title: The vitamin D receptor gene FokI polymorphism: functional impact on the immune system.
abstract: 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.
authors.affiliation: Laboratory for Experimental Medicine and Endocrinology (LEGENDO), Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Evelyne
authors.initials: E
authors.lastname: van Etten
authors.forename: Lieve
authors.initials: L
authors.lastname: Verlinden
authors.forename: Annapaula
authors.initials: A
authors.lastname: Giulietti
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ramos-Lopez
authors.forename: Dumitru D
authors.initials: DD
authors.lastname: Branisteanu
authors.forename: Gabriela B
authors.initials: GB
authors.lastname: Ferreira
authors.forename: Lut
authors.initials: L
authors.lastname: Overbergh
authors.forename: Annemieke
authors.initials: A
authors.lastname: Verstuyf
authors.forename: Roger
authors.initials: R
authors.lastname: Bouillon
authors.forename: Bart O
authors.initials: BO
authors.lastname: Roep
authors.forename: Klaus
authors.initials: K
authors.lastname: Badenhoop
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
mesh_terms: 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
chemical_list: D053762:Interleukin-12 Subunit p40; D020033:Protein Isoforms; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D014157:Transcription Factors