key: cord-0833005-5pbwpkyw authors: Zheng, Haoyi; Cao, J. Jane title: ACE gene polymorphism and severe lung injury in patients with COVID-19 date: 2020-07-29 journal: Am J Pathol DOI: 10.1016/j.ajpath.2020.07.009 sha: 7ee81a9ee9d453d82c53dc9e78607d439670536c doc_id: 833005 cord_uid: 5pbwpkyw COVID-19 has markedly varied clinical presentations, with the majority of patients being asymptomatic or having mild symptoms. However, severe acute respiratory disease caused by SARS-CoV-2 is common and associated with mortality in patients who require hospitalization. The etiology of susceptibility to severe lung injury remains unclear. Angiotensin II, converted by angiotensin-converting enzyme (ACE) from angiotensin I and metabolized by angiotensin converting enzyme 2 (ACE2), plays a pivotal role in the pathogenesis of lung injury. ACE2 is identified as an essential receptor for SARS-COV-2 to enter the cell. The binding of ACE2 and SARS-COV-2 leads to the exhaustion of ACE2 and down-regulation of ACE2. The interaction and imbalance between ACE and ACE2 result in an unopposed angiotensin II. Considering that the ACE insertion/deletion (I/D) gene polymorphism contributes to the ACE level variability in general population, in which mean ACE level in DD carriers are approximately twice that in II carriers, we propose a hypothesis of genetic predisposition to severe lung injury in patients with COVID-19. It is plausible that the ACE inhibitors and ACE receptor blockers (ARBs) may have the potential to prevent and to treat the acute lung injury after SARS-COV-2 infection especially for those with the ACE genotype associated with high ACE level. COVID-19 pandemic has resulted in more than 14 million confirmed cases and 611,823 deaths worldwide as of July 20, 2020 (https://www.worldometers.info/coronavirus/). Clinically COVID-19 has markedly varied presentations, with the majority of patients being asymptomatic or having mild symptoms 1 . A small group of patients, however, develop severe acute respiratory syndrome, which is associated with high mortality 2, 3 . While demographic features and certain comorbidities including male sex, age over 65 years, African American race, hypertension, obesity and diabetes are associated with adverse outcome 1, 3 . However many COVID-19 patients without those features also have developed severe lung injury or acute respiratory distress syndrome (ARDS) 3 . According to a report from New York, 14% hospitalized COVID-19 patients presented with a severe case requiring intensive care due to significant hypoxia 3 . However, the susceptibility of developing severe lung injury is not fully understood. Like SARS-COV, which caused an outbreak in 2002, SARS-COV-2 also uses angiotensin-converting enzyme (ACE) 2 as a binding receptor to enter the cell 4, 5 . The binding and the subsequent cell entry of SARS-COV lead to exhaustion of ACE2 and the reduced expression of cellular ACE2 [6] [7] [8] . These observations are mirrored in SARS-COV-2 infection and have renewed interest in studying the modulation of rennin-angiotensin system (RAS) in COVID-19 6 . Organ distribution of ACE2, binding of ACE2 with SARS-COV and SARS-COV-2, and subsequent modulation of RAS are discussed in detail in other reviews [9] [10] [11] . ACE and ACE2 are the two key modulators of RAS 12 . ACE converts angiotensin I to angiotensin II (ATII) and degrades the bioactive bradykinin 13 . ACE2 converts ATII to AT 1-7 14 . The interaction between ACE and ACE2 appears to be reciprocal with one down-regulated while the other up-regulated 15 as the balance between the two is critical in maintaining the physiological homeostasis of RAS. In conditions where tissue or plasma ACE activity is increased or ACE2 expression is decreased such as in SARS-COV-2 infection, ATII level becomes unopposed, which may contribute to acute lung injury through various mechanisms including the followings. It increases vascular permeability and causes vasoconstriction 14 . Moreover, it induces the apoptosis of endothelial cell and of alveolar epithelial cells 16, 17 . In addition, it promotes fibrosis 18 . Lastly, it boosts the pro-inflammatory mediators including interleukin (IL)-6 and IL-8 19 . The regulation of RAS is illustrated schematically in the Figure 1 . Experimental and clinical studies support that the imbalance between ACE and ACE2 and subsequent increased ATII play a significant pathological role in acute lung injury. In animal model with influenza the reduction of ACE2 expression appears to be associated with severe lung injury 20 . Similarly, binding of SARS-COV to mouse ACE2 in vivo causes reduced ACE2 expression and greater acute lung injury 8 . In a separate mouse model where the lung injury is induced by high-volume ventilation, there appears to be an increased lung injury related to the overproduction of lung ATII 21 . In human, serum ATII level is marked elevated in patients with ARDS and sepsis 22, 23 where the microvascular reoxygenation rate and plasma ATII level are inversely associated 23 . In a small cohort of COVID-19 patients, plasma ATII levels are markedly elevated compared with healthy controls and are linearly correlated with viral load and the severity of lung injury, 24 suggesting a systemic RAS imbalance as a result of ACE2 downregulation from SARS-COV-2 infection. 25 , where the D allele is associated with higher ACE activity 26 . Mean ACE activity levels in DD carriers were approximately twice that in II genotype individuals 25 . Therefore, we propose a hypothesis that ACE gene polymorphism may play an important role in patients with COVID-19 who are susceptible to develop severe lung injury or ARDS. There is an abundance of evidence supporting the relationship of ACE I/D polymorphism and clinical outcome of ARDS. In one study the 28-day mortality rates are significantly different between the three ACE I/D genotypes (42%, 65%, and 75% for II, ID, and DD, respectively). Patients with the II genotype have a significantly better survival than those with the non-II genotypes 27 . In another study, the DD genotype frequency is higher in patients with ARDS and is significantly associated with mortality 28 . In a prospective study of ARDS, increased mortality of more than 5 folds is found in patients with a homozygous DD genotype compared with the II genotype. 29 The relation between ACE gene polymorphism and the disease severity has The racial difference of ACE gene polymorphism is well established. For example, In the United States African Americans are known to have the highest frequency of the D allele (89%) when compared to Indians (69%), and Caucasians (69%). 33 In Europe, populations in Italy, Spain, and France have a high frequency of D allele up to 82-87% 34 . In contrast, in Asia the Eastern Asian Populations, such as Chinese, Korean, Taiwanese, and Japan have a high frequency of ACE gene II allele, which is reportedly higher than the European populations (33-51% vs. 13-27%) 35 . It is apparent that the racial variance of ACE I/D genotype seems to coincide with the differences of outcomes where the populations with high frequency of D alleles seem to suffer from higher fatality. For example, African Americans seem to have the disproportionately high fatality rate in the United States 36, 37 . Similarly, patients from Italy, Spain and France also suffer from high fatality in Europe. Conversely, the low frequency of ACE D/D and high frequency of II genotype seen in Asian populations seem to be associated with relatively low fatality of COVID-19 in those nations ( https://www.worldometers.info/coronavirus/#countries). While Socioeconomic and environmental conditions may play a role, they do not fully explain the severity of acute lung injury in COVID-19. A Scottish study concluded from the observation of influenza that socioeconomic factors do not fully explain ethnic variations in hospitalization for lower respiratory infections 38 . 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