Molecular evaluation of vitamin D responsiveness of healthy young adults

Seuter, Sabine; Virtanen, Jyrki K.; Nurmi, Tarja; Pihlajamäki, Jussi; Mursu, Jaakko; Voutilainen, Sari; Tuomainen, Tomi‐Pekka; Neme, Antonio; Carlberg, Carsten

doi:10.1016/j.jsbmb.2016.06.003

Cited by 45 publications

(46 citation statements)

References 35 publications

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“…These rises were slightly lower than the averages of 17.4 and 21.1 nM that were determined after one and two days, respectively, for the 27 vitamin D3 bolus supplemented participants of phase I of VitDbol (the 8 remaining participants of VitDbol received placebo) [22].…”

Section: Vitdbol Phase II Studycontrasting

confidence: 61%

“…In order to study vitamin D-dependent gene regulation under in vivo conditions in human, we designed the VitDbol vitamin D intervention trial (NCT02063334, ClinicalTrials.gov). In phase I of the study, 35 healthy young adults were exposed once to a vitamin D3 bolus (2,000 µg) and the change of chromatin accessibility at selected genomic regions [22] and the induction of a few primary vitamin D target genes [23] was measured from peripheral blood mononuclear cells (PBMCs) at days 0, 1 and 2. This demonstrated that a single vitamin D3 bolus is sufficient to activate genes.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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In vivo response of the human epigenome to vitamin D: A Proof-of-principle study

Carlberg

Seuter

Nurmi

et al. 2018

The Journal of Steroid Biochemistry and Molecular Biology

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In vitro cell culture studies showed that the hormonal form of vitamin D, 1α,25-dihydroxyvitamin D, significantly (p < 0.05) affects the human epigenome at thousands of genomic loci. Phase II of the VitDbol vitamin D intervention trial (NCT02063334) involved a proof-of-principle study of one individual, who was exposed three times every 28 days to an oral bolus (2000 μg) of vitamin D. Blood samples were taken directly before each supplementation as well as one and two days after, chromatin was isolated from peripheral blood mononuclear cells without any further in vitro culture and at all nine time points epigenome-wide chromatin accessibility was assessed by applying FAIRE-seq (formaldehyde-assisted isolation of regulatory elements sequencing). The vitamin D bolus resulted in an average raise in 25-hydroxyvitamin D (25(OH)D) serum concentration of 11.9 and 19.4 nM within one and two days, respectively. Consistently accessible chromatin was detected at 5205 genomic loci, the 853 most prominent of which a self-organizing map algorithm classified into early, delayed and non-responding genomic regions: 70 loci showed already after one day and 361 sites after two days significant (p < 0.0001) chromatin opening or closing. Interestingly, more than half of these genomic regions overlap with transcription start sites, but the change of chromatin accessibility at these sites has no direct effect on the transcriptome. Some of the vitamin D responsive chromatin sites cluster at specific loci within the human genome, the most prominent of which is the human leukocyte antigen region in chromosome 6. In conclusion, this study demonstrates that under in vivo conditions a rather minor rise in 25(OH)D serum levels is sufficient to result in significant changes at hundreds of sites within the epigenome of human leukocytes.

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Section: Vitdbol Phase II Studycontrasting

confidence: 61%

Section: Accepted Manuscriptmentioning

confidence: 99%

In vivo response of the human epigenome to vitamin D: A Proof-of-principle study

Carlberg

Seuter

Nurmi

et al. 2018

The Journal of Steroid Biochemistry and Molecular Biology

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“…Finally, Seuter et al [47] evaluated an interesting multiple parameter determination of the vitamin D responsiveness without regard of genetic influence. The correlation analysis is based on changes in parathyroid hormone (PTH) serum concentrations after ingestion of a single oral dose of vitamin D 800,000 IU and resultant vitamin D modulated chromatin accessibility.…”

Section: Discussionmentioning

confidence: 99%

Genetic Components of 25-Hydroxyvitamin D Increase in Three Randomized Controlled Trials

Trummer

Schweighofer

Haudum

et al. 2020

JCM

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The 25-Hydroxyvitamin D (25[OH)D) serum concentration depends on vitamin D intake, endogenous vitamin D production and genetic factors. The latter have been demonstrated in large genome-wide association studies indicating that single nucleotide polymorphisms (SNPs) in genes related to the vitamin D metabolism are as important for serum 25(OH)D levels as the influence of season. The mechanism on how these SNPs influence serum 25(OH)D levels are still unclear. The aim of the present study was to investigate the genetic effects of ten selected SNPs related to vitamin D metabolism on 25-hydroxyvitamin D increase (∆25(OH)D) after vitamin D supplementation in three randomized controlled trials. Genotypes of SNPs related to vitamin D metabolism were determined in 411 participants with 25(OH)D concentrations < 75 nmol/l receiving 20,000 IU cholecalciferol per week for 8 or 12 weeks after study inclusion. For the vitamin D receptor (VDR) rs10783219 polymorphism, the minor A-allele was associated with lower ∆25(OH)D values in the entire study population (p = 0.022), which was not consistent in all three cohorts when analysed separately. VDR rs10783219 might therefore be a genetic modulator of increasing 25-hydroxyvitamin D concentrations. Considering the wide-spread use of vitamin D supplementation, future large and well-designed randomized controlled trials (RCTs) should investigate the clinical impact of this polymorphism.

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“…However, the outcome of clinical trials has been conflicting and this is often attributed to differences in study design, baseline vitamin D status of participants, and outcome measurements. In fact, it appears that individuals can be classified into three groups: (i) those with a low response, (ii) those with a medium response, and (iii) those with a high response to vitamin D supplementation ( 15 ). These interindividual differences may result from variation in the regulation of VDR expression at both a genetic and epigenetic level ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

Methylation of the Vitamin D Receptor (VDR) Gene, Together with Genetic Variation, Race, and Environment Influence the Signaling Efficacy of the Toll-Like Receptor 2/1-VDR Pathway

et al. 2017

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BackgroundThe disparity in prevalence of infectious diseases across the globe is common knowledge. Vitamin D receptor (VDR)-mediated toll-like receptor (TLR) 2/1 signaling produces antimicrobial peptides, which is critical as a first line of defense in innate immunity. Numerous studies disclosed the independent role of genetic polymorphisms in this pathway, vitamin D status or season and more recently epigenetics, as factors contributing to infectious disease predisposition. Few studies address the interaction between environment, genetics, and epigenetics. Here, we hypothesized that VDR-mediated TLR2/1 signaling is influenced by a combination of environment, epigenetics and genetics, collectively influencing differential innate immunity.MethodsHealthy Black and White South Africans (n = 100) donated blood, while ultraviolet index (UVI) was recorded for the duration of the study. LC-MS/MS supported 25(OH)D3 quantification. Monocyte/macrophage cultures, supplemented with/without 1,25(OH)2D3, were activated with the TLR2/1 elicitor, Pam3CSK4. VDR, cathelicidin antimicrobial peptide, hCAP-18, and 25-hydroxyvitamin D3-24-hydroxylase expression were quantified by RT-qPCR or flow cytometry. Pyrosequencing facilitated VDR methylation analysis and single-nucleotide polymorphism (SNP) genotyping in regions pinpointed through a bioinformatics workflow.ResultsSeason interacted with race showing 25(OH)D3 deficiency in Blacks. UVI correlated with 25(OH)D3 and VDR methylation, likely influencing race differences in the latter. Regarding the TLR2/1 pathway, race differences in SNP genotype distribution were confirmed and functional analysis of VDR-mediated signaling showed interaction between race, season, and 25(OH)D3 status. Multivariate OPLS-DA mirrored several interactions between UVI, 25(OH)D3 status, DNA sequence, and methylation variants. Methylation of the third cytosine-phosphate-guanine dinucleotide (CpG) in the promoter CpG island (CGI) 1062, CGI 1062 CpG 3, significantly discriminated a 5.7-fold above average mean in VDR protein level upon TLR2/1 elicitation, the variation of which was further influenced by 25(OH)D3 status and the VDR SNP TaqI.ConclusionRegulation of VDR-mediated TLR2/1 signaling is multifactorial, involving interaction between environment [UVI and consequent 25(OH)D3 status], epigenetics (VDR methylation at key regulatory sites), and genetics (TLR1, TIRAP, and VDR SNPs).

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Molecular evaluation of vitamin D responsiveness of healthy young adults

Cited by 45 publications

References 35 publications

In vivo response of the human epigenome to vitamin D: A Proof-of-principle study

In vivo response of the human epigenome to vitamin D: A Proof-of-principle study

Genetic Components of 25-Hydroxyvitamin D Increase in Three Randomized Controlled Trials

Methylation of the Vitamin D Receptor (VDR) Gene, Together with Genetic Variation, Race, and Environment Influence the Signaling Efficacy of the Toll-Like Receptor 2/1-VDR Pathway

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