ulceration. J Vasc Surg 35: 718-722, 2002.
15. Bertina RM, Koeleman BP, Koster T, et al: Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 369: 64-67, 1994.
16. Van Boven HH, Reitsma PH, Rosendaal FR, et al: Factor V Leiden (FV R506Q) in families with inherited antithrombin deficiency. Thromb Haemost 75: 417-421, 1996.
17. Maessen-Visch MB, Hamulyak K, Tazelaar DJ, Crombag NH and Neumann HA: The prevalence of factor V Leiden mutation in patients with leg ulcers and venous insufficiency. Arch Dermatol 135: 41-44, 1999.
18. Peus D, von Schmiedeberg S, Pier A, et al: Coagulation factor V gene mutation associated with activated protein C resistance leading to recurrent thrombosis, leg ulcers and lymphedema: successful treatment with intermittent compression. J Am Acad Dermatol 35: 306-309, 1996.
19. Hackenjos K, Bek M, Schopf E and Vansceidt W: Recurrent ulcerations on both legs since childhood due to a factor V gene mutation. Dermatology 194: 297-298, 1997.
20. Poort SR, Rosendaal FR, Reitsma PH and Bertina RM: A common genetic variation in the 3′-untranslated region of prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 88: 3698-3703, 1996.
21. Brown K, Luddington R, Williamson D, Baker P and Baglin T: Risk of venous thromboembolism associated with a G to A transition at position 20210 in the 3′-untranslated region of the prothrombin gene. Br J Haematol 98: 907-909, 1997.
22. Cumming AM, Keeney S, Salden A, Bhavnani M, Shwe KH and Hay CRM: The prothrombin gene G20210A variant: prevalence in a UK anticoagulant clinic population. Br J Haematol 98: 353-355, 1997.
23. Hillarp A, Zöller B, Svensson PJ and Dahlbäck B: The 20210 allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis. Thromb Haemost 78: 990-992, 1997.
24. Kapur RK, Mills LA, Spitzer SG and Hultin MB: A prothrombin gene mutation is significantly associated with venous thrombosis. Arterioscler Thromb Vasc Biol 17: 2875-2879, 1997.
25. Herrmann W: The importance of hyperhomocysteinaemia as a risk factor for disease: an overview. Clin Chem Lab Med 39: 666-674, 2001.
26. Den Heijer M, Rosendaal FR, Blom HJ, Gerrits WBJ and Bos GMJ: Hyperhomocysteinaemia and venous thrombosis: a meta-analysis. Thromb Haemost 80: 874-877, 1998.
27. Ray JG: Meta-analysis of hyperhomocysteinaemia as a risk factor for venous thromboembolic disease. Arch Int Med 158: 2101-2106, 1998.
28. Sharp L and Little J: Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review. Am J Epidemiol 159: 423-443, 2004.
29. Sam RC, Burns PJ, Hobbs SD, et al: The prevalence of hyperhomocysteinaemia, methylene-tetrahydrofolate reductase C677T mutation and vitamin B12 and folate deficiency in patients with chronic venous insufficiency. J Vasc Surg 38: 904-908, 2003.
30. Cattaneo M, Tsai M, Bucciarelli P, et al: A common mutation in the methylenetetrahydrofolate reductase gene (C677T) increases the risk for deep-vein thrombosis in patients with mutant factor V (FactorV:Q506). Arterioscler Thromb Vasc Biol 17: 1662-1666, 1997.
31. Eichinger S: Are B vitamins a risk factor for venous thromboembolism? Yes. J Thromb Haemost 4: 307-308, 2006.
32. Bauer KA, Rosendaal FR and Heit JA: Hypercoagulability: too many tests, too much conflicting data. Hematology Am Soc Hematol Educ Program 353-368, 2002.
33. Key NS and McGlennen RC: Hyperhomocyst(e)inemia and thrombophilia. Arch Pathol Lab Med 126: 1367-1375, 2002.
34. Meissner MH, Eklof B, Smith PC, et al: Secondary chronic venous disorders. J Vasc Surg 46: S68-S83, 2007.
35. Yager DR, Kulina RA and Gilman LA: Wound fluids: a window into the wound environment? Int J Low Extrem Wounds 6: 262-272, 2007.
36. Baker EA and Leaper DJ: Proteinases, their inhibitors and cytokine profiles in acute wound fluid. Wound Rep Reg 8: 392-398, 2000.
37. Vaalamo M, Weckroth M, Puolakkainen P, et al: Patterns of matrix metalloproteinase and TIMP-1 expression in chronic and normally healing human cutaneous wounds. Br J Dermatol 135: 52-59, 1996.
38. Trengove NJ, Stacey MC, MacAuley S, et al: Analysis of the acute and chronic wound environments: the role of proteases and their inhibitors. Wound Rep Reg 7: 442-452, 1999.
39. Wysocki AB, Staiano-Coico L and Grinell F: Wound fluid from chronic leg ulcers contains elevated levels of metalloproteinases MMP-2 and MMP-9. J Invest Dermatol 101: 64-68, 1993.
40. Wallace HJ, Vandongen YK and Stacey MC: Tumor necrosis factor alpha gene polymorphism associated with increased susceptibility to venous leg ulceration. J Invest Dermatol 126: 923-926, 2006.
41. Hajeer AH and Hutchinson IV: Influence of TNFalpha gene polymorphisms on TNFalpha production and disease. Hum Immunol 62: 1191-1199, 2001.
42. Hoffsted J, Eriksson P, Hellstrom L, Rossner S, Ryden M and Arner P: Excessive fat accumulation is associated with the TNF-alpha -308 G/A promoter polymorphism in women but not in men. Diabetologia 43: 1085-1088, 2000.
43. Brand E, Schorr U, Kunz I, et al: Tumor necrosis factor-alpha -308 G/A polymorphism in obese Caucasians. Int J Obes Relat Metab Disord 25: 581-585, 2001.
44. Nagy N, Szolnoky G, Szabad G, et al: Tumor necrosis factor-α-308 polymorphism and leg ulceration - possible association with obesity. J Invest Dermatol 127: 1768-1769, 2007.
45. Beenken A and Mohammadi M: The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov 8: 235-253, 2009.
46. 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 124: 1085-1088, 2005.
47. Kawase T, Matsuo K, Suzuki T, et al: FGFR2 intronic polymorphisms interact with reproductive risk factors of breast cancer: results of a case control study in Japan. Int J Cancer 125: 1946-1952, 2009.
48. Raskin L, Pinchev M, Arad C, et al: FGFR2 is a breast cancer susceptibility gene in Jewish and Arab Israeli populations. Cancer Epidemiol Biomarkers Prev 17: 1060-1065, 2008.
49. Katoh M: Cancer genomics and genetics of FGFR2. Int J Oncol 33: 233-237, 2008.
50. Finch PW and Rubin JS: Keratinocyte growth factor/fibroblast growth factor-7, a homeostatic factor with therapeutic potential for epithelial protection and repair. Adv Cancer Res 91: 69-136, 2004.
51. Ashworth JJ, Smyth JV, Pendleton N, et al: The dinucleotide (CA) repeat polymorphism of estrogen receptor beta but not the dinucleotide (TA) repeat polymorphism of estrogen receptor alpha is associated with venous ulceration. J Steroid Biochem Mol Biol 97: 266-270, 2005.
52. Ashworth JJ, Smyth JV, Pendleton N, et al: Polymorphisms spanning the ON exon and promoter of the estrogen receptor-beta (ERβ) gene ESR2 are associated with venous ulceration. Clin Genet 73: 55-61, 2008.
53. Brincat M: Hormone replacement therapy and the skin. Maturitas 35: 107-117, 2000.
54. Margolis DJ, Knauss J and Bilker W: Hormone replacement therapy and prevention of pressure ulcers and venous leg ulcers. Lancet 359: 675-677, 2002.
55. Ashcroft GS, Greenwell-Wild T, Horan MA, Wahl SM and Ferguson MW: Topical estrogen accelerates cutaneous wound healing in aged humans associated with an altered inflammatory response. Am J Pathol 155: 1137-1146, 1999.
56. Distante S: Genetic predisposition to iron overload: prevalence and phenotypic expression of hemochromatosis-associated HFE-C282Y gene mutation. Scand J Clin Lab Invest 66: 83-100, 2006.
57. Hanson EH, Imperatore G and Burke W: HFE gene and hereditary hemochromatosis: a HuGE review. Human Genome Epidemiology. Am J Epidemiol 154: 193-206, 2001.
58. Beutler E: The HFE Cys282Tyr mutation as a necessary but not sufficient cause of clinical hereditary hemochromatosis. Blood 101: 3347-3350, 2003.
59. Beutler E, Felitti VJ, Koziol JA, Ho NJ and Gelbart T: Penetrance of C282Y hereditary haemochromatosis mutation in USA. Lancet 359: 211-218, 2002.
60. McCune CA, Ravine D, Worwood M, Jackson HA, Evans HM and Hutton D: Screening for hereditary haemochromatosis within families and beyond. Lancet 362: 897-898, 2003.
61. Zamboni P and Gemmati D: Clinical implications of gene polymorphisms in venous leg ulcer: a model in tissue injury and reparative process. Thromb Haemost 98: 131-137, 2007.
62. LeVine SM and Chakrabarty A: The role of iron in the pathogenesis of experimental allergic encephalomyelitis and multiple sclerosis. Ann NY Acad Sci 1012: 252-266, 2004.
63. Zamboni P, Izzo M, Tagnazzo S, et al: The overlapping of local iron overload and HFE mutation in venous leg ulcer pathogenesis. Free Radic Biol Med 40: 1869-1873, 2006.
64. Zamboni P, Tognazzo S, Izzo M, et al: Hemochromatosis C282Y gene mutation increases the risk of venous leg ulceration. J Vasc Surg 42: 309-314, 2005.
65. Bao P, Kodra A, Tomic-Canic M, Golinko MS, Ehrlich HP and Brem H: The role of vascular endothelial growth factor in wound healing. J Surg Res 153: 347-358, 2009.
66. Carmeliet P and Jain RK: Angiogenesis in cancer and other diseases. Nature 407: 249-257, 2000.
67. Kim YS, Park SW, Kim MH, et al: Novel single nucleotide polymorphism of the VEGF gene as a risk predictor for gastroduodenal ulcers. Gastoenterology 23: S131-S139, 2008.
68. Hsiao PJ, Lu MY, Chiang FY, Shin SJ, Tai YD and Juo SHH: Vascular endothelial growth factor gene polymorphisms in thyroid cancer. J Endocrinol 195: 265-270, 2007.
69. Cosín R, Gilabert-Estellés J, Ramón LA, et al: Vascular endothelial growth factor polymorphisms (-460C/T, +405G/C and 936C/T) and endometriosis: their influence on vascular endothelial growth factor expression. Fertil Steril 92: 1214-1220, 2009.
70. Renner W, Kotschan C, Hoffmann C, Obermayer-Pietsch B and Pilger E: A common 936 C/T mutation in the gene for vascular endothelial growth factor is associated with vascular endothelial growth factor plasma levels. J Vasc Res 37: 443-448, 2000.
71. Rogers MS and D'Amato RJ: The effect of genetic diversity on angiogenesis. Exp Cell Res 312: 561-574, 2006.
72. Gemmati D, Tognazzo S, Serino ML, et al: Factor XIII V34L polymorphism modulates the risk of chronic venous ulcer progression and extension. Wound Repair Regen 12: 512-517, 2004.
73. Tognazzo S, Gemmati D, Palazzo A, et al: Prognostic role of factor XIII gene variants in nonhealing venous leg ulcers. J Vasc Surg 44: 815-819, 2006.
74. Gemmati D, Tognazzo S, Catozzi L, et al: Influence of gene polymorphisms in ulcer healing process after superficial venous surgery. J Vasc Surg 44: 554-562, 2006.
75. Shen LL, Hermans J, McDonagh J, McDonagh RP and Carr M: Effects of calcium ion and covalent crosslinking on formation of elasticity of fibrin gels. Thromb Res 6: 255-265, 1975.
76. Bakker EN, Pistea A and VanBavel E: Transglutaminases in vascular biology: relevance for vascular remodeling and atherosclerosis. J Vasc Res 45: 271-278, 2008.
77. Ueyama M and Urayama T: The role of factor XIII in fibroblast proliferation. Jpn J Exp Med 48: 135-142, 1978.
78. Zamboni P, DeMattei M, Ongaro A, et al: Factor XIII contrasts the effects of metalloproteinases in human dermal fibroblast cultured cells. Vasc Endovasc Surg 38: 431-438, 2004.
79. Inbal A, Lubetsky A, Krapp T, Castel D, Shaish A and Dickneitte G: Impaired wound healing in factor XIII deficient mice. Thromb Haemost 94: 432-437, 2005.
80. Hildenbrand T, Idzko M, Panther E, Norgauer J and Herouy Y: Treatment of nonhealing leg ulcers with fibrin-stabilizing factor XIII: a case report. Dermatol Surg 28: 1098-1099, 2002.
81. Gallivan L, Markham AF and Anwar R: The Leu564 factor XIII variant results in significantly lower plasma factor XIII levels than the Pro564 variant. Thromb Haemost 82: 1368-1370, 1999.
82. Yee VC, Pedersen LC, Le Trong I, Bishop PD, Stenkamp RE and Teller DC: Three-dimensional structure of transglutaminase: human blood coagulation factor XIII. Proc Natl Acad Sci USA 91: 7296-7300, 1994.
83. Kohler HP, Ariens RA, Whitaker P and Grant PJ: A common coding polymorphism in the FXIIIA-subunit gene (FXIII Val34Leu) affects cross-linking activity. Thromb Haemost 80: 704, 1998.
84. Aderka D: The potential biological and clinical significance of the soluble tumor necrosis factor receptors. Cytokine Growth Factor Rev 7: 231-240, 1996. (Pubitemid 27200307)
85. Chae SJ, Kim H, Jee BC, Suh CS, Kim SH and Kim JG: Tumor necrosis factor (TNF)-TNF receptor gene polymorphisms and their serum levels in Korean women with endometriosis. Am J Reprod Immunol 60: 432-439, 2008.
86. Meyer KB, Maia AT, O'Reilly M, et al: Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer. PLoS Biol 6: e108, 2008.
87. Jang JH, Shin KH and Park JG: Mutations in FGFR2 genes associated with human gastric and colorectal cancers. Cancer Res 61: 3541-3543, 2001.
88. Pollock PM, Gartside MG, Dejeza LC, et al: Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes. Oncogene 26: 7158-7162, 2007.