Association and interaction analyses of eight genes under asthma linkage peaks

Background: Linkage studies have implicated the 2q33, 9p21, 11q13 and 20q13 regions in the regulation of allergic disease. The aim of this study was to test genetic variants in candidate genes from these regions for association with specific asthma traits. Methods: Ninety-five single nucleotide polymorphisms (SNP) located in eight genes (CD28, CTLA4, ICOS, ADAM23, ADAMTSL1, MS4A2, CDH26 and HRH3) were genotyped in >5000 individuals from Australian (n = 1162), Dutch (n = 99) and Danish (n = 303) families. Traits tested included doctor-diagnosed asthma, atopy, airway obstruction, total serum immunoglobulin (Ig) E levels and eosinophilia. Association was tested using both multivariate and univariate methods, with gene-wide thresholds for significance determined through simulation. Gene-by-gene and gene-by-environment analyses were also performed. Results: There was no overall evidence for association with seven of the eight genes tested when considering all genetic variation assayed in each gene. The exception was MS4A2 on chromosome 11q13, which showed weak evidence for association with IgE (gene-wide P < 0.05, rs502581). There were no significant gene-by-gene or gene-by-environment interaction effects after accounting for the number of tests performed. Conclusions: The individual variants genotyped in the 2q33, 9p21 and 20q13 regions do not explain a large fraction of the variation in the quantitative traits tested or have a major impact on asthma or atopy risk. Our results are consistent with a weak effect of MS4A2 polymorphisms on the variation of total IgE levels. © 2009 John Wiley & Sons A/S

Água de beber: a filtração doméstica e a difusão do filtro de água em São Paulo

This work studies the advent and diffusion of water filter usage in São Paulo State, during the 20th Century. The water filter, a set of two terracotta vessels equipped with a filtering device, was a product of the ceramics industry, one of the first to be developed in São Paulo. This research shows that in São Paulo at the end of 19th and beginning of 20th Centuries, with the growth of cities and rapid urbanisation, a concern about the quality of water increased due to serious public health hazards, mainly epidemics caused by the consumption of unhealthy drinking water. Despite the existence of an incipient market of domestic equipment for water filtration, these were imported and of limited usage. From the 1910's, ceramics companies, owned by Portuguese and Italian immigrants, started installing filtering devices in terracotta vessels, launching the water filter set. It caught on and became the main domestic filtering equipment after the 1930's, when several companies specialized in this kind of product and started catering for the national market, such as Filtros Salus (from São Paulo city), Pozzani (Jundiaí) and Stéfani (Jaboticabal). Studying the advent and diffusion of the water filter entails knowledge about one of the first consumer goods of the Brazilian industry and, at the same time, knowledge about the history of the ways in which the Brazilian population obtained water to drink.Este artigo trata do processo de surgimento e difusão do uso do filtro de água no Estado de São Paulo, ao longo do século XX. O filtro de água, conjunto de dois recipientes de argila equipado com vela filtrante, é um produto da indústria cerâmica, uma das primeiras a se desenvolver em São Paulo. A pesquisa mostra que, em São Paulo, no final do século XIX e início do XX, com o aumento da urbanização e o crescimento das cidades, a preocupação com a qualidade da água que se consumia ganhou importância em virtude de graves problemas de saúde pública principalmente epidemias causadas por águas impróprias para beber. Embora já existisse um incipiente mercado de equipamentos domésticos de filtração da água, eles eram ainda importados e de uso restrito. A partir da década de 1910, empresas cerâmicas, de imigrantes portugueses e italianos, passaram a acoplar velas filtrantes a recipientes de argila, dando origem ao filtro de água. Depois dos anos de 1930, o filtro difundiu-se e tornou-se o principal equipamento de filtração doméstica, quando diversas empresas, como Filtros Salus (São Paulo-SP), Pozzani (Jundiaí-SP) e Stéfani (Jaboticabal-SP), especializaram-se nesse produto e passaram a atender ao mercado nacional. Estudar o surgimento e a difusão do filtro de água significa conhecer um dos primeiros bens de consumo da indústria brasileira e, ao mesmo tempo, a história de como a população obtém água para beber

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