Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Study of Genetics, Endotoxin and Allergen (SAGE)

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Symptoms and sensitization to laboratory animals (LA) are frequent occupational hazards of research scientists, technicians, and others who work with animals. Animal allergen and endotoxin are the two main exposures for these workers. Atopy plays a role in symptom generation, with symptomatic workers more likely to be atopic, regardless of their sensitization to mice. We recently demonstrated that endotoxin is the strongest predictor of symptoms to mice, particularly in workers who are not mouse allergic. Endotoxin challenge in volunteers reproduces upper and lower respiratory symptoms reported from occupational exposures. In animal models, endotoxin challenge with allergen potentiates allergic sensitization. These findings suggest that endotoxin may act as both a respiratory irritant and as an adjuvant in allergic sensitization, and that endotoxin exposures in LA workers are important in symptom generation and in allergic sensitization in the workplace. Toll-like receptor 4 (TLR4) and CD14 are two major human endotoxin response elements. Polymorphisms in the human TLR4 coding region and in the CD14 promoter region dictate different functional responses to endotoxin and to allergen, respectively. The A896G variant of TLR4 reduces human bronchial responsiveness and cytokine release to endotoxin compared to the wild type. The CC-159 variant of CD14 is associated with increased serum IgE, a greater number of positive prick skin tests, and more frequent reports of allergic rhinitis and asthma than in those with the CT or TT genotype. The central hypothesis of this proposal is that the interaction of endotoxin and allergen in the workplace with specific host genetic variants of TLR4 and CD14 determines risk for work-related symptoms and for sensitization to laboratory mice. This hypothesis will be addressed in a cross-sectional study of research scientists, laboratory technicians, and animal handlers. Questionnaire and prick skin testing or radio-allergosorbant tests will be used to determine symptoms and sensitization status. TLR4 and CD14 genotype will be characterized. Sampling for endotoxin and mouse allergen in research laboratories and the animal facility will be conducted for determining exposure levels of endotoxin and mouse allergen for all study subjects. The proposed study will assess whether the wild type TLR4 variant or the CC-159 CD14 variant, in combination with levels of endotoxin or mouse allergen exposure, are associated with symptoms or sensitization to mice. As such, the study will provide insight into the process of allergic sensitization, determine those exposures and host risk factors necessary for symptoms and sensitization to LA, and provide information critical in limiting exposures and reducing allergic disease in research scientists and technicians.

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