Linkage of Graves’ disease to the human leucocyte antigen region in the Chinese-Han population in Taiwan
Pei-Lung Chen
Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital,
Program in Human Genetics, Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA
Search for more papers by this authorCathy Shen-Jang Fann
Institute of Biomedical Sciences, Academia Sinica,
Institute of Public Health, National Yang-Ming University, Taipei, Taiwan, and
Search for more papers by this authorChien-Ching Chang
Institute of Biomedical Sciences, Academia Sinica,
Search for more papers by this authorI-Lin Wu
Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital,
Search for more papers by this authorWei-Yih Chiu
Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital,
Search for more papers by this authorWei-Shiung Yang
Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital,
Institute of Biomedical Sciences, Academia Sinica,
Graduate Institute of Clinical Medicine and
Department of Medicine, College of Medicine, National Taiwan University,
Search for more papers by this authorTien-Chun Chang
Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital,
Department of Medicine, College of Medicine, National Taiwan University,
Search for more papers by this authorPei-Lung Chen
Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital,
Program in Human Genetics, Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA
Search for more papers by this authorCathy Shen-Jang Fann
Institute of Biomedical Sciences, Academia Sinica,
Institute of Public Health, National Yang-Ming University, Taipei, Taiwan, and
Search for more papers by this authorChien-Ching Chang
Institute of Biomedical Sciences, Academia Sinica,
Search for more papers by this authorI-Lin Wu
Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital,
Search for more papers by this authorWei-Yih Chiu
Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital,
Search for more papers by this authorWei-Shiung Yang
Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital,
Institute of Biomedical Sciences, Academia Sinica,
Graduate Institute of Clinical Medicine and
Department of Medicine, College of Medicine, National Taiwan University,
Search for more papers by this authorTien-Chun Chang
Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital,
Department of Medicine, College of Medicine, National Taiwan University,
Search for more papers by this authorSummary
Objective To investigate whether markers in the candidate chromosome regions, including the human leucocyte antigen (HLA) region, are linked to Graves’ disease (GD).
Design A familial linkage study with a candidate region approach.
Patients A total of 536 individuals in 122 multiplex Chinese-Han families with a GD proband and at least one other affected sibling, resulting in 270 affected sib-pairs. Subjects with a family history of noniatrogenic hypothyroidism or Hashimoto's thyroiditis were excluded.
Measurements We genotyped eight short tandem repeat polymorphism (STRP) markers in a 13·7 cM region covering the HLA region on chromosome 6p21 and 26 STRPs in four other candidate regions previously reported in the literature.
Results Multipoint nonparametric linkage (NPL) analysis showed significant linkage to the HLA region [the marker UniSTS:239159, nonparametric log of odds (LOD) score 3·44, P = 0·00003; NPL Z-score 4·1, P = 0·00002] from 270 affected sib-pairs. The 1-LOD support interval comprised the whole HLA region (ca. 4 Mb). By contrast, the maximal NPL Z-scores of the markers of the other candidate regions (2q33, 5q31, 7q22 and 14q31) previously reported were all less than 1·0.
Conclusions Our results provide strong support for linkage of GD to the HLA region. Further dissection of this region to identify the candidate gene for GD is warranted in our population.
References
- 1 Weetman, A.P. (2000) Graves’ disease. New England Journal of Medicine, 343, 1236–1248.
- 2 Hollowell, J.G., Staehling, N.W., Flanders, W.D., Hannon, W.H., Gunter, E.W., Spencer, C.A. & Braverman, L.E. (2002) Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). Journal of Clinical Endocrinology and Metabolism, 87, 489–499.
- 3 DeGroot, L.J. & Quintans, J. (1989) The causes of autoimmune thyroid disease. Endocrine Reviews, 10, 537–562.
- 4 Brix, T.H., Kyvik, K.O. & Hegedus, L. (1998) What is the evidence of genetic factors in the etiology of Graves’ disease? A brief review. Thyroid, 8, 727–734.
- 5 Vyse, T.J. & Todd, J.A. (1996) Genetic analysis of autoimmune disease. Cell, 85, 311–318.
- 6 Brix, T.H., Kyvik, K.O., Christensen, K. & Hegedus, L. (2001) Evidence for a major role of heredity in Graves’ disease: a population-based study of two Danish twin cohorts. Journal of Clinical Endocrinology and Metabolism, 86, 930–934.
- 7 Vaidya, B., Kendall-Taylor, P. & Pearce, S.H. (2002) The genetics of autoimmune thyroid disease. Journal of Clinical Endocrinology and Metabolism, 87, 5385–5397.
- 8 Tomer, Y. & Davies, T.F. (2003) Searching for the autoimmune thyroid disease susceptibility genes: from gene mapping to gene function. Endocrine Reviews, 24, 694–717.
- 9 Ayadi, H., Hadj Kacem, H., Rebai, A. & Farid, N.R. (2004) The genetics of autoimmune thyroid disease. Trends in Endocrinology and Metabolism, 15, 234–239.
- 10 Velaga, M.R., Wilson, V., Jennings, C.E., Owen, C.J., Herington, S., Donaldson, P.T., Ball, S.G., James, R.A., Quinton, R., Perros, P. & Pearce, S.H. (2004) The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves’ disease. Journal of Clinical Endocrinology and Metabolism, 89, 5862–5865.
- 11 Yanagawa, T., Mangklabruks, A., Chang, Y.B., Okamoto, Y., Fisfalen, M.E., Curran, P.G. & DeGroot, L.J. (1993) Human histocompatibility leukocyte antigen-DQA1*0501 allele associated with genetic susceptibility to Graves’ disease in a Caucasian population. Journal of Clinical Endocrinology and Metabolism, 76, 1569–1574.
- 12 Badenhoop, K., Walfish, P.G., Rau, H., Fischer, S., Nicolay, A., Bogner, U., Schleusener, H. & Usadel, K.H. (1995) Susceptibility and resistance alleles of human leukocyte antigen (HLA) DQA1 and HLA DQB1 are shared in endocrine autoimmune disease. Journal of Clinical Endocrinology and Metabolism, 80, 2112–2117.
- 13 Heward, J.M., Allahabadia, A., Daykin, J., Carr-Smith, J., Daly, A., Armitage, M., Dodson, P.M., Sheppard, M.C., Barnett, A.H., Franklyn, J.A. & Gough, S.C. (1998) Linkage disequilibrium between the human leukocyte antigen class II region of the major histocompatibility complex and Graves’ disease: replication using a population case control and family-based study. Journal of Clinical Endocrinology and Metabolism, 83, 3394–3397.
- 14 Huang, S.M., Wu, T.J., Lee, T.D., Yang, E.K., Shaw, C.K. & Yeh, C.C. (2003) The association of HLA-A, -B, and -DRB1 genotypes with Graves’ disease in Taiwanese people. Tissue Antigens, 61, 154–158.
- 15 Yeo, P.P., Chan, S.H., Thai, A.C., Ng, W.Y., Lui, K.F., Wee, G.B., Tan, S.H., Lee, B.W., Wong, H.B. & Cheah, J.S. (1989) HLA Bw46 and DR9 associations in Graves’ disease of Chinese patients are age- and sex-related. Tissue Antigens, 34, 179–184.
- 16 Onuma, H., Ota, M., Sugenoya, A. & Inoko, H. (1994) Association of HLA-DPB1*0501 with early-onset Graves’ disease in Japanese. Human Immunology, 39, 195–201.
- 17 Cho, B.Y., Rhee, B.D., Lee, D.S., Lee, M.S., Kim, G.Y., Lee, H.K., Koh, C.S., Min, H.K. & Lee, M. (1987) HLA and Graves’ disease in Koreans. Tissue Antigens, 30, 119–121.
- 18 Wongsurawat, T., Nakkuntod, J., Charoenwongse, P., Snabboon, T., Sridama, V. & Hirankarn, N. (2006) The association between HLA class II haplotype with Graves’ disease in Thai population. Tissue Antigens, 67, 79–83.
- 19 Simmonds, M.J., Howson, J.M., Heward, J.M., Cordell, H.J., Foxall, H., Carr-Smith, J., Gibson, S.M., Walker, N., Tomer, Y., Franklyn, J.A., Todd, J.A. & Gough, S.C. (2005) Regression mapping of association between the human leukocyte antigen region and Graves’ disease. American Journal of Human Genetics, 76, 157–163.
- 20 Vaidya, B., Imrie, H., Perros, P., Young, E.T., Kelly, W.F., Carr, D., Large, D.M., Toft, A.D., McCarthy, M.I., Kendall-Taylor, P. & Pearce, S.H. (1999) The cytotoxic T lymphocyte antigen-4 is a major Graves’ disease locus. Human Molecular Genetics, 8, 1195–1199.
- 21 Tomer, Y., Barbesino, G., Greenberg, D.A., Concepcion, E. & Davies, T.F. (1999) Mapping the major susceptibility loci for familial Graves’ and Hashimoto's diseases: evidence for genetic heterogeneity and gene interactions. Journal of Clinical Endocrinology and Metabolism, 84, 4656–4664.
- 22 Sakai, K., Shirasawa, S., Ishikawa, N., Ito, K., Tamai, H., Kuma, K., Akamizu, T., Tanimura, M., Furugaki, K., Yamamoto, K. & Sasazuki, T. (2001) Identification of susceptibility loci for autoimmune thyroid disease to 5q31-q33 and Hashimoto's thyroiditis to 8q23-q24 by multipoint affected sib-pair linkage analysis in Japanese. Human Molecular Genetics, 10, 1379–1386.
- 23 Maalej, A., Makni, H., Ayadi, F., Bellassoued, M., Jouida, J., Bouguacha, N., Abid, M. & Ayadi, H. (2001) A full genome screening in a large Tunisian family affected with thyroid autoimmune disorders. Genes and Immunity, 2, 71–75.
- 24 Jin, Y., Teng, W., Ben, S., Xiong, X., Zhang, J., Xu, S., Shugart, Y.Y., Jin, L., Chen, J. & Huang, W. (2003) Genome-wide scan of Graves’ disease: evidence for linkage on chromosome 5q31 in Chinese Han pedigrees. Journal of Clinical Endocrinology and Metabolism, 88, 1798–1803.
- 25 Tomer, Y., Ban, Y., Concepcion, E., Barbesino, G., Villanueva, R., Greenberg, D.A. & Davies, T.F. (2003) Common and unique susceptibility loci in Graves and Hashimoto diseases: results of whole-genome screening in a data set of 102 multiplex families. American Journal of Human Genetics, 73, 736–747.
- 26 Taylor, J.C., Gough, S.C., Hunt, P.J., Brix, T.H., Chatterjee, K., Connell, J.M., Franklyn, J.A., Hegedus, L., Robinson, B.G., Wiersinga, W.M., Wass, J.A., Zabaneh, D., Mackay, I. & Weetman, A.P. (2006) A genome-wide screen in 1119 relative pairs with autoimmune thyroid disease. Journal of Clinical Endocrinology and Metabolism, 91, 646–653.
- 27 Yang, H.C., Lin, C.H., Hsu, C.L., Hung, S.I., Wu, J.Y., Pan, W.H., Chen, Y.T. & Fann, C.S. (2006) A comparison of major histocompatibility complex SNPs in Han Chinese residing in Taiwan and Caucasians. Journal of Biomedical Sciences, 13, 489–498.
- 28 Cao, K., Hollenbach, J., Shi, X., Shi, W., Chopek, M. & Fernandez-Vina, M.A. (2001) Analysis of the frequencies of HLA-A, B, and C alleles and haplotypes in the five major ethnic groups of the United States reveals high levels of diversity in these loci and contrasting distribution patterns in these populations. Human Immunology, 62, 1009–1030.
- 29 Dean, M., Stephens, J.C., Winkler, C., Lomb, D.A., Ramsburg, M., Boaze, R., Stewart, C., Charbonneau, L., Goldman, D. & Albaugh, B.J. (1994) Polymorphic admixture typing in human ethnic populations. American Journal of Human Genetics, 55, 788–808.
- 30 Cao, K., Moormann, A.M., Lyke, K.E., Masaberg, C., Sumba, O.P., Doumbo, O.K., Koech, D., Lancaster, A., Nelson, M., Meyer, D., Single, R., Hartzman, R.J., Plowe, C.V., Kazura, J., Mann, D.L., Sztein, M.B., Thomson, G. & Fernandez-Vina, M.A. (2004) Differentiation between African populations is evidenced by the diversity of alleles and haplotypes of HLA class I loci. Tissue Antigens, 63, 293–325.
- 31 Ghodke, Y., Joshi, K., Chopra, A. & Patwardhan, B. (2005) HLA and disease. European Journal of Epidemiology, 20, 475–488.
- 32 Hadj Kacem, H., Rebai, A., Kaffel, N., Masmoudi, S., Abid, M. & Ayadi, H. (2003) PDS is a new susceptibility gene to autoimmune thyroid diseases: association and linkage study. Journal of Clinical Endocrinology and Metabolism, 88, 2274–2280.
- 33 O’Connell, J.R. & Weeks, D.E. (1998) PedCheck: a program for identification of genotype incompatibilities in linkage analysis. American Journal of Human Genetics, 63, 259–266.
- 34 Abecasis, G.R., Cherny, S.S., Cookson, W.O. & Cardon, L.R. (2002) Merlin – rapid analysis of dense genetic maps using sparse gene flow trees. Nature Genetics, 30, 97–101.
- 35 Kruglyak, L., Daly, M.J., Reeve-Daly, M.P. & Lander, E.S. (1996) Parametric and nonparametric linkage analysis: a unified multipoint approach. American Journal of Human Genetics, 58, 1347–1363.
- 36 Kong, A. & Cox, N.J. (1997) Allele-sharing models: LOD scores and accurate linkage tests. American Journal of Human Genetics, 61, 1179–1188.
- 37 Whittemore, A.S. & Halpern, J. (1994) A class of tests for linkage using affected pedigree members. Biometrics, 50, 118–127.
- 38 Cardon, L.R. & Bell, J.I. (2001) Association study designs for complex diseases. Nature Review Genetics, 2, 91–99.
- 39 Glazier, A.M., Nadeau, J.H. & Aitman, T.J. (2002) Finding genes that underlie complex traits. Science, 298, 2345–2349.
- 40 Armengol, M.P., Juan, M., Lucas-Martin, A., Fernandez-Figueras, M.T., Jaraquemada, D., Gallart, T. & Pujol-Borrell, R. (2001) Thyroid autoimmune disease: demonstration of thyroid antigen-specific B cells and recombination-activating gene expression in chemokine-containing active intrathyroidal germinal centers. American Journal of Pathology, 159, 861–873.
- 41 Lorini, R., Gastaldi, R., Traggiai, C. & Perucchin, P.P. (2003) Hashimoto's thyroiditis. Pediatric Endocrinology Reviews, 1 (Suppl. 2), 205–211.
- 42 Weetman, A.P. (2004) Autoimmune thyroid disease. Autoimmunity, 37, 337–340.
- 43 Miretti, M.M., Walsh, E.C., Ke, X., Delgado, M., Griffiths, M., Hunt, S., Morrison, J., Whittaker, P., Lander, E.S., Cardon, L.R., Bentley, D.R., Rioux, J.D., Beck, S. & Deloukas, P. (2005) A high-resolution linkage-disequilibrium map of the human major histocompatibility complex and first generation of tag single-nucleotide polymorphisms. American Journal of Human Genetics, 76, 634–646.
- 44 Simmonds, M.J. & Gough, S.C. (2004) Unravelling the genetic complexity of autoimmune thyroid disease: HLA, CTLA-4 and beyond. Clinical and Experimental Immunology, 136, 1–10.
- 45 Park, M.H., Park, Y.J., Song, E.Y., Park, H., Kim, T.Y., Park, D.J., Park, K.S. & Cho, B.Y. (2005) Association of HLA-DR and -DQ genes with Graves’ disease in Koreans. Human Immunology, 66, 741–747.
- 46 Risch, N.J. (2000) Searching for genetic determinants in the new millennium. Nature, 405, 847–856.
- 47 Wang, W.Y., Barratt, B.J., Clayton, D.G. & Todd, J.A. (2005) Genome-wide association studies: theoretical and practical concerns. Nature Review Genetics, 6, 109–118.
- 48 Altmuller, J., Palmer, L.J., Fischer, G., Scherb, H. & Wjst, M. (2001) Genomewide scans of complex human diseases: true linkage is hard to find. American Journal of Human Genetics, 69, 936–950.
Citing Literature
