Vitamin D Receptor Polymorphisms in Differentiated Thyroid Carcinoma

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Abstract
Background: Vitamin D receptor (VDR) expression has been shown to be upregulated in several tumors and is supposed to represent an important endogenous response to tumor progression. To investigate the role of the VDR gene and its influence on 25(OH)D3 and 1,25(OH)2D3 plasma levels in thyroid carcinoma, we analyzed four VDR polymorphisms in patients and healthy controls (HC). Methods: Patients with thyroid carcinoma (n = 172) (n = 132 for papillary and n = 40 for follicular) and HC (n = 321) were genotyped for the ApaI (rs7975232), TaqI (rs731236), BsmI (rs1544410), and FokI (rs10735810) polymorphisms within the VDR gene and correlated with 25(OH)D3 and 1,25(OH)2D3 plasma levels. Results: The genotypes AA of the ApaI (rs7975232) and FF of the FokI (rs10735810) polymorphisms were significantly less frequent (12.5% vs. 35.2% and 25% vs. 42.1%, respectively, both corrected p [pc] = 0.04) in patients with follicular thyroid cancer (FTC) than in HC. Additionally, the haplotypes, Ta (57.5% vs. 41.4%; pc = 0.0207), af (24.6% vs. 14.3%; pc = 0.0116), Tab (51.1% vs. 36.8%; pc = 0.0495), and Tabf (18.7% vs. 13.6%; pc = 0.0240) were more frequent, whereas the haplotypes AF (17.1% vs. 37.2%; pc = 0.0008), BF (11.4% vs. 31.9%; pc = 0.012), tF (7.9% vs. 25.5%; pc = 0.0016), and tABF (7.6% vs. 23%; pc = 0.0115) were less frequent in the FTC patients compared to HC. Neither genotype nor haplotype frequencies differed between patients with papillary thyroid cancer (PTC) and HC. Further, individuals with PTC and FTC had a significantly lower level of circulating 1,25(OH)2D3 compared to controls. In contrast, no differences of the 25(OH)D3 concentration between patients and HC were observed. VDR polymorphisms were not associated with 25(OH)D3 and 1,25(OH)2D3 plasma levels. Conclusions: Lower circulating levels of 1,25(OH)2D3 are observed in patients with differentiated thyroid carcinoma. Further, while the alleles AA and FF of the ApaI (rs7975232) and FokI (rs10735810) VDR polymorphisms and the haplotype tABF confer to protection from follicular carcinoma, the haplotype Tabf appeared to be associated with an increased FTC risk. Since this is the first report associating VDR polymorphisms with thyroid carcinoma, these findings need to be confirmed in studies with larger numbers of patients.