ACE Gene Variants Rise the Risk of Severe COVID-19 in Patients With Hypertension, Dyslipidemia or Diabetes: A Spanish Pilot Study

  1. María Íñiguez
  2. Patricia Pérez-Matute
  3. Pablo Villoslada-Blanco
  4. Emma Recio-Fernandez
  5. Diana Ezquerro-Pérez
  6. Jorge Alba
  7. M. Lourdes Ferreira-Laso
  8. José A. Oteo

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Abstract

Coronavirus disease 19 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to scale and threaten human health and public safety. It is essential to identify those risk factors that lead to a poor prognosis of the disease. A predisposing host genetic background could be one of these factors that explain the interindividual variability to COVID-19 severity. Thus, we have studied whether the rs4341 and rs4343 polymorphisms of the angiotensin converting enzyme (ACE) gene, key regulator of the renin-aldosterone-angiotensin system (RAAS), could explain the different outcomes of 128 COVID-19 patients with diverse degree of severity (33 asymptomatic or mildly symptomatic, 66 hospitalized in the general ward, and 29 admitted to the ICU). We found that G allele of rs4341 and rs4343 was associated with severe COVID-19 in hypertensive patients, independently of gender ( p <0.05). G-carrier genotypes of both polymorphisms were also associated with higher mortality ( p < 0.05) and higher severity of COVID-19 in dyslipidemic ( p <0.05) and type 2 diabetic patients ( p < 0.01). The association of G alleles with disease severity was adjusted for age, sex, BMI and number of comorbidities, suggesting that both the metabolic comorbidities and the G allele act synergistically on COVID-19 outcome. Although we did not find a direct association between serum ACE levels and COVID-19 severity, we found higher levels of ACE in the serum of patients with the GG genotype of rs4341 and rs4343 (p<0.05), what could explain the higher susceptibility to develop severe forms of the disease in patients with the GG genotype, in addition to hypertension and dyslipidemia. In conclusion, our preliminary study suggests that the G-containing genotypes of rs4341 and rs4343 confer an additional risk of adverse COVID-19 prognosis. Thus, rs4341 and rs4343 polymorphisms of ACE could be predictive markers of severity of COVID-19 in those patients with hypertension, dyslipidemia or diabetes. The knowledge of these genetic data could contribute to precision management of SARS-CoV-2 infected patients when admitted to hospital.

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  1. Version published to 10.3389/fendo.2021.688071
  2. ScreenIT

    SciScore for 10.1101/2021.03.24.21253576: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIACUC: This study was performed following the Helsinki Declaration and was approved by an independent ethical committee for clinical research (Comité de Ética de Investigación con medicamentos de La Rioja, CEImLAR, reference number PI-412).
    Consent: All patients or their representatives/relatives gave their consent to participate in the study.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    The rs4341 and rs4343 genotyping of the DNA samples was carried out using predesigned TaqMan SNP Genotyping Human Assays from Applied Biosciences (Foster City, CA) according to the manufacturer’s instructions.
    Applied Biosciences
    suggested: (Applied Biosciences, RRID:SCR_012275)
    Statistical analysis was performed using GraphPad Prism 6 (GraphPad Prism®, La Jolla, California, USA).
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    There are obviously several limitations in our study, such as the small size of our cohort. Thus, studies with higher number of patients could be of interest to clarify these results. Large-scale GWAS (Genome Wide Association Study) combined with WGS (whole genome sequencing) studies, such as the one being carried out by the SCOURGE consortium(26), will be very interesting to corroborate these results and to explore if they are extrapolable to the whole Spanish cohort or, in contrast, it is specific to our region. In conclusion, the G-containing genotypes of rs4341 and rs4343 confer an additional risk factor of developing severe forms of COVID-19 in patients with hypertension, dyslipidemia, or possibly with diabetes independently of gender. These genotypes are also associated with an increased risk of death, mainly in hypertensive patients. Thus, the genotyping of rs4341 and rs4343 in COVID-19 patients could facilitate a more appropriate clinical management at admission.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  3. Version published to 10.1101/2021.03.24.21253576v1 on medRxiv