Jaana Hartiala1,2,3, William S Schwartzman1,2,3, Julian Gabbay1,2,3, Anatole Ghazalpour4, Brian J Bennett5,6, Hooman Allayee7,8,9. 1. Department of Preventive Medicine, University of Southern California, Los Angeles, CA, 90033, USA. 2. Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA, 90033, USA. 3. Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, 2250 Alcazar Street, CSC202, Los Angeles, CA, 90033, USA. 4. Department of Human Genetics, David Geffen School of Medicine of UCLA, Los Angeles, CA, 90095, USA. 5. USDA Western Human Nutrition Research Center, University of California Davis, Davis, CA, 95616, USA. 6. Department of Nutrition, University of California Davis, Davis, CA, 95616, USA. 7. Department of Preventive Medicine, University of Southern California, Los Angeles, CA, 90033, USA. hallayee@usc.edu. 8. Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA, 90033, USA. hallayee@usc.edu. 9. Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, 2250 Alcazar Street, CSC202, Los Angeles, CA, 90033, USA. hallayee@usc.edu.
Abstract
PURPOSE OF REVIEW: We provide an overview of our current understanding of the genetic architecture of coronary artery disease (CAD) and discuss areas of research that provide excellent opportunities for further exploration. RECENT FINDINGS: Large-scale studies in human populations, coupled with rapid advances in genetic technologies over the last decade, have clearly established the association of common genetic variation with risk of CAD. However, the effect sizes of the susceptibility alleles are for the most part modest and collectively explain only a small fraction of the overall heritability. By comparison, evidence that rare variants make a substantial contribution to risk of CAD has been somewhat disappointing thus far, suggesting that other biological mechanisms have yet to be discovered. Emerging data suggests that novel pathways involved in the development of CAD can be identified through complementary and integrative systems genetics strategies in mice or humans. There is also convincing evidence that gut bacteria play a previously unrecognized role in the development of CAD, particularly through metabolism of certain dietary nutrients that lead to proatherogenic metabolites in the circulation. A major effort is now underway to functionally understand the newly discovered genetic and biological associations for CAD, which could lead to the development of potentially novel therapeutic strategies. Other important areas of investigation for understanding the pathophysiology of CAD, including epistatic interactions between genes or with either sex and environmental factors, have not been studied on a broad scope and represent additional opportunities for future studies.
PURPOSE OF REVIEW: We provide an overview of our current understanding of the genetic architecture of coronary artery disease (CAD) and discuss areas of research that provide excellent opportunities for further exploration. RECENT FINDINGS: Large-scale studies in human populations, coupled with rapid advances in genetic technologies over the last decade, have clearly established the association of common genetic variation with risk of CAD. However, the effect sizes of the susceptibility alleles are for the most part modest and collectively explain only a small fraction of the overall heritability. By comparison, evidence that rare variants make a substantial contribution to risk of CAD has been somewhat disappointing thus far, suggesting that other biological mechanisms have yet to be discovered. Emerging data suggests that novel pathways involved in the development of CAD can be identified through complementary and integrative systems genetics strategies in mice or humans. There is also convincing evidence that gut bacteria play a previously unrecognized role in the development of CAD, particularly through metabolism of certain dietary nutrients that lead to proatherogenic metabolites in the circulation. A major effort is now underway to functionally understand the newly discovered genetic and biological associations for CAD, which could lead to the development of potentially novel therapeutic strategies. Other important areas of investigation for understanding the pathophysiology of CAD, including epistatic interactions between genes or with either sex and environmental factors, have not been studied on a broad scope and represent additional opportunities for future studies.
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