Letter

Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC

Received:
Accepted:
Published online:

Abstract

We conducted a genome-wide association study of generalized vitiligo in the Chinese Han population by genotyping 1,117 cases and 1,429 controls. The 34 most promising SNPs were carried forward for replication in samples from individuals of the Chinese Han (5,910 cases and 9,916 controls) and Chinese Uygur (713 cases and 824 controls) populations. We identified two independent association signals within the major histocompatibility complex (MHC) region (rs11966200, Pcombined = 1.48 × 10−48, OR = 1.90; rs9468925, Pcombined = 2.21 × 10−33, OR = 0.74). Further analyses suggested that the strong association at rs11966200 might reflect the reported association of the HLA-A*3001, HLA-B*1302, HLA-C*0602 and HLA-DRB1*0701 alleles and that the association at rs9468925 might represent a previously unknown HLA susceptibility allele. We also identified one previously undescribed risk locus at 6q27 (rs2236313, Pcombined = 9.72 × 10−17, OR = 1.20), which contains three genes: RNASET2, FGFR1OP and CCR6. Our study provides new insights into the genetic basis of vitiligo.

  • Subscribe to Nature Genetics for full access:

    $59

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. 1.

    & Vitiligo (Blackwell Science, Oxford, UK, 2000).

  2. 2.

    , , , & Studies on vitiligo. I. Epidemiological profile in Calcutta, India. Genet. Epidemiol. 2, 71–78 (1985).

  3. 3.

    , & A Romanian population isolate with high frequency of vitiligo and associated autoimmune diseases. Arch. Dermatol. 144, 310–316 (2008).

  4. 4.

    & Clinical practice. Vitiligo. N. Engl. J. Med. 360, 160–169 (2009).

  5. 5.

    , , & Psychological reaction to chronic skin disorders: a study of patients with vitiligo. Gen. Hosp. Psychiatry 1, 73–77 (1979).

  6. 6.

    , , , & Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families. Pigment Cell Res. 16, 208–214 (2003).

  7. 7.

    & A review and a new hypothesis for non-immunological pathogenetic mechanisms in vitiligo. Pigment Cell Res. 19, 406–411 (2006).

  8. 8.

    The genetics of generalized vitiligo. Curr. Dir. Autoimmun. 10, 244–257 (2008).

  9. 9.

    et al. Characteristics of genetic epidemiology and genetic models for vitiligo. J. Am. Acad. Dermatol. 51, 383–390 (2004).

  10. 10.

    et al. Evidence for a susceptibility gene, SLEV1, on chromosome 17p13 in families with vitiligo-related systemic lupus erythematosus. Am. J. Hum. Genet. 69, 1401–1406 (2001).

  11. 11.

    et al. Mapping of an autoimmunity susceptibility locus (AIS1) to chromosome 1p31.3–p32.2. Hum. Mol. Genet. 11, 661–667 (2002).

  12. 12.

    , , & Novel vitiligo susceptibility loci on chromosomes 7 (AIS2) and 8 (AIS3), confirmation of SLEV1 on chromosome 17, and their roles in an autoimmune diathesis. Am. J. Hum. Genet. 74, 188–191 (2004).

  13. 13.

    et al. A novel linkage to generalized vitiligo on 4q13–q21 identified in a genomewide linkage analysis of Chinese families. Am. J. Hum. Genet. 76, 1057–1065 (2005).

  14. 14.

    et al. NALP1 in vitiligo-associated multiple autoimmune disease. N. Engl. J. Med. 356, 1216–1225 (2007).

  15. 15.

    et al. Genetic variation of promoter sequence modulates XBP1 expression and genetic risk for vitiligo. PLoS Genet. 5, e1000523 (2009).

  16. 16.

    , , & Genetic variations in NALP1 are associated with generalized vitiligo in a Romanian population. J. Invest. Dermatol. 127, 2558–2562 (2007).

  17. 17.

    et al. Linkage and association of HLA class II genes with vitiligo in a Dutch population. Br. J. Dermatol. 145, 90–94 (2001).

  18. 18.

    et al. Vitiligo: complex segregation and linkage disequilibrium analyses with respect to microsatellite loci spanning the HLA. Hum. Genet. 110, 334–342 (2002).

  19. 19.

    et al. Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo. N. Engl. J. Med. 362, 1686–1697 (2010).

  20. 20.

    et al. Association of vitiligo with HLA-A2: a meta-analysis. J. Eur. Acad. Dermatol. Venereol. 21, 205–213 (2007).

  21. 21.

    et al. Association of HLA class I alleles with vitiligo in Chinese Hans. J. Dermatol. Sci. 35, 165–168 (2004).

  22. 22.

    , , , & Association of HLA class I antigens and HLA class II alleles with vitiligo in a Turkish population. Pigment Cell Res. 17, 181–184 (2004).

  23. 23.

    et al. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat. Genet. 41, 1234–1237 (2009).

  24. 24.

    et al. Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21. Nat. Genet. 41, 205–210 (2009).

  25. 25.

    et al. Genomewide association study of leprosy. N. Engl. J. Med. 361, 2609–2618 (2009).

  26. 26.

    et al. Characterization of RNASET2, the first human member of the Rh/T2/S family of glycoproteins. Arch. Biochem. Biophys. 449, 17–26 (2006).

  27. 27.

    et al. Cloning and characterization of a senescence inducing and class II tumor suppressor gene in ovarian carcinoma at chromosome region 6q27. Oncogene 20, 980–988 (2001).

  28. 28.

    et al. RNASET2 as a tumor antagonizing gene in a melanoma cancer model. Oncol. Res. 17, 69–74 (2008).

  29. 29.

    & The RNase Rny1p cleaves tRNAs and promotes cell death during oxidative stress in Saccharomyces cerevisiae. J. Cell Biol. 185, 43–50 (2009).

  30. 30.

    et al. In vivo and in vitro evidence for hydrogen peroxide (H2O2) accumulation in the epidermis of patients with vitiligo and its successful removal by a UVB-activated pseudocatalase. J. Investig. Dermatol. Symp. Proc. 4, 91–96 (1999).

  31. 31.

    et al. Structure of the N-terminal domain of the FOP (FGFR1OP) protein and implications for its dimerization and centrosomal localization. J. Mol. Biol. 359, 863–875 (2006).

  32. 32.

    et al. The t(6;8)(q27;p11) translocation in a stem cell myeloproliferative disorder fuses a novel gene, FOP, to fibroblast growth factor receptor 1. Blood 93, 1381–1389 (1999).

  33. 33.

    et al. The centrosomal FOP protein is required for cell cycle progression and survival. Cell Cycle 8, 1217–1227 (2009).

  34. 34.

    , & The CC chemokine CCL20 and its receptor CCR6. Cytokine Growth Factor Rev. 14, 409–426 (2003).

  35. 35.

    et al. Dendritic cells rapidly recruited into epithelial tissues via CCR6/CCL20 are responsible for CD8+ T cell crosspriming in vivo. Immunity 24, 191–201 (2006).

  36. 36.

    , , & Genome-wide association study of generalized vitiligo in an isolated European founder population identifies SMOC2, in close proximity to IDDM8. J. Invest. Dermatol. 130, 798–803 (2010).

  37. 37.

    et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat. Genet. 40, 955–962 (2008).

  38. 38.

    et al. Identifying a common molecular mechanism for inhibition of MITF and STAT3 by PIAS3. Blood 107, 2839–2845 (2006).

  39. 39.

    et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436, 117–122 (2005).

  40. 40.

    et al. Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat. Genet. 41, 1335–1340 (2009).

  41. 41.

    et al. The analysis of genetics and associated autoimmune diseases in Chinese vitiligo patients. Arch. Dermatol. Res. 301, 167–173 (2009).

  42. 42.

    & The definition and assessment of vitiligo: a consensus report of the Vitiligo European Task Force. Pigment Cell Res. 20, 27–35 (2007).

  43. 43.

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

  44. 44.

    & Statistical aspects of the analysis of data from retrospective studies of disease. J. Natl. Cancer Inst. 22, 719–748 (1959).

  45. 45.

    , , & Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

  46. 46.

    et al. A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat. Genet. 38, 1166–1172 (2006).

  47. 47.

    & Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering. Am. J. Hum. Genet. 81, 1084–1097 (2007).

Download references

Acknowledgements

We thank all study participants. We also thank J.-J. Liu, J.-M. Chen and K. Seng Sim at the Genome Institute of Singapore for performing the imputation, association and LD analyses of HLA alleles. This study was supported in part by the Key Project of the Chinese National Natural Science Foundation (No. 30530670), the Cooperation Project of the Chinese Key National Natural Science Foundation for Overseas Youth (No. 30628021) and the Anhui Provincial Special Scientific Program (2007-7).

Author information

Author notes

    • Cheng Quan
    • , Yun-Qing Ren
    • , Lei-Hong Xiang
    •  & Liang-Dan Sun

    These authors contributed equally to this work.

Affiliations

  1. Department of Dermatology, No. 2 Hospital, Anhui Medical University, Hefei, Anhui, China.

    • Cheng Quan
    • , Yun-Qing Ren
    • , Liang-Dan Sun
    • , Youwen Zhou
    •  & Xue-Jun Zhang
  2. Institute of Dermatology and Department of Dermatology at No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China.

    • Cheng Quan
    • , Yun-Qing Ren
    • , Liang-Dan Sun
    • , Chao-Zhao Liang
    • , Jia-Bin Li
    • , Xian-Bo Zuo
    • , Sheng-Quan Zhang
    • , Shu-Mei Zhang
    • , Gang Chen
    • , Xiao-Dong Zheng
    • , Pan Li
    • , Jun Zhu
    • , Hui Cheng
    • , Pu-Ling Dong
    • , Da-Yan Hu
    • , Yang Li
    • , Min Li
    • , Xin Zhang
    • , Hua-Yang Tang
    • , Xian-Fa Tang
    • , Sheng-Xin Xu
    • , Su-Min He
    • , Yong-Mei Lv
    • , Cheng-Yao Zhu
    • , Qiang Xu
    • , Jin-Ping Gao
    • , Wen-Long Hu
    • , Cheng Ni
    • , Ting-Meng Pan
    • , Yun Li
    • , Sha Yao
    • , Cai-Feng He
    • , Yang-Sheng Liu
    • , Ze-Ying Yu
    • , Xian-Yong Yin
    • , Feng-Yu Zhang
    • , Sen Yang
    • , Youwen Zhou
    •  & Xue-Jun Zhang
  3. Department of Dermatology and Venereology, Anhui Medical University, Hefei, Anhui, China.

    • Cheng Quan
    • , Yun-Qing Ren
    • , Liang-Dan Sun
    • , Ai-E Xu
    • , Xiong-Ming Pu
    • , Chao-Zhao Liang
    • , Jia-Bin Li
    • , Xiu-Li Wang
    • , Rong-Ya Yang
    • , Xian-Bo Zuo
    • , Sheng-Quan Zhang
    • , Shu-Mei Zhang
    • , Gang Chen
    • , Xiao-Dong Zheng
    • , Pan Li
    • , Jun Zhu
    • , Yong-Wei Li
    • , Xiao-Dong Wei
    • , Wei-Song Hong
    • , Hui Cheng
    • , Pu-Ling Dong
    • , Da-Yan Hu
    • , Yang Li
    • , Min Li
    • , Xin Zhang
    • , Hua-Yang Tang
    • , Xian-Fa Tang
    • , Sheng-Xin Xu
    • , Su-Min He
    • , Yong-Mei Lv
    • , Xiao-Jing Kang
    • , Yu-Qin Liu
    • , Shao-Qiong Xie
    • , Cheng-Yao Zhu
    • , Qiang Xu
    • , Jin-Ping Gao
    • , Wen-Long Hu
    • , Cheng Ni
    • , Ting-Meng Pan
    • , Yun Li
    • , Sha Yao
    • , Cai-Feng He
    • , Yang-Sheng Liu
    • , Ze-Ying Yu
    • , Xian-Yong Yin
    • , Feng-Yu Zhang
    • , Sen Yang
    • , Youwen Zhou
    •  & Xue-Jun Zhang
  4. Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, Anhui, China.

    • Cheng Quan
    • , Yun-Qing Ren
    • , Liang-Dan Sun
    • , Chao-Zhao Liang
    • , Jia-Bin Li
    • , Xian-Bo Zuo
    • , Sheng-Quan Zhang
    • , Shu-Mei Zhang
    • , Gang Chen
    • , Xiao-Dong Zheng
    • , Pan Li
    • , Jun Zhu
    • , Hui Cheng
    • , Pu-Ling Dong
    • , Da-Yan Hu
    • , Yang Li
    • , Min Li
    • , Xin Zhang
    • , Hua-Yang Tang
    • , Xian-Fa Tang
    • , Sheng-Xin Xu
    • , Su-Min He
    • , Yong-Mei Lv
    • , Cheng-Yao Zhu
    • , Qiang Xu
    • , Jin-Ping Gao
    • , Wen-Long Hu
    • , Cheng Ni
    • , Ting-Meng Pan
    • , Yun Li
    • , Sha Yao
    • , Cai-Feng He
    • , Yang-Sheng Liu
    • , Ze-Ying Yu
    • , Xian-Yong Yin
    • , Feng-Yu Zhang
    • , Sen Yang
    • , Youwen Zhou
    •  & Xue-Jun Zhang
  5. Department of Dermatology, Huashan Hospital of Fudan University, Shanghai, China.

    • Lei-Hong Xiang
    • , Ying Ye
    • , Yong Zhang
    •  & Xue-Jun Zhang
  6. The Third People's Hospital of Hangzhou, Hangzhou, Zhejiang, China.

    • Ai-E Xu
    • , Yong-Wei Li
    • , Xiao-Dong Wei
    •  & Wei-Song Hong
  7. Department of Dermatology, No. 1 Hospital of China Medical University, Shenyang, Liaoning, China.

    • Xing-Hua Gao
    • , Hong-Duo Chen
    •  & Wei-Su Wu
  8. Department of Dermatology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumchi, Xinjiang, China.

    • Xiong-Ming Pu
    • , Xiao-Jing Kang
    •  & Yu-Qin Liu
  9. Department of Dermatology, the Affiliated Hospital of Inner Mongolia Medical College, Huhehot, Inner Mongolia, China.

    • Ri-Na Wu
    • , Li Sun
    •  & Zhi-Fang Liu
  10. Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.

    • Tian-Wen Gao
    •  & Kai Li
  11. Department of Dermatology, Peking University People's Hospital, Beijing, China.

    • Jian-Zhong Zhang
  12. Shanghai Skin Diseases and STD Hospital, Shanghai, China.

    • Xiu-Li Wang
    •  & Shao-Qiong Xie
  13. Department of Dermatology, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China.

    • Jun Wang
  14. Department of Dermatology, General Hospital of Beijing Military Command of PLA, Beijing, China.

    • Rong-Ya Yang
  15. Department of Dermatology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.

    • Ling Liang
  16. Department of Dermatology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.

    • Jian-Bin Yu
  17. Chinese National Human Genome Center at Shanghai, Shanghai, China.

    • Min Shen
    • , Hong-Quan Jiang
    •  & Ying Wang

Authors

  1. Search for Cheng Quan in:

  2. Search for Yun-Qing Ren in:

  3. Search for Lei-Hong Xiang in:

  4. Search for Liang-Dan Sun in:

  5. Search for Ai-E Xu in:

  6. Search for Xing-Hua Gao in:

  7. Search for Hong-Duo Chen in:

  8. Search for Xiong-Ming Pu in:

  9. Search for Ri-Na Wu in:

  10. Search for Chao-Zhao Liang in:

  11. Search for Jia-Bin Li in:

  12. Search for Tian-Wen Gao in:

  13. Search for Jian-Zhong Zhang in:

  14. Search for Xiu-Li Wang in:

  15. Search for Jun Wang in:

  16. Search for Rong-Ya Yang in:

  17. Search for Ling Liang in:

  18. Search for Jian-Bin Yu in:

  19. Search for Xian-Bo Zuo in:

  20. Search for Sheng-Quan Zhang in:

  21. Search for Shu-Mei Zhang in:

  22. Search for Gang Chen in:

  23. Search for Xiao-Dong Zheng in:

  24. Search for Pan Li in:

  25. Search for Jun Zhu in:

  26. Search for Yong-Wei Li in:

  27. Search for Xiao-Dong Wei in:

  28. Search for Wei-Song Hong in:

  29. Search for Ying Ye in:

  30. Search for Yong Zhang in:

  31. Search for Wei-Su Wu in:

  32. Search for Hui Cheng in:

  33. Search for Pu-Ling Dong in:

  34. Search for Da-Yan Hu in:

  35. Search for Yang Li in:

  36. Search for Min Li in:

  37. Search for Xin Zhang in:

  38. Search for Hua-Yang Tang in:

  39. Search for Xian-Fa Tang in:

  40. Search for Sheng-Xin Xu in:

  41. Search for Su-Min He in:

  42. Search for Yong-Mei Lv in:

  43. Search for Min Shen in:

  44. Search for Hong-Quan Jiang in:

  45. Search for Ying Wang in:

  46. Search for Kai Li in:

  47. Search for Xiao-Jing Kang in:

  48. Search for Yu-Qin Liu in:

  49. Search for Li Sun in:

  50. Search for Zhi-Fang Liu in:

  51. Search for Shao-Qiong Xie in:

  52. Search for Cheng-Yao Zhu in:

  53. Search for Qiang Xu in:

  54. Search for Jin-Ping Gao in:

  55. Search for Wen-Long Hu in:

  56. Search for Cheng Ni in:

  57. Search for Ting-Meng Pan in:

  58. Search for Yun Li in:

  59. Search for Sha Yao in:

  60. Search for Cai-Feng He in:

  61. Search for Yang-Sheng Liu in:

  62. Search for Ze-Ying Yu in:

  63. Search for Xian-Yong Yin in:

  64. Search for Feng-Yu Zhang in:

  65. Search for Sen Yang in:

  66. Search for Youwen Zhou in:

  67. Search for Xue-Jun Zhang in:

Contributions

X.-J.Z. conceived this study and obtained financial support; X.-J.Z., Y.Z. and S.Y. designed the study; C.Q., Y.-Q.R., L.-H.X. and L.-D.S. participated in the design and were responsible for sample selection, genotyping and project management; S.-M.Z., D.-Y.H., Yang Li, X.-F.T., S.-X.X., Y.-M.L., Q.X., J.-P.G., W.-L.H., C.N., T.-M.P., Yun Li, Y.-S.L. and Z.-Y.Y. conducted sample selection and managed data; A.-E.X., X.-H.G., H.-D.C., X.-M.P., R.-N.W., C.-Z.L., J.-B.L., T.-W.G., J.-Z.Z., X.-L.W., J.W., R.-Y.Y., L.L., J.-B.Y., Y.-W.L., X.-D.W., W.-S.H., Y.Y., Y.Z., W.-S.W., P.-L.D., K.L., X.-J.K., Y.-Q.L., L.S., Z.-F.L. and S.-Q.X. undertook recruitment, collected phenotype data, undertook related data handling and calculation and obtained biological samples; H.-Q.J., M.S., C.-Y.Z., Y.W., G.C., P.L., J.Z., H.C., M.L., X.Z., H.-Y.T., S.-M.H., S.Y. and C.-F.H. performed genotyping analyses; X.-B.Z., S.-Q.Z., X.-D.Z., X.-Y.Y. and F.-Y.Z. undertook data processing, statistical analysis and bioinformatics investigations; all the authors contributed to the final paper.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Youwen Zhou or Xue-Jun Zhang.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–3 and Supplementary Tables 1–4