Ethnic and age-specific acute lung injury/acute respiratory distress syndrome risk associated with angiotensin-converting enzyme insertion/deletion polymorphisms, implications for COVID-19: A meta-analysis

Abstract

Background The reported association between an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme ( ACE ) gene and the risk for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) remains controversial despite the publication of four meta-analyses on this topic. Here, we updated the meta-analysis with more studies and additional assessments that include adults and children within the context of the coronavirus disease 2019 (COVID-19) pandemic. Methods Sixteen articles (22 studies) were included. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using three genetic models (allele, recessive and dominant), in which ARDS patients were compared with non-ARDS patients (A1) and healthy controls (A2). Mortality outcomes were also assessed (A3). The influence of covariates was examined by meta-regression. Bonferroni correction was performed for multiple pooled associations. Subgroup analyses based on ethnicity (Asians, Caucasians) and life stage (adults, children) were conducted. Heterogeneity was addressed with outlier treatment. Results This meta-analysis generated 68 comparisons, 21 of which were significant. Of the 21, four A1 and three A3 highly significant (P a = 0.00001–0.0008) outcomes withstood Bonferroni correction. For A1, allele and recessive associations were found in overall (OR 0.49, 95% CI 0.39–0.61), Caucasians (OR 0.46, 95% CI 0.35–0.61) and children (ORs 0.49–0.66, 95% CI 0.33–0.84) analyses. For A3, associations were found in overall (dominant: OR 0.45, 95% CI 0.29–0.68) and Asian subgroup (allele/ dominant: ORs 0.31–0.39, 95% CIs 0.18–0.63) analyses. These outcomes were either robust, or statistically powered or both and uninfluenced by covariates. Conclusions Significant associations of the ACE I/D polymorphism with the risk of ALI/ARDS were indicated in Caucasians and children as well as in Asians in mortality analysis. These findings were underpinned by high significance, high statistical power and robustness. ACE genotypes may be useful for ALI/ARDS therapy for patients with COVID-19.

Angiotensin-converting enzyme-1 gene insertion/deletion polymorphism may be associated with COVID-19 clinical severity: a prospective cohort study

“…However, as mentioned above, the relationship between ACE I/D allele frequencies and COVID-19-related mortality is inconclusive. 7 , 10 , 16 In our study, the only significant difference in gender frequency was between the asymptomatic and mid disease patients. In the risk factor analysis, gender had no significant effect on disease severity.…”

“… 7 Similarly, a detailed systematic review published by Pabalan et al noted that the ACE DD genotype might be an important prognostic marker for mortality in Asian COVID-19 patients with acute lung injury/ARDS. 16 In contrast, another meta-analysis with data from 25 different European countries revealed a negative correlation between the frequency of the ACE D allele and the COVID-19 infection rate and mortality. 10 These findings may indicate that the course of COVID-19 may differ geographically.…”

Angiotensin–Converting Enzyme (ACE) 1 Gene Polymorphism and Phenotypic Expression of COVID-19 Symptoms

“…According to our database analysis, the ACE1 II genotype frequency in a population was significantly negatively correlated with the number of deaths due to SARS-CoV-2 infection, suggesting that the ACE1 II genotype may favorably influence the prevalence and clinical outcome of COVID-19 [1]. In addition, a detailed systematic review published by Pabalan et al shows that the ACE1 DD genotype may be an important prognostic marker for mortality in Asian COVID-19 patients with acute lung injury / ARDS [41]. Similarly, by conducting an epidemiological study in the population from 26 Asian countries, Pati et al showed that the ACE1 D allele is associated with susceptibility to SARS-CoV-2 infection and with the mortality rate [42].…”

Age and genotype dependent erythropoietin protection in COVID-19

“…The frequency of the ACE D allele was reported to be significantly higher in ARDS[ 64 ] but also in the hypoxemic group in Vietnamese patients with SARS related ARDS in the first SARS epidemic[ 65 ]. The association of the ACE D allele/DD genotype with increased mortality is now being increasingly reported in various ethnic groups in SARS-CoV-2 as well[ 59 , 66 ]. This association might reflect the effects the ACE D allele exerts via Ang II on interleukin 6 (IL-6) and plasminogen activator inhibitor-1 (PAI-1) levels (Figure 2 )[ 67 , 68 ].…”