Association of rare predicted loss-of-function variants of influenza-related type I IFN genes with critical COVID-19 pneumonia. Reply.

Povysil, Gundula; Butler‐Laporte, Guillaume; Gharavi, Ali G.; Richards, J. Brent; Goldstein, David; Kiryluk, Krzysztof

doi:10.1172/jci152475

Cited by 21 publications

(8 citation statements)

References 8 publications

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“…This and two other studies 31 , 46 have not been able to replicate the rare variant associations with the 13 immune genes reported by Zhang et al 44 , despite substantially larger sample sizes. These differences may be partially due to different definitions of COVID-19 severity, age distribution and in silico versus experimental validation of non-synonymous variants 47 , 48 . The power of rare variant discovery in COVID-19 will be improved by increased sample sizes of WES and WGS data sets, which in time may provide definitively conclusive associations.…”

Section: Genetic Findingsmentioning

confidence: 99%

The human genetic epidemiology of COVID-19

2022

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Human genetics can inform the biology and epidemiology of coronavirus disease 2019 (COVID-19) by pinpointing causal mechanisms that explain why some individuals become more severely affected by the disease upon infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Large-scale genetic association studies, encompassing both rare and common genetic variants, have used different study designs and multiple disease phenotype definitions to identify several genomic regions associated with COVID-19. Along with a multitude of follow-up studies, these findings have increased our understanding of disease aetiology and provided routes for management of COVID-19. Important emergent opportunities include the clinical translatability of genetic risk prediction, the repurposing of existing drugs, exploration of variable host effects of different viral strains, study of inter-individual variability in vaccination response and understanding the long-term consequences of SARS-CoV-2 infection. Beyond the current pandemic, these transferrable opportunities are likely to affect the study of many infectious diseases.

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Section: Genetic Findingsmentioning

confidence: 99%

The human genetic epidemiology of COVID-19

2022

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“…They reached divergent results, but different control definitions and confounder variant treatment, such as age, may have contributed. 44 The need for replication studies has been extensively discussed to assess the credibility of the initial association, therefore, avoiding the winner's curse phenomenon. 45 Whenever possible, replication studies should be performed in larger samples and consider bias due to population stratification, misclassification of clinical outcome, among others.…”

Section: Resultsmentioning

confidence: 99%

Systematic review of host genetic association with Covid‐19 prognosis and susceptibility: What have we learned in 2020?

Araújo

Menezes

Saraiva-Duarte

et al. 2021

Reviews in Medical Virology

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Summary Biomarker identification may provide strategic opportunities to understand disease pathophysiology, predict outcomes, improve human health, and reduce healthcare costs. The highly heterogeneous Covid‐19 clinical manifestation suggests a complex interaction of several different human, viral and environmental factors. Here, we systematically reviewed genetic association studies evaluating Covid‐19 severity or susceptibility to SARS‐CoV‐2 infection following PRISMA recommendations. Our research comprised papers published until December 31 st , 2020, in PubMed and BioRXiv databases focusing on genetic association studies with Covid‐19 prognosis or susceptibility. We found 20 eligible genetic association studies, of which 11 assessed Covid‐19 outcome and 14 evaluated infection susceptibility (five analyzed both effects). Q‐genie assessment indicated moderate quality. Five large‐scale association studies (GWAS, whole‐genome, or exome sequencing) were reported with no consistent replication to date. Promising hits were found on the 3p21.31 region and ABO locus. Candidate gene studies examined ACE1, ACE2, TMPRSS2, IFITM3, APOE, Furin, IFNL3, IFNL4, HLA, TNF‐ɑ genes, and ABO system. The most evaluated single locus was the ABO, and the most sampled region was the HLA with three and five candidate gene studies, respectively. Meta‐analysis could not be performed. Available data showed the need for further reports to replicate claimed associations.

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“…More recently, findings from another group queried the relationship between genetic defects in the TLR3/type I IFN pathway and severe COVID‐19 at a population statistical level 50 Thus, there remains an open debate as to what proportion of severe COVID‐19 results from defects in this pathway. 17 , 51 The two studies were very different in their aims and the constitution of the cohorts. For instance, the second study by Povysil et al .…”

Section: Previously Undiagnosed Inborn Errors Of Type I Interferon Im...mentioning

confidence: 99%

“…14 More recently, findings from another group queried the relationship between genetic defects in the TLR3/type I IFN pathway and severe COVID-19 at a population statistical level 50 Thus, there remains an open debate as to what proportion of severe COVID-19 results from defects in this pathway. 17,51 The two studies were very different in their aims and the constitution of the cohorts. For instance, the second study by Povysil et al 50 not including mild or asymptomatic COVID-19positive controls, while the composition of the CHGE including specialists in the field of inborn errors, might have resulted in an unintentional bias towards the inclusion of cases with features of possible single gene inheritance (e.g.…”

Section: Previously Undiagnosed Inborn Errors Of Type I Interferon Im...mentioning

confidence: 99%

Severe COVID‐19 represents an undiagnosed primary immunodeficiency in a high proportion of infected individuals

2022

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Since the emergence of the COVID‐19 pandemic in early 2020, a key challenge has been to define risk factors, other than age and pre‐existing comorbidities, that predispose some people to severe disease, while many other SARS‐CoV‐2‐infected individuals experience mild, if any, consequences. One explanation for intra‐individual differences in susceptibility to severe COVID‐19 may be that a growing percentage of otherwise healthy people have a pre‐existing asymptomatic primary immunodeficiency (PID) that is unmasked by SARS‐CoV‐2 infection. Germline genetic defects have been identified in individuals with life‐threatening COVID‐19 that compromise local type I interferon (IFN)‐mediated innate immune responses to SARS‐CoV‐2. Remarkably, these variants – which impact responses initiated through TLR3 and TLR7, as well as the response to type I IFN cytokines – may account for between 3% and 5% of severe COVID‐19 in people under 70 years of age. Similarly, autoantibodies against type I IFN cytokines (IFN‐α, IFN‐ω) have been detected in patients' serum prior to infection with SARS‐CoV‐2 and were found to cause c . 20% of severe COVID‐19 in the above 70s and 20% of total COVID‐19 deaths. These autoantibodies, which are more common in the elderly, neutralise type I IFNs, thereby impeding innate antiviral immunity and phenocopying an inborn error of immunity. The discovery of PIDs underlying a significant percentage of severe COVID‐19 may go some way to explain disease susceptibility, may allow for the application of targeted therapies such as plasma exchange, IFN‐α or IFN‐β, and may facilitate better management of social distancing, vaccination and early post‐exposure prophylaxis.

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Association of rare predicted loss-of-function variants of influenza-related type I IFN genes with critical COVID-19 pneumonia. Reply.

Cited by 21 publications

References 8 publications

The human genetic epidemiology of COVID-19

The human genetic epidemiology of COVID-19

Systematic review of host genetic association with Covid‐19 prognosis and susceptibility: What have we learned in 2020?

Severe COVID‐19 represents an undiagnosed primary immunodeficiency in a high proportion of infected individuals

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