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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 (, 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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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.
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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.