Year: 2013
Type: dissertation
Study design: Observational Study
Abstract: Coronary heart disease (CHD) is a major burden for public health worldwide. Several factors are known to be associated with the disease risk, including high levels of low-density lipoprotein (LDL) cholesterol and blood pressure. The established risk factors do not, however, fully predict an individual s risk for the disease. In recent years, new candidate risk factors, including genetic markers, have been extensively studied. Genome-wide association studies (GWASs) have mapped over 40 genetic regions for CHD risk and hundreds of loci for CHD risk factors. The impact of these findings on public health remains obscure. In this study, we utilized the findings from large-scale GWASs and constructed genetic risk scores (GRSs) based on panels of single-nucleotide polymorphisms (SNPs). The aim was to estimate the joint effects of common genetic markers on CHD and its risk factors, and to evaluate the incremental value of genetic information in CHD risk assessment. In Projects I and II, we studied longitudinal effects of genetic loci associated with lipids and blood pressure, and evaluated the prediction of dyslipidemia and hypertension in young adults by using the genetic information in addition to clinical measurements. Our results show that the GRSs were significantly associated with longitudinal measurements of lipid traits and blood pressure throughout childhood, adolescence and adulthood. For some traits, the genetic effect was not consistent across age groups. For example, the GRS effect for high-density lipoprotein (HDL) cholesterol was considerably larger in children than in adults, and the proportion of variance explained by the SNPs in children was twice as much as in adults. The GRS for triglycerides improved the prediction of dyslipidemia in young adults when added to childhood lipid measurement. The blood pressure GRS increased the risk of hypertension, but did not improve risk discrimination over other risk factors. In Projects III and IV, we found that the GRSs based on CHD SNPs predicted CHD events. The estimated relative risk for the GRS was similar in magnitude to the relative risk of other risk factors such as systolic blood pressure. The genetic effect was independent of family history of the disease, which has been used as a surrogate for genetic risk in many prediction algorithms. The GRS based on 28 SNPs improved the prediction of CHD events beyond traditional risk factors and family history when evaluated with reclassification or discrimination metrics. Genetic screening could be especially useful for individuals in the intermediate-risk group (10-year risk 10-20%), as current preventive strategies are focused mainly on the high-risk group (>20%). In conclusion, these findings suggest that the genetic information obtained from GWASs could be used in early identification of individuals at increased risk for lipid disorders, hypertension and CHD. Keywords: cardiovascular disease, genetic association, genetic epidemiology, risk factor
Source: Työväentutkimus Vuosikirja
Author: Emmi Tikkanen
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funder: Biomedicum Helsinki-säätiö
OpenAlex ID: W2163286598