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

Cytotoxicity and cytoprotective activity in naphthalenediols depends on their tendency to form naphthoquinones

We consider the cytotoxicity and the protection against oxidative stress for members of the naphthalenediol family and the known antioxidant epigallocatechin gallate (EGCG). Compounds include the 1,2-naphthalenediol (1,2-ND), 1,4-ND, 2,3-ND, 1,8-ND, and 1,4-dipropyl-2,3-naphthalenediol (DPND). The cell line is an adherent clone of rat pheochromocytoma (PC12-AC). Oxidative stress was induced by the peroxyl radical generator AAPH. The relative order of cytotoxicity was 1,4-ND > 1,2-ND > DPND > 2,3-ND > 1,8-ND > EGCG, with EC50's of 15, 40, 160, >250, >250, >>250 μM, respectively. Despite their high toxicity, both 1,4-ND and 1,2-ND showed narrow zones of protective behavior whereas DPND, 2,3-ND and 1,8-ND and especially EGCG showed an extended protective range. The total protection obtained for the combination of cells/oxidative stressor/protective compounds (PC12-AC/AAPH/naphthalenediols) was defined by an integrated measure, the cytoprotective area (CPA). We relate the observed cytotoxicity and CPA to the different electronic structures of the naphthalenediols, characterized by the first and second bond dissociation enthalpies and the pKa's for parent (diol) and semiquinone. Since the 2,3- and 1,8-naphthalenediols do not form quinones, their cytotoxicit

Polypyrroles as antioxidants: Kinetic studies on reactions of bilirubin and biliverdin dimethyl esters and synthetic model compounds with peroxyl radicals in solution. Chemical calculations on selected typical structures

Rate constants for hydrogen-atom transfer (HAT) from bilirubin dimethyl ester (BRDE) and biliverdin dimethyl ester (BVDE) to peroxyl radicals during inhibited autoxidation of styrene initiated by azobisisobutyronitrile (AIBN) were kinh(BRDE) = 22.5 ×4 and kinh(BVDE) = 10.2 × 104 M-1 s-1, and the stoichiometric factors (n) were 2.0 and 2.7, respectively. A synthetic tetrapyrrole (bis(dipyrromethene)) containing the α-central (2,2′) CH2 linkage gave kin