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All Studies   Meta Analysis    Recent:   

Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study

Butler-Laporte et al., PLOS Medicine, doi:10.1371/journal.pmed.1003605
Jun 2021  
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Vitamin D for COVID-19
8th treatment shown to reduce risk in October 2020
 
*, now known with p < 0.00000000001 from 120 studies, recognized in 9 countries.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
4,200+ studies for 70+ treatments. c19early.org
Mendelian randomization study not finding significant differences in COVID-19 outcomes based on vitamin D level. This study does not compare patients with deficiency/insuffiency/sufficiency, only providing ORs for increase in D levels. Authors note that their results do not apply to individuals with vitamin D deficiency.
Authors cite only 2 of the 25 vitamin D treatment studies (2 of 5 RCTs) at the time, including the only study reporting a negative effect. Authors indicate that they believe1 was a significant result, however that study used cholecalciferol with very late stage patients. In practice, calcifediol/calcitrol would be used due to the long delay in conversion of cholecalciferol, hence the study is not informative of either normal late stage treatment, or earlier treatment. That authors believe the study is important suggests a strong bias.
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 see2.
For reasons why Mendelian randomization may fail in this case, see3. 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.
4 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.
Butler-Laporte et al., 1 Jun 2021, peer-reviewed, 16 authors.
This PaperVitamin DAll
Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study
Guillaume Butler-Laporte, Tomoko Nakanishi, Vincent Mooser, David R Morrison, Tala Abdullah, Olumide Adeleye, Noor Mamlouk, Nofar Kimchi, Zaman Afrasiabi, Nardin Rezk, Annarita Giliberti, Alessandra Renieri, Yiheng Chen, Sirui Zhou, Vincenzo Forgetta, J Brent Richards
PLOS Medicine, doi:10.1371/journal.pmed.1003605
Background Increased vitamin D levels, as reflected by 25-hydroxy vitamin D (25OHD) measurements, have been proposed to protect against COVID-19 based on in vitro, observational, and ecological studies. However, vitamin D levels are associated with many confounding variables, and thus associations described to date may not be causal. Vitamin D Mendelian randomization (MR) studies have provided results that are concordant with large-scale vitamin D randomized trials. Here, we used 2-sample MR to assess evidence supporting a causal effect of circulating 25OHD levels on COVID-19 susceptibility and severity. Methods and findings Genetic variants strongly associated with 25OHD levels in a genome-wide association study (GWAS) of 443,734 participants of European ancestry (including 401,460 from the UK Biobank) were used as instrumental variables. GWASs of COVID-19 susceptibility, hospitalization, and severe disease from the COVID-19 Host Genetics Initiative were used as outcome GWASs. These included up to 14,134 individuals with COVID-19, and up to 1,284,876 without COVID-19, from up to 11 countries. SARS-CoV-2 positivity was determined by laboratory testing or medical chart review. Population controls without COVID-19 were also included in the control groups for all outcomes, including hospitalization and severe disease. Analyses were restricted to individuals of European descent when possible. Using inverse-weighted MR, genetically increased 25OHD levels by 1 standard deviation on
Supporting information S1 STROBE Checklist. STROBE case-control study checklist. (DOC) Author Contributions Visualization: Guillaume Butler-Laporte, Tomoko Nakanishi. Writing -original draft: Guillaume Butler-Laporte, Tomoko Nakanishi, J. Brent Richards. Writing -review & editing: Guillaume Butler-Laporte, Tomoko Nakanishi, Vincent Mooser, David R. Morrison, Tala Abdullah, Olumide Adeleye, Noor Mamlouk, Nofar Kimchi, Zaman Afrasiabi, Nardin Rezk, Annarita Giliberti, Alessandra Renieri, Yiheng Chen, Sirui Zhou, Vincenzo Forgetta, J. Brent Richards.
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However, vitamin D levels are associated with many ' 'confounding variables, and thus associations described to date may not be causal. Vitamin D ' 'Mendelian randomization (MR) studies have provided results that are concordant with ' 'large-scale vitamin D randomized trials. Here, we used 2-sample MR to assess evidence ' 'supporting a causal effect of circulating 25OHD levels on COVID-19 susceptibility and ' 'severity.</jats:p>\n' '</jats:sec>\n' '<jats:sec id="sec002">\n' '<jats:title>Methods and findings</jats:title>\n' '<jats:p>Genetic variants strongly associated with 25OHD levels in a genome-wide association ' 'study (GWAS) of 443,734 participants of European ancestry (including 401,460 from the UK ' 'Biobank) were used as instrumental variables. GWASs of COVID-19 susceptibility, ' 'hospitalization, and severe disease from the COVID-19 Host Genetics Initiative were used as ' 'outcome GWASs. These included up to 14,134 individuals with COVID-19, and up to 1,284,876 ' 'without COVID-19, from up to 11 countries. SARS-CoV-2 positivity was determined by laboratory ' 'testing or medical chart review. Population controls without COVID-19 were also included in ' 'the control groups for all outcomes, including hospitalization and severe disease. Analyses ' 'were restricted to individuals of European descent when possible. Using inverse-weighted MR, ' 'genetically increased 25OHD levels by 1 standard deviation on the logarithmic scale had no ' 'significant association with COVID-19 susceptibility (odds ratio [OR] = 0.95; 95% CI 0.84, ' '1.08; <jats:italic>p</jats:italic> = 0.44), hospitalization (OR = 1.09; 95% CI: 0.89, 1.33; ' '<jats:italic>p =</jats:italic> 0.41), and severe disease (OR = 0.97; 95% CI: 0.77, 1.22; ' '<jats:italic>p =</jats:italic> 0.77). We used an additional 6 meta-analytic methods, as well ' 'as conducting sensitivity analyses after removal of variants at risk of horizontal ' 'pleiotropy, and obtained similar results. These results may be limited by weak instrument ' 'bias in some analyses. Further, our results do not apply to individuals with vitamin D ' 'deficiency.</jats:p>\n' '</jats:sec>\n' '<jats:sec id="sec003">\n' '<jats:title>Conclusions</jats:title>\n' '<jats:p>In this 2-sample MR study, we did not observe evidence to support an association ' 'between 25OHD levels and COVID-19 susceptibility, severity, or hospitalization. Hence, ' 'vitamin D supplementation as a means of protecting against worsened COVID-19 outcomes is not ' 'supported by genetic evidence. 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