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DOI: 10.1055/s-0034-1372027
The CYP27B1 polymorphism and the IFN-γ production of T-cells in type 1 diabetes
Introduction: 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] is a potent immune modulator and (alone or in combination with glucocorticoids) has shown to inhibit the production of pro-inflammatory cytokines such as Interferon (IFN)-γ in T-helper (Th) cells. In addition, polymorphisms (SNPs) of the vitamin D (VD) system have been associated with the autoimmune disease Type 1 diabetes (T1D). Our aim was to investigate a possible modulatory effect of VD related SNPs on the Th cell immune response.
Methods: Th cells from 24 T1D patients were cultured for 72h with phytohemagglutinin (PHA) alone or additionally with 1,25(OH)2D3, dexamethasone (Dex) and 1,25(OH)2D3+Dex. Gene expression levels of IFN-γ and 18sRNA were measured by Taqman assay and CT-values were defined as 2-[CTtarget-CT18sRNA]. At last, the CYP27B1-rs10877012, CYP24A1-rs2296241 and VDR FokI-rs10735810 SNPs were genotyped.
Results: No association in the IFN-γ transcription was observed in cultured Th cells from T1D according to the VDR FokI and CYP24A1 SNPs. In contrast, significantly higher IFN-γ gene expression levels were observed in Th cells from T1D with the CYP27B1 CC risk genotype compared to those with non-risk genotypes AC/AA after cultivation with PHA (CC = 852 vs. AC/AA = 281 2-ΔCTx106; p = 0.05). Moreover, stronger associations in the IFN-γ transcription according to CYP27B1 risk and non-risk genotypes were detected when Th cells were additionally stimulated with 1,25(OH)2D3 or 1,25(OH)2D3+Dex (1,25(OH)2D3: CC = 291 vs. AC/AA = 60 2-ΔCTx106 and 1,25(OH)2D3+Dex: CC = 25 vs. AC/AA = 8 2-ΔCTx106; both p = 0.01).
Conclusion: Th cells from CYP27B1 CC risk carriers express significantly more IFN-γ than Th cells from non-risk carriers. These results provide evidence that the CYP27B1 SNP appears to affect the cellular immune response modifying a pro-inflammatory profile. Additionally, CYP27B1 CC risk carriers may require higher VD doses in order to achieve a more beneficial IFN-γ transcription profile than non-risk carriers.