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

被引：100

作者：

Brand, Oliver J. ^{[1
]}

Barrett, Jeffrey C. ^{[2
]}

Simmonds, Matthew J. ^{[1
]}

Newby, Paul R. ^{[1
]}

McCabe, Christopher J. ^{[1
]}

Bruce, Christopher K. ^{[1
]}

Kysela, Boris ^{[1
]}

Carr-Smith, Jackie D. ^{[1
]}

Brix, Thomas ^{[4
]}

Hunt, Penny J. ^{[1
]}

Wiersinga, Wilmar M. ^{[5
]}

Hegedus, Laszlo ^{[4
]}

Connell, John ^{[6
]}

Wass, John A. H. ^{[3
]}

Franklyn, Jayne A. ^{[1
]}

Weetman, Anthony P. ^{[7
]}

Heward, Joanne M. ^{[1
]}

Gough, Stephen C. L. ^{[1
]}

机构：

[1] Univ Birmingham, Inst Biomed Res, Coll Med & Dent Sci, Sch Clin & Expt Med, Birmingham B15 2TT, W Midlands, England

[2] Univ Oxford, Churchill Hosp, Wellcome Trust Ctr Human Genet, Oxford, England

[3] Univ Oxford, Churchill Hosp, Dept Endocrinol, Oxford, England

[4] Odense Univ Hosp, Dept Endocrinol & Metab, Odense, Denmark

[5] Univ Amsterdam, Acad Med Ctr, Dept Endocrinol & Metab, NL-1012 WX Amsterdam, Netherlands

[6] Univ Glasgow, Glasgow, Lanark, Scotland

[7] Univ Sheffield, Sch Med, Sheffield, S Yorkshire, England

来源：

HUMAN MOLECULAR GENETICS | 2009年 / 18卷 / 09期

基金：

英国惠康基金;

关键词：

HUMAN THYROTROPIN RECEPTOR; GERMLINE POLYMORPHISM; HAPLOTYPE; REGION; DOMAIN; AUTOIMMUNITY; REPLICATION; MEMBRANE; COMPLEX; LOCUS;

D O I：

10.1093/hmg/ddp087

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 (chi(2) = 32.45, P = 8.90 x 10(-8), OR = 1.53, 95% CI = 1.32-1.78) and rs12101255 (chi(2) = 30.91, P = 1.95 x 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 x 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.

引用

页码：1704 / 1713

页数：10

共 41 条

[1] Lack of association between polymorphism of the thyrotropin receptor gene and Graves' disease in United Kingdom and Hong Kong Chinese patients: Case control and family-based studies [J].

Allahabadia, A ;

Heward, JM ;

Mijovic, C ;

Carr-Smith, J ;

Daykin, J ;

Cockram, C ;

Barnett, AH ;

Sheppard, MC ;

Franklyn, JA ;

Gough, SCL .

THYROID, 1998, 8 (09) :777-780

[2] 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 [J].

Ban, Y ;

Greenberg, DA ;

Concepcion, ES ;

Tomer, Y .

THYROID, 2002, 12 (12) :1079-1083

[3] Haploview: analysis and visualization of LD and haplotype maps [J].

Barrett, JC ;

Fry, B ;

Maller, J ;

Daly, MJ .

BIOINFORMATICS, 2005, 21 (02) :263-265

[4] Accurate whole human genome sequencing using reversible terminator chemistry [J].

Bentley, David R. ;

Balasubramanian, Shankar ;

Swerdlow, Harold P. ;

Smith, Geoffrey P. ;

Milton, John ;

Brown, Clive G. ;

Hall, Kevin P. ;

Evers, Dirk J. ;

Barnes, Colin L. ;

Bignell, Helen R. ;

Boutell, Jonathan M. ;

Bryant, Jason ;

Carter, Richard J. ;

Cheetham, R. Keira ;

Cox, Anthony J. ;

Ellis, Darren J. ;

Flatbush, Michael R. ;

Gormley, Niall A. ;

Humphray, Sean J. ;

Irving, Leslie J. ;

Karbelashvili, Mirian S. ;

Kirk, Scott M. ;

Li, Heng ;

Liu, Xiaohai ;

Maisinger, Klaus S. ;

Murray, Lisa J. ;

Obradovic, Bojan ;

Ost, Tobias ;

Parkinson, Michael L. ;

Pratt, Mark R. ;

Rasolonjatovo, Isabelle M. J. ;

Reed, Mark T. ;

Rigatti, Roberto ;

Rodighiero, Chiara ;

Ross, Mark T. ;

Sabot, Andrea ;

Sankar, Subramanian V. ;

Scally, Aylwyn ;

Schroth, Gary P. ;

Smith, Mark E. ;

Smith, Vincent P. ;

Spiridou, Anastassia ;

Torrance, Peta E. ;

Tzonev, Svilen S. ;

Vermaas, Eric H. ;

Walter, Klaudia ;

Wu, Xiaolin ;

Zhang, Lu ;

Alam, Mohammed D. ;

Anastasi, Carole .

NATURE, 2008, 456 (7218) :53-59

[5] Whole-genome re-sequencing [J].

Bentley, David R. .

CURRENT OPINION IN GENETICS & DEVELOPMENT, 2006, 16 (06) :545-552

[6] Association of the interleukin-2 receptor alpha (IL-2Rα)/CD25 gene region with Graves' disease using a multilocus test and tag SNPs [J].

Brand, Oliver J. ;

Lowe, Christopher E. ;

Heward, Joanne M. ;

Franklyn, Jayne A. ;

Cooper, Jason D. ;

Todd, John A. ;

Gough, Stephen C. L. .

CLINICAL ENDOCRINOLOGY, 2007, 66 (04) :508-512

[7] The thyrotropin receptor autoantigen in Graves disease is the culprit as well as the victim [J].

Chen, CR ;

Pichurin, P ;

Nagayama, Y ;

Latrofa, F ;

Rapoport, B ;

McLachlan, SM .

JOURNAL OF CLINICAL INVESTIGATION, 2003, 111 (12) :1897-1904

[8]

Chistiakov Dimitry A, 2002, Med Sci Monit, V8, pCR180

[9] Complex association analysis of Graves disease using a set of polymorphic markers [J].

Chistyakov, DA ;

Savost'anov, KV ;

Turakulov, RI ;

Petunina, NA ;

Trukhina, LV ;

Kudinova, AV ;

Balabolkin, MI ;

Nosikov, VV .

MOLECULAR GENETICS AND METABOLISM, 2000, 70 (03) :214-218

[10] Production of bioactive amino-terminal domain of the thyrotropin receptor via insertion in the plasma membrane by a glycosylphosphatidylinositol anchor [J].

Costagliola, S ;

Khoo, D ;

Vassart, G .

FEBS LETTERS, 1998, 436 (03) :427-433

← 1 2 3 4 5 →