5 research outputs found

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

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    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

    A new method for assaying propantheline and its degradation product, xanthene-9- carboxylic acid using high performance liquid chromatography

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    A rapid, specific, and precise high-performance liquid chromatographic method is described for the simultaneous analysis of propantheline bromide and its hydrolysis product, xanthene-9-carboxylic acid. Reversed-phase chromatography was conducted using a mobile phase of 40:60, acetonitrile-0.05 M phosphate buffer (pH 2.5) delivered at 2 ml/min. Detection was at 254 nm. Methantheline bromide (internal standard), propantheline bromide, and xanthene-9-carboxylic acid gave retention times of 4.1, 5.4, and 8.3 min, respectively. Within-day, between-day, and total precision (CV) for assay of 15 mg/10 ml propantheline bromide are 1.2, 1.1, and 1.6%, respectively (n = 20). Similar precision was obtained for xanthene-9-carboxylic acid. The limit of detection was 2 ng. The assay is useful for routine quality assurance of propantheline in dosage forms and for stability and kinetic studies

    Disorders of Keratinization

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    Phosphodiesterases in the Vascular System.

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