GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19

Nature, Journal Year: 2023, Volume and Issue: 617(7962), P. 764 - 768

Published: May 17, 2023

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown

Language: Английский

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Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Genome Medicine, Journal Year: 2023, Volume and Issue: 15(1)

Published: April 5, 2023

Abstract Background We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent interferon (IFN) immunity or autoantibodies against IFN, account for 15–20% cases life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants remain be identified ~ 80% cases. Methods report here a genome-wide rare variant burden association analysis 3269 patients with COVID-19, 1373 SARS-CoV-2-infected individuals without pneumonia. Among 928 tested quarter (234) were positive excluded. Results No gene reached significance. Under recessive model, most significant at-risk variants was TLR7 , an OR 27.68 (95%CI 1.5–528.7, P = 1.1 × 10 −4 ) biochemically loss-of-function (bLOF) variants. replicated enrichment predicted LOF (pLOF) at 13 influenza susceptibility loci involved TLR3-dependent (OR 3.70[95%CI 1.3–8.2], 2.1 ). This further strengthened by (1) adding recently TYK2 loci, particularly under model 19.65[95%CI 2.1–2635.4], 3.4 −3 ), (2) considering as pLOF branchpoint potentially strong impacts on splicing among 15 4.40[9%CI 2.3–8.4], 7.7 −8 Finally, pLOF/bLOF these significantly younger (mean age [SD] 43.3 [20.3] years) than other (56.0 [17.3] years; 1.68 −5 Conclusions Rare genes can underlie inheritance, 60 years old.

Language: Английский

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Interaction between estrogen receptor-α and PNPLA3 p.I148M variant drives fatty liver disease susceptibility in women

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(10), P. 2643 - 2655

Published: Sept. 25, 2023

Abstract Fatty liver disease (FLD) caused by metabolic dysfunction is the leading cause of and prevalence rising, especially in women. Although during reproductive age women are protected against FLD, for still unknown understudied reasons some develop rapidly progressive at menopause. The patatin-like phospholipase domain-containing 3 ( PNPLA3 ) p.I148M variant accounts largest fraction inherited FLD variability. In present study, we show that there a specific multiplicative interaction between female sex determining at-risk individuals (steatosis fibrosis, P < 10 −10 ; advanced fibrosis/hepatocellular carcinoma, = 0.034) general population −7 alanine transaminase levels). with obesity, hepatic expression was higher than men 0.007) mice correlated estrogen levels. human hepatocytes organoids, induced receptor-α (ER-α) agonists. By chromatin immunoprecipitation luciferase assays, identified characterized an ER-α-binding site within enhancer demonstrated via CRISPR–Cas9 genome editing this sequence drives upregulation, to lipid droplet accumulation fibrogenesis three-dimensional multilineage spheroids stellate cells. These data suggest functional ER-α contributes

Language: Английский

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COVID-19 annual update: a narrative review

Human Genomics, Journal Year: 2023, Volume and Issue: 17(1)

Published: July 24, 2023

Abstract Three and a half years after the pandemic outbreak, now that WHO has formally declared emergency is over, COVID-19 still significant global issue. Here, we focus on recent developments in genetic genomic research COVID-19, give an outlook state-of-the-art therapeutical approaches, as gradually transitioning to endemic situation. The sequencing characterization of rare alleles different populations made it possible identify numerous genes affect either susceptibility or severity disease. These findings provide beginning new avenues pan-ethnic therapeutic well potential screening protocols. causative virus, SARS-CoV-2, spotlight, but novel threatening virus could appear anywhere at any time. Therefore, continued vigilance further warranted. We also note emphatically prevent future pandemics other world-wide health crises, imperative capitalize what have learnt from COVID-19: specifically, regarding its origins, world’s response, insufficient preparedness. This requires unprecedented international collaboration timely data sharing for coordination effective response rapid implementation containment measures.

Language: Английский

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Genetic susceptibility to severe COVID-19

Infection Genetics and Evolution, Journal Year: 2023, Volume and Issue: 110, P. 105426 - 105426

Published: March 17, 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of disease 2019 (COVID-19) pandemic. Clinical manifestations range from an asymptomatic condition to life-threatening events and death, with more severe courses being associated age, male sex, comorbidities. Besides these risk factors, intrinsic characteristics virus as well genetic factors host are expected account for COVID-19 clinical heterogeneity. Genetic studies have long been recognized fundamental identify biological mechanisms underlying congenital diseases, pinpoint genes/proteins responsible susceptibility different inherited conditions, highlight targets therapeutic relevance, suggest drug repurposing, even clarify causal relationships that make modifiable some environmental factors. Though usually take time be concluded and, above all, translate their discoveries patients' bedside, scientific community moved really fast deliver signals phenotypes. In this Review, besides a concise description symptomatology SARS-CoV-2 mechanism infection, we aimed recapitulate current literature in terms specifically associate increased severity disease.

Language: Английский

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Genome-wide association studies of COVID-19: Connecting the dots

Infection Genetics and Evolution, Journal Year: 2022, Volume and Issue: 106, P. 105379 - 105379

Published: Oct. 21, 2022

Genome-wide association studies (GWASs) are a research approach used to identify genetic variants associated with common diseases, like COVID-19. The lead (n = 41) reported by the eleven largest COVID-19 GWASs mapped 22 different chromosomal regions. loci 3q21.31 (LZTFL1 and chemokine receptor genes) 9q34.2 (ABO), disease severity susceptibility infection, respectively, were most replicated findings across studies. Genes involved mucociliary clearance (CEP97, FOXP4), viral-entry (ACE2, SLC6A20) mucosal immunity (MIR6891) risk of SARS-CoV-2 infection while genes antiviral immune response (IFNAR2, OAS1), leukocyte trafficking (CCR9, CXCR6) lung injury (DPP9, NOTCH4) severe disease. biological processes underlying occur prominently, but not exclusively, in upper airways whereas COVID-19-associated alveolar-capillary interface. has unraveled key mechanisms pathogenesis, although basis other related phenotypes (long COVID neurological impairment) remains be elucidated.

Language: Английский

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Next-generation sequencing of host genetics risk factors associated with COVID-19 severity and long-COVID in Colombian population

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: April 11, 2024

Abstract Coronavirus disease 2019 (COVID-19) was considered a major public health burden worldwide. Multiple studies have shown that susceptibility to severe infections and the development of long-term symptoms is significantly influenced by viral host factors. These findings highlighted potential genetic markers identify high-risk individuals develop target interventions reduce morbimortality. Despite its importance, factors remain largely understudied in Latin-American populations. Using case–control design custom next-generation sequencing (NGS) panel encompassing 81 variants 74 genes previously associated with COVID-19 severity long-COVID, we analyzed 56 asymptomatic or mild critical cases. In agreement previous studies, our results support association between several clinical variables, including male sex, obesity common like cough dyspnea, COVID-19. Remarkably, thirteen showed an severity. Among these variants, rs11385942 ( p < 0.01; OR = 10.88; 95% CI 1.36–86.51) located LZTFL1 gene, rs35775079 0.02; 8.53; 1.05–69.45) CCR3 strongest associations. Various respiratory systemic symptoms, along rs8178521 variant 2.51; 1.27–4.94) IL10RB were presence long-COVID. The predictive model comparison mixed model, which incorporates non-genetic outperforms models. To knowledge, this first study Colombia Latin-America proposing for long-COVID based on genomic analysis. Our highlights usefulness approaches studying risk specific methodology used allowed us validate Finally, integrated illustrates importance considering precision medicine infectious diseases.

Language: Английский

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A genome-wide arrayed CRISPR screen identifies PLSCR1 as an intrinsic barrier to SARS-CoV-2 entry that recent virus variants have evolved to resist

PLoS Biology, Journal Year: 2024, Volume and Issue: 22(9), P. e3002767 - e3002767

Published: Sept. 24, 2024

Interferons (IFNs) play a crucial role in the regulation and evolution of host–virus interactions. Here, we conducted genome-wide arrayed CRISPR knockout screen presence absence IFN to identify human genes that influence Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. We then performed an integrated analysis interacting with SARS-CoV-2, drawing from selection 67 large-scale studies, including our own. identified 28 high relevance both genetic studies Disease 2019 (COVID-19) patients functional screens cell culture, many related pathway. Among these was IFN-stimulated gene PLSCR1 . did not require induction restrict SARS-CoV-2 contribute signaling. Instead, specifically restricted spike-mediated entry. The PLSCR1-mediated restriction alleviated by TMPRSS2 overexpression, suggesting primarily restricts endocytic entry route. In addition, recent variants have adapted circumvent barrier via currently undetermined mechanisms. Finally, investigate effects present humans discuss association between severe COVID-19 reported recently.

Language: Английский

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Mental health and COVID-19 in a general population cohort in Spain (COVICAT study)

Social Psychiatry and Psychiatric Epidemiology, Journal Year: 2022, Volume and Issue: 57(12), P. 2457 - 2468

Published: May 28, 2022

Mental health conditions may affect outcome of COVID-19 disease, while exposure to stressors during the pandemic impact mental health. The purpose this study was examine these factors in relation ocurrence depression and anxiety after first outbreak Spain.We contacted 9515 participants from a population-based cohort Catalonia between May October 2020. We drew blood samples establish infection virus. Pre-pandemic were confirmed through Electronic Health Registries. used Hospital Anxiety Depression Scale assess severe post-pandemic. Exposure proximal, financial wider environment lockdown collected. calculated Relative Risks (RR), adjusting for individual- contextual covariates.Pre-pandemic disorders not associated with SARS-CoV-2 , but severity disease. People pre-existing showed higher prevalence (25.4%) (37.8%) than those without prior (4.9% 10.1%). Living alone strong predictor among patients (RR = 1.6, 95% CI 1.2-2.2). Among disorders, post-lockdown household interpersonal conflicts 2.6, 2.1-3.1; RR 2.1, 1.9-2.4) instability 2.2, 1.8-2.9; 1.9, 1.6-2.2).The increased anxiety. Patients are vulnerable group

Language: Английский

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HLA‐A*11:01 and HLA‐C*04:01 are associated with severe COVID‐19

HLA, Journal Year: 2023, Volume and Issue: 102(6), P. 731 - 739

Published: Aug. 1, 2023

We analyzed the association between HLA polymorphisms and susceptibility to SARS‐CoV‐2 infection disease severity. Genotyping data from a total of 9373 COVID‐19‐positive cases Spanish Coalition Unlock Research on Host Genetics COVID‐19 (SCOURGE) consortium 5943 population controls were included in study. found an alleles HLA‐B*14:02 HLA‐C*08:02 with lower risk ( p = 0.006, OR 0.84, 95% CI [0.75–0.95], 0.024, 0.86, [0.78–0.95], respectively). also HLA‐A*11:01 HLA‐C*04:01 associated severity 0.033, 1.16, [1.04–1.31], 0.045, 1.14, [1.05–1.25], These results suggest that effective presentation viral peptides by class I involve faster clearance, decreasing COVID‐19.

Language: Английский

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