Vitamin D receptor gene polymorphism influences the amplitude of 1,25(OH)2D3 immune impact
Evelyne van Etten1, Lieve Verlinden1, Annapaula Giulietti1, Elizabeth Ramon Lopez2, Dumitru D Branisteanu3, Gabriela Bomfim Ferreira1, Lutgaard Overbergh1, Annemieke Verstuyf1, Roger Bouillon1, Bart O Roep4, Klaus Badenhoop2 & Chantal Mathieu1
1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) influences the differentiation and cytokine secretion of various immune cell types. These immune modulating effects of 1,25(OH)2D3 are mediated through the nuclear vitamin D receptor (VDR). In the immune system, the 1,25(OH)2D3/VDR complex interacts with promoter vitamin D responsive elements (VDRE), or interferes with the signalling of other transcription factors. A common VDR gene polymorphism is the FokI polymorphism, leading either to a long f-VDR or a shorter F-VDR isoform. In transfection experiments, we investigated whether the long f-VDR and short F-VDR interacted differently with immune transcription factors, such as NFkB, NFAT and AP-1. We also checked whether FokI polymorphism affected the capacity to transactivate a reporter gene driven by a classical VDRE. Finally, the functional impact of the long f-VDR and short F-VDR on immune cell behavior was investigated in monocytes and lymphocytes, which were derived from humans differing in their VDR FokI genotype. The shorter F-VDR resulted in higher NFkB- and NFAT-driven transcription as well as higher IL-12p40 promoter-driven transcription in RAW 264.7 and Jurkat cells (P<0.05, ANOVA test and Fishers LSD multiple comparison). Marginal differences were observed for AP-1-driven transcription and no differential effects were observed for transactivation of a classical vitamin D responsive element for the osteopontin gene. Concordantly, in human monocytes and dendritic cells with a homozygous short FF VDR genotype, expression of IL-12 (mRNA and protein) was higher than in cells with a long ff VDR-genotype. Additionally, lymphocytes with a short FF VDR-genotype proliferated stronger in response to phytohemagglutinin. These data provide evidence that the VDR FokI polymorphism affects immune cell behaviour, with a more active immune system for the short F-VDR, thus possibly playing a role in immune mediated diseases.