Contribution of Vitamin D-Binding Protein Polymorphism to Susceptibility and Outcome of COVID-19 Patients.

We read with interest the paper of Bychinin et al. (1) in which they reported their investigation of the predictive value of serum 25-hydroxyvitamin D [25(OH)D] concentration for coronavirus disease 2019 (COVID-19) mortality in patients admitted to the intensive care unit (ICU). More in detail, serum 25(OH)D concentrations ≤9.9 ng/mL on admission could predict in-hospital mortality in COVID-19 patients. Here, we highlight the importance of the vitamin D–binding protein (DBP) polymorphism in the interpretation of the reported results.

DBP, also called group-specific component (GC), is the oldest member of the albuminoid family. This α-globulin is genetically very polymorphic, with 6 major phenotypes based on 3 frequent alleles [DBP1F (rs7041-T, rs4588-C), DBP1S (rs7041-G, rs4588-C), and DBP2 (rs7041-T, rs4588-A)], but in total, >120 different variants have been identified in human populations around the world (2). A near-perfect proxy for rs4588 is rs2282679: rs2282679-A is typically coinherited with rs4588-C, whereas rs2282679-C is typically coinherited with rs4588-A (3).

DBP is the major transport protein for vitamin D, binding >99% of the circulating vitamin D metabolites, along with albumin. In comparison with other transport proteins, the serum concentration of DBP is 20-fold higher than the serum concentration of the vitamin D metabolites, which results in a 5% occupation of the binding sites on DBP by vitamin D sterols, and in very low absolute and relative free concentrations of 25(OH)D [0.03% of total 25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] (0.4% of its total concentration) (2). A strong causal association (P =  3.2 × 10–19) between serum DBP and 25(OH)D concentrations has been reported (3).

The different DBP phenotypes have significant effects on total 25(OH)D, free 25(OH)D, and DBP concentrations. More specifically, the lowest total and free serum concentrations of 25(OH)D have been found in subjects with the DBP2 allele, who also tend to have the lowest serum DBP concentrations (4). Besides, the serum vitamin D concentration depends on the rs2282679 genotype, being highest in rs2282679-A/A subjects, intermediate in rs2282679-A/C carriers, and lowest in the rs2282679-C/C group (5). In a Mendelian randomization study (3), a strong association between rs2282679 and both serum 25(OH)D and DBP concentrations has been demonstrated. Individuals carrying the C-allele at rs2282679 had lower serum DBP concentrations than those with the more common A-allele. So, the higher median serum 25(OH)D concentration in survivors than in nonsurvivors of COVID-19, as reported by Bychinin al. (1), could probably be partly explained by DBP and its polymorphism. Alterations in serum DBP concentrations and different DBP polymorphisms should be considered as potential confounders in the interpretation of serum total 25(OH)D concentrations. To support this statement, we have investigated in a previous report (6) the influence of the DBP phenotypes in patients with a severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection by comparing the frequency of the DBP1 allele (a mixture of DBP1F and DBP1S) with the prevalence and mortality data of COVID-19 in 55 countries. An association was observed between the DBP1 allele frequency and a lower prevalence and mortality due to a SARS-CoV-2 infection, which could be partly explained by the potential protective effects of vitamin D. In another study (7) that investigated the impact of patient genetic background related to vitamin D pathways on COVID-19 severity, the SNP rs2282679 could explain most of the positive correlation between the metabolism score (DBP rs2282679 + CYP24A1 rs17216707) and COVID-19 severity (ρ = 0.13, P value = 0.005) (7). Besides the DBP gene, the CYP2R1 gene (rs10741657), the CYP24A1 gene (rs6013897), and the DHCR7/NADSYN1 region (rs12785878) are also genetic determinants of the 25(OH)D concentration. However, no association has been found between the vitamin D total score (DHCR7 rs12785878 + CYP2R1 rs10741657 + DBP rs2282679 + CYP24A1 rs17216707 + AMDHD1 rs10745742 + SEC23A rs8018720) and the severity of COVID-19 (7).

As DBP is a multifunctional protein, the association of the reported DBP polymorphisms with disease severity might also be partly explained by DBP's actin scavenger capacity (8). During tissue injury, large quantities of actin can be released into extracellular fluids, resulting in the formation of actin filaments (F-actin) and leading to alterations in the coagulation and fibrinolytic systems, with occlusion and damage of the microcirculation (particularly in the lungs) as a consequence. High morbidity and mortality have been associated with coagulopathy in severe COVID-19 (9). DBP and plasma gelsolin act as part of the actin scavenging system and work in tandem (8). Gelsolin severs F-actin filaments into globular actin (G-actin) monomers, whereas DBP binds G-actin in a high-affinity (Kd of 10–9 M) 1:1 molar complex for transport and eventual clearance of actin from the circulation (8). Actin-induced depletion of plasma DBP correlates with a poor prognosis in cases of sepsis (10) and has a statistical correlation similar to the other outcome metrics such as the Acute Physiology and Chronic Health Evaluation II (APACHE II) score (sepsis), Kings College criteria (liver failure), and the trauma and injury severity score (TRISS) (multiple trauma) (10, 11). So, lower serum DBP concentrations might have a link with COVID-19 mortality in patients admitted to the ICU, not only by its causal association with vitamin D deficiency, but also by decreasing the actin-binding capacity.

The question of whether the reported relations between DBP (and its polymorphisms) and the outcome of COVID-19 are causal or consequential should be further investigated.