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When Mendelian randomisation fails

Kohlmeier et al., BMJ Nutrition, Prevention & Health, doi:10.1136/bmjnph-2021-000265
Mar 2021  
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Vitamin D for COVID-19
8th treatment shown to reduce risk in October 2020
 
*, now with p < 0.00000000001 from 122 studies, recognized in 9 countries.
No treatment is 100% effective. Protocols combine treatments. * >10% efficacy, ≥3 studies.
4,300+ studies for 75 treatments. c19early.org
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.
Reviews covering vitamin D for COVID-19 include1-24.
Kohlmeier et al., 22 Mar 2021, peer-reviewed, 2 authors.
This PaperVitamin DAll
When Mendelian randomisation fails
Dr Martin Kohlmeier, Emmanuel Baah
BMJ Nutrition, Prevention & Health, doi:10.1136/bmjnph-2021-000265
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 longterm 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
Competing interests None declared. Patient consent for publication Not required.
References
Amin, Drenos, No evidence that vitamin D is able to prevent or affect the severity of COVID-19 in individuals with European ancestry: a Mendelian randomisation study of open data, BMJ Nutr Prev Health, doi:10.1136/bmjnph-2020-000151
Bikle, The free hormone hypothesis: when, why, and how to measure the free hormone levels to assess vitamin D, thyroid, sex hormone, and cortisol status, JBMR Plus, doi:10.1002/jbm4.10418
Butler-Laporte, Nakanishi, Mooser, Vitamin D and Covid-19 susceptibility and severity: a Mendelian randomization study, MedRxiv, doi:10.1101/2020.09.08.20190975
Calder, Nutrition, immunity and COVID-19, BMJ Nutr Prev Health, doi:10.1136/bmjnph-2020-000085
Castillo, Costa, Barrios, Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study, J Steroid Biochem Mol Biol, doi:10.1016/j.jsbmb.2020.105751
Hastie, Mackay, Ho, Vitamin D concentrations and COVID-19 infection BMJ Nutrition, Prevention & Health in UK Biobank, Diabetes Metab Syndr, doi:10.1016/j.dsx.2020.04.050
Kaufman, Niles, Kroll, SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels, PLoS One, doi:10.1371/journal.pone.0239252
Kohlmeier, Avoidance of vitamin D deficiency to slow the COVID-19 pandemic, BMJ Nutr Prev Health, doi:10.1136/bmjnph-2020-000096
Lanham-New, Webb, Cashman, Vitamin D and SARS-CoV-2 virus/ COVID-19 disease, BMJ Nutr Prev Health, doi:10.1136/bmjnph-2020-000089
Louca, Murray, Klaser, Dietary supplements during the COVID-19 pandemic: insights from 445,850 users of the COVID symptom study APP, BMJ Nutr Prev Health
Ma, Zhou, Heianza, Habitual use of vitamin D supplements and risk of coronavirus disease 2019 (COVID-19) infection: a prospective study in UK Biobank, Am J Clin Nutr, doi:10.1093/ajcn/nqaa381
Meltzer, Best, Zhang, Association of vitamin D status and other clinical characteristics with COVID-19 test results, JAMA Netw Open, doi:10.1001/jamanetworkopen.2020.19722
Murai, Fernandes, Sales, 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, JAMA, doi:10.1001/jama.2020.26848
Patchen, Clark, Hancock, Genetically predicted serum vitamin D and COVID-19: a Mendelian randomization study, BMJ Nutr Prev Health
Rastogi, Bhansali, Khare, Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled
Rhodes, Dunstan, Laird, COVID-19 mortality increases with northerly latitude after adjustment for age suggesting a link with ultraviolet and vitamin D, BMJ Nutr Prev Health, doi:10.1136/bmjnph-2020-000110
Smet, Smet, Herroelen, Serum 25(OH)D Level on Hospital Admission Associated With COVID-19 Stage and Mortality, Am J Clin Pathol, doi:10.1093/ajcp/aqaa252
Sollid, Hutchinson, Berg, Effects of vitamin D binding protein phenotypes and vitamin D supplementation on serum total 25(OH)D and directly measured free 25(OH)D, Eur J Endocrinol, doi:10.1530/EJE-15-1089
Yisak, Ewunetei, Kefale, Effects of vitamin D on COVID-19 infection and prognosis: a systematic review, Risk Manag Healthc Policy, doi:10.2147/RMHP.S291584
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