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Randomized controlled trial: Vitamin D and gene expression

Posted on: April 6, 2013   by  John Cannell, MD

Randomized controlled trial: Vitamin D and gene expression

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We know that vitamin D controls from anywhere between 0. 5% of the human genome to up to 5%, depending on what review one reads. New genes are being discovered every day that vitamin D either upregulates or down regulates. That is, vitamin D either increases or decreases the protein that gene transcribes.

However, no one has ever done a gene microarray analysis (a way of looking at a large number of genes) of patients before and after vitamin D administration. That is, no one had ever done it until Professor Michael Holick’s lab reported such a study recently in the PLoS One journal.

Hossein-Nezhad A, Spira A, Holick MF.  Influence of vitamin D status and vitamin D3 supplementation on genome wide expression of white blood cells: a randomized double-blind clinical trial. PLoS One. 2013;8(3):e58725.

Doctors Arash Hossein-Nezhad, Avrim Spira and Michael Holick conducted a small randomized controlled pilot trial of 8 patients, doing a gene microarray analysis at baseline and again after two months of either 400 or 2,000 IU per day. The 2,000 IU/day group only increased 25(OH)D by 9.8 ng/ml, while 400 IU per day increased 25(OH)D by 5.6 ng/ml, so the two groups were combined for analysis. The study was conducted in the winter.

First, they found 291 genes in white blood cells that vitamin D affected. Vitamin D affects different genes in different tissues so this is only what low dose vitamin D does in white blood cells. Of the 291 genes, 82 genes were downregulated and 209 were upregulated. They found the affected gene pathways controlled immune function, transcription regulation, cell cycle activity, epigenetic modification, DNA regulation, DNA repair, and cellular response to stress.

Forty-seven of the 291 affected genes had never been reported to be affected by vitamin D. That is, they discovered 47 new vitamin D regulated genes. Even the one person who had a relatively high baseline 25(OH)D (level not given) and who obtained a 25(OH)D of above 40 ng/ml after supplementation with 2,000 IU/day for two months had differential expression of 33 genes, suggesting there is a significant genetic difference between 25(OH)D levels of 30 ng/ml and 40 ng/ml.

The authors concluded:

“These results suggest that to maximize vitamin D’s effect on gene expression may require even higher doses than 2,000 IU of vitamin D3 daily.”

Yes, we think that at least 5,000 IU/day is required to obtain natural vitamin D levels. If a genetic expression difference exists between levels of 40 and 80 ng/ml, we will only learn it by further studies, similar to this breakthrough discovery by Michael Holick’s lab.

4 Responses to Randomized controlled trial: Vitamin D and gene expression

  1. IAW

    In the case of Angelina Jolie and her double mastectomy, the news states that “The (gene) mutation means a woman is far more likely to develop breast cancer—Jolie says her doctors estimated she had an 87% chance of getting breast cancer and a 50% chance of getting ovarian cancer, which is also linked to BRCA mutations.” I am not a scientist and was wondering the following. Since it is now established that Vitamin D can “turn genes on and off” and deficiency can lead to internal cancers, can that be possibly linked to this “mutation” or is a “hereditary mutation” not something that Vitamin D could affect?

    • Brant Cebulla

      Interesting train of thoughts IAW. Just did a literature search and don’t see any research in the area of BRCA and vitamin D, however.

  2. Rita and Misty

    IAW–You ask a great question regarding vitamin d and its ability to “turn genes on and off” with respect to cancer…I am especially interested in learning about vitamin d and the BRCA mutations….if anyone has knowledge on this subject…or links….I’d certainly be interested in learning more. Thanks!

  3. Rita and Misty

    Vitamin D with respect to BRCA:

    http://www.slu.edu/x71202.xml

    As taken from the above link:

    The Fix
    If lowering the levels of 53BP1 allows BRCA1 deficient cells to thrive and do their worst, increasing the levels of the protein offers a promising strategy for treatment of breast tumors.

    So, how to do this? In previous research, Gonzalo’s team showed that vitamin D inhibits CTSL-mediated degradation of 53BP1 in non-tumor cells, as efficiently as specific CTSL inhibitors. This time, they found that treatment of BRCA1-deficient tumor cells with vitamin D restores high levels of 53BP1, which results in increased genomic instability and reduced proliferation. Importantly, their evidence suggests that vitamin D treatment might restore the sensitivity to PARP inhibitors in patients who become resistant. Thus, a combination of vitamin D and PARP inhibitors could represent a novel therapeutic strategy for breast cancers with poor prognosis.

    So, with this chain of events, Gonzalo and colleagues demonstrated a pathway by which triple-negative breast cancers proliferate: BRCA1-deficient cells activate CTSL which minimizes levels of 53BP1 to overcome genomic instability and growth arrest.

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