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

Obesidade e sobrepeso em adolescentes: relação com atividade física, aptidão física, maturação biológica e "status" socioeconômico Obesity and overweight in adolescents: relationship among physical activity, physical fitness, biological maturity and socioeconomic status

Este estudo relaciona atividade física (AF), aptidão física (AptF), maturação biológica e "status" socioe-conômico (ESE) com as prevalências de risco ponderal de adolescentes. Foi desenvolvido no Concelho de Santo Tirso, região norte de Portugal e amostrou 961 alunos (463 meninos e 498 meninas) com idades variando entre os 11 e os 18 anos. O índice de massa corporal foi utilizado para estabelecer o "status" ponderal com base nos pontos de corte propostos por COLE et al. A AF foi avaliada através do questionário de Baecke e a AptF com quatro testes da bateria Fitnessgram. O ESE foi estimado a partir do acesso aos escalões atribuídos pela Ação Social Escolar e a maturação biológica a partir do "offset" maturacional. A análise estatística foi efetuada nos "softwares" Pepi versão 4.0 e SPSS 18.0. O nível de significância foi mantido em 5%. Seis por cento dos alunos eram obesos e 19,5% tinham sobrepeso; meninos e meninas têm prevalências semelhantes de sobrepeso e obesidade. Os níveis médios de AF foram baixos a moderados independentemente do sexo ou "status" ponderal. Os meninos eram mais ativos que as meninas (p < 0,001), mas não se registraram diferenças significativas entre os alunos com obesidade e sobrepeso e os normoponderais. Na AptF, um número superior a 50%, foi considerado inapto, i.e, não obtiveram taxas de sucesso em todos os testes. Os alunos com sobrepeso e obesidade foram mais inaptos. Alunos com "offset" maturacional mais avançado e os mais novos tinham mais chances de ter sobrepeso e obesidade, mas não houve relação significativa entre o ESE e o "status" ponderal. Concluímos que os jovens Tirsenses apresentam prevalências de obesidade e sobrepeso elevadas, são relativamente pouco ativos e, em grande medida, fisicamente inaptos.<br>The aim of this study was to relate physical activity, physical fitness, maturation and socioeconomic status with the prevalence of ponderal risk in adolescents. This was a transversal study made in the Council of Santo Tirso in the north of Portugal. The sample consisted of 961students (463 boys and 498 girls), aged 11 to 18. Body mass index was used to establish ponderal status based on the cut points from COLE et al. Physical activity was evaluated by Baecke's questionnaire and physical fitness with four tests from Fitnessgram battery. Socioeconomic status was ranked according to the grades assigned by state school subsidies, while biological maturation estimation was based on maturational offset. Software programs Pepi version 4.0 and SPSS 18.0 were used for statistical analysis. The level of significance was kept in 5%. Six percent of the target students were obese and 19.5% had overweight. The prevalences of overweight and obesity were similar between genders. The medium levels of physical activity were low or moderate, independent of gender or ponderal status. Boys were more active than girls (p < 0.001) but no significant differences were found between the students with obesity and overweight and normoponderal ones. On what concerns physical fitness, a high percentage of students (above 50%) were considered inapt and failed the tests. Students suffering from overweight and obesity were clearly more inapt. Students with more advanced maturational offset as well as the youngest ones were more likely to present overweight and obesity but no meaningful relationship was found between socioeconomic position and ponderal status. We concluded that young students from S. Tirso had high prevalences of obesity and overweight, were relatively inactive and largely physically unfit