Genetic determinants of cardiovascular disease : heritability and genetic risk score

摘要: Complex diseases such as cardiovascular disease (CVD) are influenced by both genetic and environmental factors. Estimation of an individual’s risk usually involves measurement factors correlated with CVD (e.g. age, sex, smoking, blood pressure, total cholesterol). Lately, several biomarkers have been evaluated for their ability to improve prediction beyond traditional The interest in novel loci is propelled notably emerging discoveries from the advent genome-Wide association studies (GWAS) variants associated common diseases. GWAS has greatly enhanced our knowledge architecture disease, yielding over 50 confirmed be date, well 200 lipids, body mass index, type 2 diabetes mellitus). This recent continuing success discovering increasing numbers robustly markers led reassessment whether data can provide clinically useful information refining moderating through a more efficient application prevention strategies. In this thesis, we first address approach survey hypertension (i.e. major factor premature CVD), then construct models coronary artery (CAD; i.e. most CVD) finally establish basis strongest predictor clinical complications CAD, subclinical atherosclerosis, add incremental prognostic value above scores across range ages. We show that, visit measurements, heritability ~25%/~45% ~30%/~37% systolic (SBP) diastolic pressure (DBP) European (N=8,901) African (N=2,860) ancestry individuals Atherosclerosis Risk Communities (ARIC) cohort, respectively, accord prior studies. Then present means combine polygenic score - effects among ensemble independent assessment using log-Link function. apply method heart (CHD) ARIC cohort. addition (GRS) (CRS) improves discrimination calibration CHD subsequently reveal how influences thus potentially management. Finally, Among 1561 cases 5068 controls, datasets available NCBI's database Genotypes Phenotypes (dbGAP), found one SD increase 49 CAD SNPs was 28% increased having advanced atherosclerosis (p = 1.43 x 10-16). significant every 15-Year age stratum (.01 > p 9.4 10-7) remarkably similar all strata test heterogeneity 0.98). obtained near identical results levels significance when restricted 32 not Accordingly, variation largely recapitulates known traits. vast majority varies chromosome, depending on its length, concentrated intronic intergenic regions genome but widely distributed allele frequency spectrum. Respectively, proposed at established susceptibility nongenetic tool facilitates standardized incorporation GRS assessment. (...)