Genes em seu ambiente: como desvendar as charadas?

Abstract

Once upon a time, as all the best children's stories begin, a lot of clever geneticists began a huge hunt for the "asthma gene." At first they thought they had found it, but then more and more of the hunters found different "asthma genes," and sometimes some gene hunters could not find the gene that previous hunters thought was the key one. Life became more and more confusing, and the root causes, A recent review 2 identified more than 30 genes which have been shown to be associated with some aspect of asthma, and the association has been replicated in at least five studies. In broad terms, these fall into one of four groups: genes relating to innate immunity and immunoregulation; genes associated with TH2 cell differentiation and effector functions; genes associated with epithelial biology and mucosal immunity; and genes associated with lung function, airway remodeling and disease severity. These classes of genes find echoes in our knowledge of the basic immunobiology of asthma. However, the bag is by no means empty; there are now three members of a class of unknown function, encoding transmembrane proteins located in the endoplasmic reticulum, which are implicated in asthma, the latest being ORMDL3. 3 A number of important methodological issues were discussed which shed light on why so many studies have been conflicting. Linkage studies may implicate a particular locus, for example 5q31-33, but the locus may contain potentially a large number of relevant genes, 4 and premature conclusions that a particular gene, and not one of its near neighbors, is important must be avoided. It is important to check the validity of the methods used for genotyping, preferably with validation by a second method; and also to check the association in at least one other population. 5,6 However, it should be noted that if the results do not appear to be important in a second population, this does not mean that the first study is invalid; it should instead provoke a careful look for differences between the studies, which may give important insights into novel gene-environment interactions.Genes are relatively easy to study, but they exist not in a vacuum but in a complex environment, which the investigator ignores at his peril. Studies in mice have shown that gene-environment interactions may explain more phenotypic variance than either genetic or environmental effects considered separately. 7 There are many facets to these interactions. Unsurprisingly, the effect of environmental smoke * MB BS (Hons) MA MD FRCP FRCPCH. Professor of Paediatric Respirology,