Exp Clin Endocrinol Diabetes 2014; 122 - P084
DOI: 10.1055/s-0034-1372101

FOXO3a Polymorphism rs4946936 and its interaction with vitamin D in differentiated thyroid cancer

N Röhlen 1, C Döring 2, ML Hansmann 2, F Grünwald 3, C Vorländer 4, WO Bechstein 5, K Holzer 5, S Zeuzem 1, K Badenhoop 1, M Penna-Martinez 1
  • 1Department of Internal Medicine I, Division of Endocrinology, Diabetes and Metabolism, University Frankfurt, Frankfurt am Main, Germany
  • 2Senckenberg Institute for Pathology, University Frankfurt, Frankfurt am Main, Germany
  • 3Department of Nuclear Medicine, University Frankfurt, Frankfurt am Main, Germany
  • 4Department of Surgery, Buergerhospital Frankfurt, Frankfurt am Main, Germany
  • 5Department of Surgery, University Frankfurt, Frankfurt am Main, Germany

Introduction: Previous studies identified 1,25(OH)2D3, the active form of vitamin D, as a protective factor in differentiated thyroid carcinoma (DTC). Furthermore, 1,25(OH)2D3 has been reported to mediate its antiproliferative actions through the transcription factor FOXO3a. Genetic variations within this pathway may affect thyroid carcinogenesis. The Single nucleotide polymorphism (SNP) rs4946936 is located in a regulatory region in FOXO3a nearby a vitamin D responsive element.

The aim of the present study was to investigate the SNP FOXO3a rs4946936 in DTC and its interaction with the vitamin D pathway.

Methods: 253 DTC (164 females, 89 males) and 353 healthy controls (HC, 199 females, 154 males) were genotyped for FOXO3a rs4946936 using Real Time PCR and the 1,25(OH)2D3 plasma concentration was measured with radioimmunoassay. In order to assess the range of physiological vitamin D action, we compiled subgroups of DTC and HC whose 1,25(OH)2D3 levels ranged within the mean value of HC+/- 1 standard deviation.

Results: Allele C was more frequent in DTC in comparison to HC (72.9% vs. 67.4% p = 0.05). This association was particularly strong in women (74.1% vs. 67.1% p = 0.0001). Female DTC patients with physiological 1,25(OH)2D3 plasma values differed from HC in both allele analysis (CC: 87.8% vs. 69.2%, TT: 12.2% vs. 30.8% p = 0.003, respectively) and in genotype analysis (CC: 75.6% vs. 44.2% CT: 24.4% vs. 50.0% TT: 0.0% vs. 5.8% p = 0.004, respectively), whereas there was no difference between DTC and HC with extreme 1,25(OH)2D3 concentrations.

Conclusion: Our results reveal an association between the SNP FOXO3a rs4946936 and differentiated thyroid cancer, particularly in women. Females carrying allele T and heterozygous CT appear protected from DTC in the context of sufficient 1,25(OH)2D3 concentrations. In conclusion, our results indicate an interaction of the 1,25(OH)2D3 signaling with the FOXO3a pathway.