Dissecting high from low responders in a vitamin D3 intervention study
The Journal of Steroid Biochemistry and Molecular Biology doi:10.1016/j.jsbmb.2014.11.012
Noora Saksaa, 1, Antonio Nemea, 1, Jussi Ryynänena, Matti Uusitupab, Vanessa D.F. de Mellob, Sari Voutilainenb, Tarja Nurmib, Jyrki K. Virtanenb, Tomi-Pekka Tuomainenb, Carsten Carlberg a, ,
Highlights
- The genes ASAP2, CAMP, CD14, CD97, DUSP10, G0S2, IL8, LRRC8A, NINJ1, NRIP1, SLC37A2 and THBD are primary VDR targets.
- On the level of the expression of primary VDR target genes only 55–62% of the study participants were vitamin D3 responders.
- Only 12 biochemical and clinical parameters show a highly significant correlation with serum 25(OH)D3 levels.
- All 24 parameters together define a network with parathyroid hormone in the center.
- Transcriptomic and serum biomarkers allow a dissection of study subjects into high and low vitamin D3 responders.
Vitamin D3 is a pleiotropic signaling molecule that has via activation of the transcription factor vitamin D receptor (VDR) a direct effect on the expression of more than 100 genes. The aim of this study was to find transcriptomic and clinical biomarkers that are most suited to identify vitamin D3 responders within 71 pre-diabetic subjects during a 5-month intervention study (VitDmet). In hematopoietic cells, the genes ASAP2, CAMP, CD14, CD97, DUSP10, G0S2, IL8, LRRC8A, NINJ1, NRIP1, SLC37A2 and THBD are known as primary vitamin D targets. We demonstrate that each of these 12 genes carries a conserved VDR binding site within its genomic region and is expressed in human peripheral blood mononuclear cells (PBMCs). The changes in the expression of these genes in human PBMCs at the start and the end of the vitamin D-intervention were systematically correlated with the alteration in the circulating form of vitamin D3, 25-hydroxyvitamin D3 (25(OH)D3).
Only 39–44 (55–62%) of the study subjects showed a highly significant response to vitamin D3, i.e., we considered them as “responders”. In comparison, we found for 37–53 (52–75%) of the participants that only 12 biochemical and clinical parameters, such as concentrations of parathyroid hormone (PTH) and insulin, or computed values, such as homeostatic model assessment and insulin sensitivity index, show a correlation with serum 25(OH)D3 levels that is as high as that of the selected VDR target genes. All 24 parameters together described the pleiotropic vitamin D response of the VitDmet study subjects. Interestingly, they demonstrated a number of additional correlations that define a network, in which PTH plays the central role. In conclusion, vitamin D3-induced changes in human PBMCs can be described by transcriptomic and serum biomarkers and allow a segregation into high and low responders.
This article is part of a Special Issue entitled ‘17th Vitamin D Workshop’ .
Abbreviations
1,25(OH)2D3, 1α,25-dihydroxyvitamin D3; 25(OH)D3, 25-dihydroxyvitamin D3; ADIPOQ, adiponectin; ASAP2, ArfGAP with SH3 domain, ankyrin repeat and PH domain 2; B2M, beta-2-microglobulin; CAMP, cathelicidin antimicrobial peptide; CD14, CD14 molecule; CD97, CD97 molecule; ChIP, chromatin immunoprecipitation; ChIP-seq, ChIP sequencing; DR3, direct repeat spaced by 3 nucleotides; DUSP10, dual specificity phosphatase 10; FFA, free fatty acid; G0S2, G0/G1switch 2; GAPDH, glycerinaldehyde-3-phosphate-dehydrogenase; GEO, gene expression omnibus; GTP, glutamic-pyruvate transaminase (alanine aminotransferase); HOMA, homeostatic model assessment; HPRTI, hypoxanthine phosphoribosyltransferase 1; IGV, integrative genomics viewer; IL6, interleukin 6; IL8, interleukin 8; INS, insulin; IR, insulin resistance; LPS, lipopolysaccharide; LRRC8A, leucine rich repeat containing 8 family, member A; NINJ1, ninjurin 1; NRIP1, nuclear receptor interacting protein 1; PBMC, peripheral blood mononuclear cell; PTH, parathyroid hormone; qPCR, real-time quantitative polymerase chain reaction; RPLP0, ribosomal protein, large, P0; SLC37A2, solute carrier family 37, member 2; TNFRSF1B, tumor necrosis factor receptor superfamily, member 1B; TSS, transcription start site; THBD, thrombomodulin; VDR, vitamin D receptor
See also Vitamin D Life
- Genetics cagetory listing with related searches
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