Suchergebnisse

SARS-CoV-2 causes a severe inflammatory syndrome (COVID-19) leading, in many cases, to bilateral pneumonia, severe dyspnea and in ∼5% of these, death. DNA methylation is known to play an important role in the regulation of the immune processes behind COVID-19 progression, however it has not been studied in depth, yet. In this study, we aim to evaluate the implication of DNA methylation in COVID-19 progression by means of a genome-wide DNA methylation analysis combined with DNA genotyping. The results reveal the existence of epigenomic regulation of functional pathways associated with COVID-19 progression and mediated by genetic loci. We found an environmental trait-related signature that discriminates mild from severe cases, and regulates IL-6 expression via the transcription factor CEBP. The analyses suggest that an interaction between environmental contribution, genetics and epigenetics might be playing a role in triggering the cytokine storm described in the most severe cases. ; This work has been supported through Consejería de Transformación Económica, Industria, Conocimiento y Universidades of the regional government of Andalucía cofounded by the European Union through European Regional Development Fund (FEDER, CV20-10150), Consejo Superior de Investigaciones científicas (CSIC-COV19-016/202020E155) and Junta de Castilla y León (Proyectos COVID 07.04.467B04.74011.0 and IBGM excellence programme CLU-2029-02). G.B. is supported by the Instituto de Salud Carlos III (ISCIII, Spanish Health Ministry) through the Sara Borrell subprogram (CD18/00153). ; Peer reviewed

Funding for the preparation of this manuscript has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115,565, resources composed of the financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and the EFPIA companies' in kind contribution. MT is supported by a Spanish grant from Health Department, Junta de Andalucia (PI/0017/2016) and through the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 806975. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. EC-M was funded by the Postdoctoral Training Subprogramme Juan de la Cierva-Ministry of Economy and Competitiveness (FJCI_2014_20652). We thank Ralf Lesche for the production of RNASeq data and Marc Torres Ciuro for design support. ; Primary Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population. ; Innovative Medicines Initiative Joint Undertaking from the European Union's Seventh Framework Program (FP7/2007-2013) 115,565 ; EFPIA companies ; Junta de Andalucia PI/0017/2016 ; Innovative Medicines Initiative 2 Joint Undertaking 806975 European Union's Horizon 2020 research and innovation programme ; EFPIA ; Postdoctoral Training Subprogramme Juan de la Cierva-Ministry of Economy and Competitiveness FJCI_2014_20652

We thank the entire COVID-19 HGI community for their contributions and continued collaboration. The work of the contributing studies was supported by numerous grants from governmental and charitable bodies. Acknowledgements specific to contributing studies are provided in Supplementary Table 13. We thank G. Butler-Laporte, G. Wojcik, M.-G. Hollm-Delgado, C. Willer and G. Davey Smith for their extensive feedback and discussion. ; The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.