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      Polymorphisms in ACE, ACE2, AGTR1 genes and severity of COVID-19 disease

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          Abstract

          Background

          Infection by the SARS-Cov-2 virus produces in humans a disease of highly variable and unpredictable severity. The presence of frequent genetic single nucleotide polymorphisms (SNPs) in the population might lead to a greater susceptibility to infection or an exaggerated inflammatory response. SARS-CoV-2 requires the presence of the ACE2 protein to enter in the cell and ACE2 is a regulator of the renin-angiotensin system. Accordingly, we studied the associations between 8 SNPs from AGTR1, ACE2 and ACE genes and the severity of the disease produced by the SARS-Cov-2 virus.

          Methods

          318 (aged 59.6±17.3 years, males 62.6%) COVID-19 patients were grouped based on the severity of symptoms: Outpatients (n = 104, 32.7%), hospitalized on the wards (n = 73, 23.0%), Intensive Care Unit (ICU) (n = 84, 26.4%) and deceased (n = 57, 17.9%). Comorbidity data (diabetes, hypertension, obesity, lung disease and cancer) were collected for adjustment. Genotype distribution of 8 selected SNPs among the severity groups was analyzed.

          Results

          Four SNPs in ACE2 were associated with the severity of disease. While rs2074192 andrs1978124showed a protector effectassuming an overdominant model of inheritance (G/A vs. GG-AA, OR = 0.32, 95%CI = 0.12–0.82; p = 0.016 and A/G vs. AA-GG, OR = 0.37, 95%CI: 0.14–0.96; p = 0.038, respectively); the SNPs rs2106809 and rs2285666were associated with an increased risk of being hospitalized and a severity course of the disease with recessive models of inheritance (C/C vs. T/C-T/T, OR = 11.41, 95% CI: 1.12–115.91; p = 0.012) and (A/A vs. GG-G/A, OR = 12.61, 95% CI: 1.26–125.87; p = 0.0081). As expected, an older age (OR = 1.47), male gender (OR = 1.98) and comorbidities (OR = 2.52) increased the risk of being admitted to ICU or death vs more benign outpatient course. Multivariable analysis demonstrated the role of the certain genotypes (ACE2) with the severity of COVID-19 (OR: 0.31, OR 0.37 for rs2074192 and rs1978124, and OR = 2.67, OR = 2.70 for rs2106809 and rs2285666, respectively). Hardy-Weinberg equilibrium in hospitalized group for I/D SNP in ACE was not showed (p<0.05), which might be due to the association with the disease. No association between COVID-19 disease and the different AGTR1 SNPs was evidenced on multivariable, nevertheless the A/A genotype for rs5183 showed an higher hospitalization risk in patients with comorbidities.

          Conclusions

          Different genetic variants in ACE2 were associated with a severe clinical course and death groups of patients with COVID-19. ACE2 common SNPs in the population might modulate severity of COVID-19 infection independently of other known markers like gender, age and comorbidities.

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          Most cited references47

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          Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

          Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
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            Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China

            In December 2019, novel coronavirus (2019-nCoV)-infected pneumonia (NCIP) occurred in Wuhan, China. The number of cases has increased rapidly but information on the clinical characteristics of affected patients is limited.
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              A pneumonia outbreak associated with a new coronavirus of probable bat origin

              Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.
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                Author and article information

                Contributors
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: Writing – original draft
                Role: Data curation
                Role: Data curationRole: Resources
                Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: Writing – original draft
                Role: Data curationRole: Writing – original draft
                Role: ConceptualizationRole: Data curationRole: ResourcesRole: Writing – original draft
                Role: Data curationRole: Formal analysisRole: Investigation
                Role: Data curationRole: Methodology
                Role: Data curationRole: Resources
                Role: Data curationRole: Resources
                Role: Data curationRole: Resources
                Role: Data curationRole: ResourcesRole: Validation
                Role: Data curationRole: InvestigationRole: ResourcesRole: Writing – original draft
                Role: Data curationRole: ResourcesRole: Validation
                Role: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ValidationRole: Writing – original draft
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                4 February 2022
                2022
                4 February 2022
                : 17
                : 2
                : e0263140
                Affiliations
                [1 ] Cardiac Department, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain
                [2 ] Cardiogenetic Laboratory, Instituto Murciano de Investigación Biosanitaria, Murcia, Spain
                [3 ] Centro de Investigación Biomédica en Red Cardiovascular (CIBERCV), Madrid, Spain
                [4 ] European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN Guard-Heart), Madrid, Spain
                [5 ] Microbiology Department, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain
                [6 ] Department of Infectious Disease, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain
                [7 ] Cardiology Department, Unidad de Cardiopatías Familiares y Muerte Súbita, Hospital Universitario y Politécnico La Fe, Valencia, Spain
                [8 ] Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain
                [9 ] Biobanco Hospital Universitario Puerta de Hierro/Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana, Madrid, Spain
                [10 ] IntensiveCareUnit, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain
                [11 ] Dirección Asistencial, Servicio de Neumología, Complejo Hospitalario Universitario de A Coruña (CHUAC), Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain
                [12 ] Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcón, Madrid, Spain
                [13 ] Cardiac Department, Complejo Hospitalario Universitario de A Coruña, A Coruña, Spain
                Unicamillus, Saint Camillus International University of Health Sciences, ITALY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0003-1352-1748
                https://orcid.org/0000-0002-6721-3487
                Article
                PONE-D-21-32344
                10.1371/journal.pone.0263140
                8815985
                35120165
                6c72bbe7-fe73-4bc0-9412-07b748774bb8
                © 2022 Sabater Molina et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 8 October 2021
                : 12 January 2022
                Page count
                Figures: 1, Tables: 4, Pages: 14
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100004587, Instituto de Salud Carlos III;
                Award ID: COV20/00420
                Award Recipient :
                The work was in part supported by grants from Instituto de Salud Carlos III and FEDER Union Europea, Una forma de hacer Europa (FONDO-COVID19 COV20/00420). The group of researchers is part of the Cardiovascular Research Network (CIBERCV) and the CIBER of Rare Diseases (CIBERER). The research group in “Hereditary Heart Diseases and Sudden Death” is registered at the University of Murcia and the IMIB. The Family Heart Disease Unit of the Virgen de la Arrixaca University Clinical Hospital is accredited as a Reference Unit (CSUR) by the Ministry of Health and is part of the network of European reference centers included in Guard-Heart (ERN). María Sabater has a research contract from the FFIS (Foundation for Sanitary Training and Research).
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