Downstream Link of Vitamin D Pathway with Inflammation Irrespective of Plasma 25OHD3: Hints from Vitamin D-Binding Protein (DBP) and Receptor (VDR) Gene Polymorphisms

<b>Background:</b> Vitamin D insufficiency/deficiency is a highly prevalent condition worldwide. At the same time, chronic inflammation is a versatile pathophysiological feature and a common correlate of various disorders, including vitamin D deficiency. <b>Methods:</b> We investigated the possible association of inflammation with 25-hydroxyvitamin D3 (25OHD3) levels and its down-stream pathway by exploring vitamin D-binding protein (<i>DBP</i>) and vitamin D receptor (<i>VDR</i>) genes for single-nucleotide polymorphisms (SNPs), in healthy non-elderly Bahraini adults. Plasma levels of 25OHD3 were measured by chemiluminescence, and six SNPs, four in the <i>GC</i> gene (rs2282679AC, rs4588CA, rs7041GT, and rs2298849TC) and two in the <i>VDR</i> gene (rs731236TC and rs12721377AG) were genotyped by real-time PCR. The concentrations of five inflammatory biomarkers, IL6, IL8, procalcitonin (PCT), TREM1, and uPAR, were measured by ELISA. <b>Results:</b> The results showed no association between the 25OHD3 level and any of the inflammatory markers' levels. However, three tested SNPs were significantly associated with the concentrations of tested biomarkers except for IL6. The TT mutant genotype of rs2298849TC was associated with lower levels of IL8 and higher levels of PCT and TREM1, the AA mutant genotype of rs2282679AC was associated with decreased levels of IL8 (<i>p</i> ≤ 0.001) and increased levels of TREM1 (<i>p</i> = 0.005), and the GG wild genotype of rs12721377AG was associated with increased levels of 25OHD3 (<i>p</i> = 0.026). <b>Conclusions:</b> Although chronic inflammation is not associated with the vitamin D system in the blood, it is downstream, as revealed by <i>DBP</i> and <i>VDR</i> genotyping. Alternatively, DBP and VDR pursue other functions beyond the vitamin D pathway.