The Impact ofACEandACE2Gene Polymorphisms in Pulmonary Diseases Including COVID-19

Abstract

Chronic and acute respiratory diseases pose a major problem for public health worldwide due to the high morbidity and mortality rates, while treatment options remain mostly symptomatic. The renin-angiotensin system (RAS) plays an important role in lung tissue, regulating pulmonary circulation and blood pressure, but also contributing to normal pulmonary function and development. Angiotensin-converting enzyme (ACE) and its homologous angiotensin-converting enzyme 2 (ACE2) are considered to be amongst the main RAS regulators and are highly expressed in the pulmonary vascular endothelium. This review discusses the impact of ACE and ACE2 functional gene polymorphisms on seven major pulmonary diseases, in terms of predisposition, course, and outcome, revealing their potential utility as both genetic markers and biomarkers. The discussed conditions include chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), asthma, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), lung cancer and pulmonary sarcoidosis (PS), as well as SARS-CoV-2 viral infection and COVID-19 disease.Chronic respiratory diseases (CRDs) have been among the leading causes of morbidity and mortality around the globe for the last two decades (1-3). Their constantly increasing rates of occurrence may vary both between the genders, but also between different regions and socio-economic backgrounds (4). Nevertheless, the common denominator includes the deterioration of patients' quality of life that can often lead to several years of disability. The main CRDs are chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), asthma and lung cancer, with COPD alone being the third leading cause of death worldwide, as reported in 2010 (1,5,6).On the other hand, acute lung diseases with an infectional etiology, pose a significant threat not only to lung health but also to human life (7). A recent great example is the 2019 outbreak of the novel coronavirus strain SARS-CoV-2 in China, causing the extremely infectious disease COVID-19, that led to a global pandemic and to millions of deaths, mainly due to severe respiratory complications (8, 9). So far, therapeutic approaches are mainly symptomatic, while knowledge on the exact pathogenetic mechanisms for complex lung-diseases remains limited. Consequently, prevention is predominantly based on general lifestyle guidelines, whereas the establishment of a priori personalized preventive measures, according to an individual's genetic predisposition, is still in its infancy (1, 5). Nevertheless, there are important known genetic markers that may be utilized for their predictive value.The renin-angiotensin system (RAS), in addition to its great importance for the overall homeostasis of the body, through the regulation of blood pressure and electrolyte balance, has a strong tissue-specific expression in the respiratory tract and functions both autonomously and 13 This article is freely accessible online.

The role of ACE1 I/D and ACE2 polymorphism in the outcome of Iranian COVID-19 patients: A case-control study

“…On the other hand, genetic variation of a gene likely modifies the function and expression of an encoded product, which could be considered the interindividual differences in susceptibility to several infectious diseases. So far, few studies have shown the roles of angiotensin-converting enzyme 1 (ACE1), ACE2, and transmembrane protease serine 2 (TMPRSS2) gene variants in the COVID-19 severity ( Gorbalenya et al, 2020 ; Hou et al, 2020 ; de Araújo et al, 2022 ; Gintoni et al, 2022 ).…”

Effect of B12 and folate deficiency in hypomethylation of ACE-2 gene and severity of disease among the ARDS patients

“…In this research, we evaluated the prevalence of ACE-2 gene polymorphisms among the studied samples. These polymorphisms were rs182366225 C > T and rs2097723 T > C. These two polymorphisms are in the regulatory region of the ACE-2 gene and cause over-expression of ACE-2 (9). Data analysis results showed that the frequency of CC, CT, and TT genotypes in rs182366225 polymorphism had no signi cant difference between mild and ARDS patients in comparison to control samples (P > 0.05) (Table I).…”

The role of angiotensin-converting enzyme 2 (ACE2) genetic variations in COVID-19 infection: a literature review

“…However, Europeans and some Africans have a higher frequency of an (rs5934250) allele that seems to downregulate ACE2 in some tissues [ 57 ]. The ACE insertion/deletion (I/D) variant, which influences enzyme levels with subsequent change in the “ACE/Ang II/AT1R axis” function, also showed many correlations with SARS-CoV-2 infection and appeared to impact the outcome of COVID-19 disease [ 4 ]. It has been observed that the (II) genotype (that is associated with the least ACE plasma levels compared to the ID/DD variants) is the most prevalent genotype among asymptomatic COVID-19 cases.…”

“…However, the (DD) genotype is predominate in COVID-19 patients, particularly in the European elderly population who present with severe disease phenotype and could increase the risk of COVID-19-related mortality [ 63 , 64 ]. More detailed associations of ACE I/D variant with COVID-19 severity and comorbidities have been covered in the interesting review by Gintoni et al [ 4 ].…”

“…Given the essential roles of the renin-angiotensin system (RAS) in maintaining the balance of lung cell proliferation/apoptosis and mediating the intra-pulmonary blood pressure, inflammation, and fibrosis, its dysregulation has been linked to several pulmonary diseases, including COVID-19 [ 3 , 4 ]. The angiotensin-converting enzyme 2 (ACE2), the homolog of ACE, is a catalytic component of RAS that has recently attracted global recognition [ 5 ].…”