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Gene effects in environmentally determined subgroups

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There has been controversy about the usefulness of stratification by environmentally determined subgroups in genetic research. In cancer epidemiology only a few genetic polymorphisms cause a substantial change in risk and many genes involved in the metabolism of mutagens have little or no effect. But the inclusion of environmental measures in genetic studies might reveal environment-gene interactions. Such combined studies have been questioned, however, on the grounds that they are unlikely to increase the power of the genetic study very much. It has been said that the effects of genes in different environmental subgroups are likely to be in the same direction even if varying in size, and this would limit the gain in power. Australian authors have listed several examples to counter this argument.

The first example they give is of the influence of maternal smoking on the effect of the CYP1A1 gene on birthweight. The gene controls the metabolism of chemicals in tobacco smoke. When all 741 mothers in a study were considered the incidence of low birthweight was identical (21.5%) in mothers with genotype AA and mothers with genotype Aa or aa. Among the 124 maternal smokers however, the incidence of low birthweight was 24% (AA) v 45% (Aa or aa).

The second example concerns the GSTP1 glutathione transferase gene, Parkinson’s disease, and exposure to pesticides. Among all subjects in one study there was no significant association between the genotype and Parkinson’s disease but among subjects exposed to pesticides one polymorphism increased the risk of Parkinson’s disease more than fivefold. In the third example they quote a study of the effect of a monoamine oxidase A polymorphism on antisocial behaviour. It has been found that the polymorphism increases the rate of antisocial behaviour only among people who suffered from maltreatment as children. Among people who had not been maltreated in childhood the polymorphism tended to be associated with less antisocial behaviour. Another example of a change in direction of gene effect according to environmental subgroup is the effect of an alcohol dehydrogenase polymorphism on HDL cholesterol concentrations according to level of alcohol consumption. Different polymorphisms may also have different effects on the outcome of a single environmental factor. An example of this is the effect of different β2 adrenoceptor gene polymorphisms on the risk of obesity at varying levels of carbohydrate consumption.

The authors of this paper conclude that inclusion of environmental data may enhance the search for disease causing genes.

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