1. INTRODUCTION
Alpha-1-antitrypsin (A1AT) belongs to the serpine protease inhibitor (serpin) family, as are alpha-1-antichymotrypsin, C1 inhibitor, antithrombin, and neuroserpine. It is known as alpha-1-antiproteinase and is also encoded as a proteinase inhibitor (PI).1A1AT is synthesized by hepatocytes, macrophages, intestinal epithelial cells, and bronchial epithelial cells.2,3 With a plasma half-life of five days, A1AT is found in all body fluids and most tissues. A1AT is an acute-phase protein and one of the potent regulators of neutrophil activation, acting through protease inhibition and other mechanisms.4 On the other hand, A1AT is the strongest inhibitor of bacterial serine proteases, proteinase 3, and neutrophil elastase.4,5
The A1AT gene consists of two alleles. Most of the genotype distribution in the human population are combinations of the M, S, and Z alleles. Furthermore, the PI*MM genotype is considered normal, which is encountered in 85-95% of the world population and can synthesize 100% normal A1AT.6 On the other hand, the genotype distributions of PI*MS, PI*SS, PI*MZ, PI*SZ, and PI*ZZ alleles are 5-15% worldwide. These alleles can achieve 80%, 60%, 55%, 40%, and 15% normal A1AT synthesis, respectively.7
Most of the mutations in the A1AT gene result in mutant protein synthesis that lacks function and damages the cell where it accumulates.8 The PI*ZZ genotype carries a high risk of diseases associated with A1AT insufficiency, while the PI*SZ, PI*SS, and PI*MZ genotypes are only potentially risky.9,10Especially the PI*SZ allele causes pulmonary emphysema in smokers.7
The SARS-CoV-2 virus (COVID-19) was identified as a result of research conducted on a group of patients with acute respiratory symptoms in the form of fever, cough, and shortness of breath in Wuhan Province, China, in late 2019.11 Approximately 81% of symptomatic patients infected with COVID-19 show mild, 14% severe, and 5% critical disease course.12
A study covering 97 countries with a total sample of 5.264 million projected that there are 190 million carriers of a risky allele in the A1AT.10 Of these alleles 142 million (74.8%) are PI*MS, 42 million (22.3%) are PI*MZ, 4 million (2.1%) are PI*SS, 1.269 million (0.7%) are PI*SZ, 181,000 (0.1%) are PI*ZZ genotype.10
We hypothesized that the geographic distributions of COVID-19 prevalence and risky A1AT allele prevalence are similar. Therefore, we aimed to investigate whether there is a relationship between the geographical density of the COVID-19 pandemic and the distributions of risky A1AT alleles.