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Asthma and Th2 immunity: The impact of genetic factors and obesity. / Gwyneth Ann Davies
Swansea University Author: Gwyneth Ann Davies
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Introduction: Th2 immune signalling is key to the pathological substrate of asthma. The primary objective of this thesis was to identify the predictive effects of genetic variants of Th2 signalling at the population level, and to examine interactions between different loci, with relation to asthma a...
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Introduction: Th2 immune signalling is key to the pathological substrate of asthma. The primary objective of this thesis was to identify the predictive effects of genetic variants of Th2 signalling at the population level, and to examine interactions between different loci, with relation to asthma and associated phenotypes. This genetic epidemiological study provided an opportunity to explore also the predictive effects of different measures of obesity on these phenotypes. Methods: An unselected population of 1614 young adults was recruited. Responses to validated questionnaires and spirometry provided clinical and physiological asthma phenotypes. Anthropometry provided the measures of obesity. Assays on venous blood provided immune phenotypes (IgE, eosinophils, eotaxin). Genotyping encompassed 22 polymorphisms in the 1L13, IL4RA and STAT6 genes, representing the Th2 immune signalling pathway. Data analysis used linear and logistic regression models, and a modified regression to address haplotypes. Results: Single polymorphisms and hapiotypes of IL13, IL4RA and STAT6 loci significantly predicted asthma, eczema and hayfever at the population level. Several novel associations were shown for serum IgE levels and airflow obstruction. Significant interaction (epistasis) was identified between variants of IL13 and STAT6 for total IgE levels. Adiposity indices (BMI, waist circumference, body fat) showed consistent associations with asthma and airflow obstruction, but also with Th2 inflammatory markers (IgE, eotaxin and eosinophils) with modulation by sex/smoking status. Conclusions: Genetic variants of Th2 immune signalling are one important source of risk for asthma and allergy in the general population, with variants operating both singly and in combination. Obesity and its causes are also likely to be significant contributors to the occurrence of asthma in the population, and may operate through pro- inflammatory mechanisms. These findings exemplify the polygenic and multifactorial determination of asthma and allergy, through genetic and environmental effects.
Swansea University Medical School