Impaired Vitamin D Activation and Association with CYP24A1 Haplotypes in Differentiated Thyroid Carcinoma

Background: Common polymorphisms of the vitamin D receptor gene have been reported to affect the risk of breast, colon, prostate, and differentiated thyroid cancer (DTC), but polymorphisms within the genes of vitamin D metabolizing enzymes have not been studied in DTC. The aim of the present study was to investigate the genes for vitamin D enzymes in patients with DTC and healthy controls (HC) as well as the vitamin D (25-hydroxyvitamin D-3, and 1,25-hydroxyvitamin) status. Methods: German patients (n=253) with DTC (papillary thyroid carcinoma [PTC] and follicular thyroid carcinoma [FTC]) and HC (n=302) were genotyped for polymorphisms within the vitamin D metabolizing enzymes such as 25-hydroxylase (CYP2R1[rs12794714, rs10741657]), 25-hydroxyvitamin D-1 alpha-hydroxylase (CYP27B1[rs10877012, rs4646536]), and 25-hydroxyvitamin D 24-hydrolase (CYP24A1[rs927650, rs2248137, rs2296241]). Furthermore, the 25-hydroxyvitamin D-3 [25(OH)D-3] and 1,25-hydroxyvitamin [1,25(OH)(2)D-3] plasma levels were measured by a radioimmunoassay. Results: There was no difference in the genotypes; however, the CYP24A1 haplotype analysis showed that rs2248137C/rs2296241A (13.1% vs. 19.1%; corrected p [pc]=0.04) was less frequent in the PTC, whereas the haplotypes rs2248137C/rs2296241G (56.0% vs. 41.9%; pc=0.03), rs927650C/rs2296241G (22.5% vs. 8.4%; pc=1.6 x 10(-3)), and rs927650C/rs2248137C/rs2296241G (21.1% vs. 7.3%; pc=1.5 x 10(-3)) were more frequent in the FTC compared with HC. Furthermore, if patients and controls were grouped according to four 25(OH)D-3 categories (severely deficient, deficient, insufficient, and sufficient), then the patients with both DTC subtypes had significantly lower levels of circulating 1,25(OH)(2)D-3, especially in the group with a deficient 25(OH)D-3 status compared with the controls. Although the polymorphisms showed no differences stratified for the four 25(OH)D-3 categories, the activation status by 1,25(OH)(2)D-3 differed significantly depending on the genotypes of the investigated CYP24A1 polymorphisms. Conclusions: A higher risk for DTC is conferred by haplotypes within the CYP24A1 gene, low circulating 25(OH)D-3 levels (deficiency), and a reduced conversion to 1,25(OH)(2)D-3. These results confirm and extend previous observations and also support a role of the vitamin D system in the pathogenesis of DTC. How deficient 25(OH)D-3 levels in combination with certain CYP24A1 haplotypes affect vitamin D activation is the subject of future studies.