Can alpha-1-antitrypsin deficiency affect severity and higher mortality in COVID-19 patients?

Alpha-1-Antitrypsin and Protection Against COVID-19  

Since December 2019, the novel coronavirus has spread from China to all corners of the world. According to available data, the highest mortality is observed in 5 European and 5 Latin American countries. To understand why this is the case, one needs to investigate the pathogen, the host, and environmental influences. The host's genome plays an important role in the course of the infection, as evident from the significantly lower morbidity and mortality rates of COVID-19 in Asians compared to Europeans.

The authors of the presented article proposed the following hypothesis: alpha-1-antitrypsin (AAT) deficiency could be one of the risk factors for severe COVID-19 infection. The SARS-CoV-2 coronavirus is activated by the membrane-anchored serine protease TMPRSS2 before binding to the ACE2 receptor, which facilitates its entry into the cell. AAT is an endogenous protease inhibitor encoded by the SERPINA1 gene. AAT also inhibits TMPRSS2, with the inhibitory effect increasing with the dose. Preliminary experimental evidence suggests the potential use of drugs used for AAT deficiency therapy against COVID-19.

Methodology and Analysis Process

AAT deficiency is highly prevalent in the European population, with the most common genetic variant rs17580. The authors used the gnomAD database, which contains genomes of more than 71,000 individuals, to find data on SERPINA1 gene variants. Out of 466 variants of this gene, they narrowed it down to 32 pathogenic or likely pathogenic variants.

They manually compared their findings with the Clinvar database to ensure sufficient clinical or functional evidence for variant pathogenicity. Using Hardy-Weinberg's law for autosomal recessive inheritance, they calculated the 2pq value to estimate the carrier rate of pathogenic variants in the population and for the percentage representation in all available ethnicities. The validity of the approach to confirm the authors' hypothesis is indicated, for example, by the correlation between the geographical prevalence of alpha-1-antitrypsin and the severe course of COVID-19 infection in Italy.

Possible Implications for Practice

Europeans and Latin Americans have a high carrier rate of alpha-1-antitrypsin deficiency (12%), with Latin American countries showing one of the highest mortalities from COVID-19. The serine protease inhibitor family (SERPIN) is an important class of proteins that play a crucial role in blood coagulation homeostasis, and if impaired, it can lead to the risk of disseminated intravascular coagulation (DIC).

The authors of the hypothesis believe that there is sufficient evidence to support future research focusing on serum levels of SERPIN, including alpha-1-antitrypsin status and smoking history in COVID-19 patients. Further studies should also focus on the therapeutic effect of AAT in animal models with this infection. Given the enormous burden of the SARS-CoV-2 pandemic, AAT values and SERPIN status could serve to predict prognosis and select at-risk individuals for more precisely targeted medical care.

Conclusion

The authors sought evidence to support the hypothesis that alpha-1-antitrypsin deficiency could be a risk factor for a severe course of COVID-19 infection. They compared the prevalence of AAT deficiency in the population with countries having the highest mortality rates from this disease. According to their conclusions, the authors confirmed the correctness of this hypothesis and, therefore, propose the use of AAT values and other serine protease inhibitors to predict disease progression in individual patients or to identify the part of the population more prone to severe infection.

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Source: Dutta A. K., Goswami K. Host genomics of COVID-19: Evidence points towards alpha 1 antitrypsin deficiency as a putative risk factor for higher mortality rate. Med Hypotheses 2021 Feb; 147: 110485, doi: 10.1016/j.mehy.2021.110485.