Department of Internal Medicine I (Division of Endocrinology, Diabetes, and Metabolism), University of Frankfurt, Frankfurt am Main, Germany.
Thyroid. 2012 Jul;22(7):709-16. doi: 10.1089/thy.2011.0330. Epub 2012 Jun 12.
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.
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-1α-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.
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=1.6×10(-3)), and rs927650C/rs2248137C/rs2296241G (21.1% vs. 7.3%; pc=1.5×10(-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.
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.
维生素 D 受体基因的常见多态性已被报道会影响乳腺癌、结肠癌、前列腺癌和分化型甲状腺癌（DTC）的风险，但维生素 D 代谢酶基因内的多态性尚未在 DTC 中进行研究。本研究的目的是研究 DTC 患者和健康对照（HC）中维生素 D 酶的基因以及维生素 D（25-羟基维生素 D(3)和 1,25-羟基维生素）状态。
德国 253 例 DTC（甲状腺乳头状癌 [PTC] 和滤泡状甲状腺癌 [FTC]）患者和 302 例 HC 被基因分型，以研究维生素 D 代谢酶中的多态性，如 25-羟化酶（CYP2R1[rs12794714、rs10741657]）、25-羟基维生素 D-1α-羟化酶（CYP27B1[rs10877012、rs4646536]）和 25-羟基维生素 D 24-水解酶（CYP24A1[rs927650、rs2248137、rs2296241]）。此外，通过放射免疫法测量 25-羟基维生素 D(3)[25(OH)D(3)]和 1,25-羟基维生素[1,25(OH)(2)D(3)]的血浆水平。
基因型无差异；然而，CYP24A1 单倍型分析显示，PTC 中 rs2248137C/rs2296241A（13.1% vs. 19.1%；校正后 p [pc]=0.04）频率较低，而 rs2248137C/rs2296241G（56.0% vs. 41.9%；pc=0.03）、rs927650C/rs2296241G（22.5% vs. 8.4%；pc=1.6×10(-3)）和 rs927650C/rs2248137C/rs2296241G（21.1% vs. 7.3%；pc=1.5×10(-3)）在 FTC 中较 HC 更为常见。此外，如果根据四个 25(OH)D(3)类别（严重缺乏、缺乏、不足和充足）对患者和对照进行分组，那么两种 DTC 亚型的患者 1,25(OH)(2)D(3)的循环水平显著降低，尤其是在缺乏 25(OH)D(3)状态的组中与对照相比。尽管多态性在四个 25(OH)D(3)类别分层时没有差异，但 1,25(OH)(2)D(3)的激活状态根据所研究的 CYP24A1 多态性的基因型显著不同。
CYP24A1 基因内的单倍型、循环 25(OH)D(3)水平（缺乏）和向 1,25(OH)(2)D(3)的转化减少会增加 DTC 的风险。这些结果证实并扩展了先前的观察结果，并支持维生素 D 系统在 DTC 发病机制中的作用。缺乏 25(OH)D(3)水平与某些 CYP24A1 单倍型如何影响维生素 D 激活是未来研究的主题。
