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Genetic predisposition to vitamin D deficiency contributes to severe COVID-19

Alysson R. Muotri, PhD Director, Stem Cell Program Professor of Pediatrics and Cellular & Molecular Medicine University of California, San Diego

Ana Teresa Freitas, PhD
Professor, Instituto Superior Técnico (IST)
University of Lisbon
CEO and Co-Founder, HeartGenetics, Genetics and Biotechnology, Lisbon

Ana Teresa Freitas turned her personal health challenges into an opportunity when an unclear diagnosis motivated her to embark on a new research path. Freitas realized that the algorithms she used in her electronic and computational work were applicable to the analysis of regulatory gene networks. As a professor at the Faculty of Computer Science and Engineering at the University of Lisbon and CEO of HeartGenetics, she now uses algorithms to explore the human genome and identify genetic data that contribute to disease prevention.

In a recent Scientific Reports In their study, Freitas and her colleagues took a unique approach to understand the genetics of the variability of the immune response to SARS-CoV-2.1 They defined polygenic risk scores – a disease predictor that uses an algorithm to assess genetic variability – for previously identified polymorphisms in genes involved in vitamin D synthesis, metabolism and downstream signaling pathways. Freitas and her team compared these polygenic risk scores to serum vitamin D levels and COVID-19 disease severity in nearly 500 hospitalized COVID-19 patients in Portugal. They identified certain polymorphisms in the G.C gene encoding vitamin D-binding protein as a risk biomarker for vitamin D deficiency and found a correlation between these variables and the severity of COVID-19.

How did the idea for this work come about?

My team and I have developed MyNutriGenes, a genetic test that analyzes the genetic predisposition to metabolic syndrome using polygenic risk scores and informs preventive strategies. This test involves an analysis of the genes associated with vitamin D pathways. After more than 9,000 studies, we found that the Portuguese population has genetic characteristics that predispose them to vitamin D deficiency, which may explain why almost 70% of our population is vitamin D deficient. At the beginning of the pandemic, I discussed this topic with Conceição Calhau. We decided to investigate the association between polygenic risk scores for polymorphisms in vitamin D-related genes, vitamin D deficiency, and COVID-19 severity, based on previous evidence of an association between vitamin D status and COVID-19 19 mortality rates.2 A higher prevalence of the DHCR7 RS12785878 variant [of the GC gene] in Portuguese compared to Europeans likely contributes to the observed prevalence of vitamin D deficiency.

What are possible applications of this work?

This work highlights the important role of serum vitamin D levels and vitamin D-binding protein in SARS-CoV-2 infection and has implications for the discovery of new SARS-CoV-2 biomarkers. Vitamin D levels and the GC gene variant described in this article can be included along with other candidate biomarkers as part of a composite score to predict COVID-19 severity. It would be interesting to compare the predictive power of a genetic score with that of a more complex multi-parameter score that includes both genetic factors3 and non-genetic markers, which use a larger dataset for validation.

This research can also be applied to studying the disease mechanisms of SARS-CoV-2. It is known that neutrophils are recruited abundantly in SARS-CoV-2 infection, but this may not be beneficial to the host. The vitamin D-binding protein acts as a neutrophil chemotactic factor, and genetic variations in its encoding gene affect outcomes of COVID-19. Therefore, this work emphasizes the need to further investigate the role of neutrophils in SARS-CoV-2 infection to understand whether modulating these immune cells could improve outcomes.

In general, the immune response depends on the concerted action of multiple cell types. In this study, a gene that would not be considered first choice in the context of immunity (GC) showed an association with the severity of SARS-CoV-2 infection. There was already some evidence of its importance in immune response, and this study reinforced that link, in this case in relation to SARS-CoV-2 infection. Therefore, this gene should be examined in future studies to assess the existence of other variants associated with immune response variability and also to investigate the underlying mechanisms via functional studies.

How could this study shape future clinical practice?

Overall, this study demonstrates the practical application of preventive genetics for viral diseases. A person’s access to information about their own genetic predispositions allows for a personalized approach to disease prevention and treatment, which in this case may include increased sun exposure or a specific supplementation plan to treat vitamin D deficiency. Several European countries, including Ireland and Spain, are already taking preventive measures by defining supplemental programs for COVID-19 and other respiratory viruses.4.5

This interview has been edited and shortened for clarity.


  1. AT Freitas et al., “Vitamin D-related polymorphisms and vitamin D levels as risk biomarkers for the severity of COVID-19 disease”, Scientific Rep11:20837, 2021.
  2. A. Daneshkhah et al., “Evidence for a possible association of vitamin D status with cytokine storm and unregulated inflammation in COVID-19 patients” Aging Clin Exp Res32(10):2141-58, 2020.
  3. TP Velavan et al., “Host Genetic Factors Determining Susceptibility and Severity of COVID-19”, EBioMedicine72:103629, 2021.
  4. “Report on tackling vitamin D deficiency as a public health measure in Ireland”, Oireachta’s Board of Healthhttps://data.oireachtas.ie/ie/oireachtas/committee/dail/33/joint_committee_on_health/reports/2021/2021-04-07_report-on-addressing-vitamin-d-deficiency-as-a-public-health – measure-in-irland_en.pdf
  5. FJ Tarazona-Santabalbina et al., “Vitamin D supplementation for the prevention and treatment of COVID-19: a statement from the Spanish Society of Geriatrics and Gerontology”, Pastor Esp Geriatr Gerontol56(3):177-82, 2021.
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