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

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

Butler-Laporte et al., Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian.., PLOS Medicine, doi:10.1371/journal.pmed.1003605

Jun 2021 Source PDF

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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 believe [Murai] 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 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., Nutrients, doi:10.3390/nu14030639, A Narrative Review of the Evidence for Variations in Serum 25-Hydroxyvitamin D Concentration Thresholds for Optimal Health, https://www.mdpi.com/2072-6643/14/3/639/pdf.

2. Murai et al., JAMA, doi:10.1001/jama.2020.26848 (preprint 11/17), Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay in Patients With Moderate to Severe COVID-19: A Randomized Clinical Trial, https://jamanetwork.com/journals/jama/fullarticle/2776738.

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

4. nutrition.bmj.com, https://nutrition.bmj.com/content/../03/22/bmjnph-2021-000265.full.pdf.

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Butler-Laporte et al., 1 Jun 2021, peer-reviewed, 16 authors.

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Abstract: RESEARCH ARTICLE Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study Guillaume Butler-Laporte ID1,2☯, Tomoko Nakanishi ID1,3,4,5☯, Vincent Mooser3,6, David R. Morrison1, Tala Abdullah ID1, Olumide Adeleye1, Noor Mamlouk1, Nofar Kimchi1,7, Zaman Afrasiabi1, Nardin Rezk ID1, Annarita Giliberti8, Alessandra Renieri ID8,9, Yiheng Chen1, Sirui Zhou1,2, Vincenzo Forgetta ID1, J. Brent Richards ID1,2,3,10* a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 OPEN ACCESS Citation: Butler-Laporte G, Nakanishi T, Mooser V, Morrison DR, Abdullah T, Adeleye O, et al. (2021) Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study. PLoS Med 18(6): e1003605. https://doi.org/10.1371/journal. pmed.1003605 Academic Editor: Cosetta Minelli, Imperial College London, UNITED KINGDOM Received: August 31, 2020 Accepted: March 31, 2021 Published: June 1, 2021 Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: https://doi.org/10.1371/journal.pmed.1003605 Copyright: © 2021 Butler-Laporte et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: Covid-19 outcome GWAS summary statistics are freely available for download directly through the Covid-19 HGI 1 Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada, 2 Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Québec, Canada, 3 Department of Human Genetics, McGill University, Montréal, Québec, Canada, 4 Kyoto–McGill International Collaborative Program in Genomic MedicineAU , Graduate : IchangedKyoto School of Medicine, McGillInternationalCollaborativeSchool:::to Kyoto University, Kyoto, Japan, 5 Japan Society for the Promotion of Science, Tokyo, Japan, 6 Canada Excellence Research Chair in Genomic Medicine, McGill University, Montréal, Québec, Canada, 7 Ruth and Bruce Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel, 8 Medical Genetics, University of Siena, Siena, Italy, 9 Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy, 10 Department of Twin Research, King’s College London, London, United Kingdom ☯ These authors contributed equally to this work. * brent.richards@mcgill.ca Abstract 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..

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