Consequences of vitamin D receptor gene polymorphisms for growth inhibition of cultured human peripheral blood mononuclear cells by 1,25-dihydroxyvitamin D-3

OBJECTIVE In the vitamin D receptor (VDR) gene a BsmI restriction fragment length polymorphism (RFLP) in intron 8 and a translational start-site polym orphism, identified as a FokI RFLP, have been described. Crucial for a prop er interpretation of these polymorphisms in association studies is the know ledge whether they have direct consequences for 1,25-(OH)(2)D-3 action at c ellular level. The present study was designed to assess functional signific ance of the FokI and BsmI VDR gene polymorphisms in peripheral blood mononu clear cells (PBMC) with a natural occurring VDR genotype for cell growth in hibition by 1,25-(OH)(2)D-3. DESIGN PBMC of women were isolated, VDR genotyped and in vitro inhibition b y 1,25-(OH)(2)D-3 of Phytohemagglutinin (PHA)-stimulated growth of PBMC was examined in relation to VDR genotype. RESULTS PHA-stimulated growth and maximal growth inhibition were independen t of VDR genotype. However, the FF genotype had a significant lower ED50 th an the Ff genotype corresponding to an allele dose effect of 0.32 nm per f allele copy (P = 0.0036). For BsmI genotypes no differences in ED50 were ob served. CONCLUSION The present study demonstrates for the first time in cells with a natural VDR genotype a direct functional consequence of the VDR gene tran slational start-site polymorphism for the action of 1,25-(OH)(2)D-3. Especi ally under conditions of vitamin D insufficiency these findings might have clinical implications.