3 research outputs found
Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2
The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality
Caracterización molecular de aislados de Trypanosoma cruzi de triatominos recolectados en los municipios del Estado de Hidalgo, México
Trypanosoma cruzi (T. cruzi), has been classified into six lineages using molecular typing markers, which are easily amplified by the polymerase chain reaction (PCR) technique. The objective of this work was to identify and geographically locate the isolates of T. cruzi that circulate naturally in triatomines of the municipalities of the State of Hidalgo, Mexico, through the amplification from the conserved region of the mini-exon gene by end point PCR. Method: 170 specimens of hematophagous insects from 14 municipalities from the state of Hidalgo, Mexico, were collected. Optic microscopy and PCR from triatomine fecal and digestive tissue samples were used for laboratory diagnostic of T. cruzi infection and T. cruzi lineage classification. Results: Three triatomines taxas were found: Triatoma dimidiata (87/170), Triatoma mexicana (14/170) y Triatoma gerstaeckeri (7/170). For 36.47% (62/170) of the collected specimens, species could not be determined and were classified as T. spp. T. cruzi infection was determined in 1.76% of the collected specimens through optic microscopy and in 11.18% through PCR. All the classified parasites correspond to the TcI biotype of T. cruzi. Most abundant populations of triatomines (80.58%), as well as, the highest percentage (10.58%) of T. cruzi infected insects, were found in the peridomestic ecotope. Conclusion: The most important vector found in the región of study was Triatoma dimidiata, followed by T. mexicana and T. gerstaekeri and the only T. cruzi biotype found to be infecting triatomines was TcI. The vectors were mainly distributed in the peridomiciliary habitats of the studied municipalities. Results indicate a T. cruzi represents a risk of infection for the inhabitants of the studied regions of the state of Hidalgo, Mexico.Trypanosoma cruzi (T. cruzi), está clasificado en seis linajes mediante marcadores moleculares de tipificación, que son fácilmente amplificados por técnicas de biología molecular. El objetivo del trabajo fue identificar y ubicar geográficamente a los aislados de T. cruzi que infectan naturalmente a los triatominos de los municipios del Estado de Hidalgo a través de la técnica de PCR, que amplifica fragmentos de la región intergénica del gen mini-exón. Método: Se recolectaron 170 muestras de insectos hematófagos en 14 municipios del Estado de Hidalgo, México. El diagnóstico de laboratorio en las muestras de heces y de tejido digestivo de los triatominos, se realizó de manera convencional por microscopia óptica y por la técnica de PCR para determinar la presencia o ausencia de T. cruzi y para la identificación del linaje correspondiente del parásito. Resultados: Se identificaron tres taxones de triatominos: Triatoma dimidiata (87/170), Triatoma mexicana (14/170) y Triatoma gerstaeckeri (7/170). En el 36.47% (62/170) de los especímenes colectados la especie no pudo ser identificada y se clasificaron únicamente como Triatoma spp. Se determinó la presencia del parásito en el 1.76% de los vectores analizados por el método parasitoscópico y en el 11.17% por el método de biología molecular. El total de los parásitos analizados corresponde al biotipo TcI de T. cruzi. En el ecotopo peridoméstico, se encontró la mayor abundancia de triatominos (80.58%) y el mayor porcentaje (10.58%) de infección por T. cruzi. Conclusiones: El vector más importante encontrado en la región en estudio fue Triatoma dimidiata seguido de T. mexicana y T. gerstaekeri y el biotipo con el que están mayormente infectados es el TcI. Los triatominos encontrados se distribuían principalmente en hábitats peridomésticos en los municipios estudiados. Los resultados indican la existencia de riesgo de infección para los habitantes de esas regiones endémicas del Estado de Hidalgo, México
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GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19
Data availability: Downloadable summary data are available through the GenOMICC data site (https://genomicc.org/data). Summary statistics are available, but without the 23andMe summary statistics, except for the 10,000 most significant hits, for which full summary statistics are available. The full GWAS summary statistics for the 23andMe discovery dataset will be made available through 23andMe to qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants. For further information and to apply for access to the data, see the 23andMe website (https://research.23andMe.com/dataset-access/). All individual-level genotype and whole-genome sequencing data (for both academic and commercial uses) can be accessed through the UKRI/HDR UK Outbreak Data Analysis Platform (https://odap.ac.uk). A restricted dataset for a subset of GenOMICC participants is also available through the Genomics England data service. Monocyte RNA-seq data are available under the title ‘Monocyte gene expression data’ within the Oxford University Research Archives (https://doi.org/10.5287/ora-ko7q2nq66). Sequencing data will be made freely available to organizations and researchers to conduct research in accordance with the UK Policy Framework for Health and Social Care Research through a data access agreement. Sequencing data have been deposited at the European Genome–Phenome Archive (EGA), which is hosted by the EBI and the CRG, under accession number EGAS00001007111.Extended data figures and tables are available online at https://www.nature.com/articles/s41586-023-06034-3#Sec21 .Supplementary information is available online at https://www.nature.com/articles/s41586-023-06034-3#Sec22 .Code availability:
Code to calculate the imputation of P values on the basis of SNPs in linkage disequilibrium is available at GitHub (https://github.com/baillielab/GenOMICC_GWAS).Acknowledgements: We thank the members of the Banco Nacional de ADN and the GRA@CE cohort group; and the research participants and employees of 23andMe for making this work possible. A full list of contributors who have provided data that were collated in the HGI project, including previous iterations, is available online (https://www.covid19hg.org/acknowledgements).Change history: 11 July 2023: A Correction to this paper has been published at: https://doi.org/10.1038/s41586-023-06383-z. -- In the version of this article initially published, the name of Ana Margarita Baldión-Elorza, of the SCOURGE Consortium, appeared incorrectly (as Ana María Baldion) and has now been amended in the HTML and PDF versions of the article.Copyright © The Author(s) 2023, Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).GenOMICC was funded by Sepsis Research (the Fiona Elizabeth Agnew Trust), the Intensive Care Society, a Wellcome Trust Senior Research Fellowship (to J.K.B., 223164/Z/21/Z), the Department of Health and Social Care (DHSC), Illumina, LifeArc, the Medical Research Council, UKRI, a BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070 and BBS/E/D/30002275) and UKRI grants MC_PC_20004, MC_PC_19025, MC_PC_1905 and MRNO2995X/1. A.D.B. acknowledges funding from the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z), the Edinburgh Clinical Academic Track (ECAT) programme. This research is supported in part by the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant MC_PC_20029). Laboratory work was funded by a Wellcome Intermediate Clinical Fellowship to B.F. (201488/Z/16/Z). We acknowledge the staff at NHS Digital, Public Health England and the Intensive Care National Audit and Research Centre who provided clinical data on the participants; and the National Institute for Healthcare Research Clinical Research Network (NIHR CRN) and the Chief Scientist’s Office (Scotland), who facilitate recruitment into research studies in NHS hospitals, and to the global ISARIC and InFACT consortia. GenOMICC genotype controls were obtained using UK Biobank Resource under project 788 funded by Roslin Institute Strategic Programme Grants from the BBSRC (BBS/E/D/10002070 and BBS/E/D/30002275) and Health Data Research UK (HDR-9004 and HDR-9003). UK Biobank data were used in the GSMR analyses presented here under project 66982. The UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government and the Northwest Regional Development Agency. It has also had funding from the Welsh Assembly Government, British Heart Foundation and Diabetes UK. The work of L.K. was supported by an RCUK Innovation Fellowship from the National Productivity Investment Fund (MR/R026408/1). J.Y. is supported by the Westlake Education Foundation. SCOURGE is funded by the Instituto de Salud Carlos III (COV20_00622 to A.C., PI20/00876 to C.F.), European Union (ERDF) ‘A way of making Europe’, Fundación Amancio Ortega, Banco de Santander (to A.C.), Cabildo Insular de Tenerife (CGIEU0000219140 ‘Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19’ to C.F.) and Fundación Canaria Instituto de Investigación Sanitaria de Canarias (PIFIISC20/57 to C.F.). We also acknowledge the contribution of the Centro National de Genotipado (CEGEN) and Centro de Supercomputación de Galicia (CESGA) for funding this project by providing supercomputing infrastructures. A.D.L. is a recipient of fellowships from the National Council for Scientific and Technological Development (CNPq)-Brazil (309173/2019-1 and 201527/2020-0)