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Published: 17 November 2021

Research published in the journal Lancet Diabetes and Endocrinology and co-authored by Dr Dipender Gill from St George’s, University of London has demonstrated a link between higher vitamin D levels and lower mortality risk. However, the link was only observed in people who are vitamin D deficient. Results from this natural experiment, in which people were compared based on their genetic make-up, suggest that taking vitamin D supplements will reduce mortality risk for those with low levels of vitamin D. 

There have been many claims of health risks of low vitamin D, such as higher rates of heart attack, stroke and cancer. However, several large randomised trials have failed to demonstrate any reductions in risk of these diseases amongst people given vitamin D supplements. This raises the question of whether taking vitamin D reduces the risk of these diseases, or whether healthier people tend to have higher vitamin D levels.  

A team led by researchers at the MRC Biostatistics Unit, University of Cambridge studied data on over 380,000 volunteers from four studies, and compared participants in a statistical analysis not by their measured level of vitamin D, but according to whether they have inherited genetic variants predisposing them to higher vitamin D levels. By making comparisons based on genetic variations rather than vitamin D levels directly, several of the pitfalls of judging causation from observational data are avoided, as it’s possible to compare like-for-like groups, which only differ in this particular genetic variation – ruling out other variables that could be having an effect.  

In analyses including all the volunteers, there was no association between genetic predisposition to higher vitamin D levels and reduced risk of coronary heart disease, stroke, or death. However, when analyses were restricted to people who are vitamin D deficient (defined as those with concentrations of a form of vitamin D found in the bloodstream, below 20 nmol/L), there was a strong association between predisposition to higher vitamin D levels and lower mortality risk. Similar associations were also observed for cardiovascular and cancer mortality.  

This study provides a potential explanation for previous negative results from randomised trials of vitamin D supplementation. Most large trials have recruited volunteers without reference to their vitamin D status, and so these trials have not been able to reliably assess evidence for beneficial effects of vitamin D in deficient people. Although it would be possible to design a trial that specifically recruits vitamin D deficient participants, if a participant is diagnosed as vitamin D deficient, they may begin to take vitamin D supplementation outside of the trial. This would limit the validity of the trial. Additionally, it would be unethical to offer a placebo to a trial volunteer diagnosed as vitamin D deficient. 

A notable limitation of the research is that the genetic analyses were restricted to people of European genetic ancestry, whereas vitamin D levels are typically lower in people with dark skin. Associations with mortality were only seen up to a threshold level of 40 nmol/L for the form of vitamin D measured. Around 25% of European descent participants in the UK Biobank study, a large study of middle-aged UK residents, had vitamin D levels below this threshold. 

Dr Stephen Burgess, a statistician based at the University of Cambridge’s Medical Research Council Biostatistics Unit, who led the study, said: “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. Maintaining adequate levels of vitamin D is important, but there appears to be no benefit in supplementation beyond a threshold level.” 

Dr Dipender Gill from the Institute for Infection and Immunity and Institute of Medical and Biomedical Education at St George’s, added: “By showing that people who are vitamin D deficient may be more likely to benefit from taking supplements, our research can inform future clinical efforts. We should aim to prioritise individuals who are deficient in order to better appreciate the potential benefits of vitamin D supplementation.” 

Dr Dipender Gill is a tutor on the Clinical Pharmacology course at St George’s. If you’re interested in applying for the course, you can sign up for a taster lecture, “Life-saving drugs: 24 hours in A&E”, here. 

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