The COVID-19 pandemic, which first swept across the world in a matter of weeks in early 2020, sparked panic and the enactment of strict public health measures that had been unheard of for decades. The initial response to the pandemic was largely borne out of a fear of the unknown. Little was known about the virus, except that it was highly infectious and capable of overwhelming healthcare systems. 

Since then, scientists have studied the virus from as many angles as possible. That we now have vaccines of proven efficacy produced in record time is testament to the depth of dedication of the scientists who spent days and nights carrying out vital research into the virus. It is thanks to them that the US is slowly emerging from the shadow of the virus today.

There is no doubt that more will be learned about the virus in the years ahead. The world can ill afford another pandemic that is capable of causing death and destruction on the scale we have witnessed so far. As we continue to deepen our knowledge on how to stop a pandemic, we need to also know how to avoid one in the first place. And that means more research into the epidemiology and etiology of this and other infectious diseases.

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In September 2020, a fascinating study examining the possible links between alpha-1 antitrypsin deficiency (AATD) and COVID-19 mortality rates was published in The Journal of the Federation of American Societies for Experimental Biology. Global statistics at the time of the study showed that infection rates, severities, and mortalities caused by COVID-19 differ across ethnicities and nationalities.

Read more about AATD testing 

The immediately obvious reasons for this are the different public safety measures imposed in different countries, as well as the cultural difference in attitudes towards them. However, could there also be a biological basis that is contributing to this discrepancy?

There have been suggestions that the plasma serine protease inhibitor alpha-1 antitrypsin (AAT) can inhibit TMPRSS2, a cell surface serine protease that is needed for SARS-CoV-2 cell entry. Therefore, it follows that higher levels of AATD in a population would cause higher levels of COVID-19. The authors of this study set out to examine if this was true. 

Methodology and Results 

Researchers studied the national allele frequency estimates for the alpha-1 antitrypsin PiS (SERPINA1 rs17580) and PiZ (SERPINA1 rs28929474) alleles. The frequencies of the PiS and PiZ alleles were summed and weighted by their approximate effect size in order to examine their combined effects on AAT serum concentration. All statistical analyses were done in the R programming environment. 

To study the epidemiological differences between nations, data from the John Hopkins University Coronavirus Center was obtained. Only countries with a population of more than a million were studied, to reduce noise from smaller nations. 

Epidemiological data showed that nearly all of the nations having more than 100 COVID-19 mortalities per million in population were in Europe or in the Americas (as of September 7, 2020). Countries in East and Southeast Asia, as well as those in Sub-Saharan Africa, fared the best. 

The authors of this study found that the PiZ allele was approximately 8-fold less frequent in East and Southeast Asian populations compared to those in South Europe (the PiZ allele is known to be the major allele responsible for AATD). For the PiS allele, the difference was even greater, around 17-fold.

Researchers applied estimated country-specific frequencies of AATD to analyze COVID-19 fatalities per thousand inhabitants vs estimated AATD in 67 countries and discovered a Pearson correlation of R =.54 (P =1.98e−6), even after accounting for possible confounding factors such as the Human Development Index (HDI), levels of urbanization, and proportions of elderly people.

“Considering the above, we propose that the low carrier frequency of alpha-1 antitrypsin deficiency PiZ and PiS alleles in East and Southeast Asian and Sub-Saharan African countries may in-part explain the lower COVID-19 infection and mortality rates in these regions,” the authors of the study wrote.

Read more about AATD complications

Untangling the Strands of a Pandemic 

Since this study was published in September 2020, various virus hotspots have come and gone. In July 2021, many countries that have successfully kept the virus at bay are now struggling with an unprecedented surge in cases due to the Delta variant. Countries that have managed to vaccinate a large percentage of their population now fare much better, with predisposing factors playing a much smaller role in determining COVID-19 fatality. 

This study suggests that the more we look into the virus in the years to come, the more we will uncover surprising associations that are not immediately obvious. The pandemic may yet present an opportunity for scientists to deepen our understanding of disease epidemiology and etiology more than ever before.


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. The FASEB Journal. Published online September 22, 2020. doi:10.1096/fj.202002097

Azouz NP, Klingler AM, Rothenberg ME. Alpha 1 antitrypsin is an inhibitor of the SARS-CoV-2–priming protease TMPRSS2. bioRxiv. Published online October 7, 2020. doi:10.1101/2020.05.04.077826