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The overall objective of our program is to identify genetic, dietary, and pharmacologic influences on lipoprotein metabolism and related metabolic traits that influence risk for cardiovascular disease (CVD). Innovative genomic and molecular approaches are applied in human studies and in cellular model systems to derive information that can lead to improved prevention of CVD.

Despite recent advances in treatment, cardiovascular disease (CVD) remains the leading cause of death in the US and will soon achieve this status globally.
Our group's research is aimed at addressing three major challenges for reducing this enormous disease burden.

Firstly, standard diagnostic procedures do not identify a high proportion of children and adults who are at risk for CVD.  We have developed and implemented a sophisticated new procedure that, by analyzing individual lipoprotein particles, provides more specific information than that afforded by ordinary cholesterol testing, and hence is capable of improving both the assessment and management of CVD risk.  This methodology has been licensed by Quest Diagnostics, and hence is now widely available to clinicians.

Second, dietary and lifestyle guidance has failed to substantially impact CVD risk factors, particularly those related to overweight and obesity. We have demonstrated that carbohydrate restriction can reverse the atherogenic dyslipidemia found in a high proportion of overweight and obese individuals even in the absence of weight loss, and that this effect is independent of saturated fat intake. These findings have helped support dietary guidelines that place a greater emphasis on limiting refined carbohydrates than fats. In addition, we have recently shown that individuals with atherogenic dyslipidemia have a reduced capacity to oxidize fat, suggesting a common metabolic defect contributing to both adiposity and dyslipidemia.  In this regard, we have found that atherogenic dyslipidemia can be dramatically improved by an experimental drug that increases fat oxidation by activating cellular PPAR-delta receptors.

Finally, despite the awareness of wide interindividual variability in response to treatments aimed at reducing CVD risk, the potential benefits of applying genomic tools for developing personalized approaches for maximizing CVD risk reduction have not been realized.  A major component of our research program, carried out under the auspices of a large NIH grant and in collaboration with Dr. Marisa Medina at CHORI and multiple investigators nation-wide, has been the application and development of genomic methodology for dissecting genetic influences on the therapeutic responses to statins, the most widely prescribed class of drugs for reducing CVD risk.  We have completed the first genome-wide study for discovery of genetic variants associated with cholesterol response to statins, and are using a unique repository of lymphocyte cell lines derived from well-characterized participants in our statin clinical trial to link statin response to variations in cholesterol metabolic pathways that are revealed by a "systems" approach that integrates genomic sequence variation and gene expression data. This approach promises to provide comprehensive molecular assessment of the full range of statin effects, with the potential for identifying factors that influence both benefits and adverse effects of treatment. A recent notable achievement in this regard is the discovery that GATM, a gene responsible for creatine synthesis, also has effects on cholesterol metabolism, and may be linked to statin-induced myopathy.


Revised: Friday, April 17, 2020 1:31 PM



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