Do gene-environment interactions play a role in COVID-19 distribution? The case of Alpha-1 Antitrypsin, air pollution and COVID-19

  • Nicola Murgia | Section of Occupational Medicine, Respiratory Diseases and Toxicology, University of Perugia, Italy.
  • Angelo Guido Corsico Center for Diagnosis of Inherited α1-Antitrypsin Deficiency, Department of Internal Medicine and Therapeutics, Pneumology Unit, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Italy.
  • Gennaro D'Amato Division of Respiratory and Allergic Diseases, Department of Chest Diseases, High Specialty A. Cardarelli Hospital, and Medical School of Specialization in Respiratory Diseases, Federico II University of Naples, Italy.
  • Cara Nichole Maesano INSERM and Sorbonne University, Epidemiology of Allergic and Respiratory Diseases Department, IPLESP, Paris, France.
  • Arturo Tozzi Center for Nonlinear Science, Department of Physics, University of North Texas, Denton TX, United States.
  • Isabella Annesi Maesano INSERM and Sorbonne University, Epidemiology of Allergic and Respiratory Diseases Department, IPLESP, Paris; Desbrest Institute of Epidemiology and Public Health, INSERM and Montpellier University, Montpellier, France.


Background: Gene-environment interactions are relevant for several respiratory diseases. This communication raises the hypothesis that the severity of COVID-19, a complex disease where the individual response to the infection may play a significant role, could partly result from a gene-environment interaction between air-pollution and Alpha-1 Antitrypsin (AAT) genes.
Methods: To evaluate the impact of the AAT and air pollution interaction on COVID-19, we introduced an AAT*air pollution global risk score summing together, in each country, an air pollution score (ozone, nitrogen dioxide and fine particulate matter) and an AAT score (which sums the ranked frequency of MZ, SZ, MS). We compared this global score with the ranking of European countries in terms of death number per million persons.
Results: The ranking of the AAT*air pollution global risk score matched the ranking of the countries in terms of the observed COVID-19 deaths per 1M inhabitants namely in the case of the first European countries:  Belgium, UK, Spain, Italy, Sweden, France. We observed parallelism between the number of COVID deaths and the AAT*air pollution global risk in Europe. AAT anti-protease, immune-modulating and coagulation-modulating activities may explain this finding, although very speculatively.
Conclusions: Even if further studies taking into account genetic background, population density, temporal dynamics of individual epidemics, access to healthcare, social disparities and immunological response to SARS-CoV2 are needed, our preliminary observation, urges to open a discussion on gene-environment interactions in COVID-19.



PlumX Metrics


Download data is not yet available.


McCoy K, Peterson A, Tian Y, Sang Y. Immunogenetic association underlying severe COVID-19. Vaccines (Basel) 2020;8:E700. DOI:

de Loyola MB, Dos Reis TTA, de Oliveira GXLM, da Fonseca Palmeira J, Argañaraz GA, Argañaraz ER. Alpha-1-antitrypsin: A possible host protective factor against Covid-19. Rev Med Virol 2020:e2157. DOI:

Blanco I, de Serres FJ, Fernandez-Bustillo E, Lara B, Miravitlles M. Estimated numbers and prevalence of PI*S and PI*Z alleles of alpha1-antitrypsin deficiency in European countries. Eur Respir J 2006;27:77-84. DOI:

Shapira G, Shomron N, Gurwitz D. Ethnic differences in alpha-1 antitrypsin deficiency allele frequencies may partially explain national differences in COVID-19 fatality rates. FASEB J 2020;34:14160-5. DOI:

Pozzer A, Dominici F, Haines A, Witt C, Münzel T, Lelieveld J. Regional and global contributions of air pollution to risk of death from COVID-19. Cardiovasc Res 2020;116:2247-53. DOI:

Barouki R, Kogevinas M, Audouze K, Belesova K, Bergman A, Birnbaum L, et al. The COVID-19 pandemic and global environmental change: Emerging research needs. Environ Int 2020;146:106272. DOI:

McElvaney OJ, McEvoy NL, McElvaney OF, Carroll TP, Murphy MP, Dunlea DMP, et al. Characterization of the inflammatory response to severe COVID-19 illness. Am J Respir Crit Care Med 2020;202:812-21. DOI:

Gonagle D, Sharif K, O'Regan A, Bridgewood C. The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease. Autoimmun Rev 2020;19:102537. DOI:

Boone PM, Scott RM, Marciniak SJ, Henske EP, Raby BA. The genetics of pneumothorax. Am J Respir Crit Care Med 2019;199:1344-57. DOI:

Tanash HA, Ekström M, Wagner P, Piitulainen E. Cause-specific mortality in individuals with severe alpha 1-antitrypsin deficiency in comparison with the general population in Sweden. Int J Chron Obstruct Pulmon Dis 2016;11:1663-9. DOI:

O'Brien ME, Fee L, Browne N, Browne N, Carroll TP, Meleady P, et al. Activation of complement component 3 is associated with airways disease and pulmonary emphysema in alpha-1 antitrypsin deficiency. Thorax 2020;75:321-30. DOI:

Cugno M, Meroni PL, Gualtierotti R, Griffini S, Grovetti E, Torri A, et al. Complement activation in patients with COVID-19: A novel therapeutic target. J Allergy Clin Immunol 2020;146:215-7. DOI:

Matricardi PM, Dal Negro RW, Nisini R. The first, holistic immunological model of COVID-19: Implications for prevention, diagnosis, and public health measures. Pediatr Allergy Immunol 2020;31:454-70. DOI:

Lippi G, Henry BM. Chronic obstructive pulmonary disease is associated with severe coronavirus disease 2019 (COVID-19). Respir Med 2020;167:105941. DOI:

De Angelis E, Renzetti S, Volta M, Donato F, Calza S, Placidi D, et al. COVID-19 incidence and mortality in Lombardy, Italy: an ecological study on the role of air pollution, meteorological factors, demographic and socioeconomic variables. Environ Res 2021;195:110777. DOI:

<a href=''>Sfondo foto creata da asierromero -</a>
Short Reports
Conflict of interest statement
The authors declare that they have no competing interests, and all authors confirm accuracy. IAM is an Associate Editor of Multidisciplinary Respiratory Medicine, GDA is a member of the Editorial Board of Multidisciplinary Respiratory Medicine
AAT, COVID-19, environment, air pollution
  • Abstract views: 1940

  • PDF: 75
  • HTML: 0
How to Cite
Murgia, N., Corsico, A. G., D’Amato, G., Maesano, C. N., Tozzi, A., & Annesi Maesano, I. (2021). Do gene-environment interactions play a role in COVID-19 distribution? The case of Alpha-1 Antitrypsin, air pollution and COVID-19. Multidisciplinary Respiratory Medicine, 16.