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

Effects of maternal iron restriction in the rat on hypoxia-induced gene expression and fetal metabolite levels

The mechanism by which maternal Fe deficiency in the rat causes fetal growth retardation has not been clearly established. This study compared the effects on the fetuses from dams fed a control diet with two groups of dams fed Fe-restricted diets. One Fe-restricted group was fed the Fe-restricted diet for 1 week prior to mating and throughout gestation and the second Fe-restricted group was fed the Fe-restricted diet for 2 weeks prior to mating and throughout gestation. On day 21 of gestation Fe-restricted dams, and their fetuses, were anaemic. Fetal weight was reduced in both Fe-restricted groups compared with controls. Expression of hypoxia-inducible factor (HIF)-1 and vascular endothelial growth factor (VEGF) are induced by hypoxia. The levels of HIF-1 mRNA were highest in placenta, then in kidney, heart and liver but were not different between the groups. Levels of plasma VEGF were not different between the groups. Maternal plasma triacylglycerol was decreased in the 1-week Fe-restricted dams compared with controls. Maternal plasma cholesterol and free fatty acid levels were not different between the groups. In fetal plasma, levels of triacylglycerol and cholesterol were decreased in both Fe-restricted groups. In maternal plasma, levels of a number of amino acids were elevated in both Fe-restricted groups. In contrast, levels of a number of amino acids in fetal plasma were lower in both Fe-restricted groups. Fetal plasma lactate was increased in Fe-restricted fetuses but fetal plasma glucose and -hydroxybutyrate were not affected. These changes in fetal metabolism may contribute to fetal growth retardation in this model. This study does not support the hypothesis that the Fe-restricted fetus is hypoxic

Effects of maternal iron restriction on placental vascularization in the rat

To investigate the effects of maternal iron deficiency and anaemia on the placenta the composition and vascularization of the placental labyrinth was investigated in iron-restricted rats. Rats in the experimental groups were placed on iron-restricted diets either 1 or 2 weeks before mating and continued on these diets throughout gestation. Placentae were studied at day 21 of gestation. Tissue sections were stained with lectin to allow identification of fetal capillaries and analyzed using stereological techniques. Capillary surface area density and total capillary surface area were decreased in both iron-restricted groups compared with the control group. Capillary length density was decreased in both iron-restricted groups compared with the control group. Total capillary length was significantly reduced in the 1-week, but not in the 2-week, iron-restricted group compared with the control group. Endothelial cell volume was increased in both iron-restricted groups compared to the controls. There were no significant differences in the volume of fetal capillaries, the volume of the maternal blood spaces or the surface area of the maternal–fetal interface between the control and iron-restricted groups. Labyrinthine volume, labyrinthine tissue volume and the surface area of the maternal fetal interface were increased in the 2-week group when compared with the 1-week group. These changes in placental vascularization may contribute to the fetal growth retardation observed in iron-restricted litters

Distinctive immunoglobulin E anti-house dust allergen-binding specificities in a tropical Australian Aboriginal community

10.1111/j.1365-2222.2007.02786.xClinical and Experimental Allergy3791357-136