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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

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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 include Andrade, Arora, Basha, Brenner, Cannell, DiGuilio, EFSA, EFSA (B), Foshati, Gotelli, Grant, Grant (B), Grant (C), Kohlmeier, McCullough, Mercola, Nicoll, Palacios, Quesada-Gomez, Schloss, Shah Alam, Xu.

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1. Andrade et al., Vitamin A and D deficiencies in the prognosis of respiratory tract infections: A systematic review with perspectives for COVID-19 and a critical analysis on supplementation, SciELO preprints, doi:10.1590/SciELOPreprints.839.scielo.org, doi.org.

2. Arora et al., Global Dietary and Herbal Supplement Use during COVID-19—A Scoping Review, Nutrients, doi:10.3390/nu15030771.mdpi.com, doi.org.

3. Basha et al., Is the shielding effect of cholecalciferol in SARS CoV-2 infection dependable? An evidence based unraveling, Clinical Epidemiology and Global Health, doi:10.1016/j.cegh.2020.10.005.sciencedirect.com, doi.org.

4. Brenner, H., Vitamin D Supplementation to Prevent COVID-19 Infections and Deaths—Accumulating Evidence from Epidemiological and Intervention Studies Calls for Immediate Action, Nutrients, doi:10.3390/nu13020411.mdpi.com, doi.org.

5. Cannell et al., Epidemic influenza and vitamin D, Epidemiol Infect., 2006, 134:6. 1129-40, doi:10.1017/S0950268806007175.nih.gov, doi.org.

6. DiGuilio et al., Micronutrient Improvement of Epithelial Barrier Function in Various Disease States: A Case for Adjuvant Therapy, International Journal of Molecular Sciences, doi:10.3390/ijms23062995.mdpi.com, doi.org.

7. EFSA, Scientific Opinion on the substantiation of health claims related to vitamin D and normal function of the immune system and inflammatory response (ID 154, 159), maintenance of normal muscle function (ID 155) and maintenance of normal cardiovascular function (ID 159) pursuant to Article 13(1) of Regulation (E, EFSA Journal, doi:10.2903/j.efsa.2010.1468.wiley.com, doi.org.

8. EFSA (B), Scientific Opinion on the substantiation of a health claim related to vitamin D and contribution to the normal function of the immune system pursuant to Article 14 of Regulation (EC) No 1924/2006, EFSA Journal, doi:10.2903/j.efsa.2015.4096.europa.eu, doi.org.

9. Foshati et al., Antioxidants and clinical outcomes of patients with coronavirus disease 2019: A systematic review of observational and interventional studies, Food Science & Nutrition, doi:10.1002/fsn3.3034.wiley.com, doi.org.

10. Gotelli et al., Understanding the immune-endocrine effects of vitamin D in SARS-CoV-2 infection: a role in protecting against neurodamage?, Neuroimmunomodulation, doi:10.1159/000533286.karger.com, doi.org.

11. Grant, W., Vitamin D and viral infections: Infectious diseases, autoimmune diseases, and cancers, Advances in Food and Nutrition Research, doi:10.1016/bs.afnr.2023.12.007.sciencedirect.com, doi.org.

12. Grant (B) 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.

13. Grant (C) et al., Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths, Nutrients, 12:4, 988, doi:10.3390/nu12040988.mdpi.com, doi.org.

14. Kohlmeier et al., When Mendelian randomisation fails, BMJ Nutrition, Prevention & Health, doi:10.1136/bmjnph-2021-000265.bmj.com, doi.org.

15. McCullough et al., Daily oral dosing of vitamin D3 using 5000 TO 50,000 international units a day in long-term hospitalized patients: Insights from a seven year experience, The Journal of Steroid Biochemistry and Molecular Biology, doi:10.1016/j.jsbmb.2018.12.010.sciencedirect.com, doi.org.

16. Mercola et al., Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity, Nutrients 2020, 12:11, 3361, doi:10.3390/nu12113361.mdpi.com, doi.org.

17. Nicoll et al., COVID-19 Prevention: Vitamin D Is Still a Valid Remedy, Journal of Clinical Medicine, doi:10.3390/jcm11226818.mdpi.com, doi.org.

18. Palacios et al., Is vitamin D deficiency a major global public health problem?, J Steroid Biochem Mol Biol., 2014, 144PA, 138–145, doi:10.1016/j.jsbmb.2013.11.003.nih.gov, doi.org.

19. Quesada-Gomez et al., Vitamin D Endocrine System and COVID-19: Treatment with Calcifediol, Nutrients, doi:10.3390/nu14132716.mdpi.com, doi.org.

20. Schloss et al., Nutritional deficiencies that may predispose to long COVID, Inflammopharmacology, doi:10.1007/s10787-023-01183-3.springer.com, doi.org.

21. Shah Alam et al., The role of vitamin D in reducing SARS-CoV-2 infection: An update, International Immunopharmacology, doi:10.1016/j.intimp.2021.107686.sciencedirect.com, doi.org.

22. Xu et al., The importance of vitamin d metabolism as a potential prophylactic, immunoregulatory and neuroprotective treatment for COVID-19, Journal of Translational Medicine, doi:10.1186/s12967-020-02488-5.biomedcentral.com, doi.org.

Kohlmeier et al., 22 Mar 2021, peer-reviewed, 2 authors.

This Paper Vitamin D All

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

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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

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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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