No response to vitamin D 7X more likely if poor CYP24A1 or VDBP genes - Feb 2023

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Variability in response to vitamin D supplementation according to vitamin D metabolism related gene polymorphisms in healthy adults

Eur J Clin Nutr . 2023 Feb;77(2):189-194. doi: 10.1038/s41430-022-01218-y
Mariem Ammar 1 2, Syrine Heni 3 4, Mohamed Sahbi Tira 3 4, Yassine Khalij 3 4, Haithem Hamdouni 3 4, Dorra Amor 3 4, Sonia Ksibi 5, Asma Omezzine 3 4, Ali Bouslama 3 4

Objective: The aim of this study was to determine the influence of polymorphisms in some key gene actors of the vitamin D (vitD) metabolic pathway on supplementation efficacy.

Methods: In total, 245 healthy participants were recruited from occupational medicine service in Sahloul University Hospital with vitD deficiency [25(OH)D ≤ 30 ng/ml]. After giving an informed consent, all participants were asked to complete a generalized questionnaire and to follow a detailed personalized supplementation protocol. Genetic study was performed by PCR-RFLP for 15 single nucleotide polymorphisms (SNPs) belonging to DBP, CYP2R1, CYP27B14, CYP24A1 and VDR genes. Statistical study was carried out with SPSS23.0.

Results: Among the studied SNPs, non-response was significantly associated with variant alleles of

• rs4588 (OR* = 11.51; p < 0.001),    (VDBP = GC)
• rs10766197 (OR* = 6.92; p = 0.008)    (CYP24R1)
• rs12794714 (OR* = 5.09; p = 0.004).    (CYP24R1)

These three SNPs contributed in 18.8% in response variability with rs4588 being the most influential (10.3%). There was a significant linear negative correlation between baseline 25(OH)D and post supplementation 25(OH)D concentration (r = -0.437; p < 0.001) as well as a linear negative association between the increase in 25(OH)D concentration and GRS (GRS: genetic risk score = the sum of risk alleles) (r = -0.149; p = 0.033).

Conclusions:DBP-rs4588, CYP2R1-rs10766197 and rs12794714 variants are associated with variations in serum 25(OH)D concentrations and efficacy of response to vitD supplementation in Tunisian adults. Taking into account these variations can help to better adapt vitD intake to ensure a higher response to supplementation.
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Authors are opposed to infrequent vitamin D doses

Recent studies have reported that the use of intermittent high-dose bolus, introduced to achieve high adherence, rather than regular daily maintenance was ineffective at preventing rickets, tuberculosis, acute respiratory infections [35] and may increase the risk of falling in elderly subjects [36]. There is a plausible biological explanation for this, since high-dose bolus supplementation induces the suppression of vitD activation by the expression of long-term catabolic enzyme 24- hydroxylase and fibroblast growth factor 23, both of which have vitD inactivating effects. It has been recognized that the increased 24- hydroxylase activity, as a feedback control response to a large bolus of vitD, may itself have a long half-life [37]. This means that a single highdose bolus of vitD could paradoxically lead to intracellular deficiency of activated vitD as a rebound phenomenon. This might be particularly important in immune cells such as the dendritic cells that are probably central to the hyperinflammatory state seen in severe COVID-19 [35]. Overall, taking into account the rs4588 minor allele frequency (0.21%) (Supplementary Table 3) and the implication of this polymorphism on the poor response to vitD supplementation by modifying its binding affinity, it seems that modest doses and daily provision of vitD supplementation is more effective rather than intermittent high-dose boluses.

Rebutal in VitaminDWiki: Better than Daily

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VitaminDWiki - Genetics chart shows the vitamin D genes

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VitaminDWiki - CYP2R1 gene reduces response to Vitamin D - many studies

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Genes and other reasons for poor blood response to Vitamin D supplementation

• Poor or no response to vitamin D was associated with poor genes (cystic fibrosis, 4 genes) Sept 2022
• Reasons for low response to vitamin D
• Autistics have half of the response to Vitamin D – RCT Oct 2018
• Poor CYP2R1 gene reduces blood response to Vitamin D supplementation – Aug 2019
• Poor Vitamin D response 4X more likely if poor Vitamin D binding proteins - July 2019
• Vitamin D Nutrigenomics - High, Medium, and Low Responders - March 2019
• Vitamin D non-responders may have one or more poor genes: GC, LIPC, CYP24A1, and PDE3B – Oct 2022

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VitaminDWiki - Vitamin D Binding Protein category listing has 176 items

Vitamin D Binding Protein (GC) gene can decrease the bio-available Vitamin D that can get to cells,

• GC is not the only such gene - there are 3 others, all invisible to standard Vitamin D tests
• The bio-available calculation does not notice the effect of GC, CYP27B1, CYP24A1, and VDR
• The actual D getting to the cells is a function of measured D and all 4 genes
• There is >2X increase in 8+ health problems if have poor VDBP (GC)
• It appears that VDBP only blocks oral vitamin D,
  • but NOT Vitamin D from sun, UV, topical or inhaled (tissue activated)
  • A clue: - Vitamin D from UV is 2X better for MS than oral Vitamin D

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VitaminDWiki - Health Problems associated with Vitamin D Binding Protein

Increased Risk	Health Problem
11 X	Preeclampsia
6.5X	T1D in SA Blacks
6 X	Food Allergy
5 X	PTSD
4 X, 5X	Kidney Cancer
4 X	Poor Response to Oral Vitamin D
3 X	Ear infection
2.8 X	MS
2 X	Colorectal Cancer
2 X	Prostate Cancer -in those with dark skins
1.3 X	Infertility