ACE2 polymorphisms as potential players in COVID-19 outcome

Khayat, André Salim; Assumpção, Paulo Pimentel de; Khayat, Bruna Cláudia Meireles; Araújo, Taíssa Maíra Thomaz; Batista-Gomes, Jéssica Almeida; Imbiriba, Luciana Carvalho; Ishak, Geraldo; Assumpção, Paula Baraúna de; Moreira, Fabiano Cordeiro; Burbano, Rommel Rodrı́guez; Ribeiro-dos-Santos, André M.; Ribeiro-dos-Santos, Ândrea; Santos, Ney Pereira Carneiro dos; Santos, Sidney

doi:10.1101/2020.05.27.20114843

Cited by 15 publications

(10 citation statements)

References 23 publications

(26 reference statements)

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“…Albeit, the study was limited to 45 patients, which is insufficient to establish significant conclusions. While another recent study highlighted the impact of the activating variant N720D (rs41303171) on epidemiological disparities, especially in Europeans when compared to other global populations [ 59 ] and stands in support of our observations.…”

Section: Discussionsupporting

confidence: 90%

ACE2 and FURIN variants are potential predictors of SARS-CoV-2 outcome: A time to implement precision medicine against COVID-19

Al-Mulla¹,

Mohammad²,

Madhoun³

et al. 2021

Heliyon

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The severity of the new COVID-19 pandemic caused by the SARS-CoV-2 virus is strikingly variable in different global populations. SARS-CoV-2 uses ACE2 as a cell receptor, TMPRSS2 protease, and FURIN peptidase to invade human cells. Here, we investigated 1,378 whole-exome sequences of individuals from the Middle Eastern populations (Kuwait, Qatar, and Iran) to explore natural variations in the ACE2, TMPRSS2, and FURIN genes. We identified two activating variants (K26R and N720D) in the ACE2 gene that are more common in Europeans than in the Middle Eastern, East Asian, and African populations. We postulate that K26R can activate ACE2 and facilitate binding to S-protein RBD while N720D enhances TMPRSS2 cutting and, ultimately, viral entry. We also detected deleterious variants in FURIN that are frequent in the Middle Eastern but not in the European populations. This study highlights specific genetic variations in the ACE2 and FURIN genes that may explain SARS-CoV-2 clinical disparity. We showed structural evidence of the functionality of these activating variants that increase the SARS-CoV-2 aggressiveness. Finally, our data illustrate a significant correlation between ACE2 variants identified in people from Middle Eastern origins that can be further explored to explain the variation in COVID-19 infection and mortality rates globally.

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Section: Discussionsupporting

confidence: 90%

ACE2 and FURIN variants are potential predictors of SARS-CoV-2 outcome: A time to implement precision medicine against COVID-19

Al-Mulla¹,

Mohammad²,

Madhoun³

et al. 2021

Heliyon

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show abstract

“…A twins study estimated that total heritability of Covid-19 risk was 50% (95% CI 29-70%) [13]. Analyses of host genomes indicate that ACE2 and OR4C5 gene variants may impact severity of Covid-19 [14,15]. OR4C5 is a pseudogene in the olfactory receptor loci region that codes for a G-protein-coupled receptor arising from a single-coding exon gene.…”

Section: Introductionmentioning

confidence: 99%

Clinical, regional, and genetic characteristics of Covid-19 patients from UK Biobank

et al. 2020

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Background Coronavirus disease 2019 (Covid-19) has rapidly infected millions of people worldwide. Recent studies suggest that racial minorities and patients with comorbidities are at higher risk of Covid-19. In this study, we analyzed the effects of clinical, regional, and genetic factors on Covid-19 positive status. Methods The UK Biobank is a longitudinal cohort study that recruited participants from 2006 to 2010 from throughout the United Kingdom. Covid-19 test results were provided to UK Biobank starting on March 16, 2020. The main outcome measure in this study was Covid-19 positive status, determined by the presence of any positive test for a single individual. Clinical risk factors were derived from UK Biobank at baseline, and regional risk factors were imputed using census features local to each participant’s home zone. We used robust adjusted Poisson regression with clustering by testing laboratory to estimate relative risk. Blood types were derived using genetic variants rs8176719 and rs8176746, and genomewide tests of association were conducted using logistic-Firth hybrid regression. Results This prospective cohort study included 397,064 UK Biobank participants, of whom 968 tested positive for Covid-19. The unadjusted relative risk of Covid-19 for Black participants was 3.66 (95% CI 2.83–4.74), compared to White participants. Adjusting for Townsend deprivation index alone reduced the relative risk to 2.44 (95% CI 1.86–3.20). Comorbidities that significantly increased Covid-19 risk included chronic obstructive pulmonary disease (adjusted relative risk [ARR] 1.64, 95% CI 1.18–2.27), ischemic heart disease (ARR 1.48, 95% CI 1.16–1.89), and depression (ARR 1.32, 95% CI 1.03–1.70). There was some evidence that angiotensin converting enzyme inhibitors (ARR 1.48, 95% CI 1.13–1.93) were associated with increased risk of Covid-19. Each standard deviation increase in the number of total individuals living in a participant’s locality was associated with increased risk of Covid-19 (ARR 1.14, 95% CI 1.08–1.20). Analyses of genetically inferred blood types confirmed that participants with type A blood had increased odds of Covid-19 compared to participants with type O blood (odds ratio [OR] 1.16, 95% CI 1.01–1.33). A meta-analysis of genomewide association studies across ancestry groups did not reveal any significant loci. Study limitations include confounding by indication, bias due to limited information on early Covid-19 test results, and inability to accurately gauge disease severity. Conclusions When assessing the association of Black race with Covid-19, adjusting for deprivation reduced the relative risk of Covid-19 by 33%. In the context of sociological research, these findings suggest that discrimination in the labor market may play a role in the high relative risk of Covid-19 for Black individuals. In this study, we also confirmed the association of blood type A with Covid-19, among other clinical and regional factors.

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“…Further research using the 100 000 genomes project has suggested that ACE2 polymorphisms could explain the higher risk of severe disease and death amongst males and those of African and East Asian origin in SARS-CoV-2 infection. The Chinese SARS-CoV-2 study could reflect the literature which suggests subjects with ‘severe disease’ may represent a sub-group with ACE2 polymorphisms 6 . It is already known that rs182366225 and rs2097723 polymorphisms are more frequent in the East Asian population and increase the expression of ACE2.…”

Section: Discussionmentioning

confidence: 87%

Case Report: Renal potassium wasting in SARS-CoV-2 infection

et al. 2020

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with many potentially fatal complications. Renal involvement in various forms is common in addition to serum electrolyte disturbances. Early reports suggest that hypokalaemia may frequent those with SARS-CoV-2 infection and various aetiological factors may cause this electrolyte disturbance. A Chinese retrospective study has demonstrated renal potassium wasting in patients infected with SARS-CoV-2, however, it is not known if these patients were receiving diuretic therapy which may be a contributing factor. This case report illustrates an example of renal potassium wasting in SARS-CoV-2 infection in the absence of diuretics and extra-renal mechanisms with important lessons learned.

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ACE2 polymorphisms as potential players in COVID-19 outcome

Cited by 15 publications

References 23 publications

ACE2 and FURIN variants are potential predictors of SARS-CoV-2 outcome: A time to implement precision medicine against COVID-19

ACE2 and FURIN variants are potential predictors of SARS-CoV-2 outcome: A time to implement precision medicine against COVID-19

Clinical, regional, and genetic characteristics of Covid-19 patients from UK Biobank

Case Report: Renal potassium wasting in SARS-CoV-2 infection

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