Genes involved in the vitamin D pathway. Vitamin D3 comes from the diet but is mostly produced in the skin by the photolytic cleavage of 7-dehydrocholesterol. From vitamin D3, two enzymatic activation steps are required to produce the biologically active form of vitamin D [1α,25-(OH)2 D3]. CYP27A1 and CYP2R1 genes encode enzymes with 25-hydroxylase activity that catalyze the C-25 hydroxylation of vitamin D3. A final activation enzyme encoded by CYP27B1 subsequently catalyzes the rate-limiting C-1 hydroxylation step in 1α,25-(OH)2 D3 synthesis. The later enzyme is tightly-regulated in the kidney by calcium homeostatic signals, but also strongly induced by immune inputs (e.g. TLR signaling) in many cells of the immune system [] (not depicted). The active form of vitamin D, 1α,25-(OH)2 D3 (orange triangle), is then transport to vitamin D target cells by the vitamin D binding protein (encoded by the GC locus) or is metabolically inactivated by the 24-hydroxylase enzyme (encoded by the CYP24A1 locus). In vitamin D target cells, 1α,25-(OH)2 D3 translocates to the nucleus and binds to the vitamin D receptor (VDR). The ligand/receptor complex binds vitamin D response element (VDRE) located in the promoter region of target genes. The DNA-bound complex interacts with nuclear coregulators, such as SKIIP [], and alters the rate of gene transcription. Five genes having a VDRE or/and being transcriptionally regulated by vitamin D stimulation are shown (blue square). Genes selected for genotyping in the SLSJ study are circled in blue.
