Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.575071
Title: Genetic variants of MMPs 1, 9 and 12 in COPD
Author: Haq, Imran
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2012
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Abstract:
Chronic Obstructive Pulmonary Disease (COPD) is a condition characterised by a progressive, irreversible obstruction of the airways. It is the fourth leading cause of mortality and morbidity worldwide. Although cigarette smoking is the main aetiological factor, not all smokers develop the disease, suggesting a genetic component. The pathogenesis of COPD is poorly understood. However, a widely accepted hypothesis for its aetiology is protease - anti protease imbalance with increased protease activity in the lung resulting in alveolar destruction. This hypothesis arose from the well described association of alpha - 1 - antitrypsin deficiency with COPD; this protein protects the lung from damage caused by uninhibited neutrophil elastase activity. The Matrix Metalloproteinases (MMPs) are a family of proteases, making them promising candidates for genetic studies as they can degrade all components of the extracellular matrix of the lung and play a key role in tissue remodeling. Specifically, MMPs 1, 9 and 12 have been implicated in COPD pathogenesis through both animal and human studies. Investigation of variation within these genes in relation to COPD is limited and provided conflicting results, probably due to small sample size, improper matching of controls and use of different COPD phenotypes. To address these issues, I undertook a case - control genetic association study in the largest sample size reported to date. This study demonstrated that A - A alleles compared to the G - G alleles of a haplotype consisting ofrs2276109 and rs652438 in MMP - 12 (p = 0.0138, OR = 1.32, n = 1929) were associated with severe forms of COPD. SNPs in MMPs 1 and 9 were not associated with COPD or severity. Functional characterisation of rs652438, in MMP - 12 showed that with the A allele there was significantly higher metalloproteinase activity and increased cellular migration compared to the G allele. Human studies showed A/A homozygotes to have increased macrophages in the airways and higher CT emphysema scores. This suggests that increased activity of MMP -12 is important in COPD pathological processes. I also undertook the functional characterisation of the disease implicated SNP rs 17576 in MMP - 9. The G allele of this SNP had higher metalloproteinase activity and increased cell migratory activity compared to the A allele in cellular models. Furthermore, GIG homozygous individuals showed increased activity of active MMP - 9 in plasma samples compared to A/A homozygotes. This is interesting due to the implication of MMP - 9 in arterial stiffness of healthy individuals, it is plausible that it could be involved in arterial stiffness in COPD patients. To conclude, I have provided genetic and functional evidence that implicates MMP - 12 as a locus in COPD pathogenesis. I did not find evidence for genetic variants of MMP 1 and 9's role in COPD susceptibility. I have also demonstrated a disease implicated SNP in MMP - 9 to significantly alter the protein's function.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.575071  DOI: Not available
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