Genetic susceptibility to severe COVID-19

https://doi.org/10.1016/j.meegid.2023.105426Get rights and content
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Highlights

  • Genetic variants of the host modulate the severity of COVID-19.

  • Association analyses identified 73 common variants corresponding to 41 different loci.

  • The chromosome 3p21.31 locus is confirmed as the most replicated and significant.

  • Enrichment analyses point to the role of the immune system in COVID-19 severity.

  • Rare variant analysis is still in its infancy and repeatedly pointed to TLR7.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of the coronavirus disease 2019 (COVID-19) pandemic. Clinical manifestations of the disease range from an asymptomatic condition to life-threatening events and death, with more severe courses being associated with age, male sex, and comorbidities. Besides these risk factors, intrinsic characteristics of the virus as well as genetic factors of the host are expected to account for COVID-19 clinical heterogeneity.

Genetic studies have long been recognized as fundamental to identify biological mechanisms underlying congenital diseases, to pinpoint genes/proteins responsible for the susceptibility to different inherited conditions, to highlight targets of therapeutic relevance, to suggest drug repurposing, and even to clarify causal relationships that make modifiable some environmental risk factors. Though these studies usually take long time to be concluded and, above all, to translate their discoveries to patients' bedside, the scientific community moved really fast to deliver genetic signals underlying different COVID-19 phenotypes.

In this Review, besides a concise description of COVID-19 symptomatology and of SARS-CoV-2 mechanism of infection, we aimed to recapitulate the current literature in terms of host genetic factors that specifically associate with an increased severity of the disease.

Keywords

SARS-CoV-2
COVID-19
Severity
Genetics
Genome-wide association study
Mutation

Abbreviations

ACE2
Angiotensin I converting enzyme 2
CCR2
C-C chemokine receptor type 2
CCR9
CC motif chemokine receptor 9
CXCR6
C-X motif chemokine receptor 6
CI
Confidence interval
COVID-19
Coronavirus disease 2019
EMT
Epithelial-mesenchymal transition response
GHS
Geisinger Health System
GRS
Genetic risk score
GWAS
Genome-wide association study
HGI
Host Genetics Initiative
ICU
Intensive care unit
IFIH1
Interferon induced with helicase C domain 1
IFN
Interferon
IRF
Interferon regulatory factor
ISG
Interferon-stimulated gene
LD
Linkage disequilibrium
LZTFL1
Leucine zipper transcription factor like 1
NGS
Next-generation sequencing
OR
Odds ratio
PMBB
Penn Medicine BioBank
PRRs
Pattern recognition receptors
PRS
Polygenic risk score
RIG-I
Retinoic acid-inducible gene I
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SLC6A20
Sodium imino-acid transporter
SNP
single-nucleotide polymorphism
TLR
Toll-like receptor
TMPRSS2
Transmembrane protease, serine 2
TLR7
Sensor toll-like receptor
UKB
UK Biobank
WGS
Whole-genome sequencing
WHO
World Health Organization

Data availability

No data was used for the research described in the article.

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