RESUMEN
Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care1 or hospitalisation2;3;4 following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study recruits critically-ill cases and compares their genomes with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases compared with 48,400 population controls to discover and replicate 22 independent variants that significantly predispose to life-threatening COVID-19. We identify 15 new independent associations with critical COVID-19, including variants within genes involved in interferon signalling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating expression of multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease. We show that comparison between critically-ill cases and population controls is highly efficient for genetic association analysis and enables detection of therapeutically-relevant mechanisms of disease. Therapeutic predictions arising from these findings require testing in clinical trials.
RESUMEN
The subset of patients who develop critical illness in Covid-19 have extensive inflammation affecting the lungs1 and are strikingly different from other patients: immunosuppressive therapy benefits critically-ill patients, but may harm some non-critical cases.2 Since susceptibility to life-threatening infections and immune-mediated diseases are both strongly heritable traits, we reasoned that host genetic variation may identify mechanistic targets for therapeutic development in Covid-19.3 GenOMICC (Genetics Of Mortality In Critical Care, genomicc.org) is a global collaborative study to understand the genetic basis of critical illness. Here we report the results of a genome-wide association study (GWAS) in 2244 critically-ill Covid-19 patients from 208 UK intensive care units (ICUs), representing >95% of all ICU beds. Ancestry-matched controls were drawn from the UK Biobank population study and results were confirmed in GWAS comparisons with two other population control groups: the 100,000 genomes project and Generation Scotland. We identify and replicate three novel genome-wide significant associations, at chr19p13.3 (rs2109069, p = 3.98 x 10-12), within the gene encoding dipeptidyl peptidase 9 (DPP9), at chr12q24.13 (rs10735079, p =1.65 x 10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), and at chr21q22.1 (rs2236757, p = 4.99 x 10-8) in the interferon receptor gene IFNAR2. Consistent with our focus on extreme disease in younger patients with less comorbidity, we detect a stronger signal at the known 3p21.31 locus than previous studies (rs73064425, p = 4.77 x 10-30). We identify potential targets for repurposing of licensed medications. Using Mendelian randomisation we found evidence in support of a causal link from low expression of IFNAR2, and high expression of TYK2, to life-threatening disease. Transcriptome-wide association in lung tissue revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe Covid-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms, and mediators of inflammatory organ damage in Covid-19. Both mechanisms may be amenable to targeted treatment with existing drugs. Large-scale randomised clinical trials will be essential before any change to clinical practice.
RESUMEN
PURPOSE: The purpose of this study was to evaluate functional outcomes, range of motion (ROM), elbow stability, and time to return to full activities after acute and subacute arthroscopic repair of a simple elbow dislocation in high-demand patients. METHODS: "High-demand patients" were defined as in-season athletes and individuals who required use of both hands for their profession and believed that they could not miss the 6 weeks of work that may be required with conservative treatment in an elbow brace. We retrospectively reviewed 14 consecutive patients with a simple elbow dislocation who underwent arthroscopic repair of the radial ulnohumeral ligament from 2008-2012. Outcomes measures included the Mayo Elbow Performance Score (MEPS), elbow ROM, elbow stability, and time to return to full activities. Each patient was contacted once by telephone to determine the current activity level and presence of any pain or functional limitations. RESULTS: The mean patient age was 25 years, with telephone follow-up at a mean of 30 months and clinical examination after a minimum of 6 months. The postoperative MEPS was excellent (mean, 99.6; range, 95 to 100) for all 14 patients, and all returned to their preinjury level of function with no restrictions or instability. Final ROM averaged -3° of full extension to greater than 130° of flexion. The mean time to return to full activities in and out of a brace was 2.7 weeks and 6.6 weeks, respectively, in the acute group and 4.6 weeks and 8.9 weeks, respectively, in the subacute group. All patients were satisfied with their outcome. CONCLUSIONS: Conservative management remains the gold standard for most simple elbow dislocations. We believe that certain high-demand patients may be candidates for acute arthroscopic ligamentous repair. Our preliminary data show that acute arthroscopic repair of the radial ulnohumeral ligament is a safe, effective procedure that restores stability to the elbow and allows patients to quickly return to full activities. LEVEL OF EVIDENCE: Level IV, therapeutic case series.