CHROMOSOME 5Q GENE VARIANTS AND ASTHMA-RELATED TRAITS

揭示哮喘复杂的遗传决定因素可能为其发病机制和新的治疗和预防方法提供重要的新线索。已经发现基于哮喘症状的临床表型和哮喘的中间表型与基因组的许多区域中的标记物相关联。有几个研究小组已经独立地发现了连锁的证据，其中一个区域是染色体5 q。我们发现染色体5 q3 l标记与嗜酸性粒细胞增多症和复合“特应性”表型之间存在连锁。这项拨款提案的目标是确定5 q3 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研究中登记的相同家庭人口进行研究，这些家庭自大约18年前索引儿童出生以来一直受到随访。在我们的第一个具体目标中，我们将在染色体5 q中的一组25个已知基因中鉴定频率为2%或更高的基因变体。我们选择了这25个基因中，已被映射到28 cM的间隔，在我们以前的研究中进行了测试的连锁。我们的第二个具体目标是使用约6.4cM区域中的100个已知多态性进行连锁不平衡作图，该区域显示包含负责嗜酸性粒细胞增多症和特应性连锁信号中的一个或两个的基因变体的可能性最高。还将使用已发表的和新发现的多态性在阳性信号区域内和周围进行详细的局部作图。根据我们以前在同一染色体区域的经验，我们希望在染色体5 q中找到几个关联/连锁信号。这将有助于更好地了解决定哮喘风险的遗传影响。

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.