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Poor genes (DBP, CYP24A1, CYP2R, etc.) restrict Vitamin D to cells, increasing COVID hospitalization – May 2022

Gen Intern Med. 2022. https://doi.org/10.1007/s11606-021-07170-0. – Letter to the Editor
Marijn M. Speeckaert MD, PhD & Joris R. Delanghe MD, PhD

With interest, we read the paper of Seal et al.,1 which investigated the association of vitamin D status and COVID-19-related hospitalization and mortality. 25-Hydroxyvitamin D [25(OH)D] concentrations were connected in an inverse dose-response relationship to COVID-19-related hospitalization and mortality in a heterogeneous population of veteran patients. Although various confounders were considered, we want to emphasize the significance of vitamin D–binding protein (DBP) and its polymorphism on the obtained results.

Normally, 25(OH)D circulates mainly bound to DBP (approximately 85%) and albumin (15%), while only 0.03% exists in free form. DBP is the main transporter of vitamin D metabolites, and an extensive DBP polymorphism with a distinct allele distribution in various geographic areas has been identified.2 The genetic polymorphisms rs7041 and rs4588 in exon 11 of the DBP gene identify the three major DBP alleles: DBP1F [rs7041-T (ASP), rs4588-C (Thr)], DBP1S [rs7041-G (ASP), rs4588-C (Thr)], and DBP2 [rs7041-T (ASP), rs4588-A (Lys)].2,3 rs2282679 is an rs4588 proxy, and rs2282679-A is generally coinherited with rs4588-C, whereas rs2282679-C is usually coinherited with rs4588-A.4 The concentrations of free and total 25(OH)D, as well as DBP, increase with the following phenotypes: DBP2-2<DBP2-1<DBP1-1.2 rs2282679-C/C allele carriers have lower vitamin D and DBP levels than rs2282679-C/C allele carriers, who, in turn, have lower vitamin D and DBP levels than rs2282679-A/A people.4 A genome-wide meta-analysis, however, revealed that, in addition to rs4588, rs7041, and rs2282679, the following SNPs had an effect on the 25(OH)D concentration: rs6013897 (at CYP24A1), rs10741657 (at CYP2R1), and rs12785878 (near DHCR7).3

The relationship between the DBP polymorphism and COVID-19 has been studied before. We observed that DBP1 carriers are less likely to contract COVID-19 and die from it, which might be explained in part by vitamin D’s supposed protective properties.3 The metabolism score (DBP, CYP24A1) has been found to be significantly linked to COVID-19 severity, which may be due to the SNP rs2282679. A GWAS meta-analysis of COVID-19 host genetics that compared hospitalized and non-hospitalized patients found a significant link between DBP rs2282679 and COVID-19 illness severity.5 Furthermore, DBP has immunologic properties, as well as other biological functions, such as macrophage activation, chemotaxis, and actin scavenging,2 which may contribute to the pathogenesis of COVID-19.

The current data show that the DBP polymorphism may have an impact on the connection between vitamin D and COVID-19-related hospitalization and death. However, the DBP haplotype effects may be less important in veterans than the effect of multiple chronic conditions.


  1. Seal KH, Bertenthal D, Carey E, Grunfeld C, Bikle DD, Lu CM. Association of Vitamin D Status and COVID-19-Related Hospitalization and Mortality. J Gen Intern Med. 2022. https://doi.org/10.1007/s11606-021-07170-0 .
  2. Bikle DD, Schwartz J. Vitamin D binding protein, total and free vitamin D levels in different physiological and pathophysiological conditions. Front Endocrinol. 2019;10:317. - DOI
  3. Speeckaert MM, De Buyzere ML, Delanghe JR. Vitamin D binding protein polymorphism and COVID-19. J Med Virol. 2021;93(2):705-707. - DOI
  4. Wang TJ, Zhang F, Richards JB, et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet. 2010;376(9736):180-188. - DOI
  5. Freitas AT, Calhau C, Antunes G, et al. Vitamin D-related polymorphisms and vitamin D levels as risk biomarkers of COVID-19 disease severity. Sci Rep. 2021;11(1):20837. - DOI

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