Positional candidate gene approach and functional genomics strategy in atopy gene discovery

As part of our effort in searching for genetic factors contributing to the susceptibility to atopy and asthma, we have focused on a 'positional candid ate' approach in identifying CC chemokine gene polymorphisms and their func tional correlates. To date, a single-nucleotide polymorphism was found in t he RANTES proximal promoter region, and a high degree of sequence variation was identified in the 3'-untranslated region -of the eotaxin gene. Also, w e are pursuing a series of functional genomics' studies designed to identif y differentially expressed genes in a panel of allergen-specific human Th2 cells and in antigen-induced hyperreactive murine airways. This is performe d using a combination of protocols including suppression-subtractive hybrid ization and cDNA array hybridizations with 18.363 nonredundant sequences. A data base is being generated from a list of subtracted cDNA sequences and array-positive clones to categorize differentially expressed genes. Sequenc es are being placed in biologically relevant categories on the basis of fun ction (i.e., receptor, signal transduction pathways, transcription, and tra nslation). With the increasing amount of sequence information compiled by t he Human Genome Project, it will be particularly challenging to integrate f unctional gene-mapping efforts to define and compare aberrant genotypes/phe notypes in atopic diseases.