In the first part of this thesis we focus on the genetic determinants of lipid metabolism as atherogenic dyslipidemia is major component of cardiometabolic disease and consequently of CVD. In the... Show moreIn the first part of this thesis we focus on the genetic determinants of lipid metabolism as atherogenic dyslipidemia is major component of cardiometabolic disease and consequently of CVD. In the second part of the thesis, we study the age-related changes of cardiometabolic risk factors over the life course across four generations. In this thesis, we aimed to gain new insights into the underlying pathophysiology of cardiometabolic disease and the long-term and cumulative exposure of its risk factors over the life course, thereby facilitating the search for preventive and curative strategies of cardiometabolic disease. In the first part of this thesis, we focused on the genetic determinants of lipid metabolism during both fasting and postprandial states. In the second part, we studied the age-related changes of cardiometabolic risk factors, in particular of body weight, overweight and obesity, over the life course across four generations. An important finding of the thesis is that obesity has worsened in the younger generations, reaching almost double the prevalence of older generations. However, after midlife the levels of obesity levelled off, which could be a reason why the adverse shift in obesity was not associated with unfavourable changes in cardiometabolic risk factors. We also found out that some genes effect body weight differently at different ages, which suggests that gene-environment interactions play an important role in body weight and consequently in obesity. Show less
Worldwide, there is an strong rise of cardiometabolic disorders, which mainly comprise obesity, cardiovascular disease (CVD) and type 2 diabetes. Therefore, the development and improvement of... Show moreWorldwide, there is an strong rise of cardiometabolic disorders, which mainly comprise obesity, cardiovascular disease (CVD) and type 2 diabetes. Therefore, the development and improvement of preventive and curative strategies for cardiometabolic disease is eagerly warranted. With the studies describes in this thesis, we aimed to disentangle the interwoven physiological, environmental and genetic factors that determine cholesterol and energy metabolism to increase our understanding of their contribution to cardiometabolic disease risk. The first part of this thesis focussed on the cholesteryl ester transfer protein (CETP). The lipid transfer properties of CETP induce a proatherogenic lipoprotein profile. Therefore, CETP inhibitory molecules have been developed and tested in clinical trials for their capability to improve the lipoprotein profile and reduce CVD risk. To fully understand the role of CETP in CVD, its physiology and biological function should be fully unravelled. The focus of the second part of this thesis was on the role of energy metabolism in cardiometabolic health. Specifically, we aimed to study the association of environmental and genetic factors, which were previously described to influence brown adipose tissue (BAT) activity, with energy expenditure and disease outcomes. Show less
In this thesis several aspects of metabolic syndrome are addressed. The focus involves questions concerning the genetics of obesity, TG and cholesterol and hyperglycemia. Since we hypothesized that... Show moreIn this thesis several aspects of metabolic syndrome are addressed. The focus involves questions concerning the genetics of obesity, TG and cholesterol and hyperglycemia. Since we hypothesized that obesity is the most important trigger of metabolic impairment, the MetS definition in this thesis was chosen to include the obesity measure waist circumference as an essential component. In the study described in chapter 2, the heritability of the metabolic syndrome was addressed and compared to the heritability of its individual components. Since the individual components of MetS were shown to be more heritable than MetS itself, the studies described in chapter 3 and 4 focused on the genetics of the individual MetS component plasma TG. For this purpose, a candidate gene approach was employed using HTG patients and healthy controls. The involvement of a series of candidate genes was confirmed. The study described in chapter 5 followed a similar approach to that used in the studies described in chapter 3 and 4. Several candidate genes were studied in patients suffering from hyperlipoproteinemia (HLP) type III, which is characterized by elevated levels of total plasma cholesterol and plasma TG. HLP type III is characterized by APOE2 homozygosity. Contributing genetic factors in the (metabolically stressed) APOE2/2 environment were confirmed. Plasma adiponectin, an adipose tissue secreted hormone (adipokine), has been suggested to be a biomarker for MetS. In chapter 6 we describe a study which particularly aimed to determine the effect of menopause on the discriminating accuracy of adiponectin to predict MetS. Especially low levels of plasma adiponectin in postmenopausal women were found to be a risk for MetS. However, the discriminating accuracy of adiponectin for the presence of MetS was exceeded by BMI in men and pre __and post menopausal women. Since plasma adiponectin levels are very well correlated with MetS components or related traits, the study described in chapter 7 addressed the question whether these correlations are caused by a genetic overlap (genetic correlation). The genetic correlation was mono-laterally validated with regard to the adiponectin gene (ADIPOQ). Chapter 8 describes a study towards finding novel loci associated with adiponectin or loci that are possibly involved in the genetic overlap between adiponectin and MetS components or related traits. This study followed a genome-wide association (GWA) approach. The results of this GWA were used in a joined analysis with two other cohorts in a meta-analysis. In addition, a selected proportion of SNPs was submitted for replication in several cohorts. Chapter 9 provides a general discussion by reviewing all previous chapters in the thesis. Furthermore, chapter 9 includes suggestions and proposals for future analyses towards unraveling genetic and environmental factors involved in the expression and manifestation of metabolic risk factors. Show less
