DESCRIPTION: (provided by the applicant) Cardiovascular disease(CVD) is the leading cause of death in the western world. Increased CVD risk is associated with low levels of high-density lipoprotein (HDL). HDL deficiency is one of the most important causes of coronary artery disease and yet, the least understood of lipid disorders. Phospholipid transfer protein (PLTP) is an important regulator of HDL metabolism and may be a potential antiatherogenic factor in plasma. Mutations in the PLTP gene that compromise PLTP function may have significant implications for development of atherosclerotic vascular disease. The specific aims of the clinical genetics training include: 1. To acquire clinical and research training in the genetic basis of cardiovascular disease. 2. To conduct research which will advance the principal investigator's knowledge and skills as a genetics researcher and for continued generation of original discovery in the genetics of cardiovascular disease. Specific aims related to the proposed research include: 1) To determine the genetic cause of HDL deficiency by screening individuals with altered HDL and/or PLTP levels for variations in the PLTP gene by denaturing gradient gel electrophoresis. 2) To employ 'brute force' sequencing to scan the immediate promoter region of the PLTP gene in these individuals to find mutations that alter the function of PLTP. 3) To genotype polymorphisms revealed by mutation detection methodologies, primarily by development of restriction fragment length polymorphism assays so as to develop a means of studying case-control sample populations. 4) To discover potential ethnic influences on HDL metabolism. 5) To characterize biochemical effects of genetic variants identified in aims 1-3 by conducting expression studies of variant alleles to assess their functional significance, thus, elucidating the mechanisms by which the mutations act. Coursework in Genetics and Clinical Research will provide the didactic foundation. Training in laboratory methodology and analysis as well as in the UCSF Lipid Clinic will be obtained. The research objectives are to provide vitalinsight into the role of PLTP in HDL deficient states as a paradigm for methodology that can be applied to any gene locus in the search for genetic causes of heart disease.