Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves' disease

Oliver J. Brand; Jaffrey C. Barrett; Mathew J. Simmonds; Paul R. Newby; Christpher J. McCabe; Christpher K. Bruce; Boris Kysela; Jackie D. Carr-Smith; Thomas Brix; Penny J. Hunt; Wilmar M. Wiersinga; Laszio Hegedüs; John Connell; John A.H. Wass; Jayne A. Franklyn; Anthony P. Weetman; Joanne M. Heward; Stephen C.L. Gough

doi:10.1093/hmg/ddp087

Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves' disease

Oliver J. Brand, Jaffrey C. Barrett, Mathew J. Simmonds, Paul R. Newby, Christpher J. McCabe, Christpher K. Bruce, Boris Kysela, Jackie D. Carr-Smith, Thomas Brix, Penny J. Hunt, Wilmar M. Wiersinga, Laszio Hegedüs, John Connell, John A.H. Wass, Jayne A. Franklyn, Anthony P. Weetman, Joanne M. Heward, Stephen C.L. Gough

Research output: Contribution to journal › Article › peer-review

108 Citations (Scopus)

Abstract

Graves' disease (GD) is a common autoimmune disease (AID) that shares many of its susceptibility loci with other AIDs. The thyroid stimulating hormone receptor (TSHR) represents the primary autoantigen in GD, in which autoantibodies bind to the receptor and mimic its ligand, thyroid stimulating hormone, causing the characteristic clinical phenotype. Although early studies investigating the TSHR and GD proved inconclusive, more recently we provided convincing evidence for association of the TSHR region with disease. In the current study, we investigated a combined panel of 98 SNPs, including 70 tag SNPs, across an extended 800 kb region of the TSHR to refine association in a cohort of 768 GD subjects and 768 matched controls. In total, 28 SNPs revealed association with GD (P < 0.05), with strongest SNP associations at rs179247 (?2 = 32.45, P = 8.90 × 10-8, OR = 1.53, 95% CI = 1.32-1.78) and rs12101255 (?2 = 30.91, P = 1.95 × 10-7, OR = 1.55, 95% CI = 1.33-1.81), both located in intron 1 of the TSHR. Association of the most associated SNP, rs179247, was replicated in 303 GD families (P = 7.8 × 10-4). In addition, we provide preliminary evidence that the disease-associated genotypes of rs179247 (AA) and rs12101255 (TT) show reduced mRNA expression ratios of flTSHR relative to two alternate TSHR mRNA splice variants. © The Author 2009. Published by Oxford University Press. All rights reserved.

Original language	Undefined/Unknown
Pages (from-to)	1704-1713
Number of pages	10
Journal	Human Molecular Genetics
Volume	18
Issue number	9
DOIs	https://doi.org/10.1093/hmg/ddp087
Publication status	Published - 2009

Keywords

messenger RNA
thyrotropin receptor
article
cohort analysis
controlled study
gene expression
gene function
gene linkage disequilibrium
gene locus
gene replication
genetic association
genetic identification
genetic susceptibility
genetic variability
genotype
Graves disease
haplotype
human
intron
major clinical study
phenotype
priority journal
promoter region
single nucleotide polymorphism
Case-Control Studies
Cohort Studies
European Continental Ancestry Group
Gene Expression
Graves Disease
Haplotypes
Humans
Introns
Linkage Disequilibrium
Polymorphism, Single Nucleotide
Receptors, Thyrotropin

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1093/hmg/ddp087

Cite this

Brand, O. J., Barrett, J. C., Simmonds, M. J., Newby, P. R., McCabe, C. J., Bruce, C. K., Kysela, B., Carr-Smith, J. D., Brix, T., Hunt, P. J., Wiersinga, W. M., Hegedüs, L., Connell, J., Wass, J. A. H., Franklyn, J. A., Weetman, A. P., Heward, J. M., & Gough, S. C. L. (2009). Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves' disease. Human Molecular Genetics, 18(9), 1704-1713. https://doi.org/10.1093/hmg/ddp087

@article{6bcf042c084b484d8a4399e574fb5791,

title = "Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves' disease",

abstract = "Graves' disease (GD) is a common autoimmune disease (AID) that shares many of its susceptibility loci with other AIDs. The thyroid stimulating hormone receptor (TSHR) represents the primary autoantigen in GD, in which autoantibodies bind to the receptor and mimic its ligand, thyroid stimulating hormone, causing the characteristic clinical phenotype. Although early studies investigating the TSHR and GD proved inconclusive, more recently we provided convincing evidence for association of the TSHR region with disease. In the current study, we investigated a combined panel of 98 SNPs, including 70 tag SNPs, across an extended 800 kb region of the TSHR to refine association in a cohort of 768 GD subjects and 768 matched controls. In total, 28 SNPs revealed association with GD (P < 0.05), with strongest SNP associations at rs179247 (?2 = 32.45, P = 8.90 × 10-8, OR = 1.53, 95% CI = 1.32-1.78) and rs12101255 (?2 = 30.91, P = 1.95 × 10-7, OR = 1.55, 95% CI = 1.33-1.81), both located in intron 1 of the TSHR. Association of the most associated SNP, rs179247, was replicated in 303 GD families (P = 7.8 × 10-4). In addition, we provide preliminary evidence that the disease-associated genotypes of rs179247 (AA) and rs12101255 (TT) show reduced mRNA expression ratios of flTSHR relative to two alternate TSHR mRNA splice variants. {\textcopyright} The Author 2009. Published by Oxford University Press. All rights reserved.",

keywords = "messenger RNA, thyrotropin receptor, article, cohort analysis, controlled study, gene expression, gene function, gene linkage disequilibrium, gene locus, gene replication, genetic association, genetic identification, genetic susceptibility, genetic variability, genotype, Graves disease, haplotype, human, intron, major clinical study, phenotype, priority journal, promoter region, single nucleotide polymorphism, Case-Control Studies, Cohort Studies, European Continental Ancestry Group, Gene Expression, Graves Disease, Haplotypes, Humans, Introns, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Receptors, Thyrotropin",

author = "Brand, {Oliver J.} and Barrett, {Jaffrey C.} and Simmonds, {Mathew J.} and Newby, {Paul R.} and McCabe, {Christpher J.} and Bruce, {Christpher K.} and Boris Kysela and Carr-Smith, {Jackie D.} and Thomas Brix and Hunt, {Penny J.} and Wiersinga, {Wilmar M.} and Laszio Heged{\"u}s and John Connell and Wass, {John A.H.} and Franklyn, {Jayne A.} and Weetman, {Anthony P.} and Heward, {Joanne M.} and Gough, {Stephen C.L.}",

note = "Cited By (since 1996): 21 Export Date: 19 March 2012 Source: Scopus CODEN: HMGEE doi: 10.1093/hmg/ddp087 PubMed ID: 19244275 Language of Original Document: English Correspondence Address: Gough, S.C.L.; School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, West Midlands B15 2TT, United Kingdom; email: [email protected] Chemicals/CAS: Receptors, Thyrotropin References: Gough, S.C., The genetics of Graves' disease (2000) Endocrinol. Metab. Clin. North Am, 29, pp. 255-266; Tunbridge, W.M., Evered, D.C., Hall, R., Appleton, D., Brewis, M., Clark, F., Evans, J.G., Smith, P.A., The spectrum of thyroid disease in a community: The Whickham survey (1977) Clin. Endocrinol. (Oxf), 7, pp. 481-493; Simmonds, M.J., Howson, J.M., Heward, J.M., Cordell, H.J., Foxall, H., Carr-Smith, J., Gibson, S.M., Franklyn, J.A., Regression mapping of association between the human leukocyte antigen region and Graves disease (2005) Am. J. Hum. Genet, 76, pp. 157-163; Simmonds, M.J., Howson, J.M., Heward, J.M., Carr-Smith, J., Franklyn, J.A., Todd, J.A., Gough, S.C., A novel and major association of HLA-C in Graves' disease that eclipses the classical HLA-DRB1 effect (2007) Hum. Mol. Genet, 16, pp. 2149-2153; Ueda, H., Howson, J.M., Esposito, L., Heward, J., Snook, H., Chamberlain, G., Rainbow, D.B., Di Genova, G., Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease (2003) Nature, 423, pp. 506-511; Smyth, D., Cooper, J.D., Collins, J.E., Heward, J.M., Franklyn, J.A., Howson, J.M., Vella, A., Maier, L., Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus (2004) Diabetes, 53, pp. 3020-3023; Brand, O.J., Lowe, C.E., Heward, J.M., Franklyn, J.A., Cooper, J.D., Todd, J.A., Gough, S.C., Association of the interleukin-2 receptor alpha (IL-2Ralpha)/CD25 gene region with Graves' disease using a multilocus test and tag SNPs (2007) Clin. Endocrinol. (Oxf), 66, pp. 508-512; Eisenberg, R., Do autoantigens define autoimmunity or vice versa? (2005) Eur. J. Immunol, 35, pp. 367-370; Cuddihy, R.M., Dutton, C.M., Bahn, R.S., A polymorphism in the extracellular domain of the thyrotropin receptor is highly associated with autoimmune thyroid disease in females (1995) Thyroid, 5, pp. 89-95; Kotsa, K.D., Watson, P.F., Weetman, A.P., No association between a thyrotropin receptor gene polymorphism and Graves' disease in the female population (1997) Thyroid, 7, pp. 31-33; Allahabadia, A., Heward, J.M., Mijovic, C., Carr-Smith, J., Daykin, J., Cockram, C., Barnett, A.H., Gough, S.C., Lack of association between polymorphism of the thyrotropin receptor gene and Graves' disease in UK and Hong Kong Chinese patients: Case control and family-based studies (1998) Thyroid, 8, pp. 777-780; Gabriel, E.M., Bergert, E.R., Grant, C.S., van Heerden, J.A., Thompson, G.B., Morris, J.C., Germline polymorphism of codon 727 of human thyroid-stimulating hormone receptor is associated with toxic multinodular goiter (1999) J. Clin. Endocrinol. Metab, 84, pp. 3328-3335; Simanainen, J., Kinch, A., Westermark, K., Winsa, B., Bengtsson, M., Schuppert, F., Westermark, B., Heldin, N.E., Analysis of mutations in exon 1 of the human thyrotropin receptor gene: High frequency of the D36H and P52T polymorphic variants (1999) Thyroid, 9, pp. 7-11; Kaczur, V., Takacs, M., Szalai, C., Falus, A., Nagy, Z., Berencsi, G., Balazs, C., Analysis of the genetic variability of the 1st (CCC/ACC, P52T) and the 10th exons (bp 1012-1704) of the TSH receptor gene in Graves' disease (2000) Eur. J. Immunogenet, 27, pp. 17-23; Chistyakov, D.A., Savost'anov, K.V., Turakulov, R.I., Petunina, N.A., Trukhina, L.V., Kudinova, A.V., Balabolkin, M.I., Nosikov, V.V., Complex association analysis of Graves' disease using a set of polymorphic markers (2000) Mol. Genet. Metab, 70, pp. 214-218; Watson, P.F., French, A., Pickerill, A.P., McIntosh, R.S., Weetman, A.P., Lack of association between a polymorphism in the coding region of the thyrotropin receptor gene and Graves' disease (1995) J. Clin. Endocrinol. Metab, 80, pp. 1032-1035; Ho, S.C., Goh, S.S., Khoo, D.H., Association of Graves' disease with intragenic polymorphism of the thyrotropin receptor gene in a cohort of Singapore patients of multi-ethnic origins (2003) Thyroid, 13, pp. 523-528; Ban, Y., Greenberg, D.A., Concepcion, E.S., Tomer, Y., A germline single nucleotide polymorphism at the intracellular domain of the human thyrotropin receptor does not have a major effect on the development of Graves' disease (2002) Thyroid, 12, pp. 1079-1083; Chistiakov, D.A., Savost'anov, K.V., Turakulov, R.I., Petunina, N., Balabolkin, M.I., Nosikov, V.V., Further studies of genetic susceptibility to Graves' disease in a Russian population (2002) Med. Sci. Monit, 8, pp. CR180-CR184; Muhlberg, T., Herrmann, K., Joba, W., Kirchberger, M., Heberling, H.J., Heufelder, A.E., Lack of association of nonautoimmune hyperfunctioning thyroid disorders and a germline polymorphism of codon 727 of the human thyrotropin receptor in a European Caucasian population (2000) J. Clin. Endocrinol. Metab, 85, pp. 2640-2643; Dechairo, B.M., Zabaneh, D., Collins, J., Brand, O., Dawson, G.J., Green, A.P., Mackay, I., Wass, J.A., Association of the TSHR gene with Graves' disease: The first disease specific locus (2005) Eur. J. Hum. Genet, 13, pp. 1223-1230; Hiratani, H., Bowden, D.W., Ikegami, S., Shirasawa, S., Shimizu, A., Iwatani, Y., Akamizu, T., Multiple SNPs in intron 7 of thyrotropin receptor are associated with Graves' disease (2005) J. Clin. Endocrinol. Metab, 90, pp. 2898-2903; Burton, P.R., Clayton, D.G., Cardon, L.R., Craddock, N., Deloukas, P., Duncanson, A., Kwiatkowski, D.P., McCarthy, M.I., Ouwehand, W.H. et al. WTCCC (2007) Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat. Genet., 39 1329-1337Simmonds, M.J., Heward, J.M., Carr-Smith, J., Foxall, H., Franklyn, J.A., Gough, S.C., Contribution of single nucleotide polymorphisms within FCRL3 and MAP3K7IP2 to the pathogenesis of Graves' disease (2006) J. Clin. Endocrinol. Metab, 91, pp. 1056-1061; Gabriel, S.B., Schaffner, S.F., Nguyen, H., Moore, J.M., Roy, J., Blumenstiel, B., Higgins, J., Faggart, M., The structure of haplotype blocks in the human genome (2002) Science, 296, pp. 2225-2229; Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M.A., Bender, D., Maller, J., Daly, M.J., PLINK: A tool set for whole-genome association and population-based linkage analyses (2007) Am. J. Hum. Genet, 81, pp. 559-575; Frazier, A.L., Robbins, L.S., Stork, P.J., Sprengel, R., Segaloff, D.L., Cone, R.D., Isolation of TSH and LH/CG receptor cDNAs from human thyroid: Regulation by tissue specific splicing (1990) Mol. Endocrinol, 4, pp. 1264-1276; Kakinuma, A., Nagayama, Y., Multiple messenger ribonucleic acid transcripts and revised gene organization of the human TSH receptor (2002) Endocr. J, 49, pp. 175-180; Hunt, N., Wiley, K.P., Abend, N., Balvers, M., Jahner, D., Northemann, W., Ivell, R., Novel splicing variants of the human thyrotropin receptor encode truncated polypeptides without a membrane-spanning domain (1995) Endocrine, 3, pp. 233-240; Frazer, K.A., Ballinger, D.G., Cox, D.R., Hinds, D.A., Stuve, L.L., Gibbs, R.A., Belmont, J.W., Leal, S.M., A second generation human haplotype map of over 3.1 million SNPs (2007) Nature, 449, pp. 851-861; Bentley, D.R., Balasubramanian, S., Swerdlow, H.P., Smith, G.P., Milton, J., Brown, C.G., Hall, K.P., Bignell, H.R., Accurate whole human genome sequencing using reversible terminator chemistry (2008) Nature, 456, pp. 53-59; Bentley, D.R., Whole-genome re-sequencing (2006) Curr. Opin. Genet. Dev, 16, pp. 545-552; Costagliola, S., Khoo, D., Vassart, G., Production of bioactive amino-terminal domain of the thyrotropin receptor via insertion in the plasma membrane by a glycosylphosphatidylinositol anchor (1998) FEBS Lett, 436, pp. 427-433; Chen, C.R., Pichurin, P., Nagayama, Y., Latrofa, F., Rapoport, B., McLachlan, S.M., The thyrotropin receptor autoantigen in Graves disease is the culprit as well as the victim (2003) J. Clin. Invest, 111, pp. 1897-1904; Nalls, M.A., Wilson, J.G., Patterson, N.J., Tandon, A., Zmuda, J.M., Huntsman, S., Garcia, M., Beamer, B.A., Admixture mapping of white cell count: Genetic locus responsible for lower white blood cell count in the Health ABC and Jackson Heart studies (2008) Am. J. Hum. Genet, 82, pp. 81-87; Jakobsson, M., Scholz, S.W., Scheet, P., Gibbs, J.R., VanLiere, J.M., Fung, H.C., Szpiech, Z.A., Guerreiro, R., Genotype, haplotype and copy-number variation in worldwide human populations (2008) Nature, 451, pp. 998-1003; Unoki, H., Takahashi, A., Kawaguchi, T., Hara, K., Horikoshi, M., Andersen, G., Ng, D.P., Jorgensen, T., SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations (2008) Nat. Genet, 40, pp. 1039-1040; McCarthy, M.I., Hirschhorn, J.N., Genome-wide association studies: Potential next steps on a genetic journey (2008) Hum. Mol. Genet, 17, pp. R156-R165; Heward, J.M., Allahabadia, A., Daykin, J., Carr-Smith, J., Daly, A., Armitage, M., Dodson, P.M., Franklyn, J.A., 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 (1998) J. Clin. Endocrinol. Metab, 83, pp. 3394-3397; Barrett, J.C., Fry, B., Maller, J., Daly, M.J., Haploview: Analysis and visualization of LD and haplotype maps (2005) Bioinformatics, 21, pp. 263-265; de Bakker, P.I., Yelensky, R., Pe'er, I., Gabriel, S.B., Daly, M.J., Altshuler, D., Efficiency and power in genetic association studies (2005) Nat. Genet, 37, pp. 1217-1223; Nicholas Hunt, K.P.W., Abend, N., Balvers, M., Jahner, D., Northemann, W., Ivell, R., Novel splicing variants of the human thyrotropin receptor encode truncated polypeptides without a membrane-spanning domain (1995) Endocrine, 3, pp. 233-240",

year = "2009",

doi = "10.1093/hmg/ddp087",

language = "Undefined/Unknown",

volume = "18",

pages = "1704--1713",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "9",

}

Brand, OJ, Barrett, JC, Simmonds, MJ, Newby, PR, McCabe, CJ, Bruce, CK, Kysela, B, Carr-Smith, JD, Brix, T, Hunt, PJ, Wiersinga, WM, Hegedüs, L, Connell, J, Wass, JAH, Franklyn, JA, Weetman, AP, Heward, JM & Gough, SCL 2009, 'Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves' disease', Human Molecular Genetics, vol. 18, no. 9, pp. 1704-1713. https://doi.org/10.1093/hmg/ddp087

TY - JOUR

T1 - Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves' disease

AU - Brand, Oliver J.

AU - Barrett, Jaffrey C.

AU - Simmonds, Mathew J.

AU - Newby, Paul R.

AU - McCabe, Christpher J.

AU - Bruce, Christpher K.

AU - Kysela, Boris

AU - Carr-Smith, Jackie D.

AU - Brix, Thomas

AU - Hunt, Penny J.

AU - Wiersinga, Wilmar M.

AU - Hegedüs, Laszio

AU - Connell, John

AU - Wass, John A.H.

AU - Franklyn, Jayne A.

AU - Weetman, Anthony P.

AU - Heward, Joanne M.

AU - Gough, Stephen C.L.

N1 - Cited By (since 1996): 21 Export Date: 19 March 2012 Source: Scopus CODEN: HMGEE doi: 10.1093/hmg/ddp087 PubMed ID: 19244275 Language of Original Document: English Correspondence Address: Gough, S.C.L.; School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, West Midlands B15 2TT, United Kingdom; email: [email protected] Chemicals/CAS: Receptors, Thyrotropin References: Gough, S.C., The genetics of Graves' disease (2000) Endocrinol. Metab. Clin. North Am, 29, pp. 255-266; Tunbridge, W.M., Evered, D.C., Hall, R., Appleton, D., Brewis, M., Clark, F., Evans, J.G., Smith, P.A., The spectrum of thyroid disease in a community: The Whickham survey (1977) Clin. Endocrinol. (Oxf), 7, pp. 481-493; Simmonds, M.J., Howson, J.M., Heward, J.M., Cordell, H.J., Foxall, H., Carr-Smith, J., Gibson, S.M., Franklyn, J.A., Regression mapping of association between the human leukocyte antigen region and Graves disease (2005) Am. J. Hum. Genet, 76, pp. 157-163; Simmonds, M.J., Howson, J.M., Heward, J.M., Carr-Smith, J., Franklyn, J.A., Todd, J.A., Gough, S.C., A novel and major association of HLA-C in Graves' disease that eclipses the classical HLA-DRB1 effect (2007) Hum. Mol. Genet, 16, pp. 2149-2153; Ueda, H., Howson, J.M., Esposito, L., Heward, J., Snook, H., Chamberlain, G., Rainbow, D.B., Di Genova, G., Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease (2003) Nature, 423, pp. 506-511; Smyth, D., Cooper, J.D., Collins, J.E., Heward, J.M., Franklyn, J.A., Howson, J.M., Vella, A., Maier, L., Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus (2004) Diabetes, 53, pp. 3020-3023; Brand, O.J., Lowe, C.E., Heward, J.M., Franklyn, J.A., Cooper, J.D., Todd, J.A., Gough, S.C., Association of the interleukin-2 receptor alpha (IL-2Ralpha)/CD25 gene region with Graves' disease using a multilocus test and tag SNPs (2007) Clin. Endocrinol. (Oxf), 66, pp. 508-512; Eisenberg, R., Do autoantigens define autoimmunity or vice versa? (2005) Eur. J. Immunol, 35, pp. 367-370; Cuddihy, R.M., Dutton, C.M., Bahn, R.S., A polymorphism in the extracellular domain of the thyrotropin receptor is highly associated with autoimmune thyroid disease in females (1995) Thyroid, 5, pp. 89-95; Kotsa, K.D., Watson, P.F., Weetman, A.P., No association between a thyrotropin receptor gene polymorphism and Graves' disease in the female population (1997) Thyroid, 7, pp. 31-33; Allahabadia, A., Heward, J.M., Mijovic, C., Carr-Smith, J., Daykin, J., Cockram, C., Barnett, A.H., Gough, S.C., Lack of association between polymorphism of the thyrotropin receptor gene and Graves' disease in UK and Hong Kong Chinese patients: Case control and family-based studies (1998) Thyroid, 8, pp. 777-780; Gabriel, E.M., Bergert, E.R., Grant, C.S., van Heerden, J.A., Thompson, G.B., Morris, J.C., Germline polymorphism of codon 727 of human thyroid-stimulating hormone receptor is associated with toxic multinodular goiter (1999) J. Clin. Endocrinol. Metab, 84, pp. 3328-3335; Simanainen, J., Kinch, A., Westermark, K., Winsa, B., Bengtsson, M., Schuppert, F., Westermark, B., Heldin, N.E., Analysis of mutations in exon 1 of the human thyrotropin receptor gene: High frequency of the D36H and P52T polymorphic variants (1999) Thyroid, 9, pp. 7-11; Kaczur, V., Takacs, M., Szalai, C., Falus, A., Nagy, Z., Berencsi, G., Balazs, C., Analysis of the genetic variability of the 1st (CCC/ACC, P52T) and the 10th exons (bp 1012-1704) of the TSH receptor gene in Graves' disease (2000) Eur. J. Immunogenet, 27, pp. 17-23; Chistyakov, D.A., Savost'anov, K.V., Turakulov, R.I., Petunina, N.A., Trukhina, L.V., Kudinova, A.V., Balabolkin, M.I., Nosikov, V.V., Complex association analysis of Graves' disease using a set of polymorphic markers (2000) Mol. Genet. Metab, 70, pp. 214-218; Watson, P.F., French, A., Pickerill, A.P., McIntosh, R.S., Weetman, A.P., Lack of association between a polymorphism in the coding region of the thyrotropin receptor gene and Graves' disease (1995) J. Clin. Endocrinol. Metab, 80, pp. 1032-1035; Ho, S.C., Goh, S.S., Khoo, D.H., Association of Graves' disease with intragenic polymorphism of the thyrotropin receptor gene in a cohort of Singapore patients of multi-ethnic origins (2003) Thyroid, 13, pp. 523-528; Ban, Y., Greenberg, D.A., Concepcion, E.S., Tomer, Y., A germline single nucleotide polymorphism at the intracellular domain of the human thyrotropin receptor does not have a major effect on the development of Graves' disease (2002) Thyroid, 12, pp. 1079-1083; Chistiakov, D.A., Savost'anov, K.V., Turakulov, R.I., Petunina, N., Balabolkin, M.I., Nosikov, V.V., Further studies of genetic susceptibility to Graves' disease in a Russian population (2002) Med. Sci. Monit, 8, pp. CR180-CR184; Muhlberg, T., Herrmann, K., Joba, W., Kirchberger, M., Heberling, H.J., Heufelder, A.E., Lack of association of nonautoimmune hyperfunctioning thyroid disorders and a germline polymorphism of codon 727 of the human thyrotropin receptor in a European Caucasian population (2000) J. Clin. Endocrinol. Metab, 85, pp. 2640-2643; Dechairo, B.M., Zabaneh, D., Collins, J., Brand, O., Dawson, G.J., Green, A.P., Mackay, I., Wass, J.A., Association of the TSHR gene with Graves' disease: The first disease specific locus (2005) Eur. J. Hum. Genet, 13, pp. 1223-1230; Hiratani, H., Bowden, D.W., Ikegami, S., Shirasawa, S., Shimizu, A., Iwatani, Y., Akamizu, T., Multiple SNPs in intron 7 of thyrotropin receptor are associated with Graves' disease (2005) J. Clin. Endocrinol. Metab, 90, pp. 2898-2903; Burton, P.R., Clayton, D.G., Cardon, L.R., Craddock, N., Deloukas, P., Duncanson, A., Kwiatkowski, D.P., McCarthy, M.I., Ouwehand, W.H. et al. WTCCC (2007) Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat. Genet., 39 1329-1337Simmonds, M.J., Heward, J.M., Carr-Smith, J., Foxall, H., Franklyn, J.A., Gough, S.C., Contribution of single nucleotide polymorphisms within FCRL3 and MAP3K7IP2 to the pathogenesis of Graves' disease (2006) J. Clin. Endocrinol. Metab, 91, pp. 1056-1061; Gabriel, S.B., Schaffner, S.F., Nguyen, H., Moore, J.M., Roy, J., Blumenstiel, B., Higgins, J., Faggart, M., The structure of haplotype blocks in the human genome (2002) Science, 296, pp. 2225-2229; Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M.A., Bender, D., Maller, J., Daly, M.J., PLINK: A tool set for whole-genome association and population-based linkage analyses (2007) Am. J. Hum. Genet, 81, pp. 559-575; Frazier, A.L., Robbins, L.S., Stork, P.J., Sprengel, R., Segaloff, D.L., Cone, R.D., Isolation of TSH and LH/CG receptor cDNAs from human thyroid: Regulation by tissue specific splicing (1990) Mol. Endocrinol, 4, pp. 1264-1276; Kakinuma, A., Nagayama, Y., Multiple messenger ribonucleic acid transcripts and revised gene organization of the human TSH receptor (2002) Endocr. 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PY - 2009

Y1 - 2009

N2 - Graves' disease (GD) is a common autoimmune disease (AID) that shares many of its susceptibility loci with other AIDs. The thyroid stimulating hormone receptor (TSHR) represents the primary autoantigen in GD, in which autoantibodies bind to the receptor and mimic its ligand, thyroid stimulating hormone, causing the characteristic clinical phenotype. Although early studies investigating the TSHR and GD proved inconclusive, more recently we provided convincing evidence for association of the TSHR region with disease. In the current study, we investigated a combined panel of 98 SNPs, including 70 tag SNPs, across an extended 800 kb region of the TSHR to refine association in a cohort of 768 GD subjects and 768 matched controls. In total, 28 SNPs revealed association with GD (P < 0.05), with strongest SNP associations at rs179247 (?2 = 32.45, P = 8.90 × 10-8, OR = 1.53, 95% CI = 1.32-1.78) and rs12101255 (?2 = 30.91, P = 1.95 × 10-7, OR = 1.55, 95% CI = 1.33-1.81), both located in intron 1 of the TSHR. Association of the most associated SNP, rs179247, was replicated in 303 GD families (P = 7.8 × 10-4). In addition, we provide preliminary evidence that the disease-associated genotypes of rs179247 (AA) and rs12101255 (TT) show reduced mRNA expression ratios of flTSHR relative to two alternate TSHR mRNA splice variants. © The Author 2009. Published by Oxford University Press. All rights reserved.

AB - Graves' disease (GD) is a common autoimmune disease (AID) that shares many of its susceptibility loci with other AIDs. The thyroid stimulating hormone receptor (TSHR) represents the primary autoantigen in GD, in which autoantibodies bind to the receptor and mimic its ligand, thyroid stimulating hormone, causing the characteristic clinical phenotype. Although early studies investigating the TSHR and GD proved inconclusive, more recently we provided convincing evidence for association of the TSHR region with disease. In the current study, we investigated a combined panel of 98 SNPs, including 70 tag SNPs, across an extended 800 kb region of the TSHR to refine association in a cohort of 768 GD subjects and 768 matched controls. In total, 28 SNPs revealed association with GD (P < 0.05), with strongest SNP associations at rs179247 (?2 = 32.45, P = 8.90 × 10-8, OR = 1.53, 95% CI = 1.32-1.78) and rs12101255 (?2 = 30.91, P = 1.95 × 10-7, OR = 1.55, 95% CI = 1.33-1.81), both located in intron 1 of the TSHR. Association of the most associated SNP, rs179247, was replicated in 303 GD families (P = 7.8 × 10-4). In addition, we provide preliminary evidence that the disease-associated genotypes of rs179247 (AA) and rs12101255 (TT) show reduced mRNA expression ratios of flTSHR relative to two alternate TSHR mRNA splice variants. © The Author 2009. Published by Oxford University Press. All rights reserved.

KW - messenger RNA

KW - thyrotropin receptor

KW - article

KW - cohort analysis

KW - controlled study

KW - gene expression

KW - gene function

KW - gene linkage disequilibrium

KW - gene locus

KW - gene replication

KW - genetic association

KW - genetic identification

KW - genetic susceptibility

KW - genetic variability

KW - genotype

KW - Graves disease

KW - haplotype

KW - human

KW - intron

KW - major clinical study

KW - phenotype

KW - priority journal

KW - promoter region

KW - single nucleotide polymorphism

KW - Case-Control Studies

KW - Cohort Studies

KW - European Continental Ancestry Group

KW - Gene Expression

KW - Graves Disease

KW - Haplotypes

KW - Humans

KW - Introns

KW - Linkage Disequilibrium

KW - Polymorphism, Single Nucleotide

KW - Receptors, Thyrotropin

U2 - 10.1093/hmg/ddp087

DO - 10.1093/hmg/ddp087

M3 - Article

C2 - 19244275

SN - 0964-6906

VL - 18

SP - 1704

EP - 1713

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 9

ER -