Using genetic variants to evaluate the causal effect of serum vitamin D concentration on COVID-19 susceptibility, severity and hospitalization traits: a Mendelian randomization study

Abstract

Background The coronavirus disease 2019 (COVID-19) pandemic has struck globally and is exerting a devastating toll on humans. The pandemic has led to calls for widespread vitamin D supplementation in public. However, evidence supporting the role of vitamin D in the COVID-19 pandemic remains controversial. Methods We performed a two-sample Mendelian randomization (MR) analysis to analyze the causal effect of the 25-hydroxyvitamin D [25(OH)D] concentration on COVID-19 susceptibility, severity and hospitalization traits by using summary-level GWAS data. The causal associations were estimated with inverse variance weighted (IVW) with fixed effects (IVW-fixed) and random effects (IVW-random), MR-Egger, weighted edian and MR Robust Adjusted Profile Score (MR.RAPS) methods. We further applied the MR Steiger filtering method, MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) global test and PhenoScanner tool to check and remove single nucleotide polymorphisms (SNPs) that were horizontally pleiotropic. Results We found no evidence to support the causal associations between the serum 25(OH)D concentration and the risk of COVID-19 susceptibility [IVW-fixed: odds ratio (OR) = 0.9049, 95% confidence interval (CI) 0.8197–0.9988, p = 0.0473], severity (IVW-fixed: OR = 1.0298, 95% CI 0.7699–1.3775, p = 0.8432) and hospitalized traits (IVW-fixed: OR = 1.0713, 95% CI 0.8819–1.3013, p = 0.4878) using outlier removed sets at a Bonferroni-corrected p threshold of 0.0167. Sensitivity analyses did not reveal any sign of horizontal pleiotropy. Conclusions Our MR analysis provided precise evidence that genetically lowered serum 25(OH)D concentrations were not causally associated with COVID-19 susceptibility, severity or hospitalized traits. Our study did not provide evidence assessing the role of vitamin D supplementation during the COVID-19 pandemic. High-quality randomized controlled trials are necessary to explore and define the role of vitamin D supplementation in the prevention and treatment of COVID-19.

Identifying factors contributing to increased susceptibility to COVID-19 risk: a systematic review of Mendelian randomization studies

“…Mendelian randomization studies have explored the role of a wide range of anthropometrics and biomarkers in COVID-19 risk, including anthropometrics, blood pressure, coagulation factors, cytokines, inflammatory markers, glycaemic traits, haematological traits, lipids, liver functions, renal functions and vitamins. 27 , 31–33 , 35 , 38–40 , 42 , 44–47 , 49 , 52 , 53 , 55 , 58–60 , 62 , 64 , 65 Consistent evidence suggested that obesity [higher body mass index (BMI) and trunk fat ratio] was associated with higher COVID-19 risk 27 , 32 , 38 , 42 , 45 , 53 and one study also showed that increase in height was associated with higher risk of COVID-19 susceptibility. 27 Consistent evidence showed systolic and diastolic blood pressure to have no role in COVID-19 risk, 27 , 32 , 42 , 49 , 53 although one study found that higher pulse pressure was associated with higher risk of COVID-19 hospitalization in people of mixed ancestry but not of European ancestry.…”

“… 59 , 65 No evidence was found for the role of leukocyte telomere length (a determinant of longevity) in COVID-19. 60 Consistent evidence showed that glycaemic traits (HbA 1c , fasting insulin, fasting glucose and 2-h glucose), 31 , 32 , 42 high density lipoprotein (HDL) cholesterol and apolipoprotein A, 27 , 32 , 39 , 42 , 62 , 65 renal traits [creatinine-based estimated glomerular filtration rate (eGFR) and serum creatinine] 27 , 42 , 59 and vitamins C and D 27 , 33 , 35 , 40 , 46 , 47 , 52 were not associated with risk of COVID-19 ( Supplementary Table S1 , available as Supplementary data at IJE online).…”

Vitamin D and SARS-CoV2 infection, severity and mortality: A systematic review and meta-analysis

“…Moreover, a Mendelian randomization study [ 102 ] found that low VD levels are not casually associated with Covid-19 susceptibility and severity.…”

Telomere Length and COVID-19 Outcomes: A Two-Sample Bidirectional Mendelian Randomization Study

“…There may be several explanations for the discrepancy between epidemiological observations and the non-significant causal relationship between genetically predicted LTL and COVID-19 severity in our study. On one hand, it is important to note that such observational studies, despite attempts to adjust for potential confounding factors, have the possibility of significant residual confounding factors due to uncontrolled or imperfectly measured covariates ( Cui and Tian, 2021 ). In particular, care must be taken to control for potential factors that might influence TL, such as technical variations in TL measurement, psychological stress, income, marital status, lifestyle, and cell-type composition ( Demanelis et al, 2021 ).…”