ACE Gene I/D Polymorphism and Acute Pulmonary Embolism in COVID19 Pneumonia: A Potential Predisposing Role

Abstract

Most recent studies have stressed a high risk of thromboembolism in patients with SARS-CoV-2 infection, particularly in those with severe COVID-19 pneumonia. Counterbalance between angiotensin-converting-enzyme (ACE) and ACE2 activities in COVID-19 disease may be crucially involved in the thrombo-inflammatory process. Currently, no study has investigated ACE I/D polymorphism involvement in COVID-19 disease complicated by pulmonary embolism, hence the aim of the present pilot study. This is a retrospective, single-center observational case-control study, conducted at the Sub-Intensive Care Unit of A.O.R.N. Ospedali dei Colli, Cotugno Hospital, Naples (Italy). We included 68 subjects with severe/critical COVID-19 pneumonia. COVID-19 patients were divided according to occurrence of PE (PE+, n = 25) or absence of thromboembolic complications (PE−, n = 43). Assessment of ACE I/D polymorphisms showed a statistically significant difference between PE+ and PE− patients (p = 0.029). Particularly, prevalence of D/D homozygous polymorphism was significantly higher in PE+ COVID-19 patients than in PE− (72 vs. 46.5%; p = 0.048), while heterozygote I/D polymorphism was significantly lower expressed in PE+ patients than in PE− (16 vs. 48.8%; p = 0.009). Computed tomographic pulmonary angiography showed predominantly mono/bilateral sub-segmental embolisms. In conclusion, our findings let us hypothesize a genetic susceptibility to thromboembolism in COVID-19 disease. ACE D/D polymorphism might represent a genetic risk factor, although studies on larger populations are needed.

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

“…Analysis using patient samples has been practiced in several countries on the Eurasian continent, providing valuable data (Table 1). Calabrese et al analyzed the association of severe/critical COVID-19 pneumonia with ACE1 I/D polymorphism in southern Italy [47]. Since the risk of thromboembolism is high, especially in patients with severe COVID-19 pneumonia, and decisive involvement of the balance between ACE1 and ACE2 activities is suggested in the thrombo-inflammatory process, 68 patients with severe COVID-19 pneumonia were divided according to the development of pulmonary embolism (PE) (25 PE + patients, 43 PE-patients).…”

Host polymorphisms and COVID-19 infection

“…An Italian study showed an inverse correlation between the I/I polymorphism and COVID-19-related deaths [60] , whereas others investigated the link between ACE I/D polymorphism and acute pulmonary embolism in COVID-19 pneumonia. The prevalence of D/D homozygous polymorphism was significantly higher in COVID-19 patients with a pulmonary embolism in comparison with those without pulmonary embolism, while heterozygote I/D polymorphism was significantly lower expressed in the group with pulmonary embolism in comparison with the group without pulmonary embolism [61] . In a meta-analysis with 48,758 healthy subjects from 30 different countries, it was also demonstrated that a higher I/D ratio was associated with a significantly increased recovery rate, but not with death rate [62] .…”

Genome interaction of the virus and the host genes and non-coding RNAs in SARS-CoV-2 infection

“…Calculations of the binding free energies between S protein and ACE2. Analysis of ACE2 gene expression in eight global populations from HapMap3 o - Significant differences of minor ACE2 AF of four missense mutations between Asians and Caucasians- K26R and I468V variants may affect binding between S protein and ACE2 receptor- Marginal differences in gene expression for some populations in HapMap3 as compared to the Chinese population Li Q et al, 2020 ACE2 Epidemiological investigation of the association between ACE2 I/D polymorphism with SARS-CoV-2 infection, mortality rate, and percentage of recovery in Asians - Positive correlation of D allele of ACE2 polymorphism with SARS-CoV-2 infection and mortality rate in Asians- ACE2 I/D polymorphism has no role in the recovery rate of the patients Pati et al, 2020 ACE1,ACE2,CTSL,TMPRSS2 Genotype analysis from high-coverage sequenced data of 1KGP (phase 3) and the Korean Personal Genome Project - Negative correlation of ACE1 II with the number of SARS-CoV-2 cases and deaths- No correlation of ACE2 , CTSL and TMPRSS2 with COVID-19 prevalence or mortality Yamamoto et al, 2020 ACE1 Collection of the literature data on the geographical variation of the ACE1 I/D polymorphism - Correlation of ACE1 polymorphisms with the prevalence of COVID-19- Association of the I/D polymorphism in intron 16 of ACE1 with reduced expression of ACE2 Delanghe et al, 2020 ACE1 Meta-analysis on the prevalence of ACE (I/D) genotype in countries most affected by the COVID-19 - Association of the increase of the I/D allele frequency ratio with the patients’ recovery rate- No significant differences in the death rate Hatami et al, 2020 ACE1 ACE I/D polymorphism involvement in COVID-19 patients with pulmonary embolism - Presence of ACE1 D/D polymorphisms higher in patients with thromboembolism in COVID 19 disease Calabrese et al, 2021 ACE1 Association of ACE1 I/D polymorphism with severity of COVID-19 in 269 cases - Association of ACE1 DD genotype, frequency of D allele, older age (≥46 years), unmarried status, and presence of diabetes and hypertension in severe COVID-19 patient Verma et al, 2020 ACE2,TMPRSS2 Analysis of whole-exome sequencing and SARS-CoV-2 infection in a familial multiple sclerosis cohort - Low level of ACE2 polymorphisms, with only 2 variants (rs41303171 and rs35803318)- High level of TMPRSS2 polymorphisms-...…”

“…However, asymptomatic individuals have not been evaluated; therefore, the conferred resistance of this genotype to viral infection cannot be excluded ( Cao et al, 2020 ). However, recent studies have reported an association of DD polymorphisms in patients with severe disease ( Verma et al, 2021 ), including thromboembolism ( Calabrese et al, 2021 ).…”