Aim of this thesis was to investigate pharmacogenetic effects on response to statin treatment and the genetics of lipid metabolism and cardiovascular disease. In chapter 4 the first results of the... Show moreAim of this thesis was to investigate pharmacogenetic effects on response to statin treatment and the genetics of lipid metabolism and cardiovascular disease. In chapter 4 the first results of the Genomic investigation of Statin Therapy (GIST) consortium are presented. We identified and validated two new GWAS loci to be associated with LDL-cholesterol response after statin treatment. In addition, we confirmed two previous identified loci. In chapter 5 we showed that we were not able to identify any loci associated with differential event reduction after statin therapy within the PROSPER study. The results presented in chapter 8 show that even at old age a genetic predisposition to high LDL-cholesterol is a risk factor for mortality. The results of this thesis show that currently the possibilities to personalize statin treatment based on genetic variants is limited. New research methods will hopefully give new opportunities to improve cardiovascular disease treatment and give more insight into the biological mechanisms of statin treatment. Show less
The aim of this thesis was to identify novel lifespan regulating loci that influence human longevity and population mortality. To this end, we performed two genome-wide association studies, one of... Show moreThe aim of this thesis was to identify novel lifespan regulating loci that influence human longevity and population mortality. To this end, we performed two genome-wide association studies, one of long-lived individuals from the family-based Leiden Longevity Study (LLS) and an extended one of long-lived individuals from multiple cohorts of European descent. Using the latter, we identified two genome-wide significant loci, the TOMM40/APOE/APOC1 locus and an intergenic locus on chromosome 5q33.3. In addition, our gene set analysis with the LLS data showed that genetic variation in genes involved in the insulin/IGF-1 signaling and telomere maintenance pathways is associated with human longevity. Since our genetic studies identified a limited number of longevity loci, we additionally examined whether leukocyte telomere length (LTL) could be used as a biomarker of healthy aging. We showed that LTL meets three of the four criteria for a biomarker of healthy aging in the LLS, i.e., LTL changes with chronological age and is associated with health, in this case immune-related parameters, and prospective mortality. To identify novel longevity loci, future research may benefit from a better definition of the healthy aging phenotype, combining study designs, and the use of novel methods and technologies, such as next-generation sequencing. Show less
