TSHR is the "thyroid stimulating hormone receptor" gene, one of many genes involved in the function of the thyroid gland and thyroid hormone balance. Some TSHR SNPs have also been found significant for bone density and insulin resistance.
[PMID 29973617] 2018 article. "Concurrent TSHR mutations and DIO2 T92A polymorphism result in abnormal thyroid hormone metabolism" Abstract: Deiodinase 2 (DIO2) plays an important role in thyroid hormone metabolism and its regulation. However, molecular mechanism that regulates DIO2 activity remains unclear; only mutaions in selenocysteine insertion sequence binding protein 2 and selenocysteine tranfer RNA (tRNA[Ser]Sec) are reported to result in decreased DIO2 activity. Two patients with clinical evidence of abnormal thyroid hormone metabolism were identified and found to have TSHR mutations as well as DIO2 T92A rs225014 single nucleotide polymorphism (SNP). Primary-cultured fibroblasts from one patient present a high level of basal DIO2 enzymatic activity, possibly due to compensation by augmented DIO2 expression. However, this high enzymatic active state yet fails to respond to accelerating TSH. Consequently, TSHR mutations along with DIO2 T92A SNP (“double hit”) may lead to a significant reduction in DIO2 activity stimulated by TSH, and thereby may have clinical relevance in a select population of hypothyroidism patients who might benefit from a T3/T4 combination therapy.
[PMID 17903292] A 2017 article "Genetics of Thyroid-Stimulating Hormone Receptor—Relevance for Autoimmune Thyroid Disease" explained that "Production of thyroid-stimulating hormone receptor (TSHR) antibodies represents the hallmark of Graves' disease (GD) pathogenesis." "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 authors listed various SNPs of the TSHR gene that are associated with GD in the literature, highlighting rs179247, rs2284720, rs12101255, rs12101261, and rs2268458. The article presented theories of the role of TSHR intron 1 variants in gene function and thyroid autoimmunity.
[PMID 17903292] A 2012 article "Delineating the autoimmune mechanisms in Graves’ disease" responded to the oversimplified view that Graves' disease involves TSHR antibodies in a single pathway that necessarily leads to hyperthyroidism and orbitopathy. They outlined how three types of TSHR antibodies (stimulating, blocking and neutral) function differently in various phenotypes of GD patients, who vary from hyperthyroid to hypothyroid. TSHR blocking antibodies may prevent TSHR from binding to the receptor to such an extent that they may induce hypothyroidism. They also explored several immune mechanisms by which thyroid gland cell death (apoptosis) occurs, resulting in hypothyroidism. Therefore, GD involves genetic risk via multiple gene polymorphisms that interact with epigenetics and environmental factors.
[PMID 22147956] A 2011 article "Genetics of thyroid function and disease" reviewed past research. Genome-wide association studies have not shown SNPs in TSHR such as rs1991517 to be associated with TSH concentrations at a high level of significance, but together with two other SNPs in other genes, (PDE8B rs4704397 and CAPZB rs10917469, the three SNPs may account for "4.5% of the variation in TSH concentrations." TSHR gene SNPs have not been associated with T3 and T4 thyroid hormone levels, while deiodinase genes such as DIO1 rs2235544 have been associated with them. The authors also cited articles claiming that the often-studied TSHR polymorphism of rs1991517 was relevant to bone density and insulin resistance.
[PMID 22313426] A 2007 study "Consecutive mutational events in a TSHR allele of Arab families with resistance to thyroid stimulating hormone" outlined that TSH resistance (RTSH) "is a syndrome of reduced sensitivity to TSH, characterized by elevated serum TSH levels, absence of goiter, and normal or low levels of thyroid hormones. "Inactivating TSHR gene mutations are the most common causes for RTSH." In cases of polymorphism, "Homozygotes or compound heterozygotes may have compensated hypothyroidism (only mild elevation of serum TSH concentration), or frank hypothyroidism that may be mild, moderate, or severe. Some heterozygotes may also manifest only an elevated level of serum TSH." RTSH was considered to be a rare condition, but one past study discovered RTSH in 9.4% of Japanese patients found to have high TSH at birth, and estimate 0.6% in the general Japanese population, and another previous study found RTSH in 22.9% in a population of young subjects with nonautoimmune subclinical hypothyroidism.