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Host genetic factors determining COVID-19 susceptibility and severity.

ABSTRACT: The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) poses an unprecedented challenge to humanity. SARS-CoV-2 infections range from asymptomatic to severe courses of COVID-19 with acute respiratory distress syndrome (ARDS), multiorgan involvement and death. Risk factors for disease severity include older age, male sex, increased BMI and pre-existing comorbidities. Ethnicity is also relevant to COVID-19 susceptibility and severity. Host genetic predisposition to COVID-19 is now increasingly recognized and whole genome and candidate gene association studies regarding COVID-19 susceptibility have been performed. Several common and rare variants in genes related to inflammation or immune responses have been identified. We summarize research on COVID-19 host genetics and compile genetic variants associated with susceptibility to COVID-19 and disease severity. We discuss candidate genes that should be investigated further to understand such associations and provide insights relevant to pathogenesis, risk classification, therapy response, precision medicine, and drug repurposing.

SUBMITTER: Velavan TP

PROVIDER: S-EPMC8512556 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Host genetic factors determining COVID-19 susceptibility and severity.

Velavan Thirumalaisamy P TP Pallerla Srinivas Reddy SR Rüter Jule J Augustin Yolanda Y Kremsner Peter G PG Krishna Sanjeev S Meyer Christian G CG

EBioMedicine 20211013

The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) poses an unprecedented challenge to humanity. SARS-CoV-2 infections range from asymptomatic to severe courses of COVID-19 with acute respiratory distress syndrome (ARDS), multiorgan involvement and death. Risk factors for disease severity include older age, male sex, increased BMI and pre-existing comorbidities. Ethnicity is also relevant to COVID-19 susceptibility and severity. Host genetic predispo ...[more]

PMID: 34655949

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Project description:The coronavirus disease 2019 (COVID-19) is an infectious disease that mainly affects the host respiratory system with ∼80% asymptomatic or mild cases and ∼5% severe cases. Recent genome-wide association studies (GWAS) have identified several genetic loci associated with the severe COVID-19 symptoms. Delineating the genetic variants and genes is important for better understanding its biological mechanisms. We implemented integrative approaches, including transcriptome-wide association studies (TWAS), colocalization analysis and functional element prediction analysis, to interpret the genetic risks using two independent GWAS datasets in lung and immune cells. To understand the context-specific molecular alteration, we further performed deep learning-based single cell transcriptomic analyses on a bronchoalveolar lavage fluid (BALF) dataset from moderate and severe COVID-19 patients. We discovered and replicated the genetically regulated expression of CXCR6 and CCR9 genes. These two genes have a protective effect on the lung and a risk effect on whole blood, respectively. The colocalization analysis of GWAS and cis -expression quantitative trait loci highlighted the regulatory effect on CXCR6 expression in lung and immune cells. In the lung resident memory CD8 + T (T RM ) cells, we found a 3.32-fold decrease of cell proportion and lower expression of CXCR6 in the severe than moderate patients using the BALF transcriptomic dataset. Pro-inflammatory transcriptional programs were highlighted in T RM cells trajectory from moderate to severe patients. CXCR6 from the 3p21 . 31 locus is associated with severe COVID-19. CXCR6 tends to have a lower expression in lung T RM cells of severe patients, which aligns with the protective effect of CXCR6 from TWAS analysis. We illustrate one potential mechanism of host genetic factor impacting the severity of COVID-19 through regulating the expression of CXCR6 and T RM cell proportion and stability. Our results shed light on potential therapeutic targets for severe COVID-19.

Project description:BackgroundThe emergence of the novel coronavirus in Wuhan, Hubei Province, China, in December 2019 marked the synchronization of the world to a peculiar clock that is counting infected cases and deaths instead of hours and minutes. The pandemic, highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has indeed caused considerable morbidity and mortality and drastically changed our everyday lives. As we continue to become acquainted with the seventh coronavirus known to infect our species, a number of its characteristics keep surprising us. Among those is the wide spectrum of clinical manifestations of the resulting coronavirus disease 2019 (COVID-19), which ranges from asymptomatic or mildly symptomatic infections to severe pneumonia, respiratory failure, and death.Main bodyData, now from patient populations, are beginning to accumulate on human genetic factors that may contribute to the observed diversified disease severity. Therefore, we deemed it prudent to review the associations between specific human genetic variants and clinical disease severity or susceptibility to infection that have been reported in the literature to date (at the time of writing this article in early August 2020 with updates in mid-September). With this work, we hope (i) to assist the fast-paced biomedical research efforts to combat the virus by critically summarizing current knowledge on the potential role of host genetics, and (ii) to help guide current genetics and genomics research towards candidate gene variants that warrant further investigation in larger studies. We found that determinants of differing severity of COVID-19 predominantly include components of the immune response to the virus, while determinants of differing susceptibility to SARS-CoV-2 mostly entail genes related to the initial stages of infection (i.e., binding of the cell surface receptor and entry).ConclusionElucidating the genetic determinants of COVID-19 severity and susceptibility to SARS-CoV-2 infection would allow for the stratification of individuals according to risk so that those at high risk would be prioritized for immunization, for example, if or when safe and effective vaccines are developed. Our enhanced understanding of the underlying biological mechanisms could also guide personalized therapeutics. Such knowledge is already beginning to provide clues that help explain, at least in part, current epidemiologic observations regarding the typically more severe or benign disease course in older males and children, respectively.

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Host genetic factors determining COVID-19 susceptibility and severity.

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Host genetic factors determining COVID-19 susceptibility and severity.

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