Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr. F.
Perry Wilson of the Yale School of Medicine. This week – we’re going to dive into the
lion’s den once again with this study, appearing in PLOS Medicine,
failing to show a causal link between Vitamin D levels and COVID-19 incidence or severity.
And I know this is one of those hot button COVID issues – I think it’s because we all really want
there to be a cheap, easy way to avoid getting COVID or getting severe COVID. And, technically,
there is – it’s a vaccine – but sure it would be nice if there were something we
had a lot more experience with – I get that. And the observational data was definitely
compelling. People with low Vitamin D levels really do have worse COVID outcomes. Much worse.
But correlation isn’t causation. You’ve heard that before, but we rarely dwell on what it
really means. Why is causation so important? It’s because if A causes B, then changing A changes B.
When we ask if low vitamin D levels cause worse COVID, what we are really saying is – if I boost
Vitamin D levels can I protect against COVID. If there is causation, the answer is yes. But
there might not be. Lots of things reduce Vitamin D levels and increase the risk for
COVID. I’ve often referred to Vitamin D level as the lifestyle biomarker – higher in healthy,
active people – the very people who you’d expect would do pretty well if they got COVID.
The classic way to assess causality in medicine is via the randomized trial,
and we have a few trials of Vitamin D supplementation in COVID out there now.
I made a quick table to highlight what is known. Mixed results here from some pretty small studies,
all of which focused on people who were already sick. The largest study says no benefit,
smaller less well-controlled studies find some benefit in soft outcomes. None of them answer
the question of whether providing Vitamin D supplementation to otherwise healthy people
would affect COVID later on. So – are we stuck?
It turns out there is a clever way to assess causality that doesn’t require a randomized
trial. It’s not perfect, but it might be the best we have. It’s called Mendelian Randomization.
Here’s how it works. We have a causality question – does
low Vitamin D level cause worse COVID? But we know that the Vitamin D level is affected
by a bunch of lifestyle and environmental factors that we can’t possibly control for. But something
else affects your Vitamin D level – your genes. Some people are genetically predisposed to have
higher Vitamin D levels, just like some people are genetically predisposed to be taller. Sure, your
actual vitamin D level will be affected by all that other stuff – but your genes don’t change.
If low vitamin D is causally linked to worse COVID, people with a genetic predisposition to low
Vitamin D will have worse COVID than people with a genetic predisposition to have high Vitamin D.
Those genes basically bypass all the noise of the real world. It’s a pretty neat trick honestly.
Of course, you need a TON of data to figure out what genes (or in this case
tiny pieces of genes called SNPs) lead to higher Vitamin D levels. Researchers in this study used
about 450,000 people to create a genetic risk profile for low Vitamin D levels. They then
used that score to assess the genomes of around 14,000 people with COVID and 1.3 million people
without COVID. If low Vitamin D levels are causally linked to worse COVID, you’d expect
the COVID group to be enriched for people with a genetic predisposition to have low Vitamin D.
But – this wasn’t seen. Not for susceptibility to COVID, not for hospitalization with COVID,
not for severe disease. This figure basically says: we tried this a bunch of different ways and
no matter what we don’t see a protective signal. At this point, we have little support for Vitamin
D supplementation as a preventative strategy. A few caveats though. First, it’s important to
remember that this analysis was not restricted to people who are Vitamin D deficient. Very
low levels, of any vitamin really, should be repleted. I mean, that’s why they’re vitamins.
There is also a subtler issue with these Mendelian randomization studies of vitamin D. You know that
genetic risk score they are calculating? It is based on the measured Vitamin D level. But
the vitamin D level we measure the blood is not the same as the bioavailable Vitamin D.
We all have a protein called Vitamin D Binding Protein that latches on to Vitamin D in our blood,
keeping it unavailable for our cells. Some of us have a D-binding protein
with a higher affinity for Vitamin D – and that is genetically determined.
In other words, two people with different measured levels of Vitamin D may have the same effective
levels of Vitamin D based on genetic variation in D-binding protein. That means that the genetic
risk score might not be capturing exactly what we think it is – limiting the validity of this
analysis. Of course, all those observational studies linking low vitamin D levels to bad
outcomes suffer from the same measurement problem. Personally, I’m not a huge fan of vitamin
supplementation in general – I recommend that my patients try to get their vitamins
through the food they eat, and, in the case of vitamin D, through the sunlight
they get while exercising a bit outside. Fortunately, summer is coming – go to it.