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HEALTH SCIENCES • An. Acad. Bras. Ciênc. 96 (suppl 3) • 2024 • https://doi.org/10.1590/0001-3765202420240274 linkcopy

Open-access Genetic variant in the AGT gene (rs699-GG) is associated with severe COVID-19 in Brazilian patients

AuthorshipSCIMAGO INSTITUTIONS RANKINGS

    Abstract

    The COVID-19 pandemic has been the largest pandemic of the past century, and various genetic factors have played a significant role in this context. This study aimed to analyze the frequency and association between specific SNPs rs3806268 (NLRP3), rs4925543 (NLRP3), rs12150220 (NLRP1), rs455060 (NLRC4), rs699 (AGT), rs1137101 (LEPR), and rs1801133 (MTHFR) and severe/critical outcomes in Brazilian patients with COVID-19. A total of 100 patients were included in the study, comprising 66 cases and 34 controls. DNA was extracted, sequenced, and genotyped via next-generation sequencing (NGS). For non-parametric data, the Mann-Whitney and Kruskal-Wallis tests were used. Fisher’s test and multivariate logistic regression, considering AIC and BIC criteria, were employed for risk analysis. Odds Ratios (OR) were calculated, with significance set at p<0.05. Among the seven evaluated SNPs, only rs699-GG (AGT) (OR=8.07; p=0.04) was significantly associated with an increased risk of developing severe/critical COVID-19. Moreover, a borderline protective association was noted between rs1801133-GA (MTHFR) and the disease, although lacking statistical significance. In conclusion, the SNP rs699-GG (AGT) was associated with an increased risk of severe/critical COVID-19.

    Key words AGT gene; COVID-19; human genetics; SARS-CoV-2; SNPs

    INTRODUCTION

    The Coronavirus Disease 2019 (COVID-19) pandemic began in Wuhan, China, and was declared a pandemic by the World Health Organization (WHO) on March 11, 2020. It is considered the largest and deadliest pandemic of the last century, caused by the etiological agent Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) (Azarpazhooh et al. 2020). As of June 2024, over 775 million cases and 7 million deaths have been reported worldwide, making this disease a continuing major threat to global health (WHO 2024).

    COVID-19 can manifest in the human body after an incubation period of 2-14 days following exposure to the virus (CDC 2024). It presents a wide spectrum of symptoms, ranging from asymptomatic cases and common flu-like symptoms (fever, cough, fatigue, myalgia, headache, sore throat, anosmia/ageusia, among others) to respiratory failure, known as Severe Acute Respiratory Syndrome (SARS), which can be fatal. Consequently, COVID-19 has various classifications based on different clinical outcomes (WHO 2021). In this context, several factors are known to contribute to these varying outcomes, including human genetic factors such as the influence of Single Nucleotide Polymorphisms (SNPs) in genes involved in the innate immune response, energy metabolism, and circulatory system (Aladag et al. 2023, Marei et al. 2023, Pastor et al. 2023).

    The genes NLRP3 (NLR family pyrin domain containing 3), NLRP1 (NLR family pyrin domain containing 1), and NLRC4 (NLR family CARD domain containing 4) play crucial roles in the innate immune response to viruses and other pathological conditions. These genes encode cytoplasmic receptors of the inflammasome pathway, which plays a role in the severity of various diseases (Sutterwala et al. 2014). Additionally, the AGT (angiotensinogen) and MTHFR (methylenetetrahydrofolate reductase) genes play important roles in vascular function within the renin-angiotensin system (RAS) and one-carbon metabolism, respectively, aiding in the conversion of homocysteine to methionine. (Foley et al. 2021, NCBI 2024, Xi et al. 2016, Sethi et al. 2023). The LEPR (Leptin Receptor) gene encodes the receptor for the hormone leptin, which is significant in fat metabolism and lymphopoiesis (NCBI 2023). Furthermore, it has been identified as a crucial signal for angiogenesis, cell proliferation, and the inhibition of cell apoptosis during SARS-CoV-2 infection (Rosa et al. 2021, Song et al. 2013).

    The functioning of many genes, including those described above, can be modulated by the action of SNPs, which may play a crucial role in regulating gene expression, protein conformation, or the splicing mechanism (Cafiero et al. 2021, Abu-Farha et al. 2020, Pastor et al. 2023). For NLRP3, it was observed that rs3806268 might have a fundamental role in COVID-19 patients with obesity as one of the comorbidities related to severe outcomes (Sá et al. 2022). Furthermore, another SNP in the same gene, rs4925543, has been investigated for its role in airway inflammation in patients with asthma (Queiroz et al. 2020). The missense variant rs12150220 (NLRP1- p.Leu155His) is related to increased IL-1ß in Peripheral Blood Mononuclear Cells (PBMCs) and has been associated with severe COVID-19 (Levandowski et al. 2013, Leal et al. 2022). The missense variant rs455060 (NLRC4) plays a fundamental role in IL-18 levels, which are important in the clinical outcome of severe COVID-19 (Zeller et al. 2015, Yin et al. 2023). For RAS, the rs699 SNP (AGT) has been identified as a potential gene target to predict clinical risk in patients infected with SARS-CoV-2 (Cafiero et al. 2021). In homocysteine metabolism, the SNP rs1801133 (MTHFR) has been found to be a potential genetic marker impacting the outcome of COVID-19 (Abu-Farha et al. 2020). For the LEPR gene, some SNPs have been studied in relation to other infectious diseases and metabolic system pathologies. For example, Lys109Arg and Gln223Arg have been associated with Hepatocellular Carcinoma (HCC) in individuals carrying the hepatitis B virus (HBV), and rs1137101-G has been associated with a reduced risk for developing the obese phenotype (Tang et al. 2020b).

    Based on the aforementioned overview, the present study aimed to investigate the association between the SNPs rs3806268 (NLRP3), rs4925543 (NLRP3), rs12150220 (NLRP1), rs455060 (NLRC4), rs699 (AGT), rs1137101 (LEPR), and rs1801133 (MTHFR) and the severe/critical outcomes in Brazilian COVID-19 patients.

    MATERIALS AND METHODS

    Data collection, ethics committee and clinical definition

    A case-control study was conducted to analyze the association between the SNPs rs3806268 (NLRP3), rs4925543 (NLRP3), rs12150220 (NLRP1), rs455060 (NLRC4), rs699 (AGT), rs1137101 (LEPR), and rs1801133 (MTHFR) and the severe/critical outcomes of COVID-19.

    Patients aged 18 years and older with suspected COVID-19 and disease confirmed by RT-PCR were screened at the Hospital das Clínicas of the Universidade Federal de Pernambuco (HC-UFPE) and Hospital Mestre Vitalino. All enrolled patients provided informed consent, and the project was approved by the UFPE Ethics Committee (approval number 4.150.959, C.A.A.E 33597220.5.0000.5208). Clinical and epidemiological details collected included age, sex, color/race, comorbidities, symptoms, blood count, and laboratory findings (ferritin, CRP, AST, ALT, and d-dimer), along with diagnosis by reverse transcriptase polymerase chain reaction (RT-PCR). The material collected for virus diagnosis consisted of approximately 4 mL of whole blood, which was obtained from patients during the acute phase of the disease.

    COVID-19 cases were classified according to the guidelines of the World Health Organization, as described (WHO 2021). Following clinical and laboratory evaluation, 100 suspected or confirmed cases of COVID-19 were stratified, comprising 34 COVID-19 negative cases, 33 severe/critical cases, and 33 mild/moderate cases.

    DNA extraction, quantification and data processing

    The extraction of genomic DNA from whole blood was conducted using the PureLink Genomic DNA Mini Kit (Invitrogen©) following the manufacturer’s instructions. The quantification of genomic material was performed using the Qubit high-sensitivity double-stranded DNA kit (Thermo Fisher©), followed by next-generation sequencing (NGS) of the exome (Mendelics©) and subsequent data processing.

    Data acquisition and selection of SNPs

    The filtering and annotation of VCF files were conducted using the VCFtools and wANNOVAR software, respectively (http://snpeff.sourceforge.net/index.html). SNP selection and genotype determination were based on the Variant Allele Frequency (VAF). Moreover, the SNPs were selected because they have also been investigated in other studies involving other viral infectious diseases as well as for their functional impacts on their respective proteins.

    Statistical analysis

    For non-parametric data, the Kruskal-Wallis test was employed to compare three samples, and the Mann-Whitney test was used to compare two samples, both conducted using Graphpad PRISM v.9.5. Crude (bivariate analysis) risk was performed using Jamovi 2.3.21 software, with the ancestral genotype considered as the reference for analysis. Adjusted (Multivariate logistic regression) analysis was conducted using Jamovi 2.3.28 software, with model adjustments based on the Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC). To determine the association between genotypes and clinical outcomes of COVID-19, Fisher’s exact test was employed, considering the odds ratio (OR) found. Values were considered significant when p < 0.05.

    RESULTS

    Initially, Hardy-Weinberg equilibrium was assessed for the studied SNPs using the chi-square test (χ2) (Table I). Socioepidemiological data, clinical characteristics, and patient outcomes were collected and analyzed. Our study population showed no significant difference in sex distribution or median ages between the outcome groups (p>0.05). Data on race/color and comorbidities were also collected, but no significant statistical differences were identified (Table II). Regarding the symptoms presented by the patients, fever, cough, dyspnea, and anosmia/ageusia were significantly more frequent in the severe/critical condition, with p-values of 0.04, 0.04, 0.0003, and 0.02, respectively (Table II). It is also noteworthy that there was a borderline result for the factors asthenia (p=0.05) and malaise (p=0.08), which may be related to the severe/critical outcome (Table II). Blood count data showed statistical significance for a higher frequency of lymphopenia and neutrophilia in patients with a severe/critical outcome, with p=0.04 (Table II). Altered laboratory biomarkers for severe/critical COVID-19, such as d-dimer and ferritin, were also more frequent in this outcome, with p-values of 0.0006 and 0.008, respectively (Table II).

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    Table I
    Chi-square values and p value for measuring Hardy-Weinberg equilibrium.
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    Table II
    Distribution by socioepidemiological data, clinical characteristics and patient evolution.

    From the NGS data for the exome, the SNPs rs3806268 (NLRP3), rs4925543 (NLRP3), rs12150220 (NLRP1), rs455060 (NLRC4), rs699 (AGT), rs1137101 (LEPR), and rs1801133 (MTHFR) were selected because they have also been investigated in other studies involving other viral infectious diseases and also for their functional effects on their respective proteins. Before conducting univariate and multivariate analyses of the SNPs considered in the present study, a frequency table was constructed to visualize the panorama of allelic and genotypic distribution across the different strata: COVID-19 (-), COVID-19 (+) mild/moderate, and COVID-19 (+) severe/critical (Table III). Genetic association analyses were initially conducted in a crude manner between the different outcomes, but no statistically significant results were identified. In the multivariate logistic regression performed, only the SNP rs699-GG (AGT) showed a significant association with susceptibility to the severe/critical outcome compared to the mild/moderate outcome, with an odds ratio (OR) of 8.07 and p=0.04 (Table IV).

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    Table III
    Genotypic and allele frequency by clinical outcome and diagnosis.
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    Table IV
    Adjusted association between the SNPs studied and different clinical stages of COVID-19.

    DISCUSSION

    This study is the first case-control investigation to identify an association between the rs699 SNP (AGT) and severe/critical outcomes in Brazilian patients suspected or confirmed with COVID-19. The suspected patients with a negative diagnosis for COVID-19 were used as the control group. Socio-epidemiological data, including age group, sex, and race/color, were also collected and analyzed for associations; however, no significant results were observed (Table II). Understanding this context is crucial for elucidating which epidemiological strata the disease affects (Islam et al. 2020). Data on comorbidities such as hypertension and type 2 diabetes mellitus were also collected to evaluate possible associations, but no statistically significant results were identified (Table II). Conversely, Angulo-Aguado et al. (2022) found significant statistical associations between hypertension, type 2 diabetes mellitus, and worse outcomes in a South American population. Additionally, existing literature consistently demonstrates the association between hypertension, diabetes, and severe outcomes in COVID-19 in other populations (Kouhpayeh et al. 2021, Feng et al. 2022).

    In the present study, we found that the symptoms of fever (p=0.04), cough (p=0.04), dyspnea (p=0.0003), and anosmia/ageusia (p=0.02) were significantly more frequent in severe/critical individuals, indicating an associative effect (Table II). Another study on Latin American patients also found an association between the symptoms of fever, cough, and dyspnea and the severity of COVID-19, corroborating our findings (Angulo-Aguado et al. 2022). Symptoms indicating poor conditions in the lower respiratory tract are often associated with severe COVID-19, as they point to lung involvement (Angulo-Aguado et al. 2022). Furthermore, literature reports that anosmia may be directly related to the severity of the infection (Mazzatenta et al. 2020).

    Regarding blood count data, we found that lymphopenia is significantly associated with severe/critical outcomes (p=0.04, Table II). Systematic reviews and meta-analyses have shown that patients with worse outcomes have significantly lower lymphocyte levels compared to patients with mild outcomes in COVID-19 (Huang & Pranata 2020, Zhao et al. 2020). Additionally, neutrophil levels play an important role in severe/critical outcomes in COVID-19 patients. In our study, we found a significant association (p=0.04) between neutrophilia and severe/critical outcomes (Table II). It is known that the pathophysiology of severe outcomes in COVID-19 is marked by elevated levels, phenotypic and functional changes in neutrophils, and their activation signatures are a prominent feature in the blood transcriptomes of severe COVID-19 patients (Reusch et al. 2021). We also investigated possible relationships between thrombocytopenia, leukocytosis, and severe/critical outcomes, but no statistically significant results were found (Table II). However, literature provides important findings on the association between thrombocytopenia, leukocytosis, and severe/critical COVID-19 (Lippi et al. 2020, Yamada et al. 2020). Thrombocytopenia is common in severe cases, possibly related to the physiological decompensation of organs and the development of intravascular coagulopathy, which can progress to disseminated intravascular coagulopathy (DIC) (Zarichanski & Houston 2017).

    Potentially predictive laboratory data for the worst outcomes in COVID-19 were also investigated (Table II). Significant associations were observed between ferritin levels and severe/critical outcomes of COVID-19 (p=0.008, Table II). Other studies have also identified high ferritin levels as important markers for severe COVID-19 outcomes (Kaushal et al. 2022). Ferritin is a key mediator of immune dysregulation that can contribute to the cytokine storm observed in individuals with severe disease outcomes (Abbaspour et al. 2014). Another important marker associated with severe/critical COVID-19 outcomes in this study is the d-dimer (p=0.0006). This finding corroborates other research showing a strong association between elevated d-dimer levels and poor prognosis in COVID-19 (Tang et al. 2020a, Rostami & Mansouritorghabeh 2020). Elevated d-dimer levels indicate a high inflammatory response in severe disease, often manifesting as a cytokine storm, which can induce disseminated intravascular coagulation (DIC) and the formation of fibrin clots (Rostami & Mansouritorghabeh 2020). In the present study, no significant results were observed for CRP, AST, and ALT, despite the literature showing important associations between these factors and severe/critical COVID-19 (Tan et al. 2020, Ceci et al. 2023).

    The rs699-A/G SNP is a missense variant located on the long arm of chromosome 1 (1q42-43), exon 2 (codon 268) of the AGT gene, and involves the substitution of methionine for threonine (M268T) (El-Garawani et al. 2021). The AGT gene encodes the precursor of angiotensinogen, which can be cleaved by renin in response to low blood pressure (NCBI 2023). In our study, the rs699-GG genotype was associated with an increased risk of developing severe/critical COVID-19 (OR=8.07; p=0.04, Table IV). According to Gaspersic & Dolzan (2022), the rs699 SNP (AGT) is one of the polymorphisms that can influence susceptibility to SARS-CoV-2 and the severity of COVID-19, as evidenced by a literature search and database analysis (Gaspersic & Dolzan 2022). Furthermore, rs699 (AGT) may serve as a valuable prognostic tool for patients infected with SARS-CoV-2, as this SNP may be related to internal organ damage during infection (Cafiero et al. 2020). Another study on Iranian patients evaluated the association between rs699 (AGT) and the risk of developing COVID-19, finding significant results for the TC genotype (8.4 times) and the C allele (2.2 times) compared to the TT genotype/T allele (Kouhpayeh et al. 2021). It is important to note that the C allele is also associated with increased plasma angiotensinogen and hypertension, which may influence the expression of TMPRSS2 and, consequently, the risk of COVID-19 (Wu et al. 2020). Additionally, research on C57BL/6J mice demonstrated that inhibiting AGT expression for 14 days significantly reduced TMPRSS2 expression levels in the lungs (Wu et al. 2020).

    Here also we observed a borderline result (OR=0.27; p=0.05) for the protective association between rs1801133-GA (MTHFR) and severe/critical outcomes in COVID-19 patients compared to COVID-19-negative individuals (Table IV). This SNP has been identified as a potential factor involved in thrombophilic disorders in individuals with COVID-19, indicating the need for more robust studies (Cafiero et al. 2020). Additionally, the rs1801133-T allele has been associated with an increased risk of developing multinodular hepatocellular carcinoma (HCC), a common type of liver cancer caused by chronic hepatitis C virus (HCV) infection (Carvalho et al. 2021).

    In the present study, other relevant SNPs from various immune response pathways were evaluated, but no significant results were found. These SNPs have been investigated for possible associations with other infectious diseases and inflammatory pathways (Cafiero et al. 2020, Nakanishi et al. 2017, Kamada et al. 2014, Zhong et al. 2022).

    The present study has some limitations, such as a small sample size and the absence of certain variables that could contribute to a more robust multivariate statistical model. These limitations are attributed to the deficiencies in resources available for DNA extraction and NGS sequencing. Therefore, it is suggested that future research be conducted with a larger sample size and greater data robustness to better understand the joint associations between the SNPs described here, clinical-laboratory data, and the different outcomes of COVID-19.

    CONCLUSIONS

    Fever, cough, and dyspnea were significantly more frequent in individuals with severe/critical outcomes of COVID-19. However, the symptoms of malaise and asthenia showed interesting borderline results that may also explain the progression of the disease. In terms of blood counts, lymphopenia and neutrophilia were significantly more frequent in severe/critical cases. Among laboratory markers, d-dimer and ferritin levels were also higher in severe/critical patients. Regarding the genetic association study, the SNP rs699-GG (AGT) was linked to an increased risk of developing severe/critical COVID-19 compared to mild/moderate outcomes. Based on these results, it is recommended that future studies involving different populations be conducted in order to investigate other associative profiles. The SNPs identified should be considered to elucidate potential pathways of disease severity and prediction, as well as to evaluate possible therapeutic alternatives.

    ACKNOWLEDGMENTS

    We are grateful to the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for their support and funding. We also thank Dr. Evônio Campello and Dr. Igor Wesland for facilitating access to patients at the Hospital das Clínicas at UFPE.

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    Publication Dates

    • Publication in this collection
      29 Nov 2024
    • Date of issue
      2024

    History

    • Received
      18 Mar 2024
    • Accepted
      30 Aug 2024
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