Association between vitamin D receptor (VDR) gene polymorphisms and systemic lupus erythematosus in Portuguese patients.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown origin, in which both genetic and environmental factors are involved. One such environmental factor is vitamin D, a vital hormone that plays a specific function in the immune system homeostasis, acting through a nuclear receptor (VDR) expressed in all immune cells. Several polymorphisms of the gene that encodes this receptor have been described. Though inconsistently, these polymorphisms have been associated with clinical manifestations and SLE development.The aim of this study was to determine the possible association between VDR gene polymorphisms (BsmI, ApaI, TaqI e FokI) and SLE susceptibility and severity, in a cohort of lupus patients from the north of Portugal.A total of 170 patients (F = 155, M = 15; age = 45 ± 13.4 years) with SLE (diagnosed according the American College of Rheumatology criteria) with at least five years of disease evolution and followed in the Autoimmune Disease Clinical Immunology Unit of Centro Hospitalar do Porto were studied. Patients and 192 ethnicity-matched controls were genotyped for BsmI (rs1544410), ApaI (rs7975232), TaqI (rs731236) and FokI (rs2228570) polymorphisms by TaqMan allelic discrimination assay. Disease severity was assessed by SLICC damage score, number of affected organs, number of severe flares and pharmacological history.SLE patients with the CT genotype of FokI polymorphism have a higher SLICC value (p = 0.031). The same result was observed for the group of patients with the TT genotype of TaqI polymorphism (p = 0.046). No differences were observed in VDR genotype between patients and controls. Also, we observed that the other clinical features analysed were not influenced by VDR polymorphisms.Our study confirms a possible role of VDR gene polymorphisms in SLE. A positive association was found between VDR polymorphisms and SLE severity (chronic damage). The presence of CT genotype of FokI and TT genotype of TaqI seems to confer a worse prognosis and may constitute a risk factor for higher long-term cumulative damage in SLE patients.

Differing shapes of 1 alpha,25-dihydroxyvitamin D3 function as ligands for the D-binding protein, nuclear receptor and membrane receptor: a status report.

1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] is the principal mediator of a wide array of biological responses through the far reaching network of the vitamin D endocine system (VDE). The steroid hormone 1 alpha,25(OH)2D3 is delivered to the various target organs of the VDE via a specific plasma transport protein, the vitamin D binding protein (DBP). Also 1 alpha,25(OH)2D3 is known to initiate biological responses through a nuclear receptor, the nVDR (50 kDa) which regulates selected gene transcription and, in addition in some target tissues, through a second receptor located in the cell membrane, the mVDR (approximately 60 kDa), which is linked to protein kinase C and/or voltage-gated Ca2+ channels so as to generate biological responses very rapidly. 1 alpha,25(OH)2D3 as a ligand is unusually conformationally flexible due to the eight carbon side chain, the seco B-ring which permits rotation about the 6-7 single carbon bond, and the A-ring which undergoes chair-chair conformational interconversion characteristic of cyclohexane rings. This paper reviews the evidence that different shapes of the 1 alpha,25(OH)2D3 satisfy the optimal requirements of the ligand binding domains of the DBP, nVDR and mVDR. The presence of a relatively rigid side chain (composed by the presence of an aromatic ring) enhances ligand interaction 2-3 fold with the DBP, but diminishes ligand affinity for the nVDR by 100 fold. The mVDR responds effectively to analogs of 1 alpha,25(OH)2D3 which are 6-s-cis locked [e.g. 1 alpha,25(OH)2-previtamin D3 or 1 alpha,25(OH)2-provitamin D3], but these same analogs have only 1-2% of the activity of 1 alpha,25(OH)2D3 in regulating gene transcription. Finally the 6-s-trans analog, 1 alpha,25(OH)2-tachysterol3, had <0.1% of the activity of 1 alpha,25(OH)2D3 in regulating gene transcription.

Identification of cDNAs encoding two subtypes of vitamin D receptor in flounder, Paralichthys olivaceus.

cDNAs encoding two subtypes of the vitamin D receptor (VDR) are cloned from a teleost (flounder, Paralichthys olivaceus). This is the first report of VDR subtypes in fish. Flounder VDR (fVDR) a and b share 86% identity at the amino acid level. With human (h), rat, mouse, quail, and Xenopus VDRs, fVDRa shares 72%, 71%, 71%, 69%, and 71% identity, and fVDRb shares 70%, 69%, 69%, 67%, and 68% identity, respectively. The peptide sequences of the DNA-binding domain (DBD) and hormone-binding domain (HBD) of both subtypes have particularly high homology to those of the tetrapods; e.g. 92% identity for DBP and 74% for HBD between fVDRa and hVDR. In an evolutionary tree constructed with peptide sequences of VDRs and related members of the nuclear receptor superfamily, fVDRa and b are more closely related to each other than to other molecules, and situated in the cluster of VDRs at a position which corresponds well with the evolutional position of fish in the vertebrates. Additional independent genome duplication which is thought to have occurred in ray-finned fish phylogeny may explain the existence of two subtypes of VDR in flounder.