SARS-CoV-2 Susceptibility and ACE2 Gene Variations Within Diverse Ethnic Backgrounds
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Abstract
There is considerable variability in the susceptibility and progression for COVID-19 and it appears to be strongly correlated with age, gender, ethnicity and pre-existing health conditions. However, to our knowledge, cohort studies of COVID-19 in clinically vulnerable groups are lacking. Host genetics has also emerged as a major risk factor for COVID-19, and variation in the ACE2 receptor, which facilitates entry of the SARS-CoV-2 virus into the cell, has become a major focus of attention. Thus, we interrogated an ethnically diverse cohort of National Health Service (NHS) patients in the United Kingdom (United Kingdom) to assess the association between variants in the ACE2 locus and COVID-19 risk. We analysed whole-genome sequencing (WGS) data of 1,837 cases who were tested positive for SARS-CoV-2, and 37,207 controls who were not tested, from the UK’s 100,000 Genomes Project (100KGP) for the presence of ACE2 coding variants and extract expression quantitative trait loci (eQTLs). We identified a splice site variant (rs2285666) associated with increased ACE2 expression with an overrepresentation in SARS-CoV-2 positive patients relative to 100KGP controls ( p = 0.015), and in hospitalised European patients relative to outpatients in intra-ethnic comparisons ( p = 0.029). We also compared the prevalence of 288 eQTLs, of which 23 were enriched in SARS-CoV-2 positive patients. The eQTL rs12006793 had the largest effect size (d = 0.91), which decreases ACE2 expression and is more prevalent in controls, thus potentially reducing the risk of COVID-19. We identified three novel nonsynonymous variants predicted to alter ACE2 function, and showed that three variants (p.K26R, p. H378R, p. Y515N) alter receptor affinity for the viral Spike (S) protein. Variant p. N720D, more prevalent in the European population ( p < 0.001), potentially increases viral entry by affecting the ACE2-TMPRSS2 complex. The spectrum of genetic variants in ACE2 may inform risk stratification of COVID-19 patients and could partially explain the differences in disease susceptibility and severity among different ethnic groups.
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SciScore for 10.1101/2021.08.18.21261804: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: Patients and relatives gave written informed consent for genetic testing.
IRB: Ethical approval for The 100,000 Genomes Project was granted by the East of England - Cambridge South Research Ethics Committee (REC Ref 14/EE/1112)Sex as a biological variable We also used WGS data from a large control group consisting of 37,207 unrelated individuals from 100KGP (males = 17,066; females = 20,141; total allele number = 57,348), to scan for ACE2 variants and eQTL distribution in different populations. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources We also used WGS data from a large control group consisting … SciScore for 10.1101/2021.08.18.21261804: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: Patients and relatives gave written informed consent for genetic testing.
IRB: Ethical approval for The 100,000 Genomes Project was granted by the East of England - Cambridge South Research Ethics Committee (REC Ref 14/EE/1112)Sex as a biological variable We also used WGS data from a large control group consisting of 37,207 unrelated individuals from 100KGP (males = 17,066; females = 20,141; total allele number = 57,348), to scan for ACE2 variants and eQTL distribution in different populations. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources We also used WGS data from a large control group consisting of 37,207 unrelated individuals from 100KGP (males = 17,066; females = 20,141; total allele number = 57,348), to scan for ACE2 variants and eQTL distribution in different populations. WGSsuggested: NoneHighest priority variants were nonsynonymous or in the splice site, with a corresponding REVEL score above the default threshold of 0.5, a GERP++ score greater than two, and PolyPhen2 prediction outcome of ‘probably damaging’. PolyPhen2suggested: NoneResults 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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.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.
Results from scite Reference Check: We found no unreliable references.
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