Genetic determinants of arterial stiffness: Results from the Rotterdam Study

Arterial stiffness increases with age. It is also associated with various diseases, such as diabetes mellitus and hypertension. Recently, arterial stiffness has also been found to independently predict cardiovascular disease. The pathogenesis of arterial stiffness, however, has not been fully explored. The aim of the studies described in this thesis was to study the influence of variation in genes that may affect arterial stiffness and cardiovascular events. All studies were based on the Rotterdam Study, a population-based cohort study, originally including 7983 participants of 55 years and older.The first studies in this thesis focused on variation in inflammatory genes in relation to cardiovascular events such as myocardial infarction and stroke. Chapter 2.1 describes the association between the well-known inflammatory interleukin 6 (IL-6) -174 G/C promoter polymorphism and risk of coronary heart disease. In chapter 2.2 several polymorphisms in the transforming growth factor β1 (TGF-β1) gene, which influences inflammatory processes, were studied in relation to risk of myocardial infarction and stroke. The remaining studies focused on inflammatory genes and genes that affect the structure of the vascular wall in relation to arterial stiffness (pulse wave velocity, the carotid distensibility coefficient and pulse pressure). Inflammatory processes may influence arterial stiffness, therefore we examined several genes related to inflammation. Chapter 3.1 described the association of the IL-6 -174 G/C polymorphism, CRP and arterial stiffness. In chapter 3.2, variation in the CRP gene was studied in relation to arterial stiffness. Chapter 3.3 focused on polymorphisms in the TGF-β1 gene in relation to arterial stiffness. Chapter 3.4 described the association between variation in the fibrinogen α and γ genes and arterial stiffness. Arterial stiffness may also be influenced by genes that structurally affect the vascular wall or the composition of the vascular wall. Genes of the renin-angiotensin (RAS) system are an important example. In chapter 4.1, variation in the angiotensin-II, angiotensinogen and angiotensin-II receptor type I genes in relation to arterial stiffness is described. Chapter 4.2 focused on the ACE I/D polymorphism in relation to changes in blood and pulse pressure during follow up. Finally, chapter 4.3 described the association between variation in the matrix-metalloproteinase-3 (MMP-3) gene and arterial stiffness.

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