A Genetic Predisposition to Vitamin D Deficiency Contributes to Severe COVID-19

Ana Teresa Freitas transformed her personal health challenges into an opportunity when an unclear diagnosis motivated her to embark on a new research trajectory. Freitas realized that the algorithms she used in her electronic and computer engineering work applied to the analysis of regulatory gene networks. She now uses algorithms to explore the human genome and identify genetic data that inform disease prevention in order to help others in similar medical situations.

Freitas and her colleagues took a unique approach to understanding the genetics of immune response variability to SARS-CoV-2.¹ They defined polygenic risk scores, predictors of disease based on individual genetics, for previously identified polymorphisms in genes involved in vitamin D synthesis, metabolism, and downstream pathways. Freitas and her team compared these polygenic risk scores to serum vitamin D levels and COVID-19 disease severity in almost 500 hospitalized COVID-19 patients in Portugal. They identified certain polymorphisms in the GC gene, which encodes vitamin D-binding protein, as risk biomarkers for vitamin D deficiency and found a correlation between these variables and COVID-19 severity.

How did the idea for this work arise?

My team and I developed MyNutriGenes, a genetic test that analyzes genetic predisposition for metabolic syndrome using polygenic risk scores and informs preventive strategies. This test includes an analysis of the genes associated with vitamin D pathways. After more than 9,000 exams, we realized that the Portuguese population had genetic characteristics that predispose them to vitamin D deficiency, which may account for why almost 70% of our population is vitamin D deficient. At the onset of the pandemic, I discussed this topic with my colleague, Conceição Calhau at the New University of Lisbon. We decided to examine 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 mortality rates.² A higher prevalence of one particular variant of the GC gene in Portuguese people versus 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 novel SARS-CoV-2 biomarker discovery. Vitamin D levels and the GC gene variant can be included as part of a composite score for predicting COVID-19 severity, along with other candidate biomarkers. It would be interesting to compare the predictive power of a genetic score with that of a more complex multiparameter score comprising both genetic³ and non-genetic markers using a larger dataset for validation.

This research can also be applied to the study of SARS-CoV-2 disease mechanisms. Neutrophils are abundantly recruited in SARS-CoV-2 infection, but this may not be beneficial to the host. Vitamin D-binding protein acts as a neutrophil chemotactic factor, and genetic variation in its encoding gene impacts COVID-19 outcomes. Therefore, this work stresses the need to further explore 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 several types of cells. In this study, a gene that would not be considered the 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 this association with SARS-CoV-2 infection. This gene should be explored in future studies to assess the existence of other variants associated with variability in immune response and also to explore the underlying mechanisms by means of functional studies.

How might this study shape future clinical practice?

Broadly speaking, this study demonstrates the practical application of preventive genetics for viral diseases. An individual’s access to information about their own genetic predispositions enables a personalized approach to disease prevention and treatment, which in this case may include increased sunlight exposure or a specific supplementation plan to address vitamin D deficiency. Several European countries, including Ireland and Spain, are already taking preventative measures by defining supplementation programs for COVID-19 and other respiratory viruses.^4,5

This interview has been condensed and edited for clarity.

References

1. A.T. Freitas et al., “Vitamin D-related polymorphisms and vitamin D levels as risk biomarkers of COVID-19 disease severity,” Sci Rep, 11:20837, 2021.

2. A. Daneshkhah et al., “Evidence for possible association of vitamin D status with cytokine storm and unregulated inflammation in COVID-19 patients,” Aging Clin Exp Res, 32(10):2141-58, 2020.

3. T.P. Velavan et al., “Host genetic factors determining COVID-19 susceptibility and severity,” EBioMedicine, 72:103629, 2021.

4. “Report on addressing Vitamin D deficiency as a public health measure in Ireland,” Oireachtas Health Committee,

5. F.J. Tarazona-Santabalbina et al., “Vitamin D supplementation for the prevention and treatment of COVID-19: a position statement from the Spanish Society of Geriatrics and Gerontology,” Rev Esp Geriatr Gerontol, 56(3):177-82, 2021.