Unraveling the complex genetic determinants of asthma may provide important new clues about its pathogenesis and novel therapeutic and preventive approaches. Both clinical phenotypes based on asthma symptoms and intermediate phenotypes for asthma have been found to be linked to markers in many areas of the genome. One area where several groups have found evidence for linkage independently is chromosome 5q. We found linkage between markers in chromosome 5q3 l and both eosinophilia and a composite """"""""atopy"""""""" phenotype. The goal of this grant proposal is to identify the gene variants in 5q3 1-33 that are responsible for these two linkage signals. We will do so using the same population of families enrolled in the Tucson Children's Respiratory Study that have now been followed since the time of the birth of the index child approximately 18 years ago. In our first specific aim, we will identify gene variants having a frequency of 2% or more in a group of 25 known genes in chromosome 5q. We have selected these 25 genes among those that have been mapped to the 28cM interval that was tested for linkage in our previous studies. Our second specific aim is to perform linkage disequilibrium mapping using 100 known polymorphisms in the region of approximately 6.4cM that shows the highest likelihood of containing the gene variants responsible for either or both of the eosinophilia and atopy linkage signals. Detailed local mapping using both published and newly discovered polymorphisms in and around areas of positive signals will also be performed. Based on our previous experience in this same chromosomal region, we expect to find several association/linkage signals in chromosome 5q. This will allow to better understand the genetic influence that determine asthma risk.
