CHROMOSOME 5Q GENE VARIANTS AND ASTHMA-RELATED TRAITS

解开哮喘的复杂遗传决定因素可能会为其发病机制和新的治疗和预防方法提供重要的新线索。基于哮喘症状的临床表型和哮喘的中间表型都被发现与基因组许多区域的标记相关联。有几个研究小组发现了独立连锁的证据，其中一个区域是染色体5q。我们发现染色体5q3上的标记L与嗜酸性粒细胞增多症和复合型“特应性”表型有关。这项资助计划的目标是确定5q3 1-33中负责这两个连锁信号的基因变异。我们将使用图森儿童呼吸系统研究中登记的家庭人口来这样做，自大约18年前索引儿童出生以来，现在一直跟踪这些家庭。在我们的第一个特定目标中，我们将在染色体5q的一组25个已知基因中识别频率为2%或更高的基因变体。我们已经从那些被定位到28 cM区间的基因中选择了这25个基因，在我们之前的研究中，这些基因被测试为连锁。我们的第二个具体目标是在大约6.4 cM的区域使用100个已知的多态进行连锁不平衡定位，该区域显示包含导致嗜酸性粒细胞增多症和特应性连锁信号之一或两者的基因变异的可能性最高。还将使用已发表的和新发现的在阳性信号区及其周围的多态进行详细的局部测绘。根据我们以前在同一染色体区域的经验，我们希望在5q染色体上发现几个关联/连锁信号。这将有助于更好地了解决定哮喘风险的基因影响。

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.