key: cord-0765601-me989b7b
authors: Izmailova, O.; Shlykova, O.; Vatsenko, A.; Ivashchenko, D.; Dudchenko, M.; Koval, T.; Kaidashev, I.
title: Allele С (rs5186) of at1r is associated with the severity of COVID-19 in the Ukrainian population
date: 2022-01-25
journal: Infect Genet Evol
DOI: 10.1016/j.meegid.2022.105227
sha: d190f28619e213b395f099bcad6b7985e9f3609d
doc_id: 765601
cord_uid: me989b7b

INTRODUCTION: The severity of SARS-CoV-2 induced coronavirus disease 19 (COVID-19) depends on the presence of risk factors and the hosts' gene variability. There are preliminary results that gene polymorphisms of the renin-angiotensin system can influence the susceptibility to and mortality from COVID-19. Angiotensin II type 1 receptor (AT1R) might be a gene candidate that exerts such influence. The aim of this study was to elaborate on the association between A1166C at1r polymorphic variants and the susceptibility to and severity of COVID-19 in the Ukrainian population. METHODS: The study population consisted of the Ukrainian population (Poltava region) with COVID-19, divided into three clinical groups in accordance with oxygen requirement: patients without oxygen therapy (n = 110), with non-invasive (n = 136) and invasive (n = 36) oxygen therapy. The A1166C polymorphism of the at1r was determined by polymerase chain reaction with subsequent restrictase analysis. In an attempt to better explain the role of the A1166C at1r polymorphism we compared its association with COVID-19, essential hypertension (n = 79), renoparenchimal hypertension (n = 30) and dyscirculatory encephalopathy (n = 112). The data for this comparison were obtained by meta-analysis. RESULTS: We observed significant differences in the frequency of AA, AC and CC genotypes in the groups of COVID-19 patients with non-invasive and invasive oxygen therapy in comparison with control subjects as well as in the frequency of combined AC + CC genotype between the groups of COVID-19 patients with any types of oxygen therapy and patients without oxygen therapy. The frequency of the 1166C allele was higher in COVID-19 patients with invasive oxygen therapy (OR = 2.06; CI (1.20–3.53); p = 0.013). We obtained important results indicating that there were no differences between the frequency of at1r polymorphisms in patients with cardiovascular disease and severe COVID-19 with invasive oxygen therapy as well as those who died due to COVID-19. CONCLUSION: Our study indicated the presence of an association between the A1166C at1r polymorphisms and the severity of COVID-19 in the Ukrainian population. It seems that in carriers of 1166C at1r, the severity of COVID-19 and oxygen dependency is higher as compared to the A allele carriers, possibly, due to cardiovascular disorders.

Medical University, Ukraine. Written informed consent was obtained from all recruited patients. The study was approved by the local Ethics Committee of Poltava State Medical University, Ukraine.

The study population consisted of the Ukrainian population with COVID-19 who had resided in the Poltava Region (central part of Ukraine). The inclusion criteria for study group were subjects with clinical signs and symptoms of COVID-19, positive results of SARS-CoV-2 PCR tests in nasopharyngeal swabs [23] .

All COVID-19 patients were divided on three clinical groups in accordance with oxygen requirement: group 1patients without oxygen therapy (n=110), group 2patients with non-invasive oxygen therapy (n=136), group 3patients with lung ventilation (invasive oxygen therapy) (n=36). The control group comprised 82 healthy persons. [24] . The relevant image of representative gel-electrophoresis is shown at Figure 1 .

Methodology of meta-analysis. We searched PubMed, Embase, Scopus, Cochrane Library as well as Google Scholar for a relevant article. Searches of the electronic databases were conducted using terms "angiotensin II receptor type 1", "polymorphism", "A1166C", "cardiovascular and vascular disease", "Ukrainian population", "Poltava Region". The selected articles were analyzed to contain primary data inclusion to assess publication bias. were considered to be significant.

Demographic characteristics of the entire studied population are shown in Table 1 .

There were no significant differences in terms of sex between all study groups. The COVID-19 patients had significantly higher age in comparison with control subjects, and COVID-19 patients who needed oxygen therapy had higher age than those without oxygen therapy. They also tend to have significantly higher body mass index (BMI).

Frequency of at1r polymorphism A1166C in the studied population. The observed at1r genotype distribution in the study groups was significantly different from that in the Hardy-Weinberg equilibrium (patients without oxygen therapy: χ 2 =7.25; p=0.03;

Heterozygosity observed -33%, expected -44%; patients with invasive oxygen therapy died from COVID-19: χ 2 =6.12; p=0.05; observed heterozygosity-83%, expected heterozygosity -49%).

There were significant differences in the frequency of the at1r polymorphism, i.e.

AA, AC and CC genotypes, in the group of COVID-19 patients with non-invasive oxygen therapy (p=0.008) and in the group with invasive oxygen therapy (p=0.047) in comparison with control subjects. There were no significant differences in the frequency of at1r polymorphism between the group of COVID-19 patients without oxygen therapy and control subjects (Table 2 ).

There were also significant differences in the frequency of combined AC+CC genotype between the groups of COVID-19 patients with any types of oxygen therapy and control subjects or patients without oxygen therapy.

The frequencies of combined AC+CC genotype increased in groups of patients in J o u r n a l P r e -p r o o f The frequency of C allele distribution was obviously higher in the group of COVID-19 patients with invasive oxygen therapy than that in control subjects (OR=2. 15 were deemed eligible for inclusion based on their titles and abstracts. Three studies were subsequently excluded because they were critical appraisal articles.

Finally, 3 studies involving 79 patients with essential hypertension [25] , 30 patients with renoparenchimal hypertension [26] , and 112 patients with dyscirculatory encephalopathy [27] were included in the analysis.

Allele frequency and genotype distribution of A1166C polymorphism of at1r in patients with essential hypertension, renoparenchimal hypertension and dyscirculatory encephalopathy are shown in Table 3 .

There were significant differences in the frequencies of at1r polymorphism between patients with essential hypertension and control subjects, COVID-19 patients without oxygen therapy or with non-invasive oxygen therapy. The patients with dyscirculatory encephalopathy had the same pattern of genotype frequencies. These differences depended on the high prevalence of the combined AC+CC genotype as well as the 1166C

allele. However, no differences were observed between the frequencies of at1r polymorphisms in patients with cardiovascular diseases and COVID-19 with invasive oxygen therapy as well as those who died due to COVID-19.

Despite SARS-CoV-2 spike protein had a strong binding affinity with ACE2 extracellular domain the elevated concentration of angiotensin II might be observed during . In contrast, a new pilot study showed no significant differences in circulating angiotensin II, angiotensin-(1-7), but reduced ACE activity compare with COVID-19-negative controls [28] .

Another important player in the renin-angiotensin system AT1R is, which exerted a number of angiotensin II effects such as vasoconstriction, angiogenesis, matrix synthesis, and aldosterone synthesis. AT1R is localized mostly in the adult cardiovascular tissue, it is present in the brain, kidneys, and adrenal glands [29] . Moreover, this receptor participated in angiotensin II-induced oxidant stress, and NF-κB activation with the enhanced expression of IL-6, VCAM-1, and MCP-1 [30] . AT1R was predicted to be involved in the host gene variability determined COVID-19 susceptibility and severity [31] . Thus, A1166C is a possible SNP of at1r, which might determine susceptibility to and severity of COVID-19.

In the first part of our study selected patients with COVID-19 were divided into three clinical groups according to the need for oxygen: without oxygen therapy, with non-

Journal Pre-proof invasive, and with invasive oxygen therapy. Additionally, the sub-group of patients who died was selected from the group with invasive oxygen therapy.

All COVID-19 patients had significantly higher age in comparison with control subjects, and COVID-19 patients who needed oxygen had higher age than those without oxygen dependency. Similarly, oxygen-dependent COVID-19 patients had elevated BMI.

The patients who died from COVID-19 had the highest BMI. These data went in parallel with studies, which showed that aging and overweight were important risk factors in COVID-19 [39] .

We observed significant differences in the frequency of AA, AC and CC genotypes Taking together, our data support the assumption that allele 1166C (rs5186) of the at1r might be associated with the severity of COVID-19.

We suppose that allele 1166C might be associated with the severity of COVID-19 due to the impaired regulation of AT1R by miRNA-155 with further AT1R over expression. Limitations of our study are the possible influence of age and BMI as well as the preexistence of or predisposition to cardiovascular diseases.

Prospects for a future research might be described as further investigation of COVID-19 susceptibility and severity associated with A1166C at1r polymorphism using an increased number of patients and analyzing comorbid cardiovascular and renal pathologies as well as experimental results are needed to prove hypothesis that A1166C

affects COVID-19. Additional studies will be required to confirm the potential role of this polymorphism in COVID-19 in other geographic populations.

Our study indicated the presence of an association between the A1166C at1r polymorphism and the severity of COVID-19 in the Ukrainian population. It seems that in carriers of 1166C at1r, the severity of COVID-19 and oxygen dependency is higher as compared to the A allele carriers, possibly, due to cardiovascular disorders. 

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