Micronutrients, Vitamin D, and Inflammatory Biomarkers in COVID-19: A Systematic Review and Meta-analysis of Causal Inference Studies

Abstract

Context: Experimental and observational studies suggest that circulating micronutrients, including vitamin D (VD), may increase COVID-19 risk and its associated outcomes. Mendelian randomization (MR) studies provide valuable insight into the causal relationship between an exposure and disease outcomes.

Objectives: The aim was to conduct a systematic review and meta-analysis of causal inference studies that apply MR approaches to assess the role of these micronutrients, particularly VD, in COVID-19 risk, infection severity, and related inflammatory markers.

Data sources: Searches (up to July 2023) were conducted in 4 databases.

Data extraction and analysis: The quality of the studies was evaluated based on the MR-STROBE guidelines. Random-effects meta-analyses were conducted where possible.

Results: There were 28 studies (2 overlapped) including 12 on micronutrients (8 on VD) and COVID-19, 4 on micronutrients (all on VD) and inflammation, and 12 on inflammatory markers and COVID-19. Some of these studies reported significant causal associations between VD or other micronutrients (vitamin C, vitamin B6, iron, zinc, copper, selenium, and magnesium) and COVID-19 outcomes. Associations in terms of causality were also nonsignificant with regard to inflammation-related markers, except for VD levels below 25 nmol/L and C-reactive protein (CRP). Some studies reported causal associations between cytokines, angiotensin-converting enzyme 2 (ACE2), and other inflammatory markers and COVID-19. Pooled MR estimates showed that VD was not significantly associated with COVID-19 outcomes, whereas ACE2 increased COVID-19 risk (MR odds ratio = 1.10; 95% CI: 1.01-1.19) but did not affect hospitalization or severity of the disease. The methodological quality of the studies was high in 13 studies, despite the majority (n = 24) utilizing 2-sample MR and evaluated pleiotropy.

Conclusion: MR studies exhibited diversity in their approaches but do not support a causal link between VD/micronutrients and COVID-19 outcomes. Whether inflammation mediates the VD-COVID-19 relationship remains uncertain, and highlights the need to address this aspect in future MR studies exploring micronutrient associations with COVID-19 outcomes.

Systematic review registration: PROSPERO registration no. CRD42022328224.

Keywords: Mendelian randomization; causal inference; inflammatory markers; micronutrients; vitamin D.

Graphical abstract

Figure 1.

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 Flow Diagram of the Study Search and Selection Process. Abbreviation: WOS, Web of Science

Figure 2.

Exposure–Outcome Associations. Mendelian randomization (MR) studies considering instrumental variables (IVs) defined by micronutrients and vitamin D (VD; 1 and 2) or inflammatory markers (3) and studies that further assessed the association between IVs and COVID-19 (1 and 3) or inflammatory markers (2) were considered in this review. The main MR assumptions are indicated. The IV is associated with the exposure, and the association of the IV with the outcome occurs through the exposure

Figure 3.

Meta-analyses of Studies Reporting Results on Vitamin D and COVID-19 Disease Outcomes. Odds ratios, 95% CIs of each study, and combined MR estimates are shown. (A) Infection. (B) Hospitalization. (C) Severity. Estimates of those studies without study population overlap at the exposure level were pooled.^,, Abbreviation: RE, Random Effects

Figure 4.

Meta-analyses of Studies Reporting Results on angiotensin-converting enzyme (ACE) 2 (ACE2) and COVID-19 Disease Outcomes. Odds ratios (ORs), 95% CIs of each study, and combined Mendelian randomization estimates are shown. (A) Infection. (B) Hospitalization. (C) Severity. There was no evidence of heterogeneity or publication bias in these analyses. Random- and fixed-effects meta-analyses yielded similar results. Estimates of those studies without study population overlap at the exposure level were pooled.^, Estimates were given per SD increase, except in the study by Yang et al, However, in this study, the results reported per 1-unit increase align with the SD increment. As reported in this study, overall, the SD of ACE2 is 1.17, which results in an OR = 1.43 (1.04–1.98) derived from β = log(estimate)/SD. Abbreviation: RE, Random Effects