When Mendelian randomisation fails
Analysis of why Mendelian randomization may fail in vitamin D studies. Authors suggest that it may come down to the use of 25(OH)D concentration in serum as a less than ideal proxy for vitamin D status of cells involved in the immune response. For most other purposes, it may not matter much that unbound (free) 25(OH)D is the better predictor of vitamin D deficiency and the resulting unfavourable outcomes. But for the MR analysis, the genetic instrument is strongly dominated by variation in the GC gene which modulates the concentration of vitamin D-binding protein (VDBP) in blood and thereby indirectly the concentrations of 25(OH)D and 1,25-dihydroxy vitamin D. Thus, the common GC alleles rs4588A and rs7041T are both associated with much lower than average vitamin D concentrations. In contrast, directly measured unbound (free) vitamin D concentrations are minimally affected by these alleles, if at all.
Kohlmeier et al., 22 Mar 2021, peer-reviewed, 2 authors.
Abstract: Open access
Editorial
Martin Kohlmeier , Emmanuel Baah
Mendelian randomisation (MR) is the
ingenious approach of using the consistent long-term modulation of interesting
exposure variables by inborn genetic
differences to mimic the effect of
different levels on outcomes of interest.
This type of analysis is particularly
important for evaluating the causal
impact of nutritional exposures on long-
term health outcomes. The MR approach
is predicated on equivalent effects of
exposure and genetic proxy on the
outcome. But what happens when the
proxy is not a good predictor of the
outcome of interest? MR analysis of the
hypothesised role of vitamin D in the
pathology related to SARS-CoV-2 infection illustrates this conundrum.
Up to this point, a growing number
of observational studies appeared to
link low 25-hydroxy vitamin D (25-
OHD) concentrations to higher risk
of infection and worsening COVID-19
outcomes.1 For instance, the analysis
of 25-OHD measurements in more than
190 000 clinical samples from across
the USA found that the likelihood to
test positive for SARS-CoV-2 was more
than twice as high for samples with low
25-OHD concentration (<20 ng/mL) than
for samples with high concentration
(>55 ng/mL).2 The findings based on
UK Biobank data which include clinical
outcomes are possibly different because
the observed 61% higher mortality risk
for the univariate association with low
vitamin D concentration disappeared
after adjustments.3 An argument can
be made that adjustments for age, sex,
ethnicity and body mass index were
inappropriate because it is exactly these
variables that are well-known causes
of low vitamin D concentrations. No
Nutrition Research Institute, University of North
Carolina at Chapel Hill, Kannapolis, North Carolina,
USA
Correspondence to Dr Martin Kohlmeier, Nutrition
Research Institute, University of North Carolina at
Chapel Hill, Kannapolis, NC 28081, USA;
mkohlmeier@unc.edu
plausible rationale was offered that they
actually confound the association, that
is, that ethnicity is the cause for higher
risk and not lower capacity for producing
vitamin D in people with darker coloured
skin.
Vitamin D concentrations tend to be
low in patients with COVID-19. Thus,
the majority of patients with COVID-19
in a Belgian hospital was found to be
vitamin D-deficient, and the ones most
severely affected by the illness had the
lowest levels.4 This is apparently not
just an acute response to the infection
and due to pathological changes occurring with COVID-19. Individuals with low
25-OHD concentrations measured long
before infection were over-represented
among patients hospitalised because
they needed treatment for COVID-19.5
Risk of infection and severity of illness
also appear to be related to vitamin
D intake. Based on data from the UK
Biobank, habitual users of vitamin D-containing supplements had a 34% lower
risk of infection.6 Another large study of
dietary supplement use assessed with a
widely distributed app also found slightly
lower risk of infection in people using
vitamin D supplements.7 As described
below, a randomised controlled trial
(RCT) found high-dose vitamin D to be
highly effective in ameliorating COVID-19
in hospitalised patients.8
Finally, ecological studies demonstrate
a strong latitudinal gradient of high to
low COVID-19 mortality from North to
South.9 10 This has been attributed to
the diminished ability of people living
at higher latitudes, such as in the UK,
Central and..
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