- To utilize in optimal populations the notion that linkage disequilibrium could be exploited in the mapping of predisposing genes in multifactorial disorders.
- To collect relevant, well characterised family materials in asthma.
- To apply DNA typing in a large scale to the collected family materials.
- To test and develop analytical strategies for the study of linkage disequilibrium in previously identified candidate gene regions and for the systematic genome-wide search of further genes.
- To identify genomic regions that are likely to carry predisposing genes in asthma.
This proposal aims at converting special European population resources and the available genetic maps into information regarding predisposing genes in asthma, a multifactorially caused disease. The identification of such genes is of great importance for understanding relevant disease processes, identifying new modalities for therapeutic intervention, and developing new pharmaceuticals. However, current knowledge on such genes is scarce despite the public health importance of asthma.
The strategy proposed here is based on the potential to utilise linkage disequilibrium that arises from local founder effects in isolated populations and results in a diminished locus and allele heterogeneity as compared to mixed populations. Such linkage disequilibrium has been observed in a number of instances where rare dominant or recessive mutations have been studied in, eg. the Finnish, Basque and Sardinian populations. Full genome screening based on the study of relative pairs combined with association studies that seek to detect linkage disequilibrium in isolated populations such as those we propose to study offer a cost-efficient route to the refined mapping of predisposing genes and testing of candidate genes.
The critical resources upon which this proposal builds are:
1) European family resources from three special, genetically distinctive populations, namely the Finnish, Basque and Sardinian populations; and
2) the recently developed and still improving human genetic linkage maps based on easily typable and highly polymorphic microsatellite markers.
A risk of studying only one isolated population is that the role of one or a few genes may be exaggerated and others missed because of a possible locus homogeneity in one population, and this caveat can be avoided by studying more than one isolated population. The collection of family materials for asthma in different populations will facilitate genome-wide gene searches by efficient affected relative-pair strategies. As soon as findings are obtained in one population sample, they can be tested in other populations by close collaboration, adding significance to the findings and promoting their exploitation. The family resources collected will provide an efficient tool to assess the role and significance of candidate genes. Finally, the amount of work needed in the typing phase of the project can be minimised by rationalisation between the participating groups.
Funding SchemeCSC - Cost-sharing contracts
08907 Hospitalet Del Llobregat