FOXE1 polyalanine tract (poly-Ala) has been associated with thyroid dysgenesis. Recently, the SNP (rs1867277:-238G>A) within the FOXE1 5'UTR was involved in the genetic susceptibility to thyroid cancer (TC). In the aim to assess the influence of FOXE1 poly-Ala length on the genetic susceptibility to TC and autoimmune thyroid diseases (AITD), a case-control design (including 261 Tunisian AITD, 170 Spanish TC and respectively 171 and 218 matched healthy subjects) was performed. The effect of Ala length and rs1867277 alleles on FOXE1 expression was investigated by mRNA relative real time quantification on 8 papillary thyroid carcinoma (PTC) and 10 Graves' disease (GD) genotyped thyroid biopsies. The fluorescent genotyping of poly-Ala polymorphism revealed nine alleles (from 12 to 22 repetitions). The association of poly-Ala polymorphism with AITD was rejected (Pc>0.05). However, a significant association was found with TC. In addition, the genotypic distributions revealed the predispositional effect of the 16/16 genotype (OR = 2.71; 95%CI: 1.36-5.42; p=0.001) and the protector effect of the 14/14 genotype (OR= 0.46; 95%CI: 0.29-0.72; p=0.003). The quantification studies reveal that FOXE1 transcripts were less abundant in PTC than GD samples. Moreover, FOXEI gene was 4,8 fold less expressed among PTC protected patients compared to homozygous 16/16-A/A. In conclusion, by exploring the poly-Ala polymorphism, we confirmed the involvement of {\it FOXE1} gene in the genetic susceptibility to TC and we reported its down expression among PTC tissues.
In this study, we show for the first time that the TG gene is a susceptibility factor for thyroid cancer. Although these conclusions are based on a large population, additional studies are warranted to support these data.
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.
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