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Novel insights into the genetic basis of chronic obstructive pulmonary disease

Radder, Josiah E (2016) Novel insights into the genetic basis of chronic obstructive pulmonary disease. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Chronic obstructive pulmonary disease (COPD), defined as irreversible airflow limitation, is caused by a complex interaction of environmental exposures, most commonly cigarette smoke, and genetic factors. Genetic studies of COPD have used tests of genome-wide linkage and association to identify loci that contribute to disease susceptibility. However, as seen in other chronic diseases, the best-replicated loci associated with COPD only account for a small portion of disease heritability. Identifying additional genetic determinants of chronic diseases offers the opportunity to better understand their biology as well as the promise of better disease prediction and patient stratification, first steps in the development of precision medicine.

The genetic architecture underlying chronic disease is complex, and it is likely that there is still common variation contributing to COPD that has been masked from association studies by phenotypic and genotypic heterogeneity. Further, there is evidence that rare variation contributes to chronic disease susceptibility, and rare variants in SERPINA1 leading to alpha-1 antitrypsin deficiency support this in COPD. The trio of studies presented in this work aim to detect both of these types of variation. In the first, we employ an extreme-trait study design to detect rare variants in the first whole genome sequencing study of COPD. Using this approach, we identify a previously unreported non-synonymous variant associated with COPD, and two suggestively associated candidate genes, PTPRO and ZNF816. In the second and third studies, we integrate mouse and human genetic data to identify undetected common variants associated with human disease and mouse models of disease. The first study uses a mouse model of cigarette smoke-induced emphysema and identifies the gene ABI3BP as a potential candidate gene. The second looks at early life determinants of chronic disease by measuring airspace size in mice at maturity, leading to identification of IL1R2, which plays a previously undescribed role in lung development. Finally, we demonstrate that by integrating the results of genetic studies, it is possible to gather additional information about the genetic architecture of chronic diseases like COPD.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Radder, Josiah Eradder.josiah@medstudent.pitt.eduJOR54
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorShapiro, Steven
Committee ChairMars, Wendy
Committee MemberSciurba,
Committee MemberBarmada, M
Committee MemberNikiforov,
Date: 7 September 2016
Date Type: Publication
Defense Date: 9 August 2016
Approval Date: 7 September 2016
Submission Date: 14 August 2016
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 200
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: "chronic obstructive pulmonary disease", "whole genome sequencing", "pulmonary disease", "lung disease", genetics, sequencing
Date Deposited: 07 Sep 2016 15:02
Last Modified: 07 Sep 2017 05:15

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