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Small increases in Vitamin D are not predicted to decrease in COVID-19 (Mendelian randomization) – June 2021

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

PLoS Med. 2021 Jun 1;18(6):e1003605. doi: 10.1371/journal.pmed.1003605. eCollection 2021 Jun.
Guillaume Butler-Laporte 1 2, Tomoko Nakanishi 1 3 4 5, Vincent Mooser 3 6, David R Morrison 1, Tala Abdullah 1, Olumide Adeleye 1, Noor Mamlouk 1, Nofar Kimchi 1 7, Zaman Afrasiabi 1, Nardin Rezk 1, Annarita Giliberti 8, Alessandra Renieri 8 9, Yiheng Chen 1, Sirui Zhou 1 2, Vincenzo Forgetta 1, J Brent Richards 1 2 3 10

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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 the logarithmic scale had no significant association with COVID-19 susceptibility (odds ratio [OR] = 0.95; 95% CI 0.84, 1.08; p = 0.44), hospitalization (OR = 1.09; 95% CI: 0.89, 1.33; p = 0.41), and severe disease (OR = 0.97; 95% CI: 0.77, 1.22; p = 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.

Conclusions: 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. Other therapeutic or preventative avenues should be given higher priority for COVID-19 randomized controlled trials.


Clipped from discussion

  • "Differences between our findings and those reported in observational studies 6 may reflect the fact that associations between vitamin D and COVID-19 may be confounded due to factors difficult to control for even with advanced statistical adjustments, such as socioeconomic status, institutionalizaton, or medical comorbidities associated with lower vitamin D"
  • "Our study still has limitations. First, our results do not apply to individuals with vitamin D deficiency, and it remains possible that truly deficient patients may benefit from supplementation for COVID-19-related protection and outcomes."s

Comment on study by Dr. Grant on PLOS website

Vitamin D status is inversely associated with risk and severity of COVID-19 despite the null findings in Mendelian randomization studyies
Posted by wbgrant on 03 Jun 2021 at 03:07 GMT

The Mendelian randomization study by Butler-Laporet and colleagues failed to find a link between vitamin D status and susceptibility and severity of COVID-19 using the Mendelian randomization (MR) study approach [1]. The study was based on 14,134 individuals with COVID-19 and up to 1,284,876 without COVID-19 of European ancestry from eleven countries. The authors concluded “In conclusion, using a method that has consistently replicated RCT results from vitamin D supplementation studies in large sample sizes, we find no evidence to support a protective role for higher 25OHD in COVID-19 outcomes. Specifically, vitamin D supplementation as a public health measure to improve COVID-19 outcomes is not supported by this MR study.”

First, the MR study approach has not been demonstrated to be a reliable method by which to determine whether vitamin D status is associated with risk or severity of disease. For example, the MR approach has not confirmed the inverse correlations for colorectal cancer [2] but found in observational studies [3]. Likewise for breast cancer: MR [4] vs. observational studies [5]. The observational studies are strongly supported by geographical ecological studies and an understanding of the mechanisms of vitamin D in reducing risk of cancer incidence and death [6]. On the other hand, one MR study did find an inverse relationship between vitamin D status and type 2 diabetes mellitus [7] although two others did not [8, 9], as did a careful secondary analysis of a vitamin D RCT [10].

Regarding randomized controlled trials (RCTs) of vitamin D supplementation for prevention of disease, most have been poorly designed and conducted. Most are based on the guidelines for pharmaceutical drugs. The primary assumption for drugs is that the trial is the only source of the agent. This is not the case for vitamin D. Robert Heaney outlined the guidelines for nutrient trials in 2014 [11]. The guidelines recommend basing the trial on nutrient status, not nutrient dose, using results from observational studies to determine the nutrient-health outcome of interest, measuring nutrient status of prospective participants, supplementing with doses large enough to result in beneficial effects, then measure achieved nutrient status. My colleagues outlined these guidelines for vitamin D in 2018 [12]. The Harvard VITamin D and OmegA-3 TriaL (VITAL) [13] followed guidelines for drugs resulting in enrolling participants with mean 25-hydroxyvitamin D [25(OH)D] for those who reported values of 31 ng/ml, giving a small vitamin D dose (2000 IU/d) and finding no significant reduction in cancer incidence for the entire cohort of over 25,000 participants. However, significantly reduced risk was found for those with BMI <25 kg/m2 and an almost significant reduction for Blacks [13, 14]. The Tufts University Vitamin D and Type 2 diabetes (D2d) RCT of progression from prediabetes to diabetes [15], which used 4000 IU/d in the treatment arm, did not find reduced risk for the entire group, but, again, did find reduced risk in the secondary analyses such as participants with BMI <30 kg/m2 [14, 15]. Subsequently, the data were reanalyzed in terms of 25(OH)D and a beneficial effect of vitamin D was found [10]. Thus, failure of large-scale vitamin D RCTs is not grounds for supporting null findings from MR studies.

Another proposed justification for MR studies stated on p. 2 of Butler-Laporte et al. [1] was “to reduce confounding that has traditionally biased vitamin D observational studies”. A quick perusal of any of the 55 vitamin D COVID-19 sufficiency studies (https://c19vitamind.com/, https://vdmeta.com/) will show that confounding factors are included in the adjusted analyses. It also turns out that having a chronic disease does not seem to affect the finding regarding 25(OH)D concentration cutoff for incidence or death [16]. In that study, 12 ng/ml was the cutoff value of 25(OH)D concentration which yielded a significant difference between survival and death. Ref. [1] mentioned that their MR study was not sensitive to 25(OH)D concentrations in the vitamin D deficiency range, i.e., below 20 ng/ml.

The conclusion in the abstract: “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. Other therapeutic or preventative avenues should be given higher priority for COVID-19 randomized controlled trials.”

This conclusion overlooks the fact that the tremendous reduction in death using calcifediol [25(OH)D] found in the pilot RCT conducted in Cordoba, Spain [17] has further support now in an observational study of calcifediol treatment in five hospitals in southern Spain [18]. There were significant differences in mortality for patients receiving calcifediol compared with patients not receiving it (OR = 0.16 (95% CI 0.03 to 0.80). The advantage of using calcifediol is that serum 25(OH)D concentrations are raised rapidly since the conversion from vitamin D to 25(OH)D is not needed. Thus, even high-dose vitamin D (cholecalciferol) given at the first symptoms of COVID-19 might also be effective in reducing death. See, e.g, two observational studies from France [19, 20].

In sum, all types of studies regarding serum 25(OH)D concentration and vitamin D supplementation on health outcomes have strengths and limitations. Unless the strengths and limitations are understood through careful study of each approach and comparison of results using different approaches, it is unwise to claim that the results of any given study do not support the role of vitamin D in reducing risk of a particular outcome in general.
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References

  • 1. Butler-Laporte G, Nakanishi T, Mooser V, Morrison DR, Abdullah T, Adeleye O, et al. Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study. PLoS Med. 2021;18(6):e1003605. doi: 10.1371/journal.pmed.1003605. PubMed PMID: 34061844.
  • 2. He Y, Timofeeva M, Farrington SM, Vaughan-Shaw P, Svinti V, Walker M, et al. Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study. BMC Med. 2018;16(1):142. doi: 10.1186/s12916-018-1119-2. PubMed PMID: 30103784; PubMed Central PMCID: PMCPMC6090711.
  • 3. McCullough ML, Zoltick ES, Weinstein SJ, Fedirko V, Wang M, Cook NR, et al. Circulating Vitamin D and Colorectal Cancer Risk: An International Pooling Project of 17 Cohorts. J Natl Cancer Inst. 2019;111(2):158-69. doi: 10.1093/jnci/djy087. PubMed PMID: 29912394; PubMed Central PMCID: PMCPMC6376911.
  • 4. Jiang X, Dimou NL, Al-Dabhani K, Lewis SJ, Martin RM, Haycock PC, et al. Circulating vitamin D concentrations and risk of breast and prostate cancer: a Mendelian randomization study. Int J Epidemiol. 2019;48(5):1416-24. doi: 10.1093/ije/dyy284. PubMed PMID: 30597039; PubMed Central PMCID: PMCPMC6934026.
  • 5. McDonnell SL, Baggerly CA, French CB, Baggerly LL, Garland CF, Gorham ED, et al. Breast cancer risk markedly lower with serum 25-hydroxyvitamin D concentrations >/=60 vs <20 ng/ml (150 vs 50 nmol/L): Pooled analysis of two randomized trials and a prospective cohort. PLoS One. 2018;13(6):e0199265. doi: 10.1371/journal.pone.0199265. PubMed PMID: 29906273;
  • 6. Moukayed M, Grant WB. Molecular link between vitamin D and cancer prevention. Nutrients. 2013;5(10):3993-4021. doi: 10.3390/nu5103993. PubMed PMID: 24084056; PubMed Central PMCID: PMCPMC3820056.
  • 7. Xu Y, Zhou Y, Liu J, Wang C, Qu Z, Wei Z, et al. Genetically increased circulating 25(OH)D level reduces the risk of type 2 diabetes in subjects with deficiency of vitamin D: A large-scale Mendelian randomization study. Medicine (Baltimore). 2020;99(51):e23672. doi: 10.1097/MD.0000000000023672. PubMed PMID: 33371106; PubMed Central PMCID: PMCPMC7748166.
  • 8. Ye Z, Sharp SJ, Burgess S, Scott RA, Imamura F, InterAct C, et al. Association between circulating 25-hydroxyvitamin D and incident type 2 diabetes: a mendelian randomisation study. Lancet Diabetes Endocrinol. 2015;3(1):35-42. doi: 10.1016/S2213-8587(14)70184-6. PubMed PMID: 25281353; PubMed Central PMCID: PMCPMC4286815.
  • 9. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020. doi: 10.1001/jama.2020.1585. PubMed PMID: 32031570.
  • 10. Dawson-Hughes B, Staten MA, Knowler WC, Nelson J, Vickery EM, LeBlanc ES, et al. Intratrial Exposure to Vitamin D and New-Onset Diabetes Among Adults With Prediabetes: A Secondary Analysis From the Vitamin D and Type 2 Diabetes (D2d) Study. Diabetes Care. 2020;43(12):2916-22. doi: 10.2337/dc20-1765. PubMed PMID: 33020052.
  • 11. Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014;72(1):48-54. doi: 10.1111/nure.12090. PubMed PMID: 24330136.
  • 12. Grant WB, Boucher BJ, Bhattoa HP, Lahore H. Why vitamin D clinical trials should be based on 25-hydroxyvitamin D concentrations. J Steroid Biochem Mol Biol. 2018;177:266-9. doi: 10.1016/j.jsbmb.2017.08.009. PubMed PMID: 28842142.
  • 13. Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, et al. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. N Engl J Med. 2019;380(1):33-44. doi: 10.1056/NEJMoa1809944. PubMed PMID: 30415629; PubMed Central PMCID: PMCPMC6425757.
  • 14. Grant WB, Boucher BJ. Why Secondary Analyses in Vitamin D Clinical Trials Are Important and How to Improve Vitamin D Clinical Trial Outcome Analyses-A Comment on "Extra-Skeletal Effects of Vitamin D, Nutrients 2019, 11, 1460". Nutrients. 2019;11(9). doi: 10.3390/nu11092182. PubMed PMID: 31514355; PubMed Central PMCID: PMCPMC6769676.
  • 15. Pittas AG, Dawson-Hughes B, Sheehan P, Ware JH, Knowler WC, Aroda VR, et al. Vitamin D Supplementation and Prevention of Type 2 Diabetes. N Engl J Med. 2019;381(6):520-30. doi: 10.1056/NEJMoa1900906. PubMed PMID: 31173679; PubMed Central PMCID: PMCPMC6993875.
  • 16. AlSafar H, Grant WB, Hijazi R, Uddin M, Alkaabi N, Tay G, et al. COVID-19 Disease Severity and Death in Relation to Vitamin D Status among SARS-CoV-2-Positive UAE Residents. Nutrients. 2021;13:1714. doi: 10.3390/nu13051714.
  • 17. Entrenas Castillo M, Entrenas Costa LM, Vaquero Barrios JM, Alcala Diaz JF, Miranda JL, Bouillon R, et al. "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. 2020:105751. doi: 10.1016/j.jsbmb.2020.105751. PubMed PMID: 32871238.
  • 18. Alcala-Diaz JF, Limia-Perez L, Gomez-Huelgas R, Martin-Escalante MD, Cortez-Rodriguez AL, Lopez-Carmona MD. Calcifediol Treatment and Hospital Mortality Due to COVID-19: A Cohort Study. Nutrients. 2021;13(6):1760. doi: 10.3390/nu13061760.
  • 19. Annweiler G, Corvaisier M, Gautier J, Dubee V, Legrand E, Sacco G, et al. Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study. Nutrients. 2020;12(11). doi: 10.3390/nu12113377. PubMed PMID: 33147894; PubMed Central PMCID: PMCPMC7693938.
  • 20. Annweiler C, Hanotte B, Grandin de l'Eprevier C, Sabatier JM, Lafaie L, Celarier T. Vitamin D and survival in COVID-19 patients: A quasi-experimental study. J Steroid Biochem Mol Biol. 2020;204:105771. doi: 10.1016/j.jsbmb.2020.105771. PubMed PMID: 33065275; PubMed Central PMCID: PMCPMC7553119.
  • Competing interests declared: My organization, Sunlight, Nutrition and Health Research Center, receives a grant from Bio-Tech Phrmacal, Inc. (Fayatteville, AR) for research and education regarding vitamin D.


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