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 hospitalization2,3,4 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

Association of statin pretreatment with collateral circulation and final infarct volume in acute ischemic stroke patients: A meta-analysis

Background and aims: Statin pretreatment (SP) is associated with improved outcomes in acute ischemic stroke (AIS) patients. Collateral circulation status and final infarct volume (FIV) are independent predictors of functional outcome in AIS. Methods: We sought to evaluate the association of SP with collateral circulation and FIV in AIS patients. We used a random-effects model for all the analyses, and pooled standardized mean differences (SMDs) and odds ratios (OR) on the FIV and collateral status according to SP history, respectively. Results: We identified 9 eligible studies (1186 AIS patients). History of SP was associated with lower FIV (SMD = 0.25, 95%CI: 0.07–0.42, p = 0.005) compared to negative history of SP. A trend towards good collateral scores was observed in the SP group (OR = 1.45; 95% CI, 0.92–2.29, p = 0.11). Subgroup analysis demonstrated reduced FIV among atherosclerotic stroke patients with history of SP (SMD = 0.49; 95% CI, 0.19–0.80, p = 0.001). Conclusions: SP appears to be associated with decreased FIV, especially in atherosclerotic AIS. © 2019 Elsevier B.V