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