The role of genetic and environmental variation in the respiratory phenotype of alpha 1 antitrypsin deficiency

[摘要] Alpha 1 antitrypsin deficiency (AATD) is the only established genetic predisposition to chronic obstructive pulmonary disease (COPD). The development of COPD in AATD is highly variable, probably relating to complex interactions between multiple genetic and environmental factors. This thesis will describe the COPD phenotypes observed in AATD and their inter-relationships, forming the basis for examining phenotypic associations with specific candidate genes and HLA class II type. Finally it examines the potential role of ambient air pollution. Associations were seen for TNFA with chronic bronchitis, SFTPB with FEV1, TGFB with small airways disease and GC with bronchiectasis, consistent with the role of protein products in pathogenesis. Of four MMPs studied, association with gas transfer occurred in two. HLA-DQA1*0301 and HLA-DRB1*04 contributed significantly to gas transfer in regression models, and anti elastin antibodies were higher in HLA-DRB1*04 and HLA-DQA1*0301 homozygotes. Ozone levels contributed to the burden of disease in cross sectional and longitudinal models of pollution exposure, whilst PM10, NO2 and SO2 were associated only in the longitudinal model. In conclusion this thesis demonstrates the importance of genetic variation and environmental factors in determining respiratory phenotype in AATD. It also suggests a key role for adaptive immunity in pathogenesis of emphysema.

[发布机构] University:University of Birmingham;Department:Institute of Cardiovascular Sciences

[关键词] R Medicine;R Medicine (General)