Genetic risks for cardiovascular diseases

Abstract

Atherosclerotic cardiovascular disease (CVD), which involves the heart, brain, and peripheral circulation, is a major health problem world-wide. The development of atherosclerosis is a complex process, and several established risk factors are involved. Nevertheless, these established risk factors do not fully explain the occurrence of CVD and further insight is required in factors such as genetic determinants that may identify individuals at risk. In this thesis we worked on the genetic basis of CVD in three parts. Part one focuses on genes in lipid metabolism pathway and association with CVD. In chapters 2 and 3 we studied the association of the T64A polymorphism in the β3–adrenergic receptor gene (ADRB3) and the peroxisome proliferator-activated receptor gamma-2 (PPARG2) gene polymorphism (P12A), respectively, with coronary heart disease (CHD). Our studies in combination with meta-analyses of previous reports did not provide support for a role of these polymorphisms in CHD risk. In chapter 4 we examined the relationship between the cholesteryl ester transfer protein (CETP) gene polymorphisms and HDL levels and future CHD. Strong associations between higher HDL cholesterol levels and the CETP (-629)A, the CETP I405V V, and the CETP TaqIB B2 alleles and the haplotypes that comprised these alleles were found and the C(-629)A polymorphism was also related to a lower plasma LDL cholesterol. None of the CETP polymorphisms or haplotypes were, however, related to risk of CHD. Part two focuses on genes in blood pressure regulation pathway and association with CVD. In chapter 5 we showed that presence of the α-adducin Gly460Trp polymorphism increases the risk of stroke, but not the risk of CHD or AMI. This risk is particularly elevated in the presence of systolic hypertension. In chapter 6 we showed in a meta-analysis that the presence of the T allele of the angiotensinogen gene (AGT) M235T polymorphism is associated with increased risk to develop preeclampsia/eclampsia. The latter is a risk factor of development of CVD in later life. We also showed in chapter 7 that this polymorphism is associated with self-reported hypertensive disorders in pregnancy among Caucasian Dutch women. In chapter 8, the pooled odds ratio of the meta-analysis, including our own data, presented evidence that there is an increase in the risk of CHD conferred by the M235T variant of the AGT gene. However, the relevance of this weakly positive overall association remained uncertain because it might be due to various residual biases, including Hardy-Weinberg equilibrium violation and publication biases. In part three we showed that combination of genetic factors aggregated to a single genetic risk score (GRS) can be used in prediction of incident CHD and the GRS along with conventional risk scores improves the estimation of CHD risk in healthy Dutch women, chapter 9. We also addressed some considerations with regard to meta-analysis of genetic association studies, forming consortia in this ongoing field, and predictive genetic testing, as well as the new findings in genome-wide association studies and implications of this thesis for clinical practice and future research directions in chapter 10.