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

SPERMATOZOAL VELOCITY AND MOTILITYAND ITS RELATIONSHIP TO FERTILITY IN THE RABBIT INSEMINATED WITH LOW SPERM NUMBERS

[EN] The objective of this study was to examine the relationship between velocity and fertility of rabbit sperm, using low sperm numbers per insemination. Semen was collected weekly for 5 weeks from two fertile males. To study the effect of high dilution of sperm in media without macromolecules, each semen sample was split with one portien retained as whole semen, and the remainder was centrifuged and washed with saline. The washed sperm were resuspended with seminal plasma (SP), phosphatebuffered saline (PBS), or PBS containing 1 % (wt/vol) of bovine serum albumin (BSA). Each week two non-lactating does per buck were each inseminated at the cervix with 0.5 X 106 total sperm, for a total of 80 does inseminated. This was followed immediately with injection of luteinizing hormone. Sperm were video taped at this time. The velocity of 25 sperm from each semen sample was determined by each of two observers (50 sperm total). The two observers also estimated the percentage of motile sperm. Fertilized and unfertilized oocytes (1635 total) were recovered from the oviducts 42 hours after insemination. Both the percentage of motile sperm and their velocity were greatly affected by the washing and diluting fluid used. The ranges for these two variables, respectively, were 1 to 50% and 11 to 100 Fm/second. The percentage of motile sperm and velocity were highly correlated (P<0.05) in the different treatments (BSA=O. 77; SP=0.59; PBS=0.81; WS=0.86). Fertility ranged from 42 to 85%. Velocity was not more useful than the percentage of motile sperm in predicting fertility. The importance of including macromolecules in the diluting fluids to maintain motility of highly diluted sperm was obvious from the five-fold or greater improvement in motility and velocity of sperm by adding BSA. Good fertility was obtained with low sperm numbers inseminated on the cervix in media containing macromolecules, even following extensive washing and storage.Hagen, D.; Gilkey, A.; Foote, R. (2002). SPERMATOZOAL VELOCITY AND MOTILITYAND ITS RELATIONSHIP TO FERTILITY IN THE RABBIT INSEMINATED WITH LOW SPERM NUMBERS. World Rabbit Science. 10(4):135-140. doi:10.4995/wrs.2002.485SWORD13514010