Habitual use of vitamin D supplements and risk of coronavirus disease 2019 (COVID-19) infection: a prospective study in UK Biobank 

In this prospective study, the self-reported use of vitamin D supplements was associated with a lower risk of COVID-19 infection, independent of lifestyle, socio-economic status, prevalent chronic diseases and circulating vitamin D levels. Circulating vitamin D levels at baseline or genetically predicted vitamin D levels were not associated with the risk of COVID-19 infection. 

UK Biobank recruited 502,624 participants aged 37-73 years across England, Scotland and Wales between 2006 and 2010. Its aim was to identify the causes of disease and death in middle and old age by following up participants over time. At baseline, biological measurements were recorded and touch-screen questionnaires were administered according to a standardized protocol. The current analyses were restricted to participants who have records of COVID-19 test results from 22 UK assessment centers. Exclusion criteria include participants with incomplete data on the use of vitamin D supplements, serum vitamin D levels and/or cigarette use. A total of 8297 participants were included in the final analysis. 

A positive COVID-19 test result between March 16, 2020 and June 29, 2020. 

• A total of 4.4% (N=363) of the participants reported regular use of vitamin D.  
• Compared with participants not using vitamin D supplements, the self-reported habitual users of  vitamin D supplements were older; more likely to be non-white, female and non-current smokers; and were more likely to have a healthy diet and lower prevalence of obesity and cardiovascular disease but higher prevalence of cancer or COPD at baseline. Users of vitamin D supplements also tended to take more other ot types of supplements.  
• Compared with the nonusers, the self-reported habitual users of vitamin D had a significantly higher level of circulating vitamin D (56.0 ± 20.8 nmol/L vs. 47.0 ± 21.1 nmol/L, respectively.  
• Of 8297 participants who had records of COVID-19 test results, 16.6% (1378/8297) of the total study population tested positive for COVID-19.  
• In the unadjusted model, vitamin D users did not have a significantly lower risk of COVID-19 infection as compared with nonusers However, further adjustment for age, sex, race, research centers, laboratory, origin (outpatient or inpatient), blood-type haplotype, years of education, TDI, smoking, moderate drinking, physical activity, healthy diet score, and use of any other supplements strengthened the association, and a significant, inverse association between habitual use of vitamin D supplements and risk of COVID-19 infection was observed (OR, 0.67; 95% CI, 0.46–0.98; P = 0.038). An additional adjustment for baseline disease status (obesity, diabetes, hypertension, high cholesterol, cardiovascular diseases, cancer, asthma, and COPD) and circulating vitamin D did not appreciably alter the results (OR, 0.66; 95% CI, 0.45–0.97; P = 0.034. 
•  No significant association was found between baseline circulating vitamin D levels and the risk of COVID-19 infection. The risk of COVID-19 was similar for participants with vitamin D deficiency (defined as <25 nmol/L), vitamin D insufficiency (defined as 25–50 nmol/L) and vitamin D sufficiency (defined as >50 nmol/L). 

• This study might be subjected to selection bias. If COVID-19 testing was more likely in vitamin D users than nonusers, this might introduce a selection bias.   However, a significant association between the use of vitamin D supplements and receiving COVID-19 tests was not found in the study population.  
• In addition, COVID-19 tests were largely restricted to participants with symptoms in hospitals during the spring period,who might not represent the whole population in the United Kingdom. Therefore, caution should be taken in interpreting the observations.  
• The information about vitamin D supplement use was collected a median of 10 years before the COVID-19 tests, meaning our results might only reflect the association between “ever” use of vitamin D supplements and the risk of COVID-19 infection. Potential effects of changes in the use of vitamin D supplements during the follow-up period cannot be ruled out.  
• Use of vitamin D supplements might be a marker for a healthier lifestyle or a higher socio-economic level, as compared with non–use.  
• Almost all the vitamin D users also took other supplements. However, no significant inverse association between use of other individual supplements and a risk of COVID-19 infection was observed. 
• A previous study showed that low circulating vitamin D levels were associated with the severity of COVID-19. Therefore, the lack of data on the severity of COVID-19 is another limitation in this study. 

The habitual use of vitamin D supplements was associated with a lower risk of COVID-19 infection in the current study. However, the possibility that the observed inverse association was due to unmeasured related factors or bias related to subject participation cannot be ruled out, since a consistent inverse association between baseline serum vitamin D levels or genetically predicted vitamin D levels was not found. Further clinical trials are needed to verify the inverse association between the habitual use of vitamin D supplements and the risk of COVID-19 infection.

• Information on vitamin D supplement use was collected through the baseline touch-screen questionnaire (2006–2010). Participants were asked “Do you regularly take any of the following?”. The available options included vitamins A, B, C, D and E; folic acid; a multivitamin; calcium; zinc; iron; selenium; glucosamine; fish oil; “prefer not to answer;” and “none of the above.” If a participant selected “prefer not to answer,” it was treated as a missing variable and excluded from the analysis.  
• The questionnaire also identified confounders at baseline (2006–2010), including age, sex, race, assessment centers, education level, Townsend deprivation index (TDI; TDI is a  composite measure of deprivation based on unemployment, non–car ownership, no non- home ownership, and household overcrowding); physical activity, smoking status, alcohol intake, and dietary intakes (red meat, vegetable, fruit and fish intake).  
• Obesity was defined as a BMI ≥30 kg/m2. Medical histories of hypertension, hypercholesterolemia, diabetes, cardiovascular disease, cancer and chronic obstructive pulmonary disease were also recorded. 
• The primary outcome for the current study was the risk of COVID-19 infection.  The vast majority of samples tested for COVID-19 were from combined nose/throat swabs that were transported in a medium suitable for PCR testing to be performed. 
• Logistic regression models were used to calculate the ORs when comparing COVID-19 infection rates in participants who did and did not use vitamin D supplements. Potential confounders were adjusted in these models. 

Ma H, Zhou T, Heianza Y, Qi L. 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. 2021 Jan 29:nqaa381. doi: 10.1093/ajcn/nqaa381. Epub ahead of print. PMID: 33515005; PMCID: PMC7929381. 

https://pubmed.ncbi.nlm.nih.gov/33515005/