Genetic Predisposition in Severe COVID-19 Cases

As of August 2020, over 22 million cases of COVID-19 have been reported worldwide, including almost 800,000 deaths [1]. More and more studies show that genetic predisposition could play a significant role in progression and outcome of COVID-19.

The disease is diagnosed with nearly equal distribution in men and women, but mortality rate is higher in men in almost all countries [2]. A study found that the gene for Angiotensin-converting enzyme 2 (ACE2), the protein used by SARS-CoV-2 as a viral receptor for cell-entry, is located on the X-chromosome. Therefore, men with rare ACE2 coding variants express those variants in all ACE2-expressing cells. Women however, can suppress the expression by X-inactivation. This distinction in ACE2 expression could have implications for the difference of COVID-19 in men and women.

The impact of additional factors for high mortality in COVID-19 needs to be considered as well. Men have a higher occurrence of many of the preconditions that are risk factors for severe COVID-19, such as diabetes and cardiovascular disease. Other gender-based drivers of inequality, such as response to disease or difference in access to health services also play a significant role. [3]

Independent of gender, genetic predisposition that determine COVID-19 progression have been reported. Molecular characterization of patients with severe COVID-19 identified genetic susceptibility loci for the development of respiratory failure in COVID-19 patients. [4, 5]

Studies also showed that blood type is a biomarker for different susceptibility of COVID-19. Blood group A was associated with an increased risk of infection with SARS-CoV-2, as well as a higher mortality rate. Blood group O was associated with a decreased risk for both infection and mortality rate. [6, 7] How blood types influence the probability of infection and outcome of COVID-19 is still unclear, but one theory is that blood type characteristics on red blood cells play a role in the elimination of the von Willebrand factor (VWF), a protein involved in hemostasis. VWF promotes the formation of venous thromboembolism, which occurs often in severe COVID-19 cases and can lead to an unfavorable outcome. [8, 9]

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1. WHO. Coronavirus disease (COVID-19). Situation Report – 209. Data as received by WHO from national authorities by 10:00 CEST, 16 August 2020.

2 . Global Health 50/50. COVID-19 Sex-disaggregated Data Tracker. [accessed on 27.08.2020]

3. Gibson W, et al. ACE 2 coding variants: a potential x-linked risk factor for COVID-19 disease. bioRxiv (2020).

4. Ellinghaus D, et al. The ABO blood group locus and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis. medRxiv (2020).

5. Benetti E, et al. Clinical and molecular characterization of COVID-19 hospitalized patients. medRxiv (2020).

6. Zhao J, et al. Relationship between the ABO Blood Group and the COVID-19 Susceptibility. medRxiv (2020).

7. Zietz M. Testing the association between blood type and COVID-19 infection, intubation, and death. MedRxiv (2020).

8. Kosta MI, et al. ABO blood group, glycosyltransferase activity and risk of venous thromboembolism. Thrombosis Research (2020).

9. Huisman, Albert, et al. "Involvement of ADAMTS13 and von Willebrand factor in thromboembolic events in patients infected with SARS‐CoV‐2." International Journal of Laboratory Hematology (2020).