Genetically predicted serum vitamin D and COVID-19: a Mendelian randomization study

Patchen et al., BMJ Nutrition, Prevention & Health, doi:10.1136/bmjnph-2021-000255

Feb 2021

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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 nature.com.

For reasons why Mendelian randomization may fail in this case, see nutrition.bmj.com. 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.

Grant 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.

1. Grant et al., A Narrative Review of the Evidence for Variations in Serum 25-Hydroxyvitamin D Concentration Thresholds for Optimal Health, Nutrients, doi:10.3390/nu14030639.mdpi.com, doi.org.

2. nature.com, www.nature.com/articles/d41586-019-03754-3.www.nature.com/articles/d41586-019-03754-3.

3. nutrition.bmj.com, nutrition.bmj.com/content/bmjnph/early/2021/03/22/bmjnph-2021-000265.full.pdf.nutrition.bmj.com/content/bmjnph/early/2021/03/22/bmjnph-2021-000265.full.pdf.

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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.

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This Paper Vitamin D All

Genetically predicted serum vitamin D and COVID-19: a Mendelian randomisation study

Bonnie K Patchen, Andrew G Clark, Nathan Gaddis, Dana B Hancock, Dr Patricia A Cassano

BMJ Nutrition, Prevention & Health, doi:10.1136/bmjnph-2021-000255

Objectives To investigate causality of the association of serum vitamin D with the risk and severity of COVID-19 infection. 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 hospitalisation. 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 genomewide 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 genomewide significant associations with risk of vitamin D deficiency or insufficiency. Conclusions These findings suggest that genetically predicted differences in long-term vitamin D nutritional status do not causally affect susceptibility to and severity of COVID-19 infection, and that associations observed in previous studies may have been driven by confounding. These results do not exclude the possibility of low-magnitude causal effects or causal effects of acute responses to therapeutic doses of vitamin D.

BMJ Nutrition, Prevention & Health Provenance and peer review Not commissioned; externally peer reviewed by Xia Jiang, Karolinska Institute, Sweden and Dr Emmanuel Baah, University of North Carolina System. Data availability statement All data used for this analysis are publicly available. UK Biobank and COVID-19 Host Genetics Initiative data used for the main analysis are available in a public, open access repository. UK Biobank data used for stratified anayses of SNP-vitamin D associations are available on reasonable request from the UK Biobank. Code implementing the MR analysis is available on request from the corresponding author. Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0)..

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