4. DISCUSSION
Produced in the liver, A1AT has a
protective function against proteolytic damage by inhibiting neutrophil
elastase activity in the lungs. It provides approximately 90% of the
protection against elastolytic activity caused by elastase released from
neutrophils in the lower respiratory tract.5,14,15
Very few people infected with the SARS-CoV-2 virus develop respiratory
failure that requires mechanical ventilation. This clinical situation
associated with high mortality shows a wide geographic
variation.16 The hypothesis that there may be a
relationship between severe disease and A1AT distribution is supported
in our study. As a matter of fact, a highly significant correlation has
been found between the numbers of COVID-19 cases and deaths in European
countries and the numbers of individuals with the A1AT PI*SZ and PI*ZZ
genotypes.
In the European continent, the prevalence of the A1AT PI*SZ genotype is
highest in the southern (1: 483) and western (1: 581) regions and lowest
in the eastern part (1: 11818).7 When the distribution
of COVID-19 pandemics is investigated, it seems that Southern and
Western European countries are more affected by the intensity of
infection.13 Additionally, mortality rates are high in
this population.17
In a screening study conducted in Italy, 70 of 859 samples were found to
have A1AT deficiency, and 80% had the PI*ZZ
genotype.18 Interestingly, more than 90% of the
patients with this insufficiency are in the northern regions. It was
also claimed that the proportion of both PI*S and PI*Z alleles of the
A1AT gene was higher in the Northern Italy region.19Similarly, the current database of the COVID-19 pandemic shows that
infection rates are higher in the Northern Italy
region.20 In addition, an Italy-focused study
suggested that the distribution of the COVID-19 pandemic and A1AT
deficiency coincided geographically, and this could not be explained by
a random relationship.21
In a study conducted in the USA, it was claimed that the highest risk
for A1AT deficiency was in whites, that is, those of European descent,
followed by Mexicans and blacks, and the lowest risk was among those of
Asian descent.22 While the prevalence of the A1AT
PI*ZZ allele in the world is around 0.3%, it is estimated to be about
1% in the European continent.23 In addition, almost
half of the total 1.269 thousand PI*SZ genotypes calculated in the world
are in Europe (74% in Spain, Portugal, France, and England), one fifth
in North and Central America (60% in the USA), and one-sixth in South
America (55% in Brazil).10 In countries such as the
USA and Brazil, especially in Southern and Western Europe, both the case
and death rates of the COVID-19 pandemics appear to be significantly
higher.13 In our study, in line with this geographical
distribution, a highly significant correlation was found between the
numbers of COVID-19 cases and deaths belonging to the American continent
and the number of individuals with the A1AT PI*SZ and PI*ZZ genotypes.
In a similar study conducted in the first months of the pandemic, it was
suggested that there may be a relationship between the geographic
distribution of A1AT deficiency and covid deaths.24
Furthermore, the proportion of individuals with the PI*MM genotype that
synthesize the normal A1AT protein varies between 85% and 95%,
depending on the countries.7 Among alleles that cause
A1AT insufficiency, the proportion of individuals with the PI*MS and
PI*MZ genotypes that are considered low risk is 96%, and the rate of
individuals with the PI*SS, PI*SZ, and PI*ZZ genotypes that are regarded
as high risk is around 4%.10 Due to the fact that
81% of symptomatic patients infected with COVID-19 have a mild, 14%
have severe, and 5% have a critical illness, it is thought that the
severity of the disease goes hand in hand with the A1AT allele
rates.12