Genetically predicted serum vitamin D and COVID-19: a Mendelian randomization study
Patchen et al.
, Genetically predicted serum vitamin D and COVID-19: a Mendelian randomization study
, BMJ Nutrition, Prevention & Health, doi:10.1136/bmjnph-2021-000255
UK Biobank Mendelian randomization study not finding significant differences in COVID-19 risk. The number of people predicted to have vitamin D deficiency does not appear to be provided.
Mendelian randomization studies compare the estimated effect of SNPs
associated with variation in vitamin D levels on the health outcomes in large
numbers of patients. For more background on Mendelian randomization studies
and their limitations see
For reasons why Mendelian randomization may fail in this case,
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
suggest that the primary reasons for Mendelien
randomization failure include that the total SNP-induced variation in 25(OH)D
has often been less than assay variance, and that genome-wide association
studies of SNP effects have been made on the full range of 25(OH)D levels,
while the data is non-linear with a significant percentage in the low and high
plateaus of the outcome relationships.
risk of severe case, 2.0% lower, RR 0.98, p = 0.11, inverted to make RR<1 favor high D levels, odds ratio converted to relative risk, >50nmol/L, baseline risk approximated with overall risk.
risk of hospitalization, no change, RR 1.00, p = 1.00, inverted to make RR<1 favor high D levels, odds ratio converted to relative risk, >50nmol/L, baseline risk approximated with overall risk.
risk of case, no change, RR 1.00, p = 1.00, inverted to make RR<1 favor high D levels, odds ratio converted to relative risk, >50nmol/L, baseline risk approximated with overall risk.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Patchen et al., 1 Feb 2021, retrospective, United Kingdom, peer-reviewed, 5 authors.
Abstract: Open access
Bonnie K Patchen ,1 Andrew G Clark,2 Nathan Gaddis,3 Dana B Hancock,3
Patricia A Cassano 1,4
To cite: Patchen BK, Clark AG,
Gaddis N, et al. Genetically
predicted serum vitamin D
and COVID-19: a Mendelian
randomisation study. BMJ
Nutrition, Prevention &
Health 2021;0. doi:10.1136/
►► Additional supplemental
material is published online only.
To view, please visit the journal
online (http://dx.d oi.org/10.
Division of Nutritional Sciences,
Cornell University, Ithaca, New
Department of Molecular
Biology and Genetics, Cornell
University, Ithaca, New York, USA
GenOmics, Bioinformatics and
Translational Research Center,
Research Triangle Institute,
Research Triangle Park, North
Population Health Sciences,
Weill Cornell Medical College,
New York, New York, USA
Dr Patricia A Cassano, Division
of Nutritional Sciences, Cornell
University, Ithaca, NY 14853,
USA; p email@example.com du
Received 11 February 2021
Revised 9 April 2021
Accepted 10 April 2021
© Author(s) (or their
employer(s)) 2021. Re-use
permitted under CC BY-NC. No
commercial re-use. See rights
and permissions. Published by
Objectives To investigate causality of the association of
serum vitamin D with the risk and severity of COVID-19
Design Two-sample Mendelian randomisation study.
Setting Summary data from genome-wide analyses in the
population-based UK Biobank and SUNLIGHT Consortium,
applied to meta-analysed results of genome-wide analyses
in the COVID-19 Host Genetics Initiative.
Participants 17 965 COVID-19 cases including 11 085
laboratory or physician-confirmed cases, 7885 hospitalised
cases and 4336 severe respiratory cases, and 1 370 547
controls, primarily of European ancestry.
Exposures Genetically predicted variation in serum vitamin
D status, instrumented by genome-wide significant single
nucleotide polymorphisms (SNPs) associated with serum
vitamin D or risk of vitamin D deficiency/insufficiency.
Main outcome measures Susceptibility to and severity of
COVID-19 infection, including severe respiratory infection and
Results Mendelian randomisation analysis, sufficiently
powered to detect effects comparable to those seen in
observational studies, provided little to no evidence for
an effect of genetically predicted serum vitamin D on
susceptibility to or severity of COVID-19 infection. Using
SNPs in loci related to vitamin D metabolism as genetic
instruments for serum vitamin D concentrations, the OR per
SD higher serum vitamin D was 1.04 (95% CI 0.92 to 1.18)
for any COVID-19 infection versus population controls, 1.05
(0.84 to 1.31) for hospitalised COVID-19 versus population
controls, 0.96 (0.64 to 1.43) for severe respiratory COVID-19
versus population controls, 1.15 (0.99 to 1.35) for COVID-19
positive versus COVID-19 negative and 1.44 (0.75 to 2.78)
for hospitalised COVID-19 versus non-hospitalised COVID-19.
Results were similar in analyses using SNPs with genome-
wide significant associations with serum vitamin D (ie,
including SNPs in loci with no known relationship to vitamin
D metabolism) and in analyses using SNPs with genome-
wide significant associations with risk of vitamin D deficiency
Conclusions These findings suggest that genetically
predicted differences in long-term vitamin D nutritional
status do not causally affect susceptibility to..
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