Genetic and lifestyle risks of cardiovascular disease

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Over the past 5 decades, the identification and modification of cardiovascular risk factors, as well as the development of pharmaceutical and interventional therapies, have resulted in declining CVD mortality rates. To develop better and innovative preventive strategies, a better understanding of the pathophysiological mechanisms underlying CVD is necessary. Studying the genetic factors underlying CVD and their risk factors may aid us in this undertaking.Genome-wide association studies have identified thousands of associations between genetic variants with risk factors and diseases, thereby increasing our understanding of the biology underlying these traits. The evidence for a causal relationship between a risk factor and a disease can then be investigated using these genetic variants.This thesis presents evidence for causal relationships between risk factors such as telomere length and iron parameters, with CVD. We uncovered novel genetic variants associated with lipoprotein(a), but also with lifestyle factors such as caffeine intake and sedentary behaviors. We subsequently provide evidence for their causal relations with coronary artery disease. Additionally, we found genetic and lifestyle factors had additive effects on the risk of developing CVD. A healthy lifestyle was associated with lower risks compared to an unhealthy lifestyle, regardless of the genetic risk, and a high genetic risk with an unhealthy lifestyle both increased the risk of developing CVD. The findings described in this thesis help us better understand the pathophysiological mechanisms underlying CVD and may aid in improving risk stratifications