We have read with great interest several recent articles on the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene and its potential relevance to the risk of a SARS-CoV-2 infection and the severity of the consequent coronavirus disease 2019 (COVID-19).1, 2, 3, 4, 5, 6 These epidemiological studies, which analyzed either European populations1 , 5 , 6 or global populations that included Europe,2, 3, 4 have reported conflicting results (Table 1 ). Variability in results may arise, due to various factors, including differences in the ethnicities/countries included in the analysis, which might reflect differences in genetic background; differences in other biological, environmental, and social risk parameters; and differences in the prevalence of the ACE I/D polymorphism. Indeed, it is well documented that the frequency of the ACE-D allele varies according to the ethnic/geographic origin of the study cohort. The prevalence of the ACE-D allele increases from Eastern to Western countries, worldwide. The prevalence in Asian populations (approximately 25–40%) is lower than the prevalence in Caucasian (generally approximately 40–60%) and African (60%) populations. Therefore, we focused our interest on studies that analyzed the European region, which also provided conflicting results, despite the similarities among these populations, in terms of ancestry, other risk covariates for COVID-19, and strategies for controlling the pandemic.
Table 1.
Epidemiological studies on associations between ACE I/D polymorphisms and COVID-19 prevalence/mortality.
| Author (reference) | Geographic region | Date assessed | ACE I/D allele/genotype | Association with COVID-19 prevalence and/or mortality |
|---|---|---|---|---|
| Delanghe (1) | Europe (25 countries) | 20 March 2020 | D allele | negative association |
| Delanghe (2) | European (26 countries), North African and Middle Eastern countries | 1 April 2020 | D allele | negative association |
| Yamamoto (3) | European (19 countries), Middle Eastern, South Asian, and East Asian countries | 23 May 2020 | II genotype | negative association |
| Aung (4) | Worldwide countries (9 European) | 8 June 2020 | DD genotype | no association |
| II genotype | negative association | |||
| Cenanovic (5) | Europe (18 countries) | 10 July 2020 | D allele | no association |
| Bellone (6) | Europe (24 countries) | 5 August 2020 | DD genotype | positive association |
| II genotype | negative association |
Several factors could potentially explain the variable results, including the study design (i.e., the source and method of data collection), the approach to data analysis (e.g., adjustments for potential confounders), or the timing of the analysis. In addition, previous studies analyzed data during the first wave of the pandemic, when most European countries were under total lockdown. The opening of borders at the end of June 2020 led to an increase in social contacts and virus transmission, which caused the second COVID-19 wave in the early autumn of 2020. The epidemiological situation changed markedly during the second wave of the pandemic. Countries that had largely avoided the pandemic during the first wave, such as the Czech Republic, or countries with a favorable epidemiological situation, such as those in Southeast Europe, were affected by the second wave.
In this study, we conducted a replication analysis in the European population to investigate the impact of the ACE I/D polymorphism on the prevalence and mortality of COVID-19 after the second wave of the pandemic. Data were collected on February 1, 2021, one year after the World Health Organization declared the outbreak as a Public Health Emergency of International Concern and at a time when the populations of European countries had not yet been immunized by vaccinations.
Thirty-four European countries were included in the analysis: Albania, Austria, Belarus, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, the Czech Republic, Croatia, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Lithuania, Moldova, Montenegro, The Netherlands, Norway, Poland, Portugal, Romania, Russia, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey, the United Kingdom, and Ukraine. We performed a multiple regression analysis, after adjusting for possible confounders, including the number of diagnostic tests, the onset of the epidemic (days) in each country, and the Human Development Index (HDI). We retrieved data on the prevalence (number of cases/106 inhabitants), mortality (number of deaths/106 inhabitants), the number of diagnostic tests per 106 persons, and the time elapsed since the onset of the epidemic (days since January 1, 2020), in each country, from the Worldometer website (https://www.worldometers.info/coronavirus/#countries).7 The HDI reflects three main dimensions of human development: life expectancy at birth, education, and gross national income per capita. For each country, these data were obtained from the United Nations Human Development Reports website (http://hdr.undp.org/en/content/latest-human-development-index-ranking).8 Data on the distribution of ACE genotypes were collected from recent studies.3 , 5 , 6
The multiple regression analysis revealed no significant associations between the ACE I/D polymorphism and the log-transformed prevalence of COVID-19 (DD genotype: partial r = 0.161, P = 0.386; ID genotype: partial r = −0.375, P = 0.841; II genotype: partial r = −0.129, P = 0.490). Moreover, the ACE I/D polymorphism was not associated with the log-transformed mortality (DD genotype: partial r = 0.191, P = 0.302; ID genotype: partial r = 0.343, P = 0.855; II genotype: partial r = −0.218, P = 0.238).
The lack of associations between the ACE I/D polymorphisms and COVID-19 prevalence or mortality could arise from the fact that there was a significant change in the age structure of patients during the pandemic. During the second pandemic wave, the number of younger patients increased. Importantly, in European populations, the prevalence of the ACE-D allele was found to be age-dependent; thus, higher frequencies of the ACE-D allele were detected among older individuals,9 who were most affected by COVID-19 infections during first pandemic wave.
Population-level studies have some inherent limitations, due to the ecological study design. Therefore, future studies are needed, based on the different clinical strata of COVID-19 manifestations (i.e., asymptomatic, mild, severe and fatal), to clarify the impact of the ACE I/D polymorphism on SARS-CoV-2 infections. Moreover, the frequencies of the ACE-D allele and ACE-DD genotype are associated with many different diseases and/or conditions,10 including some that might increase the risk of COVID-19 mortality, such as diabetes and hypertension. Therefore, it might be relevant, in future studies, to include those diseases and/or conditions as potential confounders.
Declarations of Competing Interest
The authors declare no conflict of interest.
Funding
This work was supported by the University of Rijeka, Croatia (uniri-biomed-18-137).
References
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