Heart diseases remain the leading cause of death in the US and is an important focus area for the Healthy People 2020 initiative. The long term goal of this application is to determine the causes of aggregation of multiple biological, psychological and life-style related cardiovascular disease (CVD) risk factors in individuals and their covariation in populations. It is possible that genetic variation associated with central physiological mechanisms, lil<e the serotonergic and inflammatory pathways, may partially mediate the aggregation of CVD risk phenotypes. The proposed project aims to comprehensively test several genes in the serotonin pathway (SLC6A4, MAOA, TPH1, TPH2, HTR1A, HTR1B, HTR2A, HTR2C) and genes of inflammatory markers (ILIp, IL6, CRP, TNFa, SELE, SELP, ICAM 1, VCAM 1) for association with multiple CVD risk domains. Specifically, this project aims to: 1)To examine the association between polymorphisms (individually and as haplotypes) in the above mentioned genes and psychological, biological and lifestyle-related CVD risk factors in samples of 1173 European American (EA) and 861 African American (AA) individuals enrolled in the HeartSCORE project, using multivariate and univariate models;2) To confirm genotype associations after controlling for population stratification using genomic control methods in EA and individual admixture based methods in AA. 3) To examine whether investigated polymorphisms underlie the covariation of CVD risk factors, using structural equation modeling. 4)To determine whether studied polymorphisms predict progression of biological risk factors in EA and AA using multivariate statistics and mixed models. The work during the ROO phase will follow from the work done during the current K99 phase which focused on SLC6A4, HTR2A and CRP genes and on aims 1-3. Once identified, a common genetic variant underlying multiple dimensions of CVD risk may provide avenues towards development of new and novel therapeutics. Simultaneous investigation in two different populations is also expected to provide insights into potential causes underlying racial disparities in CVD risk and prevalence.