Saturday, May 4, 2024
5/4/2024
SUMMARY Allergic diseases represent a major public health burden characterized as an epidemic that involves the interplay between genetic factors and environmental exposures. Allergens are one of the many multiple triggers that produce IgE and cause inflammation of the airways, two crucial components of allergic disorders, including atopic asthma. Spleen associated tyrosine kinase (aka tyrosine-protein kinase SYK) is critically involved in the earliest steps of signaling reaction following aggregation of IgE/FceRI on the basophil/mast cell surface after re-exposure to the same environmental substance (allergen). There is a considerable body of evidence and a consistent set of observations, based on cellular functions and clinical associations, highlighting the deeper relevance of SYK to the IgE-mediated reaction in humans. In addition, we have demonstrated that basophil traits, such as SYK expression and IgE-mediated histamine release, can serve as biomarkers for predicting the clinical efficacy of omalizumab in allergic diseases like asthma. However, little is known about the genetic regulation of SYK, which is crucial in determining how IgE-dependent allergy disorders manifest. We confirmed that the expression levels of SYK and histamine release in human basophils were correlated with single nucleotide polymorphisms (SNPs) in the promoter of the SYK gene. Exploration of cis-expression quantitative trait loci (cis-eQTL) discovered a genomic region encompassing the SYK transcription start site (TSS), and it contained multiple variants with a high potential for transcriptional regulation. We hypothesize that genetic factors interact with specific local cell/tissue environments to modify either SYK expression or its function; therefore defining a unique molecular phenotype of human basophils, which can serve as biomarkers for clinical efficacy of anti-IgE therapy as well as being potential drug targets for novel therapeutics. This application's specific aims are to: (1) determine the genetic regulation of SYK transcriptional activity and function; (2) identify common haplotypes that influence SYK expression and function in individuals of European and African ancestry; and (3) compare transcriptome gene signatures among IgE-bearing cell types. Results from these studies will provide strong motivation to explore the larger impact of their influences on atopic disorders.
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