Severe alpha 1-antitrypsin deficiency (i.e. PI ZZ) is the one proven genetic risk factor for chronic obstructive pulmonary disease (COPD). The frequent development of COPD in PI ZZ individuals has provided a foundation for the protease-antiprotease hypothesis for the pathogenesis of emphysema. Nonetheless, the development of COPD among PI ZZ subjects is quite variable, and other genetic and environmental factors likely contribute to this variability. Cigarette smoking is the major environmental risk factor for COPD in PI ZZ individuals; PI-by-smoking interaction has been previously demonstrated by our group. In addition, previous work by our group suggests that genetic modifiers of COPD in PI ZZ subjects likely exist. To identify genetic modifiers of COPD in alpha 1-antitrypsin deficiency, we propose to assemble a total of 400 families with at least one pair of adult PI ZZ siblings, and to assess COPD-related phenotypes in these families including spirometry, bronchodilator responsiveness, and chronic bronchitis. We will perform genome screen genotyping of the 400 families using short tandem repeat (STR) markers, and we will perform multipoint linkage analysis. In regions of linkage from the genome screen, fine mapping will be undertaken by using linkage analysis of additional STR markers and family-based association studies of single nucleotide polymorphisms (SNPs) within positional candidate genes. With this approach, the genomic region(s) containing modifier genes will be identified and narrowed, and candidate modifier genes will be tested. The homogeneity of PI ZZ subjects at the PI locus and the increased susceptibility of PI ZZ subjects to COPD increase the probability that we will identify novel genetic influences on COPD that may also be applicable to subjects without severe alpha 1-antitrypsin deficiency. This project will provide the largest collection of alpha 1-antitrypsin deficient families ever assembled, and it will apply state-of-the-art genetic epidemiological methods to identify regions of the genome likely to contain modifier genes for the development of lung disease in alpha 1-antitrypsin deficiency.
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