key: cord-0797862-ybxrey0e
authors: Dutta, Atanu Kumar; Goswami, Kalyan
title: Host genomics of COVID-19: Evidence point towards Alpha 1 antitrypsin deficiency as a putative risk factor for higher mortality rate
date: 2021-01-09
journal: Med Hypotheses
DOI: 10.1016/j.mehy.2021.110485
sha: abc8d7c556821f0580a9d1a77d79663ec772715a
doc_id: 797862
cord_uid: ybxrey0e

Corona Virus Disease 2019 (COVID-19) has emerged as a pandemic leading to unprecedented disruption of global health and economy. Transmembrane protease serine 2 (TMPRSS2) has been found to be critical in priming the viral spike protein and the host ACE2 receptor before the virus enters into the host cell. Recent studies have experimentally demonstrated that Alpha 1 antitrypsin (encoded by SERPINA1 gene) is an inhibitor of TMPRSS2 and provided support to the already approved therapy as a candidate for COVID-19. Interestingly Alpha 1 antitrypsin deficiency is common among Europeans. Here we have provided in silico evidence that Alpha 1 antitrypsin can interact with TMPRSS2 and both of them are co-expressed in the human liver and lung. We then analyzed the gnomAD dataset to show that Europeans and Latinos have a substantially higher carrier frequency of Alpha 1 Antitrypsin Deficiency (~12%) compared to other large ethnicities. Therefore, we hypothesize that Alpha 1 antitrypsin deficiency might be a risk factor for severe infection with SARS-CoV-2. We propose Alpha 1 antitrypsin status as a potential prognostic predictor of COVID-19 outcome.

In December 2019 China reported a new Coronavirus emerging from Wuhan city. Since then the virus has traveled to all corners of the world with 29,593,883confirmed infections and 935,446 deaths globally as of 16.09.2020 (https://coronavirus.jhu.edu/map.html). As per available data, five out of the top ten countries with the highest COVID-19 related fatality/million population are from Europe and rest of the five are from Latin America (https://www.worldometers.info/coronavirus/) (supplementary table 1).

Understandings the cause behind the difference would need an investigation of the trinityagent, host, and environment. Concerning the virus, SARS-CoV-2 uses the ACE2 receptor for entry and the serine protease TMPRSS2 for S protein priming [1] . In addition, the host genetics is also likely to play a major part since Asians have fared much better in terms of morbidity and mortality of COVID-19 compared to other ethnicities like Europeans. Moreover, there is a significant difference in terms of morbidity and mortality of COVID-19 in different ethnicities which can hardly be explained by environmental factors alone. TMPRSS2 also being under the regulation of androgen [2] also might explain higher infection as well as the mortality rate of COVID -19 among the males across the ethnicities and geographic regions. Notably, recent large GWAS studies have revealed several emerging chemokine genes like CXCR6, CCR1 and SLC6A20 gene coding the amino acid transporter SIT1 which is known to interact with ACE2 receptor [3] .

The Hypothesis:

Concerning other genetic predisposing factors, of particular interest is a study that experimentally demonstrated that Alpha 1 antitrypsin is an inhibitor of Transmembrane protease serine 2 (TMPRSS2) enzyme in a dose-dependent manner and this may explain the preventive effect of COVID-19 infection naïve plasma for viral entry in model systems [1, 4] .

Indeed, the Structure-based computational predictions of protein-protein interactions (Struct2Net-http://cb.csail.mit.edu/cb/struct2net/webserver ) also showed the probability of interaction to be 0.386 using the 1k9o and 1ezx PDB crystal structures. Which corresponds to 95% specificity for this interaction which is very close to the suggested specificity of 96% (corresponding to suggested threshold of 0.4 http://cb.csail.mit.edu/cb/struct2net/webserver/sens_spec.csv ). Given the Alpha 1

Antitrypsin undergoes significant modifications including glycosylation before it interacts with any of the serine proteases and TMPRSS2 is also glycosylated the actual specificity of their interaction may be higher than predicted as glycosylation in both the partners is known to increase the probability of interaction [5] . Also, the GTEx database showed a co-expression of TMPRSS2 and SERPINA1 (Alpha 1 antitrypsin) in the human liver and lung [6] . Further studies are required to investigate if TMPRSS2 upregulates the expression of SERPINA1. Thus, these preliminary experimental and in Silico pieces of evidence opens up a new possibility of repurposing the existing therapy for Alpha 1 antitrypsin deficiency for COVID-19.

Though it is well known that Alpha 1 antitrypsin deficiency is highly prevalent in Europeans to date most of the studies have focused their effort on the most common deficiency variant rs17580. Thus, we undertook an unbiased approach of a comprehensive evaluation of the gnomAD database which contains exome and genome data of 71702 individuals as on 5th (3). Serine protease inhibitor family or SERPIN is an important class of proteins that plays a crucial role in the homeostasis of blood coagulation [9] ;

intriguingly, autopsy reports of the deceased showed that the DIC is an important pathogenic factor [10] .

Thus, we believe that there is substantial evidence to warrant further studies involving 

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Dr Kalyan Goswami Table 1 Pathogenic and likely pathogenic variants 

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Androgen regulation of the TMPRSS2 gene and the effect of a SNP in an androgen response element

Genomewide Association Study of Severe Covid-19 with Respiratory Failure

In plain sight: the role of alpha-1-antitrypsin in COVID-19 pathogenesis and therapeutics. Microbiology

Overview of the Structural and Functional Impact of Protein Glycosylation in Mediating Protein -Protein Interactions

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

Geographical Overlap Between Alpha-1 Antitrypsin Deficiency and COVID-19 Infection in Italy: Casual or Causal? Archivos de

The prevalence of diagnosed α 1 -antitrypsin deficiency and its comorbidities: results from a large population-based database

Estimates of PI*S and PI*Z Alpha-1 antitrypsin deficiency alleles prevalence in the Caribbean and North, Central and South America

Alpha-1-antitrypsin : A possible host protective factor against Covid-19

Autopsy Findings and Venous Thromboembolism in Patients With