CONTRIBUTION OF CARBOXYLESTERASE VARIANTS TO HEART DISEASE RISK

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project will determine whether variants of carboxylesterase 1 (CES1) and 2 (CES2) contribute to differences in susceptibility towards heart disease. Hypothesis: Variation in CES1 and CES2 are associated with phenotypic variation in serum LDL cholesterol (LDLC) and/or HDL cholesterol (HDLC) concentrations and lipoprotein profiles in baboons and this variation influences risk of susceptibility to heart disease. Specific aims: 1) To identify polymorphisms in CES1 and CES2 that influence LDLC and/or HDLC levels and associated lipoprotein profiles. 2) To determine the impact of the encoded amino acid variants on CES1 and CES2 structures. Outcomes: We predict that differences observed among variants will influence CES1 and CES2 structure and LDLC and/or HDLC phenotypes observed in the population and that CES1 and CES2 genetic variants will modify enzyme structures in key positions influencing catalytic activity and binding of cholesterol and fatty acid metabolites. Significance: Identification of CES1 and CES2 polymorphisms that influence cholesterol and fatty acid metabolism will provide new targets for the prevention of heart disease and will assist in targeting drugs for the treatment of heart disease. Furthermore, these results will provide crucial preliminary data for submission of an NIH grant application to elucidate the mechanisms by which these variants influence heart disease traits.