The researchers in Poland who formed as part of the Nutriome cohort received funding from the European Union’s Horizon 2020 project to identify circadian genes targeted by vitamin D, explore whether vitamin D modulates circadian rhythms and understand interindividual variability of the response to vitamin D at the gene expression level.
“Findings highlight a novel link between vitamin D signaling and circadian gene regulation, with potential implications for personalized supplementation strategies,” they wrote in the journal Nutrients.
Vitamin D and circadian rhythm
Vitamin D’s molecular actions revolve around its nuclear receptor, VDR (vitamin D receptor), which strongly binds to the active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). As a transcription factor, VDR controls vitamin D’s genomic effects, with 1,25(OH)2D3 as its only activator. VDR is present in most tissues, except the brain, and regulates hundreds of genes in a tissue- and individual-specific way.
This variability in gene response leads to the vitamin D response index, which categorizes individuals as high, mid or low responders to vitamin D supplementation. This diversity in response may explain the challenges in finding consistent health benefits from vitamin D3 supplementation in general population studies, the researchers noted.
They previously conducted studies in Finland to investigate how vitamin D affects the body at the molecular level under healthy conditions. Participants received a total of 80,000 IU of vitamin D3 in two equal doses with breakfast and lunch for one month.
In one of the studies, the PER1 gene, a key regulator of circadian rhythms, emerged as a major vitamin D target. Since the body naturally produces vitamin D3 in a day-night rhythm, the researchers examined whether vitamin D also influences circadian gene expression.
Study details
In the VitDHiD intervention study, the researchers discovered 87 vitamin D target genes that showed circadian expression patterns in immune cells. Those genes were found to form a regulatory network focused on transcription factors and membrane receptors. Under normal conditions, they showed limited variation in activity, but after vitamin D3 supplementation, 80% of them were downregulated.
The researchers then used clustering analysis to group these genes into six distinct categories. The two largest groups are mainly regulated by the transcription factor CSRNP1 and GAS7, a protein known to promote cell differentiation.
Among the 25 participants in the study, the researchers found two subgroups based on how strongly 14 of the vitamin D target genes responded to the supplementation. The 14 genes included transcription factors and genes for metabolic enzymes and transporters. All of these genes were found to have a vitamin D receptor-binding enhancer located close to their transcription start site, which likely explains their responsiveness to vitamin D.
“This study provides new insights into the circadian expression of vitamin D target genes in vivo, demonstrating a significant overlap between genes responsive to vitamin D3 supplementation and those exhibiting circadian rhythmicity,” the researchers noted.
The results of the research highlight the variability in individual responses to vitamin D supplementation, potentially opening up opportunities in personalized nutrition, where supplements could be tailored to individual needs based on factors like genetic makeup and circadian rhythm, they added.
It also linked vitamin D supplementation with circadian gene regulation, showing how vitamin D impacts genes related to the body’s day-night cycles, meaning that the timing of vitamin D intake could become more important.
Nutrients 2025, 17(7), 1204. doi: 10.3390/nu17071204. “Circadian Regulation of Vitamin D Target Genes Reveals a Network Shaped by Individual Responsiveness”. Authors: Maissan, P. et al.