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

Efeito do exercício aeróbico e resistido no controle autonômico e nas variáveis hemodinâmicas de jovens saudáveis Effect of resistance and aerobic exercise on the autonomic control and hemodynamic variables in health young individuals

A prática de exercícios aeróbicos e resistidos provoca ajustes agudos e crônicos distintos. Já foram documentadas diferenças hemodinâmicas e musculares entre os exercícios; todavia, quanto aos ajustes autonômicos, os estudos são escassos e controversos. O objetivo deste estudo foi analisar as adaptações hemodinâmicas e autonômicas após uma sessão de exercício aeróbico (30 minutos, bicicleta ergométrica) e resistido (três séries de 12 repetições para os principais grupamentos musculares), em indivíduos jovens e saudáveis. Para tanto, utilizamos medidas da pressão arterial (PA), frequência cardíaca (FC), cálculo do duplo produto e análise da variabilidade da FC (VFC) nos domínios do tempo e da frequência e a Plotagem de Poincaré. Neste protocolo, a FC durante o exercício aeróbico foi maior do que no resistido (153,32 ± 2,76 vs. 143,10 ± 3,38 bpm, respectivamente). O exercício aeróbico gerou aumento da PA sistólica durante o exercício (7,25 ± 1,97 mmHg). Já o exercício resistido provocou aumento tanto da PA sistólica quanto da diastólica durante sua execução (14,83 ± 1,53; 11,92 ± 1,69 mmHg, respectivamente). Não foi observada hipotensão pós-exercício para nenhuma das sessões. Ao comparar o exercício aeróbico com o resistido na fase de recuperação, verificamos diminuição na VFC no resistido nas variáveis: RMSSD (37,74 ± 5,30 vs. 19,50 ± 2,32), NN50 (94,13 ± 23,65 vs. 27,63 ± 6,68), PNN50 (16,10 ± 4,72 vs. 3,53 ± 0,89), SD1 (26,65 ± 3,85 vs. 13,73 ± 1,66), SD2 (88,98 ± 10,71 vs. 61,88 ± 5,49) e HF (257,25 ± 45,08 vs. 102,75 ± 18,75 ms²). Concluiu-se que, para os protocolos investigados, o trabalho cardiovascular durante o exercício foi semelhante, resultando principalmente do aumento da FC no exercício aeróbico e do aumento da PAS no resistido. No período de recuperação, o exercício resistido promoveu maior alteração autonômica, compatível com manutenção do balanço simpatovagal aumentado.<br>The practice of aerobic and resistance exercises provokes distinct acute and chronic adjustments. Hemodynamic and muscular differences between both exercises have been already documented; nevertheless, regarding the autonomic adjustments, there are few and controversial studies. Therefore, the aim of this study was to analyze the hemodynamic and autonomic adaptations after one bout of aerobic exercise (30 minutes, ergometric bicycle) and resistance exercise (three series of 12 repetitions to the main muscle groups), in young and healthy individuals. For this purpose, blood pressure (BP) and heart rate (HR) were measured, as well as the calculation of the double product and analysis of heart rate variability in time and frequency domains and by Poincaré's Plot. In this protocol, HR during the aerobic exercise was higher than in the resistance exercise (153.32 ± 2.76 vs. 143.10 ± 3.38 bpm, respectively). Aerobic exercise caused an increase in systolic BP during the exercise (7.25 ± 1.52 mmHg) whereas resistance exercise provoked an increase in both, systolic and diastolic BP during its execution (14.83 ± 1.53; 11.92 ± 1.69 mmHg, respectively). Post-exercise hypotension was not observed after none of the exercise sessions. When comparing aerobic exercise with resistance exercise in the recovery phase, it was verified a decrease in HR variability in the resistance session for the following variables: RMMSD (37.74 ± 5.30 vs. 19.50 ± 2.32), NN50 (94.13 ± 23.65 vs. 27.63 ± 6.68), PNN50 (16.10 ± 4.72 vs. 3.53±0.89), SD1 (26.65 ± 3.85 vs. 13.73 ± 1.66), SD2 (88.98 ± 10.71 vs. 61.88 ± 5.49) e HF (257.25 ± 45.08 vs. 102.75 ± 18.75 ms²). In conclusion, in the investigated protocol, the cardiovascular work during the exercise sessions was similar, due to HR increase in the aerobic exercise and of systolic BP increase in the resistance exercise. In the recovery phase, resistance exercise promoted enhanced autonomic alteration, compatible with the maintenance if an increased sympatho-vagal balance