Vitamin D Deficiency Clearly Linked to Inflammation


Nancy A. Melville
August 19, 2022

Vitamin D deficiency has a causative role in the systemic inflammation that commonly accompanies it, with inflammation declining, reflected by reductions in elevated C-reactive protein (CRP), as vitamin D levels increase to normal levels, new research shows.

However, there is no reverse effect between the two: changes in CRP levels did not appear to affect vitamin D levels.

“This is the first study of its kind, and the first to show that the well-known relationship between vitamin D status and CRP is at least in part driven by vitamin D,” first author Elina Hypponen, PhD, a professor in nutritional and genetic epidemiology and director of the Australian Center for Precision Health in Adelaide, Australia, told Medscape Medical News.

“Given that the serum CRP level is a widely used biomarker for chronic inflammation, these results suggest that improving vitamin D status may reduce chronic inflammation, but only for people with vitamin D deficiency,” Hypponen and coauthors report in their study, published in the International Journal of Epidemiology.

Vitamin D Associated With CRP in an ‘L-Shaped’ Manner

Nutritional factors are known to influence systemic inflammation in a variety of ways. However, there has been debate over the association between vitamin D — specifically, serum 25(OH)D, an indicator of vitamin D status — and CRP, with some reports of observational associations between the two disputed in more robust randomized trials.

To further evaluate the relationship, the authors performed a bidirectional Mendelian randomization analysis, using a cohort of 294,970 unrelated participants of White/British ancestry in the UK Biobank, the largest cohort to date with measured serum 25(OH)D concentrations, they note.

Overall, the average 25(OH)D concentration was 50.0 nmol/L (range 10–340 nmol/L), with 11.7% (n = 34,403) of participants having concentrations of < 25 nmol/L, considered deficient.

The analysis showed that genetically predicted serum 25(OH)D was associated with serum CRP in an L-shaped manner, with CRP levels, and hence inflammation, sharply decreasing in relation to increasing 25(OH)D concentration to normal levels.

However, the relationship was only significant among participants with 25(OH)D levels in the deficiency range (< 25 nmol/L), with the association leveling off at about 50 nmol/L of 25(OH)D, which is generally considered a normal level.

The association was supported in further stratified Mendelian randomization analyses, which confirmed an inverse association between serum 25(OH)D in the deficiency range and CRP, but not with higher concentrations of serum vitamin D.

Conversely, neither linear nor non-linear Mendelian randomization analyzes showed a causal effect of serum CRP level on 25(OH)D concentrations.

The findings suggest that “improving vitamin D status in the deficiency range could reduce systemic low-grade inflammation and potentially mitigate the risk or severity of chronic illnesses with an inflammatory component,” the authors note.

Hypponen added that the greatest reductions in CRP are observed with correction of the most severe vitamin D deficiency.

“The strongest benefits of improving concentrations will be seen for people with severe deficiency,” Hypponen told Medscape Medical News.

“In our study, much of the benefit was achieved when people reached the National Academy of Sciences endorsed cut-off of 50 nmol/L [for vitamin D sufficiency].”

Pro-Hormone Effects?

The anti-inflammatory effects observed with serum vitamin D could be related to its role as a pro-hormone that can impact vitamin D receptor-expressing immune cells, such as monocytes, B cells, T cells, and antigen-presenting cells, the authors notes.

“Indeed, cell experiments have shown that active vitamin D can inhibit the production of pro-inflammatory cytokines, including TNF-alpha, interleukin (IL)-1b, IL-6, IL-8, and IL-12, and promote the production of IL-10, an anti-inflammatory cytokine,” they explain.

In that regard, adequate vitamin D concentrations could be important in preventing inflammation-related complications from obesity and reducing the risk or severity of chronic illnesses with an inflammatory component, such as cardiovascular diseases, diabetes, autoimmune diseases, neurodegenerative conditions, and others, the authors note.

Previous Studies Unable to Assess Effect of Deficiency

While the current findings contradict other studies that have used Mendelian randomization and showed no causal effect of 25(OH)D on CRP, those previous studies only used a standard linear Mendelian randomization method that could not rule out the possibility of a ‘threshold effect’ restricted to vitamin D deficiency, the authors note.

“Indeed, it is logical to expect that improving vitamin D status would be relevant only in the presence of vitamin D deficiency, whereas any further additions may be redundant and, in the…extreme of supplementation, might become toxic,” they write .

However, the nonlinear Mendelian randomization approach used in the current study allows for better detection of the association, and the authors point out that the method has also been recently used in research showing an adverse effect of vitamin D deficiency on cardiovascular disease (CVD) risk and mortality, which would not be visible using the standard linear Mendelian randomization approach.

Meanwhile, the current findings add to broader research showing benefits of increases in vitamin D to be mainly limited to those who are deficient, with limited benefit of supplementation for those who are not, Hypponen emphasized.

“We have repeatedly seen evidence for health benefits for increasing vitamin D concentrations in individuals with very low levels, while for others, there appears to be little to no benefit,” Hypponen said in a press statement.

“These findings highlight the importance of avoiding clinical vitamin D deficiency and provide further evidence for the wide-ranging effects of hormonal vitamin D,” she added.

The study was financially supported by the National Health and Medical Research Council, Australia. The authors have reported no relevant financial relationships.


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