The objective of our continuing effort has been to define the molecular genetic and functional basis of common and often debilitating allergic diseases, asthma and food allergy, involving a complex array of genetic networks and environmental influence. While supported by this application, we have made significant contributions to the understanding of the genetic sequence variants and their relationships with asthma and IgE responsiveness in various populations. Our fine-mapping studies of 1500 SNPs have identified sub- regions of chromosome 11 (Chr. 11) with strong evidence of association with asthma in an African American population, which may contain genetic variants critical for the etiology of asthma. Further, we have used positional candidate gene approaches and published findings on functional sequence variants of nine candidate genes in various populations, including African American, Chinese and Japanese populations. Notably, sequence variants of the genes encoding a Clara cell secretory 10 kd protein (CC10, an immunomodulator and steroid-inducible protein) and IL-17F were shown to be associated with atopic phenotypes, including bronchial hyperresponsiveness. Moreover, supported by this application, we have initiated a collaborative study focusing on the genetic influence of the genes encoding members of the C-type lectin receptor (CLR) family, known to be critical in innate immunity, on the genesis of allergy and asthma, in which we have provided initial evidence for genetic association of several candidate CLR genes and allergic phenotypes, including asthma and IgE responsiveness. We propose, therefore, in this new grant period, to continue these ongoing efforts and to identify specific functional polymorphisms in these candidate genes, and to relate the polymorphism to the expression of IgE, asthma and food allergy phenotypes in different groups of families and unrelated subjects. Specifically, we intend to test three hypotheses: Hypothesis #1: Chr. 11 contains susceptibility genes for asthma; Hypothesis #2: Sequence variants of CC10 and IL-17F along with their respective receptors, formyl peptide receptor-like 1 (FPRL1) and IL-17R, differentially regulate the expression of asthma; Hypothesis #3: Sequence variants of the genes encoding members of the CLRs influence the development of asthma and food allergy. ? ? ?
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