Genetic Variations of the Vitamin D Metabolic Pathway and COVID-19 Susceptibility and Severity: Current Understanding and Existing Evidence

Abstract

The immunomodulatory and metabolic effects of vitamin D receptor (VDR) activation have been considered beneficial in mitigating the susceptibility and severity of COVID-19 infection. Furthermore, vitamin D-binding protein (DBP) has pleiotropic effects on the immune system that may influence inflammation associated with COVID-19. Multiple observational studies have demonstrated an association between low levels of serum 25-hydroxyvitamin D and risk and the severity of COVID-19 infection. However, the impact of vitamin D supplementation as an adjunctive treatment for COVID-19 based on evidence from randomized clinical trials is unclear. Equally important is that certain variations of the genes involved in the vitamin D metabolic pathway have been shown to affect immune function and linked with various clinical outcomes, including cardio-metabolic disorders, autoimmune diseases, infections, and cancers. This indicates inter-individual difference in body response to vitamin D. There is also emerging evidence that common polymorphisms of these genes may influence the susceptibility and severity of COVID-19, although the confidence of these findings is limited by a small number of studies and participants. Further studies are needed to address the potential role of VDR activation and DBP in the pathophysiology of COVID-19 which take into account the genetic variations of vitamin D metabolic pathway.

Exploring demographical, clinical, and dietary determinants of vitamin D deficiency among adults in Douala, Cameroon during the COVID-19 era

“…Differences in design, definitions used for vitamin D deficiency, methodological quality, and populations of individual studies included in these systematic reviews and meta-analyses could explain discrepancies in conclusions. Also, it was proposed that certain variations of the vitamin D binding protein, vitamin D receptor, or genes involved in the vitamin D metabolic pathway may modulate the COVID-19 susceptibility and severity outcomes [ 46 ]. The evidence on the association between such genetic variations and COVID-19 outcomes is still missing in Africa, especially in Cameroon.…”

Understanding the Immune-Endocrine Effects of Vitamin D in SARS-CoV-2 Infection: A Role in Protecting against Neurodamage

“…FokI (rs2228570), TaqI (rs731236), BsmI (rs1544410), and ApaI (rs7975232) are VDR single-nucleotide polymorphisms which have been variously associated with different aspects of COVID-19 (susceptibility, severity, mortality). However, the results of observational, retrospective, or casecontrol studies on this topic have been conflicting and do not allow to determine with certainty which polymorphisms contribute most to mitigating or aggravating the disease, also considering the different viral variants [25][26][27].…”

“…Cholecalciferol binds to circulating vitamin D-binding protein (VBP), and in the liver it is hydroxylated to calcifediol (25[OH]D 3 ) by 25-hydroxylase enzyme (cytochrome CYP2R1). Calcifediol is then further hydroxylated to calcitriol (1,25[OH] 2 D 3 ) by 1αhydroxylase enzyme (cytochrome CYP27B1). Calcitriol is the active hormonal final form of vitamin D 3 and can play both non-genomic and genomic effects, acting on vitamin D-receptor (VDR).…”

Pharmacological evaluation of vitamin D in COVID-19 and long COVID-19: recent studies confirm clinical validation and highlight metformin to improve VDR sensitivity and efficacy

“…Changes in the 25 (OH) D levels alter the dynamics and kinetics of VD. For example, increased endogenous production of vitamin D3 could be due to decreased enzymatic activity of 7-dehydrocholesterol reductase, encoded by the DHCR7 gene (Charoenngam et al 2023 ).…”