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Most information about risk factors for cardiovascular disease has emerged from epidemiological analyses of older adults who already have the disease. Using this retrospective approach, cigarette smoking was established as a major risk factor for cardiovascular disease, as well as a number of other risk factors related to diet and behaviors. Few studies, however, have been able to analyze the development of the atherosclerotic process over time. Research utilizing such a longitudinal design may be better situated for identifying young subjects at risk for premature cardiovascular disease. In addition, the developmental approach to studying atherosclerosis may allow investigators to develop clues about the pathogenetic processes through which a risk factor like smoking contributes to the development of atherosclerosis.
The purpose of the proposed research is to identify interactions between genetic variants of a large number of cardiovascular disease-related genes and early manifestations of atherosclerosis. The proposed research program will use data and DNA samples from the Muscatine Cohort Study. Established in 1970 with school age children (grades K through 12) from Muscatine, Iowa, this longitudinal cohort study is designed to assess whether established cardiovascular disease risk factors measured in childhood are predictive of risk factors and the atherosclerotic process in later years. A representative cohort of these subjects (n=856) has been followed with risk factors measured in childhood and at several stages during young adulthood, including anthropometrical measurements, blood pressure measurements, serum lipid profiles and other biochemical indices, dietary surveys, and behavioral questionnaires. Between 33 and 42 years, each subject was studied for manifestations of early atherosclerosis using two noninvasive measurements, carotid artery intimal media thickness and coronary artery calcification. The proposed study will allow us to establish whether candidate genotypes are not only associated with unfavorable risk factor levels in childhood, but also whether such genotypes are related to the early atherosclerotic process as assessed by carotid artery intimal media thickness and coronary artery calcification. The research will particularly focus on potential interactions between a known major risk factor for cardiovascular disease, cigarette smoking, and genetic variation of proteins involved with pathogenetic processes that may be related to smoking’s contribution to the development of atherosclerosis. We have proposed to genotype the subjects in the Muscatine Cohort (n=856) using several new high throughput multi-locus genotyping assays that will allow us to measure genetic variation of more than 60 candidate genes, but using only minimal amounts of DNA. Candidate genes were selected because of their role in lipid metabolism/transport, coagulation and thrombosis, mediation of inflammatory responses, or biotransformation of toxins in tobacco smoke. Many of these genetic variants are single nucleotide polymorphisms that are known to affect the function of the proteins that they encode, or levels of those proteins, and the variants are either known, or thought to have, biological or clinical significance. The Muscatine Cohort is a unique dataset because of its size and its comprehensive longitudinal collection of clinical and biochemical measures related to the development of atherosclerosis in a group of young people who have been followed for 30 years. The Muscatine Cohort also has an unusually high percentage of smokers, and thus it represents an excellent population in which to study relationships between smoking, gene variants, and development of atherosclerosis. We propose to enhance the Muscatine Cohort dataset by generating genotypic data for a large number candidate genes related to the atherosclerotic process and smoking. The proposed research represents one of the initial attempts to investigate the interplay between environmental exposures such as cigarette smoking and genetic variation of cardiovascular disease-related genes in determining risk for developing atherosclerosis. Should genotypes and behaviors such as smoking relate to the development of measurable atherosclerosis in young adulthood, it will indicate that specific genotypes and behaviors may be identified in youth, when the process initiates, and when preventive measures may be initiated. |
