|Title:||Biomarkers and Genetics in Marfan Syndrome|
Congenital thoracic aortic aneurysm
Transforming growth factor beta
Angiotensin converting enzyme
|Publisher:||University of Sydney.|
Dicipline of Pathology.
School of Medical Sciences
|Abstract:||Marfan syndrome (MFS) is an autosomal dominant inherited connective tissue disorder, associated with sudden death of affected individuals due to dissection of a thoracic aortic aneurysm (TAA). The detailed pathogenesis remains uncertain, but all patients have a mutation in the fibrillin 1 gene, which appears to be associated with excessive TGF-beta signalling. Diagnosis of people at risk of dissection is critical but difficult; therefore, there is a need for improved diagnostic accuracy, better risk-stratification and more effective therapeutic intervention for individuals and their families. Our aim was to discover potential circulating biomarkers of disease. Matrix metalloprotease (MMP)-3 has been implicated in TAA formation. We have shown that the levels of circulating MMP-3 are significantly higher in both control and MFS males compared to females. Paradoxically, MMP-3 levels fall in MFS patients, presumably as a compensatory mechanism to limit pathological extra-cellular matrix remodelling. We observed no difference in the level of circulating TGF-beta1 in MFS patients compared to controls. However, a consistent, small, non-significant trend towards higher levels was observed across all MFS patient groups. Although no significant differences were seen between MFS patients and controls for the circulating biomarkers MMP-2, MMP-9, TIMP-1 and TIMP-2, a consistent trend was observed for several biomarkers towards higher levels in the MFS patients group. Specifically, MMP-2 levels (overall trend, plus weakly significant difference in female surgical MFS patients) and TIMP-2 (weakly significant difference) support the possibility that these two biomarkers may be slightly elevated in MFS compared to controls. The ACE insertion/deletion (I/D) polymorphism DD genotype has been associated with cardiovascular disease severity, thus we hypothesised the D allele would be over-represented in MFS patients. We found no difference in the allelic or genotypic frequency of the ACE I/D polymorphism in MFS patients compared to controls and no differences were observed when MFS patients were stratified by severity.|
|Type of Work:||PhD Doctorate|
|Type of Publication:||Doctor of Philosophy Ph.D.|
|Appears in Collections:||Sydney Digital Theses (Open Access)|
|LU Yaxin - Final thesis.pdf||8.67 MB||Adobe PDF|
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