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Genetic evidence suggests a link between genetic predisposition to high vitamin D levels and mortality risk. Ezra Bailey/Getty Images
  • Researchers conducted a study to see whether genetic predisposition to high vitamin D levels affects overall health.
  • They found that genetic predisposition to higher vitamin D levels reduces all-cause mortality by 30% in people with low vitamin D levels.
  • Genetic predisposition had no effect on mortality among those with higher levels of vitamin D.
  • The researchers conclude that genetic evidence suggests a causal relationship between vitamin D levels and mortality only in people with low vitamin D levels.

Vitamin D is an essential nutrient thought to reduce the risk of chronic diseases, including cancer and cardiovascular disease. Observational studies have consistently found that vitamin D deficiency increases the risk of developing these conditions and of death from any cause.

Scientists do not know how exactly vitamin D levels might influence multiple health conditions. Some have suggested it may protect against cancer by regulating cadherins, which are proteins involved in cell-cell adhesion responsible for maintaining tissue architecture and regulation of cell growth and differentiation.

Despite this, several large randomized trials have not been able to find evidence that vitamin D supplementation for vitamin D deficiency has any benefit for cancer or cardiovascular disease.

This has made researchers question whether vitamin D levels really play a part in reducing the risk of these diseases or whether healthier people have naturally higher levels of the vitamin for other reasons.

Researchers led by the University of Cambridge in the United Kingdom conducted a study to see whether inherited genetic variants predisposing people to have higher vitamin D levels play a role in overall health.

“Our investigation provides intriguing new evidence that suggests raising vitamin D levels may reduce the risk of major disease and mortality, but only for people who have low vitamin D levels,” says Dr. Stephen Burgess, lead author of the study.

“Maintaining adequate levels of vitamin D is important, but there appears to be no benefit in supplementation beyond a threshold level,” he adds.

The study appears inThe Lancet Diabetes & Endocrinology.

The researchers initially gathered data from the UK Biobank, the European Prospective Investigation into Cancer and Nutrition Cardiovascular Disease study, and 31 studies from the Vitamin D Studies Collaboration.

Altogether, they analyzed health data from 386,406 middle-aged individuals with European ancestry. Each was followed for an average of 9.5 years, underwent 25-hydroxyvitamin D (25(OH)D) measurements, and did not have cardiovascular disease at baseline.

25(OH)D is the major circulating form of vitamin D in the body. It is measured via blood test to indicate vitamin D supply in the body from sunlight and nutrition.

Over the study period, 33,546 people developed coronary heart disease, 18,166 people had a stroke, and 27, 885 people died.

To understand the role of vitamin D levels in these health outcomes, the researchers investigated the participants’ inherited genetic variants predisposing them to higher vitamin D levels and analyzed their 25(OH)D measurements.

Similarly to authors of other studies, they found no link between genetic predisposition to higher vitamin D levels and coronary heart disease, stroke, or death.

However, among those with vitamin D deficiency, defined as lower than 25 nanomoles per liter (nmol/l), the researchers identified a strong link between genetic predisposition to higher vitamin D levels and a lower mortality risk.

They also found a link between a genetic predisposition to 10 nmol/l higher levels of 25(OH)D and a 30% lower all-cause mortality risk. Their analyses suggested similar effects on cardiovascular and cancer mortality.

These effects, however, were only evident in individuals with extremely low vitamin D levels, or those below 40 nmol/l.

“Previous […] studies assumed a linear association between genetically predicted 25(OH)D, the main marker of vitamin D status, and cardiovascular disease, despite the evidence from cohort studies of observed 25(OH)D having a nonlinear association with cardiovascular disease,” Prof. Robert Scragg, head of the School of Population Health at the University of Auckland in New Zealand, who was not involved in the study, told Medical News Today.

“However, the current study […] shows a nonlinear association for genetically predicted 25(OH)D [and cardiovascular disease]. […] To my knowledge, this is the first study to do this type of analysis to see if the association is nonlinear. Interestingly, the study also shows no association when you combine all participants, which is what previous […] studies reported. The key difference is the stratification by baseline 25(OH)D level.”

“The fact that the beneficial effect is mainly in people with 25(OH)D levels below 25 nmol/l explains why the recent clinical trials observed null results — as they did not have enough participants with very low 25(OH)D levels. In the ViDA study, we only had 91, while the VITAL study has been estimated to have had only about 500 — not enough to show any effect.”

The researchers highlight several potential mechanisms underlying the effects of vitamin D.

For example, animal studies have shown that vitamin D could regulate cardiac function due to its action on cardiac ​​metalloproteinases, a group of enzymes that break down proteins, and fibroblasts, which are the most common type of cell in connective tissue.

Vitamin D also plays a role in endothelial cell function. These cells form the lining of blood vessels and regulate exchanges between blood and surrounding tissues. Via its effects on endothelial cells, vitamin D modulates:

  • vascular tone, which is how constricted blood vessels are
  • atherosclerosis, which is the buildup of fats, cholesterol, and other substances on blood vessel walls
  • arterial calcification, which is a common part of the aging process in which calcium is deposited inside of blood vessels, making them lose elasticity and become more vulnerable to stress

The researchers add that vitamin D status also affects gene expression related to cell division and programed cell death, which could affect the growth of neoplasms — that is, excessive growth and division of cells — as well as DNA repair and immunomodulation in cancer.

The authors of the study conclude that genetic evidence suggests a causal relationship between 25(OH)D concentrations and mortality in people with low vitamin D levels.

However, they note some limitations to their results. For instance, they highlight that their analysis only included middle-aged individuals with European ancestry, meaning their results may not apply to people with different skin tones. Further analysis is needed, as people with dark skin often have lower vitamin D levels.

“This study has addressed an important question of whether taking vitamin D will have an impact on reducing the risk of chronic diseases, such as cardiovascular diseases and cancer,” Prof. Vimal Karani, professor in nutrigenetics and nutrigenomics at the University of Reading in the U.K., who was not involved in the study, told MNT. “However, the findings can be generalized only to the European populations, given that the study has focused on participants of European ancestries.”

“Moreover, the effect has been observed only in those who have low vitamin D concentrations, which could be partly attributed to the choice of genetic instrument. […] The genetic risk score was generated using 21 genetic variants from four different gene regions, of which two genes are involved in the ‘synthesis’ of [25(OH)D], and the other two are involved in the ‘metabolism’ of vitamin D,” he added.

“Previous studies have shown that the variation in [25(OH)D] concentrations explained by ‘synthesis’ genes is lesser than the variation explained by the ‘metabolism’ genes. Even though the authors had performed a sensitivity analysis to see if the results were driven by a single gene region, the study did not look at the individual impact of synthesis and metabolism genetic risk scores, respectively, on the risk of major disease and mortality, and this might partly explain the effects seen only in those who have low vitamin D levels,” he explained.

“However, given that nearly 40% of Europeans are vitamin D deficient, and 13% are severely deficient, this study has significant public health implications in suggesting the need for taking vitamin D supplementation to overcome the risk of chronic diseases.”

– Prof. Vimal Karani

“This study will rekindle the debate about vitamin D and cardiovascular disease,” said Prof. Scragg. “I think most researchers thought the matter was resolved after the findings of null results from two clinical trials of vitamin D supplementation — the VITAL study from the [United States] and the ViDA study from New Zealand — particularly in the light of previous […] studies, which showed no association between genetic markers of vitamin D status and cardiovascular disease.”

“Given that there is only a moderate beneficial effect in a small proportion of participants in the current study, it would take a huge clinical trial to [make similar observations for] vitamin D supplementation. I don’t think a further clinical trial now will ever be done, particularly since participants in a trial can always purchase their own vitamin D if they believe they have been allocated to the placebo group, and thus weaken any effect from vitamin D,” he explained.

“Consequently, this study is likely to provide the strongest and most definitive evidence on whether vitamin D protects against cardiovascular disease and all-cause mortality,” he concluded.