A Global Effort to Define the Human Genetics of Protective Immunity to SARS-CoV-2 Infection

Lau, Yu Lung; Su, Helen C.; Effort, COVID Human Genetic

doi:10.1016/j.cell.2020.05.016

Cited by 209 publications

(244 citation statements)

References 15 publications

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“…The considerations outlined above highlights the need for consortia aimed at coordinating multidisciplinary efforts to elucidate the genetic determinants of COVID-19 [15,93]. To date, several dedicated programmes were launched within the European National Health Systems.…”

Section: Lessons Learned and Perspectivesmentioning

confidence: 99%

“…Immune response is the primary arm which should be explored in infectious diseases. Seminal studies on human Mendelian disorders causing deficiencies of the immune response to viruses (reviewed in Casanova JL et al 2020 [15]) provided the background to investigate the influence of germline genetic variations in other, much more common, sporadic infectious diseases. According to the current paradigm for the complex disorder, the model to explain the genetic susceptibility to infection is not Mendelian-but may be either monogenic or polygenic-and postulates that any single genetic biomarker may be associated with a risk with low to very low effect.…”

Section: Introductionmentioning

confidence: 99%

“…In turn, this tragic experience is an unprecedented opportunity to explore the genetic determinants of an emerging infection. Therefore, the human genetics community should endorse an extraordinary scientific effort to comprehensively investigate the influence of human genetic factors involved in the variability of susceptibility to viral infection and, in particular, in the variability of the clinical manifestations caused by SARS-CoV-2 [15,22].…”

Section: Introductionmentioning

confidence: 99%

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Genetic variants of the human host influencing the coronavirus-associated phenotypes (SARS, MERS and COVID-19): rapid systematic review and field synopsis

et al. 2020

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The COVID-19 pandemic has strengthened the interest in the biological mechanisms underlying the complex interplay between infectious agents and the human host. The spectrum of phenotypes associated with the SARS-CoV-2 infection, ranging from the absence of symptoms to severe systemic complications, raised the question as to what extent the variable response to coronaviruses (CoVs) is influenced by the variability of the hosts’ genetic background. To explore the current knowledge about this question, we designed a systematic review encompassing the scientific literature published from Jan. 2003 to June 2020, to include studies on the contemporary outbreaks caused by SARS-CoV-1, MERS-CoV and SARS-CoV-2 (namely SARS, MERS and COVID-19 diseases). Studies were eligible if human genetic variants were tested as predictors of clinical phenotypes. An ad hoc protocol for the rapid review process was designed according to the PRISMA paradigm and registered at the PROSPERO database (ID: CRD42020180860). The systematic workflow provided 32 articles eligible for data abstraction (28 on SARS, 1 on MERS, 3 on COVID-19) reporting data on 26 discovery cohorts. Most studies considered the definite clinical diagnosis as the primary outcome, variably coupled with other outcomes (severity was the most frequently analysed). Ten studies analysed HLA haplotypes (1 in patients with COVID-19) and did not provide consistent signals of association with disease-associated phenotypes. Out of 22 eligible articles that investigated candidate genes (2 as associated with COVID-19), the top-ranked genes in the number of studies were ACE2, CLEC4M (L-SIGN), MBL, MxA (n = 3), ACE, CD209, FCER2, OAS-1, TLR4, TNF-α (n = 2). Only variants in MBL and MxA were found as possibly implicated in CoV-associated phenotypes in at least two studies. The number of studies for each predictor was insufficient to conduct meta-analyses. Studies collecting large cohorts from different ancestries are needed to further elucidate the role of host genetic variants in determining the response to CoVs infection. Rigorous design and robust statistical methods are warranted.

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Section: Lessons Learned and Perspectivesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genetic variants of the human host influencing the coronavirus-associated phenotypes (SARS, MERS and COVID-19): rapid systematic review and field synopsis

et al. 2020

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“…A possible contribution of human gene polymorphisms involved in the host antiviral responses to SARS-CoV-2 has been recently postulated, and there is growing evidence that some gene polymorphisms could affect susceptibility and severity of the COVID-19 course [ 7 ]. Family clustering of severe cases has been reported worldwide, which supports further efforts in exploring these genetic determinants in order to be better prepared for future waves [ 8 , 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Viral Load, IFNλ Polymorphisms and the Course of COVID-19: An Observational Study

Amodio

Pipitone

Grimaudo

et al. 2020

JCM

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The course of SARS-CoV-2 infection ranges from asymptomatic to a multiorgan disease. In this observational study, we investigated SARS-CoV-2 infected subjects with defined outcomes, evaluating the relationship between viral load and single nucleotide polymorphisms of genes codifying for IFNλs (interferon). The study enrolled 381 patients with laboratory-confirmed SARS-CoV-2 infection. For each patient, a standardized form was filled including sociodemographic variables and clinical outcomes. The host’s gene polymorphisms (IFNL3 rs1297860 C/T and INFL4 rs368234815 TT/ΔG) and RtReal-Time PCR cycle threshold (PCR Ct) value on SARS-CoV-2 were assessed on nasal, pharyngeal or nasopharyngeal swabs. Higher viral loads were found in patients aged > 74 years and homozygous mutant polymorphisms DG in IFNL4 (adj-OR = 1.16, 95% CI = 1.01–1.34 and adj-OR = 1.24, 95% CI = 1.09–1.40, respectively). After adjusting for age and sex, a statistically significantly lower risk of hospitalization was observed in subjects with higher RtReal-Time PCR cycle threshold values (adj-OR = 0.95, 95% CI = 0.91, 0.99; p = 0.028). Our data support the correlation between SARS-CoV-2 load and disease severity, and suggest that IFNλ polymorphisms could affect the ability of the host to modulate viral infection without a clear impact on the outcome of COVID-19.

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“…SARS-CoV-2 is an enveloped positive-strand RNA virus and the etiological agent of Covid-19 (Wu et al 2020), a highly infectious human disease at the center of a world pandemic that has taken thousands of lives worldwide (Casanova et al 2020;Gates 2020;Sempowski et al 2020). This virus is a member of the family of coronaviruses, known for having the largest genomes among all RNA viruses (Fehr and Perlman 2015).…”

Section: Introductionmentioning

confidence: 99%

The global and local distribution of RNA structure throughout the SARS-CoV-2 genome

Tavares

Mahadeshwar

Pyle

2020

Preprint

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AbstractSARS-CoV-2 is the causative viral agent of COVID-19, the disease at the center of the current global pandemic. While knowledge of highly structured regions is integral for mechanistic insights into the viral infection cycle, very little is known about the location and folding stability of functional elements within the massive, ~30kb SARS-CoV-2 RNA genome. In this study, we analyze the folding stability of this RNA genome relative to the structural landscape of other well-known viral RNAs. We present an in-silico pipeline to locate regions of high base pair content across this long genome and also identify well-defined RNA structures, a method that allows for direct comparisons of RNA structural complexity within the several domains in SARS-CoV-2 genome. We report that the SARS-CoV-2 genomic propensity to stable RNA folding is exceptional among RNA viruses, superseding even that of HCV, one of the most highly structured viral RNAs in nature. Furthermore, our analysis reveals varying levels of RNA structure across genomic functional regions, with accessory and structural ORFs containing the highest structural density in the viral genome. Finally, we take a step further to examine how individual RNA structures formed by these ORFs are affected by the differences in genomic and subgenomic contexts. The conclusions reported in this study provide a foundation for structure-function hypotheses in SARS-CoV-2 biology, and in turn, may guide the 3D structural characterization of potential RNA drug targets for COVID-19 therapeutics.

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A Global Effort to Define the Human Genetics of Protective Immunity to SARS-CoV-2 Infection

Cited by 209 publications

References 15 publications

Genetic variants of the human host influencing the coronavirus-associated phenotypes (SARS, MERS and COVID-19): rapid systematic review and field synopsis

Genetic variants of the human host influencing the coronavirus-associated phenotypes (SARS, MERS and COVID-19): rapid systematic review and field synopsis

SARS-CoV-2 Viral Load, IFNλ Polymorphisms and the Course of COVID-19: An Observational Study

The global and local distribution of RNA structure throughout the SARS-CoV-2 genome

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