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

Desenvolvimento pós-desmame, escores visuais ao sobreano e características de carcaça de novilhas desmamadas aos 100 ou 180 dias de idade Post-weaning growth, visual scores at yearling age and carcass traits of heifers weaned at 100 or 180 days of age

O trabalho foi realizado com o objetivo de avaliar a influência do desmame aos 100 (DP) ou 180 (DC) dias de idade no desenvolvimento de fêmeas Braford até os 18 meses. As bezerras do DP foram suplementadas diariamente por 63 dias a 1% do peso vivo com ração comercial contendo 18% de proteína bruta e 74% de nutrientes digestíveis totais. Avaliou-se o ganho médio diário do nascimento aos 205 dias (G205), deste aos 365 dias (G365) e do último aos 550 dias (G550). Tomou-se o peso vivo ajustado aos 205 (P205), 365 (P365) e 550 dias de idade (P550). Ao sobreano, os escores visuais de conformação (C), precocidade (P) e musculatura (M) foram avaliados e a área de olho de lombo (AOL) e a espessura de gordura subcutânea (EGS), medidas pela técnica de ultra-som. O G205 e o P205 foram significativamente inferiores para as novilhas do DP (0,752 kg/dia; 187,0 kg) em relação às novilhas do DC (0,885 kg/dia; 214,1 kg). Entretanto, as novilhas do DP tiveram G365 significativamente superiores (0,231 kg/dia) às novilhas do DC (0,112 kg/dia), ocasionando P365 semelhantes entre tratamentos (DP = 223,9 kg; DC = 231,9 kg). O G550 não diferiu entre tratamentos, sendo 0,525 kg/dia para as novilhas do DP e 0,513 kg/dia para as novilhas do DC. Conseqüentemente, o P550 também não sofreu influência da idade de desmame (DP = 320,6 kg; DC = 326,3 kg). Os escores visuais de C, P e M não foram influenciados pela idade de desmame, sendo as médias para as novilhas do DP de 4,0; 4,1 e 3,6 para C, P e M e para as do DC de 4,2; 4,1 e 3,9, respectivamente. A idade de desmame também não influenciou a AOL (DP = 41,4 cm²; DC = 43,3 cm²) e a EGS (DP = 2,5 mm; DC = 2,7 mm). Os resultados indicam que novilhas desmamadas aos 100 dias de idade são mais leves ao desmame, porém, com nível nutricional adequado, alcançam aos 12 e 18 meses pesos vivos semelhantes às desmamadas aos seis meses de idade.<br>This work was conducted with the aim to evaluate the influence of weaning age at 100 (EW) or 180 (CW) days old on the growth of Braford heifers until approximately 18 months old. The calves of EW were daily supplemented during 63 days, at quantity of 1% of their live weight, with a comercial ration with 18% of crude protein and 74% of total digestible nutrients. Average daily gain from birth to 205 days (G205), from this one until 365 days (G365) and from the last one until 550 days (G550) were evaluated. Live weight adjusted at 205 days (W205), at 365 days (W365) and at 550 days old (W550) were recorded. At yearling age, the visual scores of conformation (C), precocity (P) and musculature (M) were evaluated and the rib eye area (REA) and the subcutaneous fat thickness (SFT) were measured by ultrasound technique. G205 and the W205 were significantly lower for EW heifers (0.752 kg/day; 187.0 kg) than CW heifers (0.885 kg/day; 214.1 kg). However, EW heifers had G365 significantly higher (0.231 kg/day) than the CW heifers (0.112 kg/day) and, consequently, both were similar at W365 (EW= 223.9 kg; CW= 231.9 kg). The G550 did not differ among treatments, being 0.525 kg/day for the EW heifers and 0.513 kg/day for the CW heifers. Consequently, W550 was not affected by weaning age (EW= 320.6 kg; CW= 326.3 kg). The visual scores of C, P and M were not affected by the weaning age, and the means for the EW heifers were of 4.0; 4.1 and 3.6 and for the CW heifers of 4.2; 4.1 and 3.9, respectively. Weaning age also did not affect REA (EW= 41.4 cm²; CW= 43.3 cm²) and the SFT (EW= 2.5 mm; CW= 2.7 mm). The results showed that heifers weaned at 100 days of age are lighter at weaning however, with an adequate post weaning nutritional level, they get at 18 months similar live weights to that ones weaned at six months of age

Productivity and efficiency of cow herds submitted to two weaning ages Produtividade e eficiência de rebanhos de vacas submetidas a duas idades de desmame

It was aimed in this work to evaluate the productivity and efficiency of beef cows submitted to weaning of their calves at 76 days (early weaning) or at 148 days (weaning at conventional age) after calving during three consecutive years. It was evaluated pregnancy rate, birth and weaning, gain weight of the calves and cows at conventional weaning, weight at conventional weaning of calves and cows, production of weaned calves per cow and calf production index. Pregnancy rate in the herd submitted to early weaning (86.34%) was higher than in the conventional weaning (55.5%). Early weaning cows showed higher birth and weaning rates when compared to conventional weaning (83.6 and 83.6% vs. 47.5 and 44.5%, respectively) besides a higher production of calves (183 vs. 114). Early weaning cows produced 60.5% more calves than the conventional weaning cows. Conventional weaning calves gained more weight from birth to weaning (97.9 vs. 83.4 kg, respectively). Early weaning cows had more weight gain from calving to weaning (42.5 vs. 18.7 kg, respectively), and regarded to calf production index, they were more efficient (efficiency of the herds). At the average of the three years, the early weaning of the calves allows higher calving rates and weaning to the cows, in addition to a higher index of calf kilogram index produced in relation to weaning at conventional age.<br>A produtividade e a eficiência de vacas de corte submetidas ao desmame de seus bezerros aos 76 dias (desmame precoce) ou aos 148 dias (desmame à idade convencional) pós-parto foram medidas durante três anos consecutivos. Avaliaram-se as taxas de prenhez, natalidade e desmama, o ganho de peso de bezerros e de vacas do parto ao desmame convencional, o peso à desmama convencional de bezerros e vacas, a produção de bezerros desmamados por vaca e o índice de produção de bezerros. A taxa de prenhez no rebanho submetido ao desmame precoce (86,4%) foi superior à do desmame convencional (55,5%). Vacas do desmame precoce tiveram maiores taxas natalidade e de desmame em comparação às do desmame convencional (83,6 e 83,6% vs 47,5 e 44,5%, respectivamente), além de maior produção de bezerros (183 vs. 114). As vacas do desmame precoce produziram 60,5% a mais de bezerros que as vacas do desmame convencional. Os bezerros de desmame convencional foram os que ganharam mais peso desde o nascimento até o desmame (97,9 vs 83,4 kg, respectivamente). As vacas do desmame precoce tiveram maior ganho de peso do parto até o desmame (42,5 vs 18,7 kg, respectivamente) e foram mais eficientes quanto ao índice de produção de bezerros (eficiência dos rebanhos). Na média dos três anos, o desmame precoce dos bezerros permite às vacas maiores taxas de prenhez e de desmame, além de maior índice de quilos de bezerro produzido em relação ao desmame em idade convencional

Efeito da idade do desmame no desenvolvimento de novilhas de corte até os 14/15 meses de idade Effect of weaning age on beef heifers growth until 14/15 months of age

Avaliou-se a influência do desmame precoce, em média aos 77 dias pós-parto, e do desmame convencional, em média aos 147 dias pós-parto, no desenvolvimento de novilhas de corte. Foram utilizadas 161 bezerras Braford, nascidas nos anos de 2004, 2005 e 2006. Após os desmames as bezerras foram mantidas em pastagens cultivadas de verão (Pennisetum americanum) e de inverno e primavera (Avena strigosa Schreb + Lolium multiflorum Lam). Foram avaliados os pesos corporais, ganhos de pesos médios diários e condição corporal a cada 28 dias. Houve interação entre idades de desmame e ano para peso corporal e ganho de peso. O desmame precoce não influenciou os pesos corporais, embora o peso corporal tenha sido menor aos 147 dias nos animais nascidos em 2005 e 2006. O ganho médio diário entre as idades de desmame foi similar nos três anos no desmame precoce (0,538; 0,477 e 0,472 kg, respectivamente) e aumentou significativamente no desmame convencional com o avançar dos anos (0,516; 0,704 e 1,040 kg, respectivamente). Na pastagem de Avena strigosa + Lolium multiflorum, o ganho médio diário foi similar entre idades de desmame. O peso no início do período reprodutivo no desmame precoce em 2004 (283,4 kg) foi maior que em 2005 (260,7 kg), enquanto no desmame convencional não houve diferença entre os anos (272,9 e 263,8 kg, respectivamente). A condição corporal no início do período reprodutivo foi afetada pelo ano de observação. A idade da bezerra esteve positivamente correlacionada com os pesos ao desmame convencional (r = 0,510) e ao início do período reprodutivo (r = 0,491). O desmame precoce e o convencional não inviabilizam o acasalamento das novilhas aos 14-/15 meses de idade.<br>The influence of the early weaning, on average 77 days after the birth, or the conventional weaning, on average 147 days on beef heifer development was evaluated. One hundred and sixty-one Braford calves, born in 2004, 2005 and 2006 were kept after weaning on cultivated summer (Pennisetum americanum) and winter/spring (Avena strigosa Schreb and Lolium multiflorum Lam) cultivated pastures. Body weight, daily Body weight gain and body condition were assessed every 28 days. There was interaction between weaning age and year for body weight and weight gain. Early weaning did not influence body weight but the body weight was smaller at 147 days in the animals born in 2005 and 2006. The avegage daily gain between the weaning ages was similar in the three years for early weaning (0.538, 0.477 and 0.472 kg, respectively), but increased significantly in the conventional weaning as the years progressed (0.516, 0.704 and 1.040 kg respectively). The average daily weight gain on Avena strigosa + Lolium multiflorum pasture was similar for both treatments. The weight at the beginning of the reproduction period for early weaned heifers in 2004 (283.4 kg) was higher than in 2005 (260.7 kg), while for conventional weaning there was no difference between years (272.9 and 263.8 kg, respectively). The body condition at the beginning of the reproduction period was affected by the year of observation. Calf age was positively correlated to weight at conventional weaning (r = 0.510) and beginning of the reproduction period (r = 0.491). Both weaning ages showed the possibility of mating beef heifers at 14/15 months of age