Archives of Plastic Surgery

Korean Society of Plastic and Reconstructive Surgeons (대한성형외과학회)
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Keloid Scarring: Understanding the Genetic Basis, Advances, and Prospects

  • Halim, Ahmad Sukari (Reconstructive Sciences Unit, School of Medical Sciences, Universiti Sains Malaysia) ;
  • Emami, Azadeh (Reconstructive Sciences Unit, School of Medical Sciences, Universiti Sains Malaysia) ;
  • Salahshourifar, Iman (Human Genome Center, School of Medical Sciences, Universiti Sains Malaysia) ;
  • Kannan, Thirumulu Ponnuraj (Human Genome Center, School of Medical Sciences, Universiti Sains Malaysia)
  • Received : 2012.02.08
  • Accepted : 2012.02.15
  • Published : 2012.05.15
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Abstract

Keloid disease is a fibroproliferative dermal tumor with an unknown etiology that occurs after a skin injury in genetically susceptible individuals. Increased familial aggregation, a higher prevalence in certain races, parallelism in identical twins, and alteration in gene expression all favor a remarkable genetic contribution to keloid pathology. It seems that the environment triggers the disease in genetically susceptible individuals. Several genes have been implicated in the etiology of keloid disease, but no single gene mutation has thus far been found to be responsible. Therefore, a combination of methods such as association, gene-gene interaction, epigenetics, linkage, gene expression, and protein analysis should be applied to determine keloid etiology.

Keywords

References

  1. Kelly AP. Medical and surgical therapies for keloids. Dermatol Ther 2004;17:212-8. https://doi.org/10.1111/j.1396-0296.2004.04022.x
  2. Kelly AP. Keloids. Dermatol Clin 1988;6:413-24.
  3. Child FJ, Fuller LC, Higgins EM, et al. A study of the spectrum of skin disease occurring in a black population in south-east London. Br J Dermatol 1999;141:512-7. https://doi.org/10.1046/j.1365-2133.1999.03047.x
  4. Shaffer JJ, Taylor SC, Cook-Bolden F. Keloidal scars: a review with a critical look at therapeutic options. J Am Acad Dermatol 2002;46:S63-97. https://doi.org/10.1067/mjd.2002.120788
  5. Marneros AG, Norris JE, Olsen BR, et al. Clinical genetics of familial keloids. Arch Dermatol 2001;137:1429-34. https://doi.org/10.1001/archderm.137.11.1429
  6. LeFlore IC. Misconceptions regarding elective plastic surgery in the black patient. J Natl Med Assoc 1980;72:947-8.
  7. Alhady SM, Sivanantharajah K. Keloids in various races: a review of 175 cases. Plast Reconstr Surg 1969;44:564-6. https://doi.org/10.1097/00006534-196912000-00006
  8. Bayat A, Arscott G, Ollier WE, et al. "Aggressive keloid": a severe variant of familial keloid scarring. J R Soc Med 2003; 96:554-5. https://doi.org/10.1258/jrsm.96.11.554
  9. Marneros AG, Norris JE, Watanabe S, et al. Genome scans provide evidence for keloid susceptibility loci on chromosomes 2q23 and 7p11. J Invest Dermatol 2004;122:1126-32. https://doi.org/10.1111/j.0022-202X.2004.22327.x
  10. Chen Y, Gao JH, Liu XJ, et al. Characteristics of occurrence for Han Chinese familial keloids. Burns 2006;32:1052-9. https://doi.org/10.1016/j.burns.2006.04.014
  11. Bella H, Heise M, Yagi KI, et al. A clinical characterization of familial keloid disease in unique African tribes reveals distinct keloid phenotypes. Plast Reconstr Surg 2011;127:689-702. https://doi.org/10.1097/PRS.0b013e3181fed645
  12. Ramakrishnan KM, Thomas KP, Sundararajan CR. Study of 1,000 patients with keloids in South India. Plast Reconstr Surg 1974;53:276-80. https://doi.org/10.1097/00006534-197403000-00004
  13. Omo-Dare P. Genetic studies on keloid. J Natl Med Assoc 1975;67:428-32.
  14. Shih B, Bayat A. Genetics of keloid scarring. Arch Dermatol Res 2010;302:319-39. https://doi.org/10.1007/s00403-009-1014-y
  15. Stevens CA, Pouncey J, Knowles D. Adults with Rubinstein- Taybi syndrome. Am J Med Genet A 2011;155A:1680-4.
  16. Siraganian PA, Rubinstein JH, Miller RW. Keloids and neoplasms in the Rubinstein-Taybi syndrome. Med Pediatr Oncol 1989;17:485-91.
  17. Petrij F, Giles RH, Dauwerse HG, et al. Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature 1995;376:348-51. https://doi.org/10.1038/376348a0
  18. Nadeau A, Kinali M, Main M, et al. Natural history of Ullrich congenital muscular dystrophy. Neurology 2009;73:25-31. https://doi.org/10.1212/WNL.0b013e3181aae851
  19. Goeminne L. A new probably X-linked inherited syndrome: congenital muscular torticollis, multiple keloids cryptorchidism and renal dysplasia. Acta Genet Med Gemellol (Roma) 1968;17:439-67. https://doi.org/10.1017/S1120962300012634
  20. Sidgwick GP, Bayat A. Extracellular matrix molecules implicated in hypertrophic and keloid scarring. J Eur Acad Dermatol Venereol 2012;26:141-52. https://doi.org/10.1111/j.1468-3083.2011.04200.x
  21. Chalmers RL. The evidence for the role of transforming growth factor-beta in the formation of abnormal scarring. Int Wound J 2011;8:218-23. https://doi.org/10.1111/j.1742-481X.2011.00771.x
  22. Murata H, Zhou L, Ochoa S, et al. TGF-beta3 stimulates and regulates collagen synthesis through TGF-beta1-dependent and independent mechanisms. J Invest Dermatol 1997;108: 258-62. https://doi.org/10.1111/1523-1747.ep12286451
  23. Thompson SA, Canady JW, Coberly DM, et al. Effects of TGFbeta2 on collagen synthesis in cultured normal and wounded fetal mouse palates. Cleft Palate Craniofac J 1999; 36:425-33. https://doi.org/10.1597/1545-1569(1999)036<0425:EOTOCS>2.3.CO;2
  24. Bettinger DA, Yager DR, Diegelmann RF, et al. The effect of TGF-beta on keloid fibroblast proliferation and collagen synthesis. Plast Reconstr Surg 1996;98:827-33. https://doi.org/10.1097/00006534-199610000-00012
  25. Peltonen J, Hsiao LL, Jaakkola S, et al. Activation of collagen gene expression in keloids: co-localization of type I and VI collagen and transforming growth factor-beta 1 mRNA. J Invest Dermatol 1991;97:240-8. https://doi.org/10.1111/1523-1747.ep12480289
  26. Messadi DV, Le A, Berg S, et al. Effect of TGF-beta 1 on PDGF receptors expression in human scar fibroblasts. Front Biosci 1998;3:a16-22. https://doi.org/10.2741/A246
  27. Fujiwara M, Muragaki Y, Ooshima A. Upregulation of transforming growth factor-beta1 and vascular endothelial growth factor in cultured keloid fibroblasts: relevance to angiogenic activity. Arch Dermatol Res 2005;297:161-9. https://doi.org/10.1007/s00403-005-0596-2
  28. Gao Z, Wang Z, Shi Y, et al. Modulation of collagen synthesis in keloid fibroblasts by silencing Smad2 with siRNA. Plast Reconstr Surg 2006;118:1328-37. https://doi.org/10.1097/01.prs.0000239537.77870.2c
  29. Wang Z, Gao Z, Shi Y, et al. Inhibition of Smad3 expression decreases collagen synthesis in keloid disease fibroblasts. J Plast Reconstr Aesthet Surg 2007;60:1193-9. https://doi.org/10.1016/j.bjps.2006.05.007
  30. Chen Y, Gao JH, Liu XJ, et al. Linkage analysis of keloid susceptibility loci on chromosome 7p11 in a Chinese pedigree. Nan Fang Yi Ke Da Xue Xue Bao 2006;26:623-5.
  31. Yan X, Gao JH, Chen Y, et al. Preliminary linkage analysis and mapping of keloid susceptibility locus in a Chinese pedigree. Zhonghua Zheng Xing Wai Ke Za Zhi 2007;23: 32-5.
  32. Chen Y, Gao JH, Yan X, et al. Location of predisposing gene for one Han Chinese keloid pedigree. Zhonghua Zheng Xing Wai Ke Za Zhi 2007;23:137-40.
  33. Bayat A, Bock O, Mrowietz U, et al. Genetic susceptibility to keloid disease and transforming growth factor beta 2 polymorphisms. Br J Plast Surg 2002;55:283-6. https://doi.org/10.1054/bjps.2002.3853
  34. Bayat A, Bock O, Mrowietz U, et al. Genetic susceptibility to keloid disease and hypertrophic scarring: transforming growth factor beta1 common polymorphisms and plasma levels. Plast Reconstr Surg 2003;111:535-43. https://doi.org/10.1097/01.PRS.0000041536.02524.A3
  35. Bayat A, Bock O, Mrowietz U, et al. Genetic susceptibility to keloid disease: transforming growth factor beta receptor gene polymorphisms are not associated with keloid disease. Exp Dermatol 2004;13:120-4. https://doi.org/10.1111/j.0906-6705.2004.00165.x
  36. Bayat A, Walter JM, Bock O, et al. Genetic susceptibility to keloid disease: mutation screening of the TGFbeta3 gene. Br J Plast Surg 2005;58:914-21. https://doi.org/10.1016/j.bjps.2005.04.009
  37. Lu WS, Zhang WY, Li Y, et al. Association of HLA-DRB1 alleles with keloids in Chinese Han individuals. Tissue Antigens 2010;76:276-81. https://doi.org/10.1111/j.1399-0039.2010.01509.x
  38. Zhang G, Jiang J, Luo S, et al. Analyses of CDC2L1 gene mutations in keloid tissue. Clin Exp Dermatol 2012;37:277-83. https://doi.org/10.1111/j.1365-2230.2011.04225.x
  39. Brown JJ, Ollier WE, Thomson W, et al. Positive association of HLA-DRB1*15 with keloid disease in Caucasians. Int J Immunogenet 2008;35:303-7. https://doi.org/10.1111/j.1744-313X.2008.00780.x
  40. Yan L, Lu XY, Wang CM, et al. Association between p53 gene codon 72 polymorphism and keloid in Chinese population. Zhonghua Zheng Xing Wai Ke Za Zhi 2007;23:428-30.
  41. Grainger DJ, Heathcote K, Chiano M, et al. Genetic control of the circulating concentration of transforming growth factor type beta1. Hum Mol Genet 1999;8:93-7. https://doi.org/10.1093/hmg/8.1.93
  42. Brown JJ, Ollier W, Arscott G, et al. Genetic susceptibility to keloid scarring: SMAD gene SNP frequencies in Afro- Caribbeans. Exp Dermatol 2008;17:610-3. https://doi.org/10.1111/j.1600-0625.2007.00654.x
  43. Shih B, Bayat A. Comparative genomic hybridisation analysis of keloid tissue in Caucasians suggests possible involvement of HLA-DRB5 in disease pathogenesis. Arch Dermatol Res. 2012;304:241-9. https://doi.org/10.1007/s00403-011-1182-4
  44. Nakashima M, Chung S, Takahashi A, et al. A genome-wide association study identifies four susceptibility loci for keloid in the Japanese population. Nat Genet 2010;42:768-71. https://doi.org/10.1038/ng.645
  45. Chung S, Nakashima M, Zembutsu H, et al. Possible involvement of NEDD4 in keloid formation; its critical role in fibro blast proliferation and collagen production. Proc Jpn Acad Ser B Phys Biol Sci 2011;87:563-73. https://doi.org/10.2183/pjab.87.563
  46. Russell SB, Russell JD, Trupin KM, et al. Epigenetically altered wound healing in keloid fibroblasts. J Invest Dermatol 2010;130:2489-96. https://doi.org/10.1038/jid.2010.162

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