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.

  • Original Article
  • Published:

Family-based association study of cytotoxic T-lymphocyte antigen-4 with susceptibility to Graves' disease in Han population of Taiwan

Genes & Immunity volume 9, pages 87–92 (2008)Cite this article

Abstract

Graves' disease (GD) is a common organ-specific autoimmune disorder inherited as a complex trait. Although there has not been consensus regarding the genuine susceptibility alleles, many population-based genetic studies showed association of the cytotoxic T-lymphocyte antigen-4 (CTLA4) gene with GD. In contrast, evidence utilizing family-based studies came only from the Caucasian population. Here we performed a family-based association study in the Han population in Taiwan. We enrolled 374 affected individuals and 347 unaffected family members in 151 GD pedigrees. Four single-nucleotide polymorphisms (SNP) and a short tandem repeat polymorphism (STRP) at CTLA4 were genotyped. Association of GD with a novel risk SNP at the 5′ upstream region, CTLA4_−1722_T/C (rs733618), was demonstrated (P=0.0096). We also replicated the association signal of a coding SNP, CTLA4_+49_G/A (rs231775, P=0.0219). A common haplotype composed of CTLA4_−1722_T/C and CTLA4_(AT)n (an STRP marker: UniSTS:48500) showed protective effect (P=0.0004). Our results of family-based association study, taken together with those from the Caucasian population, provide evidence that CTLA4 confers susceptibility to GD across different ethnic backgrounds.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Weetman AP . Graves’ disease. N Engl J Med 2000; 343: 1236–1248.

    Article  CAS  Google Scholar 

  2. Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf) 1977; 7: 481–493.

    Article  CAS  Google Scholar 

  3. Jacobson DL, Gange SJ, Rose NR, Graham NM . Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 1997; 84: 223–243.

    Article  CAS  Google Scholar 

  4. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988–1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002; 87: 489–499.

    Article  CAS  Google Scholar 

  5. DeGroot LJ, Quintans J . The causes of autoimmune thyroid disease. Endocr Rev 1989; 10: 537–562.

    Article  CAS  Google Scholar 

  6. Brix TH, Kyvik KO, Hegedus L . What is the evidence of genetic factors in the etiology of Graves’ disease? A brief review. Thyroid 1998; 8: 727–734.

    Article  CAS  Google Scholar 

  7. Vyse TJ, Todd JA . Genetic analysis of autoimmune disease. Cell 1996; 85: 311–318.

    Article  CAS  Google Scholar 

  8. Brix TH, Kyvik KO, Christensen K, Hegedus L . Evidence for a major role of heredity in Graves’ disease: a population-based study of two Danish twin cohorts. J Clin Endocrinol Metab 2001; 86: 930–934.

    CAS  PubMed  Google Scholar 

  9. Farid NR . Understanding the genetics of autoimmune thyroid disease—still an illusive goal! J Clin Endocrinol Metab 1992; 74: 495A–495B.

    Article  CAS  Google Scholar 

  10. Vaidya B, Kendall-Taylor P, Pearce SH . The genetics of autoimmune thyroid disease. J Clin Endocrinol Metab 2002; 87: 5385–5397.

    Article  CAS  Google Scholar 

  11. Rudd CE, Schneider H . Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nat Rev Immunol 2003; 3: 544–556.

    Article  CAS  Google Scholar 

  12. Tomer Y, Davies TF . Searching for the autoimmune thyroid disease susceptibility genes: from gene mapping to gene function. Endocr Rev 2003; 24: 694–717.

    Article  CAS  Google Scholar 

  13. Simmonds MJ, Gough SC . Unravelling the genetic complexity of autoimmune thyroid disease: HLA, CTLA-4 and beyond. Clin Exp Immunol 2004; 136: 1–10.

    Article  CAS  Google Scholar 

  14. Heward JM, Allahabadia A, Carr-Smith J, Daykin J, Cockram CS, Gordon C et al. No evidence for allelic association of a human CTLA-4 promoter polymorphism with autoimmune thyroid disease in either population-based case–control or family-based studies. Clin Endocrinol (Oxf) 1998; 49: 331–334.

    Article  CAS  Google Scholar 

  15. Djilali-Saiah I, Larger E, Harfouch-Hammoud E, Timsit J, Clerc J, Bertin E et al. No major role for the CTLA-4 gene in the association of autoimmune thyroid disease with IDDM. Diabetes 1998; 47: 125–127.

    Article  CAS  Google Scholar 

  16. Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 2003; 423: 506–511.

    Article  CAS  Google Scholar 

  17. Vaidya B, Imrie H, Perros P, Young ET, Kelly WF, Carr D et al. The cytotoxic T lymphocyte antigen-4 is a major Graves’ disease locus. Hum Mol Genet 1999; 8: 1195–1199.

    Article  CAS  Google Scholar 

  18. Heward JM, Allahabadia A, Armitage M, Hattersley A, Dodson PM, Macleod K et al. The development of Graves’ disease and the CTLA-4 gene on chromosome 2q33. J Clin Endocrinol Metab 1999; 84: 2398–2401.

    CAS  PubMed  Google Scholar 

  19. Freedman ML, Reich D, Penney KL, McDonald GJ, Mignault AA, Patterson N et al. Assessing the impact of population stratification on genetic association studies. Nat Genet 2004; 36: 388–393.

    Article  CAS  Google Scholar 

  20. Cardon LR, Palmer LJ . Population stratification and spurious allelic association. Lancet 2003; 361: 598–604.

    Article  Google Scholar 

  21. Schulze TG, McMahon FJ . Genetic association mapping at the crossroads: which test and why? Overview and practical guidelines. Am J Med Genet 2002; 114: 1–11.

    Article  Google Scholar 

  22. Clayton D . A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission. Am J Hum Genet 1999; 65: 1170–1177.

    Article  CAS  Google Scholar 

  23. Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    Article  CAS  Google Scholar 

  24. Ramirez-Soriano A, Lao O, Soldevila M, Calafell F, Bertranpetit J, Comas D . Haplotype tagging efficiency in worldwide populations in CTLA4 gene. Genes Immun 2005; 6: 646–657.

    Article  CAS  Google Scholar 

  25. Hudson LL, Rocca K, Song YW, Pandey JP . CTLA-4 gene polymorphisms in systemic lupus erythematosus: a highly significant association with a determinant in the promoter region. Hum Genet 2002; 111: 452–455.

    Article  CAS  Google Scholar 

  26. Fernandez-Blanco L, Perez-Pampin E, Gomez-Reino JJ, Gonzalez A . A CTLA-4 polymorphism associated with susceptibility to systemic lupus erythematosus. Arthritis Rheum 2004; 50: 328–329.

    Article  CAS  Google Scholar 

  27. Yanagawa T, Hidaka Y, Guimaraes V, Soliman M, DeGroot LJ . CTLA-4 gene polymorphism associated with Graves’ disease in a Caucasian population. J Clin Endocrinol Metab 1995; 80: 41–45.

    CAS  PubMed  Google Scholar 

  28. Kotsa K, Watson PF, Weetman AP . A CTLA-4 gene polymorphism is associated with both Graves disease and autoimmune hypothyroidism. Clin Endocrinol (Oxf) 1997; 46: 551–554.

    Article  CAS  Google Scholar 

  29. Chang YP, Liu X, Kim JD, Ikeda MA, Layton MR, Weder AB et al. Multiple genes for essential-hypertension susceptibility on chromosome 1q. Am J Hum Genet 2007; 80: 253–264.

    Article  CAS  Google Scholar 

  30. Consortium TIH . The International HapMap Project. Nature 2003; 426: 789–796.

    Article  Google Scholar 

  31. Chen PL, Fann CS, Chang CC, Wu IL, Chiu WY, Lin CY et al. Linkage of Graves’ disease to the human leucocyte antigen region in the Chinese-Han population in Taiwan. Clin Endocrinol (Oxf) 2007; 66: 646–651.

    Article  CAS  Google Scholar 

  32. Simmonds MJ, Howson JM, Heward JM, Cordell HJ, Foxall H, Carr-Smith J et al. Regression mapping of association between the human leukocyte antigen region and Graves disease. Am J Hum Genet 2005; 76: 157–163.

    Article  CAS  Google Scholar 

  33. Yang WS, Yang YC, Chen CL, Wu IL, Lu JY, Lu FH et al. Adiponectin SNP276 is associated with obesity, the metabolic syndrome, and diabetes in the elderly. Am J Clin Nutr 2007; 86: 509–513.

    Article  CAS  Google Scholar 

  34. O'Connell JR, Weeks DE . PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 1998; 63: 259–266.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank all the GD patients and their families who graciously agreed to participate in the study. This work was supported by grants NSC nos. 91-3112-B-002-003, 92-3112-B-002-009, 93-3112-B-002-015 and NSC 95-3112-B-002-026 from National Science Council, Taiwan. We also apologize to the authors whose work regarding this issue was not included in the references due to word count limitation.

Author information

Authors and Affiliations

  1. Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

    P-L Chen, I-L Wu, W-Y Chiu, W-S Yang & T-C Chang

  2. Program in Human Genetics, Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA

    P-L Chen

  3. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

    C S-J Fann, C-C Chang & C-Y Lin

  4. Institute of Public Health, National Yang-Ming University, Taipei, Taiwan

    C S-J Fann

  5. Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan

    W-S Yang

  6. Department of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan

    W-S Yang & T-C Chang

Authors
  1. P-L Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C S-J Fann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C-C Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. I-L Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. W-Y Chiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C-Y Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. W-S Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. T-C Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to W-S Yang or T-C Chang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, PL., Fann, CJ., Chang, CC. et al. Family-based association study of cytotoxic T-lymphocyte antigen-4 with susceptibility to Graves' disease in Han population of Taiwan. Genes Immun 9, 87–92 (2008). https://doi.org/10.1038/sj.gene.6364445

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6364445

Keywords

Search

Advanced search

Quick links