Association and Linkage Studies Between Arterial Stiffness and the Fibrillin-1 Gene

Professor Cheung, Yiu Fai   (Principal Investigator (PI))

Professor Sham Pak Chung   (Co-Investigator)

Professor Lau Yu Lung   (Co-Investigator)

36

2005-09-01

79380

Association and Linkage Studies Between Arterial Stiffness and the Fibrillin-1 Gene

arterial stiffness, fibrillin gene

Others - Biological Sciences

200507176044

Small Project Funding

2005

Completed

Arterial stiffness is recently recognized as an independent cardiovascular risk factor. With arterial stiffening, the left ventricular afterload is increased while coronary perfusion is altered. The secondary increase in pulse pressure has further been shown to be an independent predictor of cardiovascular mortality and future cardiovascular events. Although arterial stiffening has traditionally been regarded as part of the normal aging process, there is growing evidence that it may precede clinical disease and predict a higher risk for developing atherosclerosis, hypertension and stroke. Recently, the genetic aspect of arterial stiffness is beginning to unveil. In particular, there is a growing body of evidence that suggests a contributory role of genetic variations in extracellular matrix proteins to arterial stiffening. Fibrillin-1, being a matrix glycoprotein and the principal constituent of microfibrils that provide load-bearing and anchoring functions within the arterial wall, is particularly relevant in this context. Indeed, mutation and polymorphism of the fibrillin-1 gene has been associated with aortic stiffening in patients with Marfan syndrome and brachial pulse pressure in a healthy middle-aged male population, respectively. Nonetheless, whether variations in the fibrillin-1 genotype contribute to arterial stiffness in the general population have hitherto remained unknown. The primary objective of the proposed study is to test the hypothesis that arterial stiffness in the general population is associated with variations in the fibrillin-1 genotype. To test the hypothesis, sibling pair association and linkage studies between arterial stiffness and fibrillin-1 gene will be performed. The central (aortic and carotid) and peripheral (brachio-radial) arterial stiffness will be related to demographic variables, cardiovascular risk factors and a variable nucleotide tandem repeat polymorphism in intron 28 of the fibrillin-1 gene. Additionally, the single nucleotide polymorphism at intron C in the upstream region of the fibrillin-1 gene will be determined. Based on findings of these studies, the following issues will be addressed: - heritability of central and peripheral conduit arterial stiffness - association between variations in fibrillin-1 genotypes and arterial stiffness - linkage between fibrillin-1 gene and arterial stiffness - gene-environment interaction of fibrillin-1 genotypic variations in relation to arterial stiffness