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      The host’s angiotensin-converting enzyme polymorphism may explain epidemiological findings in COVID-19 infections

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          Abstract

          The outbreak of the COVID-19 pandemia in 2019/2020 has stimulated research on clinical laboratory findings in this condition, as evidenced by two recent papers in this journal [1], [2]. We know that angiotensin converting enzyme is involved in corona virus infection. Pathogenic coronaviruses (severe acute respiratory syndrome coronavirus [SARS-CoV] and SARS-CoV-2) bind to their target cells through angiotensin-converting enzyme 2 (ACE2), [3], [4]. Not only has ACE2 facilitated the invasion of SARS virus for rapid replication, but also ACE2 is depleted from the cell membrane and therefore the damaging effects of Ang II are enhanced, resulting in acute deterioration of lung tissues [5]. The angiotensin-converting 1 (ACE1) enzyme is characterized by a genetic deletion/insertion (D/I) polymorphism in intron 16, which is associated with alterations in circulating and tissue concentrations of ACE. The D allele is associated with a reduced expression of ACE2. Although ACE2 and ACE share only 42% of amino acid identity, they both act as carboxypeptidases to cleave amino acids from the peptides’ carboxyl terminal [6]. As this D/I polymorphism shows an important geographical variation [7], we postulated that the variability in D/I genotype distribution might partly explain the variable prevalence of the COVID-19 infection amongst continental European countries. Therefore, we compared the D-allele frequency of the ACE1 gene as obtained in 25 different European countries with the prevalence and mortality of COVID-19, as calculated on March 20 2020 by Johns Hopkins [8]. Figure 1 shows the regression data. Data from Austria, Belgium, Croatia, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Israel, Italy, Lithuania, Moldova, the Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, and Turkey were included in the analysis. The log transformed prevalence of COVID-19 infections inversely correlates with the ACE D allele frequency: log (prevalence; number of cases/106 inhabitants) = 6.358 – 0.079 (D-allele frequency, %), r2= 0.378; p = 0.001. About 38% of the variability of the prevalence can be explained by the relative frequency of the ACE1 D-allele. Similarly, a significant correlation could be noted between COVID-19 caused mortality (Spearman r = -0.510, p=0.01) and the prevalence of the ACE1 D-allele. It should also be noted that the two Asian countries which were initially severely hit by the virus, China and Korea, are also characterized by low D allele frequencies. Fig. 1 Prevalence of COVID 19 in 25 European countries (on March 19 2020 vs. ACE1 D-allele frequency (%): log (prevalence; no. of cases/106 inhabitants) = 6.358 - 0.079 (D-allele frequency, %), r2= 0.378; p = 0.001. These data suggest that ACE1 D/I polymorphism may be regarded as a confounder in the spread of COVID-19 and the outcome of the infection in various European populations. These findings are in agreement with the role of ACE in pulmonary infections caused by coronaviruses [4]. The ACE D/I genotype may affect the clinical course of the infection.

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          The geographic distribution of the ACE II genotype: a novel finding

          Angiotensin converting enzyme (ACE) gene polymorphism insertion (I) or deletion (D) has been widely studied in different populations, and linked to various functional effects and associated with common diseases. The purpose of the present study was to investigate the relationship between the ACE I/D frequency in different populations and geographic location; ACE I/D allele frequency in the Lebanese population and ACE II genotype contribution to the geographic trend were also identified. Five hundred and seventy healthy volunteers were recruited from the Lebanese population. Genomic DNA was extracted from buccal cells, and amplified by polymerase chain reaction; products were then identified by gel electrophoresis. The frequencies of the different ACE I/D genotypes were determined and tested for Hardy–Weinberg equilibrium (HWE). To assess the relationship between ACE I/D frequency and geographic location, and to identify how the Lebanese population contributes to the geographic trend in ACE I/D frequencies, Eurasian population samples and Asians were incorporated in the analyses from the literature. The frequency of the I allele in the Lebanese population was 27% and the corresponding II genotype was at a frequency of 7·37% (in HWE; P =0·979). The ACE I allele and genotype frequencies show an association with longitude, with frequencies increasing eastwards and westwards from the Middle East.
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            Author and article information

            Contributors
            Journal
            Clin Chim Acta
            Clin. Chim. Acta
            Clinica Chimica Acta; International Journal of Clinical Chemistry
            Elsevier
            0009-8981
            1873-3492
            24 March 2020
            24 March 2020
            Affiliations
            [a ]Dept. of Clinical Chemistry, Ghent University, Belgium
            [b ]Dept. of Internal Medicine, Ghent University, Belgium
            Author notes
            [* ]Corresponding author at: Dept. of Clinical Chemistry, Ghent University, C. Heymanslaan 10, B-9000 Gent, Belgium. joris.delanghe@ 123456ugent.be
            Article
            S0009-8981(20)30133-9
            10.1016/j.cca.2020.03.031
            7102561
            32220422
            © 2020 Elsevier B.V. All rights reserved.

            Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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            Article

            Clinical chemistry

            polymorphism, covid-19, angiotensin-converting enzyme

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