The vitamin D receptor gene FokI polymorphism: functional impact on the immune system.
1Alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) has important effects on the growth and function of multiple cell types. These pleiotropic effects of 1,25(OH)2D3 are mediated through binding to the vitamin D receptor (VDR). Several polymorphisms of the human VDR gene have been identified, with the FokI polymorphism resulting in VDR proteins with different structures, a long f-VDR or a shorter F-VDR. The aim of this study was to investigate the functional consequences of the FokI polymorphism in immune cells. In transfection experiments, the presence of the shorter F-VDR resulted in higher NF-kappaB- and NFAT-driven transcription as well as higher IL-12p40 promoter-driven transcription. Marginal differences were observed for AP-1-driven transcription, and no differential effects were observed for transactivation of a classical vitamin D-responsive element. 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 more strongly in response to phytohemagglutinin. Together, these data provide the first evidence that the VDR FokI polymorphism affects immune cell behavior, with a more active immune system for the short F-VDR, thus possibly playing a role in immune-mediated diseases.
van Etten
Evelyne
E
Laboratory for Experimental Medicine and Endocrinology (LEGENDO), Katholieke Universiteit Leuven, Leuven, Belgium.
Verlinden
Lieve
L
Giulietti
Annapaula
A
Ramos-Lopez
Elizabeth
E
Branisteanu
Dumitru D
DD
Ferreira
Gabriela B
GB
Overbergh
Lut
L
Verstuyf
Annemieke
A
Bouillon
Roger
R
Roep
Bart O
BO
Badenhoop
Klaus
K
Mathieu
Chantal
C
D000328:Adult; D000818:Animals; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D053762:Interleukin-12 Subunit p40 / Q000276:immunology / Q000378:metabolism; D019169:Jurkat Cells; D051379:Mice; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D011110:Polymorphism, Genetic / Q000276:immunology*; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D018167:Receptors, Calcitriol / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
D053762:Interleukin-12 Subunit p40; D020033:Protein Isoforms; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D014157:Transcription Factors