Vitamin D-related polymorphisms and vitamin D levels as risk biomarkers of COVID-19 disease severity

Ana Teresa Freitas, Conceição Calhau, Gonçalo Antunes, Beatriz Araújo, Matilde Bandeira, Sofia Barreira, Filipa Bazenga, Sandra Braz, Daniel Caldeira, Susana Constantino Rosa Santos, Ana Faria, Daniel Faria, Marta Fraga, Beatriz Nogueira-Garcia, Lúcia Gonçalves, Pavlo Kovalchuk, Luísa Lacerda, Hugo Lopes, Daniel Luís, Fábio Medeiros, Ana M P Melo, José Melo-Cristino, Ana Miranda, Clara Pereira, Ana Teresa Pinto, João Pinto, Helena Proença, Angélica Ramos, João P R Rato, Filipe Rocha, Júlio César Rocha, André Moreira-Rosário, Helena Vazão, Yuliya Volovetska, João-Tiago Guimarães, Fausto J Pinto, Ana Teresa Freitas, Conceição Calhau, Gonçalo Antunes, Beatriz Araújo, Matilde Bandeira, Sofia Barreira, Filipa Bazenga, Sandra Braz, Daniel Caldeira, Susana Constantino Rosa Santos, Ana Faria, Daniel Faria, Marta Fraga, Beatriz Nogueira-Garcia, Lúcia Gonçalves, Pavlo Kovalchuk, Luísa Lacerda, Hugo Lopes, Daniel Luís, Fábio Medeiros, Ana M P Melo, José Melo-Cristino, Ana Miranda, Clara Pereira, Ana Teresa Pinto, João Pinto, Helena Proença, Angélica Ramos, João P R Rato, Filipe Rocha, Júlio César Rocha, André Moreira-Rosário, Helena Vazão, Yuliya Volovetska, João-Tiago Guimarães, Fausto J Pinto

Abstract

Vitamin D is a fundamental regulator of host defences by activating genes related to innate and adaptive immunity. Previous research shows a correlation between the levels of vitamin D in patients infected with SARS-CoV-2 and the degree of disease severity. This work investigates the impact of the genetic background related to vitamin D pathways on COVID-19 severity. For the first time, the Portuguese population was characterized regarding the prevalence of high impact variants in genes associated with the vitamin D pathways. This study enrolled 517 patients admitted to two tertiary Portuguese hospitals. The serum concentration of 25 (OH)D, was measured in the hospital at the time of patient admission. Genetic variants, 18 variants, in the genes AMDHD1, CYP2R1, CYP24A1, DHCR7, GC, SEC23A, and VDR were analysed. The results show that polymorphisms in the vitamin D binding protein encoded by the GC gene are related to the infection severity (p = 0.005). There is an association between vitamin D polygenic risk score and the serum concentration of 25 (OH)D (p = 0.04). There is an association between 25 (OH)D levels and the survival and fatal outcomes (p = 1.5e-4). The Portuguese population has a higher prevalence of the DHCR7 RS12785878 variant when compared with its prevalence in the European population (19% versus 10%). This study shows a genetic susceptibility for vitamin D deficiency that might explain higher severity degrees in COVID-19 patients. These results reinforce the relevance of personalized strategies in the context of viral diseases.Trial registration: NCT04370808.

Conflict of interest statement

All authors affiliated with the company HeartGenetics, Genetics and Biotechnology SA, declare that the company developed a genetic test, the MyVitDGenes®, that was used to evaluate all the polymorphisms under analysis in this work. All other authors have declared that no conflict of interest exists.

© 2021. The Author(s).

Figures

Figure 1
Figure 1
PRSs are represented as a continuous value. Patients were divided in three groups (Deficient—red; Insufficient—yellow; Sufficient—blue) considering its vitamin D level (a continuous variable). In each group, patients are sorted in ascending order of PRSs.
Figure 2
Figure 2
Vitamin D level (ng/mL) (continuous) and COVID-19 disease severity (binomial: survived, dead).
Figure 3
Figure 3
Comparison of the impact genotypes’ frequency in the Portuguese and European populations. Circles highlight the risk genotype. The red circles show the risk genotypes from variants with a statistically significant difference between these two populations (p-value = 2.5e−7 for DHCR7 RS12785878, and p-value = 2.8e−4 for AMDHD1 RS10745742).

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