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

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. 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. Searches (up to July 2023) were conducted in 4 databases. The quality of the studies was evaluated based on the MR-STROBE guidelines. Random-effects meta-analyses were conducted where possible. 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. 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. PROSPERO registration no. CRD42022328224.