CYP24A1 haplotypes are associated with differentiated thyroid carcinoma
Marissa Penna-Martinez1, Elizabeth Ramos-Lopez1, Julienne Stern1, Heinrich Kahles1, Nora Hinsch2, Martin-Leo Hansmann2, Ivan Selkinski3, Frank Grünwald3, Christian Vorländer4, Robert A Wahl4, Wolf O Bechstein5, Stefan Zeuzem1, Katharina Holzer5 & Klaus Badenhoop1
Background: Previously, we reported an association of vitamin D receptor (VDR) polymorphisms and differentiated thyroid cancer (DTC) risk. The aim of the present study was to investigate other vitamin D pathway genes such as CYP27B1, CYP2R1 and CYP24A1 which code for enzymes that, respectively, synthesize and degrade 1,25(OH)2D3 in patients with DTC and healthy controls (HC). Also its influence on 25(OH)D3 and 1,25(OH)2D3 plasma levels in DTC was evaluted.
Patients and methods: Two hundred fifty-five patients with DTC (papillary (PTC): n=205; follicular (FTC): n=50) and HC (n=269) German origin, were genotyped for CYP2R1 (rs10741657), CYP27B1 (rs10877012) and CYP24A1 (rs2248137, rs2296241) using real time PCR. Furthermore, the 25(OH)D3, and 1,25(OH)2D3 plasma levels in patients were measured by RIA.
Results: No difference was observed between DTC patients and HC in the genotype frequencies of the named polymorphisms. However, the haplotype rs2248137C/ rs2296241A for CY24A1 (13.1 vs 20.4%; p corrected (pc)=0.02) was less frequent in the PTC whereas the haplotype rs2248137C/rs2296241G (57.8 vs 41.4%; pc=0.01) was more fequent in the FTC compared to HC. In addition there was no correlation between 25(OH)D3 or 1,25(OH)2D3 levels and the rs10741657, rs10877012, rs2248137 and rs2296241 polymorphisms in DTC patients.
Conclusion: Haplotypes within of the CYP24A1 gene appear to be associated with differentiated thyroid cancer in Germans. While the haplotype CA for CYP24A1 polymorphisms confer to protection from PTC, the haplotype CG appeared to be associated with an increased FTC risk. These findings suggest further alterations in the vitamin D system that possibly influence the pathogenesis of DTC. Such an alteration of vitamin D pathways may affect the thyroid tissue and may not be apparent in the circulation. Since, this is the first report associating CYP24A1 polymorphisms with thyroid carcinoma, these findings need to be confirmed in studies with larger numbers of patients and in other populations.