Abstract
Thyroid hormone receptors, THRA and THRB, together with the TSH receptor, TSHR, are key regulators of thyroid function. Alterations in the genes of these receptors (THRA, THRB and TSHR) have been related to thyroid diseases, including thyroid cancer. Moreover, there is evidence suggesting that predisposition to differentiated thyroid cancer (DTC) is related to common genetic variants with low penetrance that interact with each other and with environmental factors. In this study, we investigated the association of single nucleotide polymorphisms (SNPs) in the THRA (one SNP), THRB (three SNPs) and TSHR (two SNPs) genes with DTC risk. A case–control association study was conducted with 398 patients with sporadic DTC and 479 healthy controls from a Spanish population. Among the polymorphisms studied, only THRA-rs939348 was found to be associated with an increased risk of DTC (recessive model, odds ratio=1.80, 95% confidence interval=1.03–3.14, P=0.037). Gene–gene interaction analysis using the genotype data of this study together with our previous genotype data on TG and TRHR indicated a combined effect of the pairwises: THRB-TG (P interaction=0.014, THRB-rs3752874 with TG-rs2076740; P interaction=0.099, THRB-rs844107 with TG-rs2076740) and THRB-TRHR (P interaction=0.0024, THRB-rs3752874 with TRHR-rs4129682) for DTC risk in a Spanish population. Our results confirm that THRA is a risk factor for DTC, and we show for the first time the combined effect of THRB and TG or TRHR on DTC susceptibility, supporting the importance of gene–gene interaction in thyroid cancer risk.
Highlights
Thyroid cancer is of special concern in endocrinology practice, accounting for more than 90% of all endocrine cancers
We postulated that genetic variants in THRA, THRB and TSH receptor (TSHR) genes individually or in combination with genetic variants in other thyroid function/regulator genes (i.e. TG and TRHR) could be important in Differentiated thyroid carcinoma (DTC) development
We provide evidence for the association of THRA with DTC
Summary
Thyroid cancer is of special concern in endocrinology practice, accounting for more than 90% of all endocrine cancers. Its incidence is increasing in developed countries (1, 2). Represents more than 90% of thyroid neoplasms, and it comprises papillary (PTC) and follicular (FTC) histological subtypes (3).
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