Thyroid stimulating hormone receptor (TSHR) intron 1 variants are major risk factors for Graves' disease in three European Caucasian cohorts

• Published in: PloS one 2010-11, Vol.5 (11), p.e15512-e15512
• Main Authors: Płoski, Rafał, Brand, Oliver J, Jurecka-Lubieniecka, Beata, Franaszczyk, Maria, Kula, Dorota, Krajewski, Paweł, Karamat, Muhammad A, Simmonds, Matthew J, Franklyn, Jayne A, Gough, Stephen C L, Jarząb, Barbara, Bednarczuk, Tomasz
• Format: Article
• Language: English
• Subjects: Antigens; Autoimmune diseases; Biology; Cancer; Case-Control Studies; Child development; Chromosomes; Cohort Studies; Collections; Deoxyribonucleic acid; Diabetes; Disease susceptibility; DNA; Endocrinology; Ethics; European Continental Ancestry Group - genetics; Family medical history; Female; Forensic medicine; Gene Frequency; Gene mapping; Genetic aspects; Genetic Predisposition to Disease - genetics; Genomes; Genotype; Glycoproteins; Graves Disease - ethnology; Graves Disease - genetics; Graves' disease; Haplotypes; Health risks; Heredity; Humans; Hyperthyroidism; Introns - genetics; Linkage Disequilibrium; Logistic Models; Male; Medical research; Medicine; Metabolism; Nuclear medicine; Oncology; Patients; Phosphatase; Pituitary hormones; Poland; Polymorphism, Single Nucleotide; Receptors, Thyrotropin - genetics; Risk analysis; Risk Factors; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Studies; Susceptibility; Thyroid; Thyroid diseases; Thyroid-stimulating hormone receptors; United Kingdom; White people
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0015512

The thyroid stimulating hormone receptor (TSHR) gene is an established susceptibility locus for Graves' disease (GD), with recent studies refining association to two single nucleotide polymorphisms (SNPs), rs179247 and rs12101255, within TSHR intron 1. We aimed to validate association of rs179247 and rs12101255 in Polish and UK Caucasian GD case-control subjects, determine the mode of inheritance and to see if association correlates with specific GD clinical manifestations. We investigated three case-control populations; 558 GD patients and 520 controls from Warsaw, Poland, 196 GD patients and 198 controls from Gliwice, Poland and 2504 GD patients from the UK National collection and 2784 controls from the 1958 British Birth cohort. Both rs179247 (P = 1.2×10(-2)-6.2×10(-15), OR = 1.38-1.45) and rs12101255 (P = 1.0×10(-4)-3.68×10(-21), OR = 1.47-1.87) exhibited strong association with GD in all three cohorts. Logistic regression suggested association of rs179247 is secondary to rs12101255 in all cohorts. Inheritance modeling suggested a co-dominant mode of inheritance in all cohorts. Genotype-phenotype correlations provided no clear evidence of association with any specific clinical characteristics. We have validated association of TSHR intron 1 SNPs with GD in three independent European cohorts and have demonstrated that the aetiological variant within the TSHR is likely to be in strong linkage disequilibrium with rs12101255. Fine mapping is now required to determine the exact location of the aetiological DNA variants within the TSHR.