Human Molecular Genetics, 2001, Vol. 10, No. 13 1379-1386
© 2001 Oxford University Press
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
1Department of Immunobiology and Neuroscience, Division of Immunogenetics, Medical Institute of Bioregulation, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan, 2Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Japan, 3Ito Hospital, Tokyo 150-0001, Japan, 4Kuma Hospital, Kobe 650-0011, Japan, 5Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan, 6Department of Child Ecology, National Children’s Medical Research Center, Tokyo 154-0004, Japan and 7Research Institute, International Medical Center of Japan, Tokyo 162-8655, Japan
Received February 22, 2001; Revised and Accepted April 25, 2001.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIAL AND METHODSREFERENCES |
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Autoimmune thyroid disease (AITD), including Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), is caused by multiple genetic and environmental factors. The clinical and immunological features of GD and HT are distinct; however, there are multiplex families with both GD and HT, and cases in which GD evolves into HT. Thus, there may be specific susceptibility loci for GD or HT, and common loci controlling the susceptibility to both GD and HT may exist. A genome-wide analysis of data on 123 Japanese sib-pairs affected with AITD was made in which GD- or HT-affected sib-pairs (ASPs) were studied to detect GD- or HT-specific susceptibility loci, and all AITD-ASPs were used to detect AITD-common susceptibility loci. Our study revealed 19 regions on 14 chromosomes (1, 2, 3, 5, 6, 8, 9, 10, 11, 12, 13, 15, 18 and 22) where the multipoint maximum LOD score (MLS) was >1. Especially, chromosome 5q31–q33 yielded suggestive evidence for linkage to AITD as a whole, with an MLS of 3.14 at D5S436, and chromosome 8q23–q24 yielded suggestive evidence for linkage to HT, with an MLS of 3.77 at D8S272. These observations suggest the presence of an AITD susceptibility locus at 5q31–q33 and a HT susceptibility locus at 8q23–q24.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIAL AND METHODSREFERENCES |
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Autoimmune thyroid disease (AITD), including Graves’ disease and Hashimoto’s thyroiditis (HT), is caused by immune responses related to the thyroid gland. Twin studies and familial aggregation showed that AITD is a complex disease with genetic factors (1,2). Furthermore, GD and HT cluster in a family (3), in identical twins and triplets (4), and those in whom GD evolved into HT (5); thus, there may exist common susceptibility loci shared by GD and HT. On the other hand, there are clear differences in the clinical and immunological features between GD and HT, and statistical association of specific human leukocyte antigen (HLA) alleles with GD and HT (6–8), respectively; hence specific susceptibility loci for GD or HT may exist.
Several susceptibility loci, including GD-1 (14q31), GD-2 (20q11.2) and GD-3 (Xq21) for GD; AITD-1 (6p) for AITD; and HT-1 (13q32) and HT-2 (12q22) for HT, were noted in a linkage analysis using multiplex families (9–14). Non-parametric linkage analysis using affected sib-pairs (ASPs) showed evidence for linkage of HLA, the cytotoxic T lymphocyte-associated-4 (CTLA-4) and IDDM6 to GD (15,16). In addition, significant associations were noted between AITD and specific HLA alleles (6–8,17–19), and between AITD and CTLA-4 gene polymorphism (20–28).
Here, we carried out a genome-wide screening using 392 microsatellite markers, HLA and CTLA-4 genes. We used the non-parametric sib-pair method in 123 Japanese sib-pairs affected with AITD to identify the possible susceptibility loci for AITD.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIAL AND METHODSREFERENCES |
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ASP linkage analysis
Whole genome linkage analysis using the ASP method with 392 microsatellite markers was carried out on 123 ASPs with AITD, including 67 GD-ASPs, 25 HT-ASPs and 31 GD-HT mixed families’ ASPs (Table 1). Multipoint linkage analysis on AITD-ASPs as a whole, GD-ASPs and HT-ASPs at all chromosomes using the MAPMAKER/SIBS program revealed 19 regions on 14 chromosomes (1, 2, 3, 5, 6, 8, 9, 10, 11, 12, 13, 15, 18 and 22) where the maximum LOD score (MLS) was >1, and nine other chromosomes (4, 7, 14, 16, 17, 19, 20, 21 and X) which did not have the region where the MLS was >1 (Table 2; Fig. 1).
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The highest MLS for AITD was 3.14 at D5S436 on chromosome 5. The MLSs at D5S436 for GD, HT and GD-HT mixed ASPs were 1.48, 0.42 and 0.90, respectively. These findings suggest that D5S436 will be closely linked to a common susceptibility locus for GD and HT. Figure 2A and B show a multipoint LOD score map of AITD, GD and HT and the allele sharing proportion corrected by MAPMAKER/SIBS for AITD on chromosome 5, respectively. As shown in Table 2, besides D5S436, there were eight regions (D5S407, D6S462, D8S272, D11S905, D12S336, D13S159, D18S487 and D22S423) where the MLS was >1 in AITD-ASPs.
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The highest MLS for HT was 3.77 at D8S272 on chromosome 8. The MLSs at D8S272 for AITD and GD were 2.31 and 1.13, respectively (Table 2). Figure 3A and B show a multipoint LOD score map of AITD, GD and HT, and the allele sharing proportion of HT-ASPs on chromosome 8, respectively. These results provide suggestive evidence for linkage of D8S272 specifically to HT, although a possible linkage of this marker with GD should not be ignored. On the other hand, in the case of GD-ASPs, none of the markers examined showed an MLS >2, and the highest MLS was 1.48 at chromosome 15 (D15S1007) (Table 2). The MLSs at this marker for AITD and HT were 0.65 and 0.02, respectively.
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To examine the relation between the population we analyzed and the loci reported to be linked to these diseases, the markers, including HLA-DPB1, CTLA-4[AT]n, D18S487 (IDDM6) (15,16), D6S257 (AITD-1), D12S351 (HT-2), D13S173 (HT-1), D14S81 (GD-1), D20S195 (GD-2) and DXS8020 (GD-3) (9–14), were used to examine linkage with the diseases. The MLS for AITD at the marker D18S487 near IDDM6 was 1.12, supporting the susceptibility locus in a previous report (16); however, all other markers showed an MLS <1 (Table 3).
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Association of HLA and CTLA-4 with AITD
Association analyses of HLA-DPB1*0501 and HLA-DRB4*0101 with AITD, which we previously reported to be associated with GD (7) and HT (8), respectively, are summarized in Table 4. A statistically significant increase in the frequency of HLA-DPB1*0501 was shown in 113 unrelated AITD patients [P value = 0.00003, odds ratio (OR) = 3.1] and 78 unrelated GD patients (P value = 0.00004, OR = 3.8). The significant increase in the frequency of HLA-DRB4*0101 was observed in AITD (P value = 0.00099, OR = 2.6), GD (P value = 0.0081, OR = 2.2), and HT patients (P value = 0.024, OR = 2.8). These results support data in our previous studies, and would validate the population analyzed in this study.
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The frequency of the 106 bp allele of CTLA-4[AT]n in the present study was 36.0% in 111 AITD patients, 40.8% in 76 GD patients, 25.7% in 35 HT patients and 31.7% in 218 controls, which suggests a weak association of the 106 bp allele of CTLA-4[AT]n with GD (P = 0.041), but not with AITD and HT. The G allele and the genotype of GG of the A/G polymorphism in exon 1 of the CTLA-4 gene were also reported to be associated with GD (21,22,27), HT (23) and AITD (26). We found no significant association of AITD, GD and HT with the G allele and the genotype of GG (data not shown).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIAL AND METHODSREFERENCES |
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ASP analysis using 392 microsatellite markers in 123 Japanese AITD-ASPs showed an MLS >3 at 5q31–q33 on AITD-ASPs, which means that a susceptibility gene for AITD may exist around this region. A cytokine gene cluster, including IL-3, IL-4, IL-5, IL-9, IL-13 and a granulocyte-macrophage colony-stimulating factor were mapped within 5q31–q33, a region reported to be linked to allergic diseases such as asthma and atopic dermatitis (29–31). AITD is characterized by an abnormality in immune regulation, hence a disturbed cytokine secretion may be involved in the pathogenesis of AITD. Serum levels of IL-5 secreted from Th2 cells were found to be increased in thyrotoxic patients with GD (32). Thus the possible linkage of 5q31–q33 to AITD provides the basis for further investigation of these cytokine genes in AITD; however, it is also important to explore other unknown genes in this region.
The MLS at D8S272 for HT exceeded 3. The frequency of the pairs sharing two alleles in HT-ASPs was extremely high (Z2 = 0.724, Z1 = 0.189, Z0 = 0.087) at D8S272 (Fig. 2). It is interesting to note that the thyroglobulin gene is mapped close to D8S272 since HT is characterized by increased serum levels of the anti-thyroglobulin antibody. Polymorphisms of the thyroglobulin gene were noted in patients with congenital goiter and were suggested to cause defective thyroglobulin synthesis (33,34). Although there are pathologic differences between HT and congenital goiter, polymorphisms of the thyroglobulin gene might vary functions of thyroglobulin, contributing to the susceptibility to HT. As there seem to be several genes in the 8q23–q24 region apart from the thyroglobulin gene (35), we should examine not only the thyroglobulin gene but also other known and unknown genes in this candidate region.
Among the nine regions reported to be linked to AITD in Caucasians, only D18S487 showed an MLS >1 (MLS = 1.12). The MLSs at D18S487 for GD and HT were 0.82 and 0.53, respectively (Table 3). Therefore, D18S487 may be a common susceptibility locus for GD and HT. This region was found to be linked to other autoimmune diseases, such as type 1 diabetes (36–38), rheumatoid arthritis (39) and systemic lupus erythematosus (40), thereby suggesting that this region may include a common susceptibility gene for these autoimmune diseases.
Other suggested susceptibility loci for AITD, HLA (6p21.3), CTLA-4 (2q33) (15), GD-1 (14q31), GD-2 (20q11.2), GD-3 (Xq21), AITD-1 (6p), HT-1 (13q32) and HT-2 (12q22) (9–14) did not show an MLS >1. This discrepancy may be explained by the following reasons. (i) The ethnic difference between subjects used in our study and previous studies. (ii) The difference in ascertainment of the families analyzed. The analyses in previous whole genome studies were done in order to detect HT (or GD) susceptibility loci, based on the assumption that GD (or HT) patients were unaffected in GD-HT mixed families. In our study, GD-HT mixed ASPs including both GD and HT were excluded, and analyses were made on HT-HT ASPs or GD-GD ASPs to detect HT- or GD-specific loci. (iii) A weak statistical power of the current study may also be responsible.
Our first attempt of the whole genome analysis of Japanese AITD demonstrated a suggestive linkage of 5q31–q33 to AITD and 8q23–q24 to HT. These data will need to be confirmed in larger numbers of patients and in additional ethnic populations.
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MATERIAL AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIAL AND METHODSREFERENCES |
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Families
A total of 236 Japanese members affected with AITD in 113 families (61 from Ito Hospital, 26 from Kuma Hospital and 26 from Kyoto University Hospital) were genotyped. Each participant was interviewed and examined and gave written informed consent before participating in this study. There were 67 GD-ASPs, 25 HT-ASPs and 31 GD-HT mixed ASPs (Table 1). Of the 236 affected individuals, 200 were women and 36 were men. Diagnosis of thyroid disease was established based on clinical findings and results of routine examinations; circulating thyroid hormone and thyroid stimulating hormone (TSH) concentrations, serum levels of antibodies against thyroglobulin, thyroid microsomes and TSH receptors, ultrasonography, [99m]TCO4– (or [123I]) uptake and thyroid scintigraphy.
Genotyping
DNA was isolated from peripheral blood cells using QIAamp DNA Blood Midi Kits (Qiagen). In addition to ABI PRISM Linkage Mapping Set Version 2, we genotyped microsatellite markers around loci reported to be linked to AITD, CTLA-4[AT]n (20), D14S81, D18S487, D20S118 and DXS8020 given on the Genethon genetic linkage map. PCR was performed using the GeneAmp PCR System 9700 with standard protocols. Genotyping of 392 microsatellite markers, 
9.0 cM apart, was performed using an ABI 377 automatic sequencer (Applied Biosystems). Analyses and assignment of the marker alleles were done with GENESCAN and GENOTYPER (ABI) software.
HLA class II were genotyped using a PCR-sequence-specific-oligonucleotide probe (SSOP) method. Genomic DNA was amplified for the second exon of the DPB1 gene and the second exon of the DRB gene. PCR and hybridization procedures with SSOPs have been described previously (7,8).
The CTLA-4A/G polymorphism in exon 1 of the CTLA-4 gene was amplified using primers 5'-CCA CGG CTT CCT TTC TCG TA-3' and 5'-AGT CTC ACT CAC CTT TGC AG-3', and the restriction fragment length polymorphism analysis was performed on 4 µl of PCR products, digested with 2.5 U of Bst71I (Promega) in a final volume of 20 µl under appropriate buffer conditions at 50°C for 3 h (15,24). DNA fragments were resolved in 1.5% agarose gels stained with ethidium bromide.
Linkage and association analysis
Multipoint analysis for LOD score was carried out on weighted all pairs, using the MAPMAKER/SIBS program (41). Allele frequencies were estimated using data from unrelated individuals.
Association analyses between controls and patients were carried out using a contingency 2 x 2 table to calculate an OR and 
2. 113 AITD probands were analyzed, including 78 GD and 35 HT probands. As a control population, 317 healthy unrelated Japanese persons (7,8) were studied in the HLA association analysis, and 279 unrelated controls were studied in the CTLA-4 association analysis.
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ACKNOWLEDGEMENTS |
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We thank all patients and family members for participating in this study, I. Inoue and K. Ikari for comments, and T. Tokuyasu, M. Nishioka, M. Sonoda, K. Fukuyama and M. Obo for technical assistance. M. Ohara provided language assistance. This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas (C) ‘Medical Genome Science’ from the Ministry of Education, Science, Technology, Sports and Culture of Japan, a Grant-in-Aid for Scientific Research (A) from the Japan Society for the Promotion of Science and a Research Grant on Human Genome and Gene Therapy from the Ministry of Health and Welfare, Japan, and the Japan Science and Technology Corporation.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +81 92 642 6828; Fax: +81 92 632 0150; Email: sasazuki@bioreg.kyushu-u.ac.jp
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J. C. Taylor, S. C. Gough, P. J. Hunt, T. H. Brix, K. Chatterjee, J. M. Connell, J. A. Franklyn, L. Hegedus, B. G. Robinson, W. M. Wiersinga, et al. A Genome-Wide Screen in 1119 Relative Pairs with Autoimmune Thyroid Disease J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 646 - 653. [Abstract] [Full Text] [PDF]
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B. Golden, L. Levin, Y. Ban, E. Concepcion, D. A. Greenberg, and Y. Tomer Genetic Analysis of Families with Autoimmune Diabetes and Thyroiditis: Evidence for Common and Unique Genes J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4904 - 4911. [Abstract] [Full Text] [PDF]
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Y. Hiromatsu, T. Fukutani, M. Ichimura, T. Mukai, H. Kaku, H. Nakayama, I. Miyake, S. Shoji, Y. Koda, and T. Bednarczuk Interleukin-13 Gene Polymorphisms Confer the Susceptibility of Japanese Populations to Graves' Disease J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 296 - 301. [Abstract] [Full Text] [PDF]
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R. M. Belin, B. C. Astor, N. R. Powe, and P. W. Ladenson Smoke Exposure Is Associated with a Lower Prevalence of Serum Thyroid Autoantibodies and Thyrotropin Concentration Elevation and a Higher Prevalence of Mild Thyrotropin Concentration Suppression in the Third National Health and Nutrition Examination Survey (NHANES III) J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6077 - 6086. [Abstract] [Full Text] [PDF]
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J. E. Collins, J. M. Heward, J. M. M. Howson, H. Foxall, J. Carr-Smith, J. A. Franklyn, and S. C. L. Gough Common Allelic Variants of Exons 10, 12, and 33 of the Thyroglobulin Gene Are Not Associated with Autoimmune Thyroid Disease in the United Kingdom J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6336 - 6339. [Abstract] [Full Text] [PDF]
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S. Shirasawa, H. Harada, K. Furugaki, T. Akamizu, N. Ishikawa, K. Ito, K. Ito, H. Tamai, K. Kuma, S. Kubota, et al. SNPs in the promoter of a B cell-specific antisense transcript, SAS-ZFAT, determine susceptibility to autoimmune thyroid disease Hum. Mol. Genet., October 1, 2004; 13(19): 2221 - 2231. [Abstract] [Full Text] [PDF]
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K Yamamoto, E Ishii, M Sako, S Ohga, K Furuno, N Suzuki, I Ueda, M Imayoshi, S Yamamoto, A Morimoto, et al. Identification of novel MUNC13-4 mutations in familial haemophagocytic lymphohistiocytosis and functional analysis of MUNC13-4-deficient cytotoxic T lymphocytes J. Med. Genet., October 1, 2004; 41(10): 763 - 767. [Abstract] [Full Text] [PDF]
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Y. Ban, E. S. Concepcion, R. Villanueva, D. A. Greenberg, T. F. Davies, and Y. Tomer Analysis of Immune Regulatory Genes in Familial and Sporadic Graves' Disease J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4562 - 4568. [Abstract] [Full Text] [PDF]
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Y. Bayer, S. Neumann, B. Meyer, F. Ruschendorf, A. Reske, T. Brix, L. Hegedus, P. Langer, P. Nurnberg, and R. Paschke Genome-Wide Linkage Analysis Reveals Evidence for Four New Susceptibility Loci for Familial Euthyroid Goiter J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 4044 - 4052. [Abstract] [Full Text] [PDF]
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Y. Tomer and T. F. Davies Searching for the Autoimmune Thyroid Disease Susceptibility Genes: From Gene Mapping to Gene Function Endocr. Rev., October 1, 2003; 24(5): 694 - 717. [Abstract] [Full Text] [PDF]
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J. E. Collins, J. M. Heward, J. Carr-Smith, J. Daykin, J. A. Franklyn, and S. C. L. Gough Association of a Rare Thyroglobulin Gene Microsatellite Variant with Autoimmune Thyroid Disease J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 5039 - 5042. [Abstract] [Full Text] [PDF]
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H. H. Kacem, A. Rebai, N. Kaffel, S. Masmoudi, M. Abid, and H. Ayadi PDS Is a New Susceptibility Gene to Autoimmune Thyroid Diseases: Association and Linkage Study J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 2274 - 2280. [Abstract] [Full Text] [PDF]
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B. Vaidya, P. Kendall-Taylor, and S. H. S. Pearce The Genetics of Autoimmune Thyroid Disease J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5385 - 5397. [Full Text] [PDF]
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