Abstract
Production of thyroid-stimulating hormone receptor (TSHR) antibodies represents the hallmark of Graves’ disease (GD) pathogenesis. Thus, for more than two decades the TSHR gene has been at the center of studies intended to elucidate its contribution to disease pathology. The advent of genome-wide association technology allowed to establish a strong association of the TSHR gene with GD. Subsequent fine-mapping studies narrowed the disease-susceptibility region to a 40 kb sequence in intron 1, where at least five GD-associated SNPs in tight linkage disequilibrium were identified. The current challenge is to understand the functional mechanisms by which these polymorphisms modify physiological processes and trigger disease. The aim of this review is to summarize the current knowledge on the role of the TSHR gene in GD pathogenesis, which has been gained through linkage and association studies, as well as to discuss the emerging mechanisms underlying biological implications of TSHR variants in the development of GD.
Highlights
Autoimmune thyroid diseases (AITD), including Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), affect 2–5% of the general population, representing the most frequent autoimmune conditions [1, 2]
The aim of this review is to summarize the current knowledge of the role of thyroid-stimulating hormone receptor (TSHR) gene in GD pathology, gained through linkage analysis, association, and functional studies
The same year, an independent case–control study conducted in 400 patients with AITD and 238 controls of Japanese descent found several adjacent Single nucleotide polymorphisms (SNPs) in TSHR intron 7 significantly associated with GD, but not with autoimmune hypothyroidism, suggesting that polymorphisms in the TSHR intron 7 could contribute to GD susceptibility [32]
Summary
Autoimmune thyroid diseases (AITD), including Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), affect 2–5% of the general population, representing the most frequent autoimmune conditions [1, 2]. During the last three decades, several approaches from linkage and association studies to candidate genes analysis and whole-genome screening enabled significant progress in the identification of genes that confer susceptibility to AITD. These genes are broadly grouped as either immune-modulating genes (including the HLA family, CD40, CD25, FOXP3, PTPN22) or thyroid-specific genes [thyroid-stimulating hormone receptor (TSHR) and TG]. The TSHR gene, located on chromosome 14q31, consists of 10 exons and encodes for a G protein-coupled receptor that plays a central role in the regulation of thyroid development, growth, and function. The aim of this review is to summarize the current knowledge of the role of TSHR gene in GD pathology, gained through linkage analysis, association, and functional studies
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