Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Comunicazione e produzione culturale di un centro culturale con al suo interno i servizi di una biblioteca contemporanea. Il caso studio di Ginestra Fabbrica della Conoscenza

Ginestra è un centro culturale, un luogo fisico adesso in ristrutturazione ma che ospiterà la nuova Biblioteca Comunale di Montevarchi, spazi per laboratori artistici e didattici votati alla creazione di produzioni originali, presentazioni e performance dal vivo. È un organismo di produzione di idee, arte e cultura: una rete multidisciplinare di soggetti, un centro di attività creative, dove sperimentare processi di apprendimento basati sull’imparare facendo. Luogo di antica memoria, è stata ..

POSSIBLE PRESENCE OF AN AMH-IMMUNO-LIKE PROTEIN IN THE INTERSTITIAL CELLS OF EUTOPIC SCROTAL TESTIS OF PREPUBERTAL UNILATERAL CRYPTORCHID SWINE

The anti-Müllerian hormone (AMH), a homodimeric cytokine of the transforming growth factor-β supe family is synt esi ed in t e gonads of all ve teb ate species examined to date (1). AMH plays crucial roles in sexual differentiation and gonadal functions of both sexes. In mammal males, AMH is expressed by the testis Sertoli cells, triggers the regression of the Müllerian ducts during the early fetal life, modulates the gonadal function during the postnatal life up to puberty, and has extra-gonadal effects on the hypothalamic-pituitary-gonadal axis (2). In mammals, circulating AMH appears to be entirely derived from the gonads and its concentrations have been used to assess several testicular pathologies (3) as in hemi-castrated unilateral cryptorchid horses (4). Since the possible role of AMH as an endocrine marker of cryptorchidism in boars is unexplored, the aim of this study was to investigate the gene and protein expression of AMH in testes of neonatal and prepubertal unilateral cryptorchid swine at different ages. Cryptorchid and contro-lateral normally descended testes of neonatal (8 days, n = 4) and prepubertal unilateral cryptorchid swine of different age (2, 3, and 5 months, n = 12) were used. Immunohistochemical investigation was performed using two different commercial polyclonal anti-AMH swine specific primary antibodies. Western blotting was performed using the same immunohistochemistry primary antibodies. AMH gene expression was evaluated by RT-PCR using primers designed on the specific mRNA sequence. Independently of the antibody used for immunohistochemistry, the Sertoli cells of all neonatal and prepubertal cryptorchid testes showed strong positive signals for AMH. By converse, positive signals progressively decreased in the Sertoli cells of contro-lateral, normally descended testes from neonatal to late prepubertal phase. Surprisingly, the interstitial cells of descended prepubertal testes showed an age-related increase of positive immunosignals for AMH. Western blotting data confirmed the specificity of the two antisera used for immunohistochemistry. AMH gene expression was observed in all testes. Even if our data need to be confirmed, we think that it is important to present such preliminary findings that suggest the possible presence of an AMH-immuno-like protein in the Leydig cells of normally descended testis of prepubertal unilateral cryptorchid swine. 1) Cimino I, et al. Nat Commun. 2016; 7:10055. 2) McLennan IS, Pankhurst MW. J Endocrinol 2015; 226:R45–R57. 3) Ball BA, et al. Theriogenology. 2008; 69:624-31. 4) Murase H, et al. J Equine Sci 2015; 26:15-20

Mapping the human genetic architecture of COVID-19

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

1. Seminario Nazionale di Biblioteconomia

DIDATTICA E RICERCA NELL’UNIVERSITA ITALIANA E CONFRONTI INTERNAZIONALI Il volume raccoglie la maggior parte dei contributi che sono stati presentati e discussi il 30 e 31 maggio 2013, nel corso del primo “Seminario nazionale di biblioteconomia” organizzato, nell’ambito delle attività scientifiche del Dipartimento di Scienze documentarie, linguistico-filologiche e geografiche dell’Università di Roma La Sapienza, da Alberto Petrucciani e Giovanni Solimine, con il patrocinio della Facoltà di Lettere, dell’Associazione italiana biblioteche (AIB) e della Società italiana di scienze bibliografiche e biblioteconomiche (SISBB)

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

Abstract Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 x 10(⁻⁸)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.A Publisher Correction to this article was published on 16 March 2021

Mapping the human genetic architecture of COVID-19

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 diseases3,4,5,6,7. 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