Vascular risk of lipid genotype and phenotype in patients with arterial disease

Abstract

Plasma lipid levels are important risk factors for vascular events. Although this has been thoroughly studied, many questions remain unanswered. Some of these questions are addressed in the present thesis. Plasma lipid levels are determined by genetic factors and secondary factors, of which adiposity is an important contributor. We review the literature regarding the effect of adiposity on plasma lipid levels and the consequences of this effect for the risk of vascular events. Furthermore, we study whether single nucleotide polymorphisms (SNPs) that are associated with low density lipoprotein (LDL)-cholesterol or plasma triglyceride level in the general population are still related with LDL-cholesterol or triglyceride level in patients with arterial disease, of whom a large part uses lipid-lowering medication. We show that these SNPs are still related with the respective lipid levels and that they are related with the probability to be at the lipid treatment target. Despite lipid-lowering medication, these SNPs still influence plasma lipid levels. Our results suggested that the LDL-cholesterol related SNPs were associated with vascular events in patients using lipid-lowering medication. In addition, we study the effect of plasma triglyceride (TG) and high density lipoprotein (HDL)-cholesterol levels on vascular events in patients with established vascular disease. We show that plasma TG levels increase the risk of vascular events, after adjustment for confounding factors and even after adjustment for nonHDL-cholesterol. Furthermore, show that the inverse association between HDL-cholesterol and vascular events gradually weakens with increasing intensity of LDL-cholesterol reducing therapy. This finding seemed independent of the attained plasma LDL-cholesterol levels. Recent reports have indicated that statin treatment may increase the risk of type 2 diabetes mellitus, but it is not fully clear which patients are in particular at risk to develop type 2 diabetes mellitus. We confirm the increased risk of type 2 diabetes mellitus with statin therapy in patients with established vascular disease. The increase in risk was independent of the number of metabolic syndrome criteria or insulin resistance, but the increase in risk of type 2 diabetes mellitus with statin therapy seems in particular present in patients with low baseline glucose. To estimate the risk of recurrent vascular events, a 10-year risk estimation could be used, but these risk estimates by definition provide low risk estimates in young patients. Therefore, a long-term or lifetime risk model may provide additional information in these patients. In this thesis we develop and validate a model to estimate the risk of vascular events up to an age of 85 year in patients with vascular disease. Although the average 10-year risk in patients aged 45 up to 54 year of age was only 14%, the lifetime risk up to 85 year was 45% in these patients. For patients up to 65 year of age, using the lifetime risk model resulted in classification of patients into higher risk categories. Our results show that the lifetime risk model could be used to provide additional information about the risk of vascular events for patients up to 65 year of age.