Abstract

A growing body of evidence suggests that vitamin D deficiency has been associated with an increased susceptibility to viral and bacterial respiratory infections. In this study, we aimed to examine the association between vitamin D and COVID-19 risk and outcomes. We used logistic regression to identify associations between vitamin D variables and COVID-19 (risk of infection, hospitalisation and death) in 417,342 participants from UK Biobank. We subsequently performed a Mendelian Randomisation (MR) study to look for evidence of a causal effect. In total, 1746 COVID-19 cases (399 deaths) were registered between March and June 2020. We found no significant associations between COVID-19 infection risk and measured 25-OHD levels after adjusted for covariates, but this finding is limited by the fact that the vitamin D levels were measured on average 11 years before the pandemic. Ambient UVB was strongly and inversely associated with COVID-19 hospitalization and death overall and consistently after stratification by BMI and ethnicity. We also observed an interaction that suggested greater protective effect of genetically-predicted vitamin D levels when ambient UVB radiation is stronger. The main MR analysis did not show that genetically-predicted vitamin D levels are causally associated with COVID-19 risk (OR = 0.77, 95% CI 0.55–1.11, P = 0.160), but MR sensitivity analyses indicated a potential causal effect (weighted mode MR: OR = 0.72, 95% CI 0.55–0.95, P = 0.021; weighted median MR: OR = 0.61, 95% CI 0.42–0.92, P = 0.016). Analysis of MR-PRESSO did not find outliers for any instrumental variables and suggested a potential causal effect (OR = 0.80, 95% CI 0.66–0.98, p-val = 0.030). In conclusion, the effect of vitamin D levels on the risk or severity of COVID-19 remains controversial, further studies are needed to validate vitamin D supplementation as a means of protecting against worsened COVID-19.

Highlights

  • Abbreviations 25-OHD 25-Hydroxyvitamin D body mass index (BMI) Body mass index COVID-19 Corona Virus Disease 2019 IQR Interquartile range Mendelian Randomisation (MR) Mendelian randomisation odds ratio (OR) Odds ratio Standard Deviation (SD) Standard deviation ultraviolet B (UVB) Ultraviolet radiation b vitD Vitamin D weighted genetic risk score (wGRS) Weighted genetic risk score

  • We consistently found that vitD-UVB dose was strongly and inversely associated with the hospitalization (OR = 0.98, 95% CI 0.97–0.99, p-val < 2 × ­10–16) and death (OR = 0.97, 95% CI 0.96–0.98, p-val < 2 × 1­ 0–16) from COVID19 in multivariable models, while null findings were reported for other vitamin D variables (Table 2)

  • We assessed whether there is an association between vitamin D and COVID-19 risk and severity by examining a comprehensive set of key vitamin D variables jointly for the first time, and applying a number of analyses to probe consistency of our findings

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Summary

Introduction

Abbreviations 25-OHD 25-Hydroxyvitamin D BMI Body mass index COVID-19 Corona Virus Disease 2019 IQR Interquartile range MR Mendelian randomisation OR Odds ratio SD Standard deviation UVB Ultraviolet radiation b vitD Vitamin D wGRS Weighted genetic risk score. To explore the causal role of vitamin D in COVID-19 risk, there have been at least three Mendelian Randomisation studies using the genetic variants associated with serum 25OHD as instrumental v­ ariables[6,7,8]. The main aim of the current study is to perform Mendelian Randomisation (MR) analyses investigating the effect of genetically-predicted vitamin D levels on COVID-19 risk while taking into account ambient UVB radiation at the time of the infection, and compare these findings with results obtained from the observational analysis. We performed a MR analysis by using genetically-predicted vitamin D levels and applied a novel approach that enabled us to estimate the UVB exposure preceding disease onset to COVID-19 to account for seasonal differences

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