Extreme phenotypes approach to investigate host genetics and COVID-19 outcomes

Naslavsky, Michel Satya; Vidigal, Mateus; Matos, Larissa do Rêgo Barros; Coria, Vivian Romanholi; Batista, Pedro Benedito; Razuk, Alvaro; Saldiva, Paulo Hilário Nascimento; Dolhnikoff, Marisa; Schidlowski, Laire; Prando, Carolina; Cunha‐Neto, Edécio; Condino‐Neto, Antônio; Passos‐Bueno, Maria Rita; Zatz, Mayana

doi:10.1590/1678-4685-gmb-2020-0302

Cited by 6 publications

(7 citation statements)

References 75 publications

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“…In other words, healthy subjects from previously organized biobanks may include patients who will present a worse prognosis when infected, thus biasing the control group. Analysis with asymptomatic or paucisymptomatic individuals could also provide relevant results on the genetic basis related to all Covid‐19 manifestations 50 . Secondly, we observed divergences in the clinical or molecular inclusion criteria for negative patients.…”

Section: Discussionmentioning

confidence: 81%

“…Analysis with asymptomatic or paucisymptomatic individuals could also provide relevant results on the genetic basis related to all Covid‐19 manifestations. 50 Secondly, we observed divergences in the clinical or molecular inclusion criteria for negative patients. Some studies required molecular testing while others didn't, that is, only clinical symptomatology was assessed.…”

Section: Discussionmentioning

confidence: 91%

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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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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 91%

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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“…In the early stages of the pandemic, morbidity and mortality was skewed toward older patients with significant underlying comorbidities, however, over time it has become increasingly clear that clinical outcomes with COVID-19 following infection with SARS-CoV-2 is heterogeneous with outcomes even in young adults and children without medical comorbidities unpredictably ranging from ranging from asymptomatic infection to death (57). An objective of our study was to determine if heterogeneity in airway epithelial IFN responses to SARS-CoV-2 between individual pediatric and adult donors was associated with SARS-CoV-2 replication.…”

Section: Discussionmentioning

confidence: 99%

Airway epithelial interferon response to SARS-CoV-2 is inferior to rhinovirus and heterologous rhinovirus infection suppresses SARS-CoV-2 replication

Vanderwall¹,

Barrow²,

Rich³

et al. 2021

Preprint

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IntroductionCommon alphacoronaviruses and human rhinoviruses (HRV) induce type I and III interferon (IFN) responses important to limiting viral replication in the airway epithelium. In contrast, highly pathogenic betacoronaviruses including SARS-CoV-2 may evade or antagonize RNA-induced IFN I/III responses.MethodsIn airway epithelial cells (AECs) from children and older adults we compared IFN I/III responses to SARS-CoV-2 and HRV-16, and assessed whether pre-infection with HRV-16, or pretreatment with recombinant IFN-β or IFN-λ, modified SARS-CoV-2 replication. Bronchial AECs from children (ages 6-18 yrs.) and older adults (ages 60-75 yrs.) were differentiated ex vivo to generate organotypic cultures. In a biosafety level 3 (BSL-3) facility, cultures were infected with SARS-CoV-2 or HRV-16, and RNA and protein was harvested from cell lysates 96 hrs. following infection and supernatant was collected 48 and 96 hrs. following infection. In additional experiments cultures were pre-infected with HRV-16, or pre-treated with recombinant IFN-β1 or IFN-λ2 before SARS-CoV-2 infection.ResultsDespite significant between-donor heterogeneity SARS-CoV-2 replicated 100 times more efficiently than HRV-16. IFNB1, INFL2, and CXCL10 gene expression and protein production following HRV-16 infection was significantly greater than following SARS-CoV-2. IFN gene expression and protein production were inversely correlated with SARS-CoV-2 replication. Treatment of cultures with recombinant IFNβ1 or IFNλ2, or pre-infection of cultures with HRV-16, markedly reduced SARS-CoV-2 replication.DiscussionIn addition to marked between-donor heterogeneity in IFN responses and viral replication, SARS-CoV-2 elicits a less robust IFN response in primary AEC cultures than does rhinovirus, and heterologous rhinovirus infection, or treatment with recombinant IFN-β1 or IFN-λ2, markedly reduces SARS-CoV-2 replication.

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“…It is being felt that extending the GWAS to systems’ levels with deeper phenotypes and composite traits can accelerate predictive marker discoveries [ 8 , 21 ]. Exome sequencing of extreme phenotypes in smaller sample sizes (i.e., hundreds) is also being used as another approach to identify variants with larger phenotypic effects in single attributes or for variable clinical outcomes in diseases [ 22 , 23 , 24 , 25 , 26 , 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Whole Exome Sequencing in Healthy Individuals of Extreme Constitution Types Reveals Differential Disease Risk: A Novel Approach towards Predictive Medicine

Abbas

Chaturvedi

Prakrithi

et al. 2022

JPM

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Precision medicine aims to move from traditional reactive medicine to a system where risk groups can be identified before the disease occurs. However, phenotypic heterogeneity amongst the diseased and healthy poses a major challenge for identification markers for risk stratification and early actionable interventions. In Ayurveda, individuals are phenotypically stratified into seven constitution types based on multisystem phenotypes termed “Prakriti”. It enables the prediction of health and disease trajectories and the selection of health interventions. We hypothesize that exome sequencing in healthy individuals of phenotypically homogeneous Prakriti types might enable the identification of functional variations associated with the constitution types. Exomes of 144 healthy Prakriti stratified individuals and controls from two genetically homogeneous cohorts (north and western India) revealed differential risk for diseases/traits like metabolic disorders, liver diseases, and body and hematological measurements amongst healthy individuals. These SNPs differ significantly from the Indo-European background control as well. Amongst these we highlight novel SNPs rs304447 (IFIT5) and rs941590 (SERPINA10) that could explain differential trajectories for immune response, bleeding or thrombosis. Our method demonstrates the requirement of a relatively smaller sample size for a well powered study. This study highlights the potential of integrating a unique phenotyping approach for the identification of predictive markers and the at-risk population amongst the healthy.

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Extreme phenotypes approach to investigate host genetics and COVID-19 outcomes

Cited by 6 publications

References 75 publications

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

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

Airway epithelial interferon response to SARS-CoV-2 is inferior to rhinovirus and heterologous rhinovirus infection suppresses SARS-CoV-2 replication

Whole Exome Sequencing in Healthy Individuals of Extreme Constitution Types Reveals Differential Disease Risk: A Novel Approach towards Predictive Medicine

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