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

• Published in: Human molecular genetics Vol. 18; no. 9; pp. 1704 - 1713
• Main Authors: Brand, Oliver J., Barrett, Jeffrey C., Simmonds, Matthew J., Newby, Paul R., McCabe, Christopher J., Bruce, Christopher K., Kysela, Boris, Carr-Smith, Jackie D., Brix, Thomas, Hunt, Penny J., Wiersinga, Wilmar M., Hegedüs, Laszlo, Connell, John, Wass, John A.H., Franklyn, Jayne A., Weetman, Anthony P., Heward, Joanne M., Gough, Stephen C.L.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.05.2009; Oxford Publishing Limited (England)
• Subjects: Biological and medical sciences; Case-Control Studies; Cell receptors; Cell structures and functions; Cohort Studies; Endocrinopathies; Fundamental and applied biological sciences. Psychology; Gene Expression; Genetics of eukaryotes. Biological and molecular evolution; Graves Disease - genetics; Graves Disease - metabolism; Haplotypes; Humans; Introns; Linkage Disequilibrium; Medical sciences; Miscellaneous; Molecular and cellular biology; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Polymorphism, Single Nucleotide; Receptors, Thyrotropin - genetics; Receptors, Thyrotropin - metabolism; Thyroid. Thyroid axis (diseases); White People - genetics; Endocrinopathy; Immunopathology; Association; Adenohypophyseal hormone; Gene; Hyperthyroidism; Thyroid diseases; Graves disease; Genetics; Autoimmune disease; Thyroid stimulating hormone; Biological receptor
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddp087

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 (χ2 = 32.45, P = 8.90 × 10−8, OR = 1.53, 95% CI = 1.32–1.78) and rs12101255 (χ2 = 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.