Consequences of vitamin D receptor gene polymorphisms for growth inhibition of cultured human peripheral blood mononuclear cells by 1,25-dihydroxyvitamin D3

OBJECTIVE In the vitamin D receptor (VDR) gene a BsmI restriction fragment length polymorphism (RFLP) in intron 8 and a translational start‐site polymorphism, identified as a FokI RFLP, have been described. Crucial for a proper interpretation of these polymorphisms in association studies is the knowledge whether they have direct consequences for 1,25‐(OH)2D3 action at cellular level. The present study was designed to assess functional significance of the FokI and BsmI VDR gene polymorphisms in peripheral blood mononuclear cells (PBMC) with a natural occurring VDR genotype for cell growth inhibition by 1,25‐(OH)2D3. DESIGN PBMC of women were isolated, VDR genotyped and in vitro inhibition by 1,25‐(OH)2D3 of Phytohemagglutinin (PHA)‐stimulated growth of PBMC was examined in relation to VDR genotype. RESULTS PHA‐stimulated growth and maximal growth inhibition were independent of VDR genotype. However, the FF genotype had a significant lower ED50 than 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 observed. CONCLUSION The present study demonstrates for the first time in cells with a natural VDR genotype a direct functional consequence of the VDR gene translational start‐site polymorphism for the action of 1,25‐(OH)2D3. Especially under conditions of vitamin D insufficiency these findings might have clinical implications.