ACE 2 Coding Variants: A Potential X-linked Risk Factor for COVID-19 Disease

Gibson, William T.; Evans, Daniel M.; An, Jianghong; Jones, Steven J.M.

doi:10.1101/2020.04.05.026633

Cited by 37 publications

(36 citation statements)

References 35 publications

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Section: Coronavirus Infection and Therapeutic Targetsmentioning

confidence: 99%

“…Different ACE2 variants are reported that show sexspecific expression [30][31][32]. Since ACE2 is an X chromosome encoded gene, the presence of disease or risk variants in men will be more detrimental [31]. It is suggested that the missense ACE2 variants could influence binding with spike proteins and this, in turn, will affect the progression of COVID-19 [31].…”

Section: Coronavirus Infection and Therapeutic Targetsmentioning

confidence: 99%

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Sex differences in severity and mortality from COVID-19: are males more vulnerable?

2020

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Coronavirus disease 2019 (COVID-19) has shown high infection and mortality rates all over the world, and despite the global efforts, there is so far no specific therapy available for COVID-19. Interestingly, while the severity and mortality of COVID-19 are higher in males than in females, the underlying molecular mechanisms are unclear. In this review, we explore sex-related differences that may be contributing factors to the observed male-biased mortality from COVID-19. Males are considered the weaker sex in aspects related to endurance and infection control. Studies show that viral RNA clearance is delayed in males with COVID-19. A recent study has indicated that the testis can harbor coronavirus, and consequently, males show delayed viral clearance. However, the role of testis involvement in COVID-19 severity and mortality needs further research. Males and females show a distinct difference in immune system responses with females eliciting stronger immune responses to pathogens. This difference in immune system responses may be a major contributing factor to viral load, disease severity, and mortality. In addition, differences in sex hormone milieus could also be a determinant of viral infections as estrogen has immunoenhancing effects while testosterone has immunosuppressive effects. The sex-specific severity of COVID-19 infections indicates that further research on understanding the sex differences is needed. Inclusion of both males and females in basic research and clinical trials is required to provide critical information on sex-related differences that may help to better understand disease outcome and therapy.

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Section: Coronavirus Infection and Therapeutic Targetsmentioning

confidence: 99%

Section: Coronavirus Infection and Therapeutic Targetsmentioning

confidence: 99%

Sex differences in severity and mortality from COVID-19: are males more vulnerable?

2020

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“…Some of this response is known to be linked to variation in how the immune system responds to infection, with some individuals experiencing a hyperinflammatory 'cytokine storm', which in turn aggravates respiratory failures and increases mortality risk 32,33 . There may also be some variation among humans in initial susceptibility to infection, such that approaches examining variation in ACE2 tissue expression and gene sequences can offer insight into variation in human susceptibility to COVID-19 [34][35][36][37] . Similarly, we can use such an approach to compare sequence variation across species, and hence try to predict the likely interspecific variation in susceptibility to initial infection.…”

Section: Introductionmentioning

confidence: 99%

Comparative ACE2 variation and primate COVID-19 risk

Melin

Janiak

Marrone

et al. 2020

Preprint

116

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The emergence of the novel coronavirus SARS-CoV-2, which in humans is highly infectious and leads to the potentially fatal disease COVID-19, has caused tens of thousands of deaths and huge global disruption. The viral infection may also represent an existential threat to our closest living relatives, the nonhuman primates, many of which have already been reduced to small and endangered populations. The virus engages the host cell receptor, angiotensin-converting enzyme-2 (ACE2), through the receptor binding domain (RBD) on the spike protein. The contact surface of ACE2 displays amino acid residues that are critical for virus recognition, and variations at these critical residues are likely to modulate infection susceptibility across species. While infection studies have shown that rhesus macaques exposed to the virus develop COVID-19-like symptoms, the susceptibility of other nonhuman primates is unknown. Here, we show that all apes, including chimpanzees, bonobos, gorillas, and orangutans, and all African and Asian monkeys (catarrhines), exhibit the same set of twelve key amino acid residues as human ACE2.Monkeys in the Americas, and some tarsiers, lemurs and lorisoids, differ at significant contact residues, and protein modeling predicts that these differences should greatly reduce the binding affinity of the ACE2 for the virus, hence moderating their susceptibility for infection. Other lemurs are predicted to be closer to catarrhines in their susceptibility. Our study suggests that apes and African and Asian monkeys, as well as some lemurs are all likely to be highly susceptible to SARS-CoV-2, representing a critical threat to their survival. Urgent actions may be necessary to limit their exposure to humans.

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“…This ACE2 variant was absent from the East Asian population (13,784 exomes) and was significantly rarer in the Middle East and Africa (Table 1). This particular variant has been reported before, but its clinical relevance was persistently dismissed because the codon 720, being far from ACE2-Spike protein interface, does not appear to be an obvious candidate for ACE2 receptor binding to the S-protein of SARS-CoV-2 18,29 . However, we noted that N720D is located 4 amino acids proximal to the TMPRSS2 cleavage site (aa 697-716) as shown in Supplementary Fig.…”

Section: Ace2 N720d Receptor Variation and Structural Modelingmentioning

confidence: 98%

A comprehensive germline variant and expression analyses ofACE2,TMPRSS2and SARS-CoV-2 activatorFURINgenes from the Middle East: Combating SARS-CoV-2 with precision medicine

Al-Mulla

Mohammad

Madhoun

et al. 2020

Preprint

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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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ACE 2 Coding Variants: A Potential X-linked Risk Factor for COVID-19 Disease

Cited by 37 publications

References 35 publications

Sex differences in severity and mortality from COVID-19: are males more vulnerable?

Sex differences in severity and mortality from COVID-19: are males more vulnerable?

Comparative ACE2 variation and primate COVID-19 risk

A comprehensive germline variant and expression analyses ofACE2,TMPRSS2and SARS-CoV-2 activatorFURINgenes from the Middle East: Combating SARS-CoV-2 with precision medicine

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