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SARS-CoV-2 Susceptibility and ACE2 Gene Variations Within Diverse Ethnic Backgrounds
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 geneti...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9091502/ https://www.ncbi.nlm.nih.gov/pubmed/35571054 http://dx.doi.org/10.3389/fgene.2022.888025 |
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author | Vadgama, Nirmal Kreymerman, Alexander Campbell, Jackie Shamardina, Olga Brugger, Christiane Research Consortium, Genomics England Deaconescu, Alexandra M. Lee, Richard T. Penkett, Christopher J. Gifford, Casey A. Mercola, Mark Nasir, Jamal Karakikes, Ioannis |
author_facet | Vadgama, Nirmal Kreymerman, Alexander Campbell, Jackie Shamardina, Olga Brugger, Christiane Research Consortium, Genomics England Deaconescu, Alexandra M. Lee, Richard T. Penkett, Christopher J. Gifford, Casey A. Mercola, Mark Nasir, Jamal Karakikes, Ioannis |
author_sort | Vadgama, Nirmal |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9091502 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-90915022022-05-12 SARS-CoV-2 Susceptibility and ACE2 Gene Variations Within Diverse Ethnic Backgrounds Vadgama, Nirmal Kreymerman, Alexander Campbell, Jackie Shamardina, Olga Brugger, Christiane Research Consortium, Genomics England Deaconescu, Alexandra M. Lee, Richard T. Penkett, Christopher J. Gifford, Casey A. Mercola, Mark Nasir, Jamal Karakikes, Ioannis Front Genet Genetics 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. Frontiers Media S.A. 2022-04-27 /pmc/articles/PMC9091502/ /pubmed/35571054 http://dx.doi.org/10.3389/fgene.2022.888025 Text en Copyright © 2022 Vadgama, Kreymerman, Campbell, Shamardina, Brugger, Research Consortium, Deaconescu, Lee, Penkett, Gifford, Mercola, Nasir and Karakikes. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Genetics Vadgama, Nirmal Kreymerman, Alexander Campbell, Jackie Shamardina, Olga Brugger, Christiane Research Consortium, Genomics England Deaconescu, Alexandra M. Lee, Richard T. Penkett, Christopher J. Gifford, Casey A. Mercola, Mark Nasir, Jamal Karakikes, Ioannis SARS-CoV-2 Susceptibility and ACE2 Gene Variations Within Diverse Ethnic Backgrounds |
title | SARS-CoV-2 Susceptibility and ACE2 Gene Variations Within Diverse Ethnic Backgrounds |
title_full | SARS-CoV-2 Susceptibility and ACE2 Gene Variations Within Diverse Ethnic Backgrounds |
title_fullStr | SARS-CoV-2 Susceptibility and ACE2 Gene Variations Within Diverse Ethnic Backgrounds |
title_full_unstemmed | SARS-CoV-2 Susceptibility and ACE2 Gene Variations Within Diverse Ethnic Backgrounds |
title_short | SARS-CoV-2 Susceptibility and ACE2 Gene Variations Within Diverse Ethnic Backgrounds |
title_sort | sars-cov-2 susceptibility and ace2 gene variations within diverse ethnic backgrounds |
topic | Genetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9091502/ https://www.ncbi.nlm.nih.gov/pubmed/35571054 http://dx.doi.org/10.3389/fgene.2022.888025 |
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