SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

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Virology analysis in HCV genotype 1-infected patients treated with the combination of simeprevir and TMC647055/ritonavir, with and without ribavirin, and JNJ-56914845

Abstract Background In study TMC647055HPC2001, a 3-direct-acting-antiviral (DAA) regimen combining NS3/4A protease inhibitor simeprevir (SMV), non-nucleoside NS5B inhibitor TMC647055/ritonavir (RTV) and NS5A inhibitor JNJ-56914845 resulted in high sustained virologic response 12 weeks after actual end of treatment (SVR12) in chronic hepatitis C virus (HCV) genotype 1-infected patients. SVR12 rates were generally lower in the 2-DAA regimen SMV + TMC647055/RTV with or without ribavirin. The objective of this study was to identify and characterise pre-existing and emerging resistance-associated variants (RAVs) in patients enrolled in study TMC647055HPC2001. Methods HCV population sequencing analyses were performed on baseline isolates from all patients (n = 90) and post-baseline isolates from patients with virologic failure (n = 22). In addition, deep sequencing and phenotypic analyses were performed on selected baseline and post-baseline isolates. Results The majority of patients with virologic failure had emerging RAVs to all study drugs at the time of failure: in all 22 patients SMV RAVs emerged at NS3 positions 80, 155, 156 and/or 168, consistent with the known SMV resistance profile. Emerging TMC647055 RAVs at NS5B position 495 were detected in the majority of patients (16/22), and all 5 patients who failed the 3-DAA regimen had emerging JNJ-56914845 RAVs at NS5A positions 30 and/or 31. While at the end of study emerging SMV and TMC647055 RAVs were no longer observed by population sequencing in 40% (8/20) and 62.5% (10/16) of patients with follow-up data available, respectively, emerging JNJ-56914845 RAVs were still detected in all (5/5) patients. Conclusions Virologic failure in the 2- and 3-DAA combinations was, in the majority of patients, associated with the emergence of RAVs to all study drugs. While emerging SMV and TMC647055 RAVs became undetectable during follow-up, JNJ-56914845 RAVs in NS5A were still observed at end of study. Trial registration number NCT01724086 (date of registration: September 26, 2012

Integrated approaches to health : concepts and experiences in framing, integration and evaluation of One Health and EcoHealth

Integrated approaches to health address health challenges arising from the intertwined spheres of humans, animals and ecosystems. This eBook is the product of an interdisciplinary effort to establish how One Health, EcoHealth and other integrated approaches to health are conceptualized, framed, implemented and evaluated today. It supplements the handbook for the evaluation of One Health, published by the COST Action “Network for Evaluation of One Health (NEOH)” with in depth reflections on the theory behind integrated approaches to health and One Health more specifically, a brief version of the NEOH evaluation framework, a supplementary evaluation approach, and eight case studies in which the NEOH framework was applied. The eBook is intended for practitioners, researchers, evaluators as well as funders of integrated approaches to health and beyond. Without the outstanding support and leadership from the management committee, this work would not have been achieved. Our gratitude goes to Maria-Eleni Filippitzi (BE), Véronique Renault (BE), Nihad Fejzic (BA), Sabina Seric-Haracic (BA), Nenad Turk (HR), Relia Beck (HR), Luca Guardabassi (DK), Liza Rosenbaum Nielsen (DK) Flavie Goutard (FR), Vladimir Grosbois (FR), Brigitte Petersen (DE), Martin Hamer (DE), Elias Papadopoulos (GR), Ilias Chaligiannis (GR), Gábor Földvári (HU), Anthony Staines (IE), Helen O’Shea (IE), Shimon Harrus (IL), Gad Baneth (IL), Valeria Grieco (IT), Maurizio Aragrande (vice chair, IT), Jovita Mažeikienė (LT), Sandra Buttigieg (MT), Elaine Lautier (MT), Helmut Saatkamp (NL), Kitty Maassen (NL), Vlatko Ilieski (MK), Mijalce Santa (MK), Merete Hofshagen (NO), Yngvild Wasteson (NO), Paulo Roriz (PT), Jorge Torgal (PT), Andrei D. Mihalca (RO), Razvan Chereches (RO), Dragan Milićević (RS), Sara Savic (RS), Joze Staric (SI), Mojca Juričič (SI), Pedro Soto-Acosta (ES), Francisco Giménez Sánchez (ES), Ann Lindberg (SE), Josef Järhult (SE), Jakob Zinsstag (CH), Simon Rüegg (CH), Barbara Häsler (chair, UK), K. Marie McIntyre (UK), Martha Betson (UK), Marieta Braks (NL), Chinwe Ifejika Speranza (DE), Spela Sinigoj (SI), Martijn Bouwknegt (NL), Andras Lakos (HU) and their substitutes Merel Postma (BE), Semra Cavaljuga (BA), Estella Prukner Radovcic (HR), Maria Vang Johansen (DK), Elena Boriani (DK), Ricarda Schmithausen (DE), Maryla Hanna Obszarski (DE), Smaragda Sotiraki (GR), Theofilos Papadopoulos (GR), Barry McMahon (IE), Massimo Canali (IT), Fabrizio Ceciliani (IT), Daniele De Meneghi (IT), Dalia Jurevičiūtė (LT), Miroslav Radeski (MK), Toni Vekov (MK); Manuela Vilhena (PT), Carla Maia (PT), Alexandru Coman (RO), Branka Vidic (RS), Gospava Lazić (RS), Ksenija Sinigoj Gacnik (SI), Juan Gabriel Cegarra Navarro (ES), Asta Tvarijonaviciute (ES), José Cerón (ES), Helene Wahlström (SE), Karin Artursson (SE), Laura Cornelsen (UK), Jonathan Rushton (UK). We also would like to thank the 240+ researchers that have engaged with the COST Action throughout and participated actively. Our gratitude also goes to the Royal Veterinary College in London, who acted as a grant holder.peer-reviewe

Editorial: Concepts and Experiences in Framing, Integration and Evaluation of One Health and EcoHealth

International audienc

Additional file 1: of Virology analysis in HCV genotype 1-infected patients treated with the combination of simeprevir and TMC647055/ritonavir, with and without ribavirin, and JNJ-56914845

Study design. HCV NS3/4A, NS5B and NS5A sequence analysis. (DOCX 32 kb

Health status in routine clinical practice: validity of the clinical COPD questionnaire at the individual patient level

<p>Abstract</p> <p>Background</p> <p>There is a growing interest to use health status or disease control questionnaires in routine clinical practice. However, the validity of most questionnaires is established using techniques developed for group level validation. This study examines a new method, using patient interviews, to validate a short health status questionnaire, the Clinical COPD Questionnaire (CCQ), at the individual patient level.</p> <p>Methods</p> <p>Patients with COPD who visited an outpatient clinic completed the CCQ before the consultation, and the specialist physician completed it after the consultation. After the consultation all patients had a semi-structured in-depth interview. The patients' CCQ scores were compared with those of the treating clinician, and with mean scores from 5 clinicians from a pool of 20 who scored the CCQ after reading the transcript of the in-depth interviews only. Agreement was assessed using Lin's concordance correlation coefficient (CCC), and Blant and Altman plots. Interviews with patients with low agreement were reviewed for possible explanations.</p> <p>Results</p> <p>A total of 44 COPD patients (32 male, mean age 66 years, FEV₁45% of predicted) participated. Agreement between the patients' CCQ scores and those of the treating clinicians (CCC = 0.87) and the mean score of the reviewing clinicians (CCC = 0.86) was very high. No systematic error was detected. No explanation for individuals with low agreement was found.</p> <p>Conclusion</p> <p>The validity of the CCQ on the individual patient level, as assessed by these methods, is good. Individual health status assessment with the CCQ is therefore sufficiently accurate to be used in routine clinical practice.</p

Breast cancer-derived transforming growth factor-β and tumor necrosis factor-α compromise interferon-α production by tumor-associated plasmacytoid dendritic cells

International audienceWe previously reported that plasmacytoid dendritic cells (pDCs) infiltrating breast tumors are impaired for their interferon‐α (IFN‐α) production, resulting in local regulatory T cells amplification. We designed our study to decipher molecular mechanisms of such functional defect of tumor‐associated pDC (TApDC) in breast cancer. We demonstrate that besides IFN‐α, the production by Toll‐like receptor (TLR)‐activated healthy pDC of IFN‐β and TNF‐α but not IP‐10/CXCL10 nor MIP1‐α/CCL3 is impaired by the breast tumor environment. Importantly, we identified TGF‐β and TNF‐α as major soluble factors involved in TApDC functional alteration. Indeed, recombinant TGF‐β1 and TNF‐α synergistically blocked IFN‐α production of TLR‐activated pDC, and neutralization of TGF‐β and TNF‐α in tumor‐derived supernatants restored pDCs' IFN‐α production. The involvment of tumor‐derived TGF‐β was further confirmed in situ by the detection of phosphorylated Smad2 in the nuclei of TApDC in breast tumor tissues. Mechanisms of type I IFN inhibition did not involve TLR downregulation but the inhibition of IRF‐7 expression and nuclear translocation in pDC after their exposure to tumor‐derived supernatants or recombinant TGF‐β1 and TNF‐α. Our findings indicate that targeting TApDC to restore their IFN‐α production might be an achievable strategy to induce antitumor immunity in breast cancer by combining TLR7/9‐based immunotherapy with TGF‐β and TNF‐α antagonists