Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A genome-wide association study identifies four susceptibility loci for keloid in the Japanese population

Abstract

Keloid is a dermal fibroproliferative growth that results from dysfunction of the wound healing processes. Through a multistage genome-wide association study using 824 individuals with keloid (cases) and 3,205 unaffected controls in the Japanese population, we identified significant associations of keloid with four SNP loci in three chromosomal regions: 1q41, 3q22.3–23 and 15q21.3. The most significant association with keloid was observed at rs873549 (combined P = 5.89 × 10−23, odds ratio (OR) = 1.77) on chromosome 1. Associations on chromosome 3 were observed at two separate linkage disequilibrium (LD) blocks: rs1511412 in the LD block including FOXL2 with P = 2.31 × 10−13 (OR = 1.87) and rs940187 in another LD block with P = 1.80 × 10−13 (OR = 1.98). Association of rs8032158 located in NEDD4 on chromosome 15 yielded P = 5.96 × 10−13 (OR = 1.51). Our findings provide new insights into the pathophysiology of keloid formation.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Results from a two-stage genome-wide association study.
Figure 2: Case-control association results and linkage disequilibrium maps of the candidate regions.

References

  1. Marneros, A.G. & Krieg, T. Keloids–clinical diagnosis, pathogenesis, and treatment options. J. Dtsch. Dermatol. Ges. 2, 905–913 (2004).

    Article  PubMed  Google Scholar 

  2. Robles, D.T. & Berg, D. Abnormal wound healing: keloids. Clin. Dermatol. 25, 26–32 (2007).

    Article  PubMed  Google Scholar 

  3. Kelly, A.P. Keloids. Dermatol. Clin. 6, 413–424 (1988).

    Article  CAS  PubMed  Google Scholar 

  4. Marneros, A.G., Norris, J.E., Olsen, B.R. & Reichenberger, E. Clinical genetics of familial keloids. Arch. Dermatol. 137, 1429–1434 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Bayat, A., Bock, O., Mrowietz, U., Ollier, W.E. & Ferguson, M.W. Genetic susceptibility to keloid disease and transforming growth factor beta 2 polymorphisms. Br. J. Plast. Surg. 55, 283–286 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Bayat, A., Bock, O., Mrowietz, U., Ollier, W.E. & Ferguson, M.W. Genetic susceptibility to keloid disease and hypertrophic scarring: transforming growth factor beta1 common polymorphisms and plasma levels. Plast. Reconstr. Surg. 111, 535–543 discussion 544–546 (2003).

    Article  PubMed  Google Scholar 

  7. Bayat, A. et al. Genetic susceptibility to keloid disease: mutation screening of the TGFbeta3 gene. Br. J. Plast. Surg. 58, 914–921 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Brown, J.J. et al. Genetic susceptibility to keloid scarring: SMAD gene SNP frequencies in Afro-Caribbeans. Exp. Dermatol. 17, 610–613 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Marneros, A.G., Norris, J.E., Watanabe, S., Reichenberger, E. & Olsen, B.R. Genome scans provide evidence for keloid susceptibility loci on chromosomes 2q23 and 7p11. J. Invest. Dermatol. 122, 1126–1132 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Leonid, L. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat. Genet. 22, 139–144 (1999).

    Article  Google Scholar 

  11. Yamaguchi-Kabata, Y. et al. Japanese population structure, based on SNP genotypes from 7003 individuals compared to other ethnic groups: effects on population-based association studies. Am. J. Hum. Genet. 83, 445–456 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Okada, Y. et al. A genome-wide association study in 19633 Japanese subjects identified LHX3-QSOX2 and IGF1 as adult height loci. Hum. Mol. Genet. 19, 2303–2312 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Ellsworth, B.S. et al. The gonadotropin releasing hormone (GnRH) receptor activating sequence (GRAS) is a composite regulatory element that interacts with multiple classes of transcription factors including Smads, AP-1 and a forkhead DNA binding protein. Mol. Cell. Endocrinol. 206, 93–111 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Pisarska, M.D., Bae, J., Klein, C. & Hsueh, A.J. Forkhead l2 is expressed in the ovary and represses the promoter activity of the steroidogenic acute regulatory gene. Endocrinology 145, 3424–3433 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Crisponi, L. et al. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat. Genet. 27, 159–166 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Moustafa, M.F., Abdel-Fattah, M.A. & Abdel-Fattah, D.C. Presumptive evidence of the effect of pregnancy estrogens on keloid growth. Case report. Plast. Reconstr. Surg. 56, 450–453 (1975).

    Article  CAS  PubMed  Google Scholar 

  17. Chau, D. et al. Tamoxifen downregulates TGF-beta production in keloid fibroblasts. Ann. Plast. Surg. 40, 490–493 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Hu, D., Hughes, M.A. & Cherry, G.W. Topical tamoxifen–a potential therapeutic regime in treating excessive dermal scarring? Br. J. Plast. Surg. 51, 462–469 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Kumar, S. et al. cDNA cloning, expression analysis, and mapping of the mouse Nedd4 gene. Genomics 40, 435–443 (1997).

    Article  CAS  PubMed  Google Scholar 

  20. Wang, X. et al. NEDD4–1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell 128, 129–139 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Vecchione, A., Marchese, A., Henry, P., Rotin, D. & Morrione, A. The Grb10/Nedd4 complex regulates ligand-induced ubiquitination and stability of the insulin-like growth factor I receptor. Mol. Cell. Biol. 23, 3363–3372 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Morén, A., Imamura, T., Miyazono, K., Heldin, C.H. & Moustakas, A. Degradation of the tumor suppressor Smad4 by WW and HECT domain ubiquitin ligases. J. Biol. Chem. 280, 22115–22123 (2005).

    Article  PubMed  Google Scholar 

  23. Izzi, L. & Attisano, L. Ubiquitin-dependent regulation of TGFbeta signaling in cancer. Neoplasia 8, 677–688 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Izzi, L. & Attisano, L. Regulation of the TGFbeta signalling pathway by ubiquitin-mediated degradation. Oncogene 23, 2071–2078 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Bettinger, D.A., Yager, D.R., Diegelmann, R.F. & Cohen, I.K. The effect of TGF-beta on keloid fibroblast proliferation and collagen synthesis. Plast. Reconstr. Surg. 98, 827–833 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Nakamura, Y. The BioBank Japan project. Clin. Adv. Hematol. Oncol. 5, 696–697 (2007).

    PubMed  Google Scholar 

  27. Kelly, A.P. Update on the management of keloids. Semin. Cutan. Med. Surg. 28, 71–76 (2009).

    Article  CAS  PubMed  Google Scholar 

  28. Saito, A. & Kamatani, N. Strategies for genome-wide association studies: optimization of study designs by the stepwise focusing method. J. Hum. Genet. 47, 360–365 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Ohnishi, Y. et al. A high-throughput SNP typing system for genome-wide association studies. J. Hum. Genet. 46, 471–477 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. de Bakker, P.I. et al. Efficiency and power in genetic association studies. Nat. Genet. 37, 1217–1223 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We express our heartfelt gratitude to all the subjects who participated in this study and the members of the Rotary Club of Osaka-Midosuji District 2660 Rotary International in Japan for supporting our study. We would like to thank S.-K. Low for her assistance in the statistical analysis. We also thank the technical staff of the Laboratory for Genotyping Development in RIKEN. We would like to express our gratefulness to T. Tamamoto and K. Matsuda for their outstanding technical assistance. This work was conducted as a part of the BioBank Japan Project that was supported by the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government.

Author information

Authors and Affiliations

Authors

Contributions

Y.N. conceived the study. Y.N., H.Z., M.N., S.C. and M.K. designed the study. M.N., N.H. and M.K. performed the genotyping. M.N., A.T., N.K., T.K. and T.T. performed the data analyses. Y.N., H.Z. and M.K. managed DNA samples belonging to BioBank Japan. M.N. summarized the results. M.N., H.Z., M.K. and Y.N. wrote the manuscript. Y.N. obtained funding for the study.

Corresponding author

Correspondence to Yusuke Nakamura.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1 and 2 and Supplementary Figure 1 (PDF 361 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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 42, 768–771 (2010). https://doi.org/10.1038/ng.645

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.645

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing