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A multidisciplinary team of UM Miller School investigators have received a $2.8 million grant from the NIH’s National Institute of Neurological Disorders and Stroke to search for genetic determinants of subclinical carotid disease, cardiac hypertrophy, and left atrial enlargement. The team is led by Ralph L. Sacco, M.D., M.S., the Olemberg Chair of Neurology and Professor of Neurology, Epidemiology and Public Health, Human Genetics, and Neurological Surgery.

The competitive five-year grant continues the work Sacco began at Columbia University in 2002 to study the genetic determinants of stroke among the rapidly growing Hispanic community. Although race-ethnic variations in the prevalence of cardiovascular risk factors among Hispanics are known, most epidemiological studies regarding cardiovascular risk factors have not included large numbers of Hispanics. For this study, researchers will perform state-of-the-art exome sequencing on about 1,500 members of 100 extended Dominican families living in the U.S. and in the Dominican Republic who have well-characterized risk factors for cardiovascular disease.

“Innovative strategies are needed to detect vascular risk, initiate risk reduction earlier, identify novel mechanisms, and further elucidate the biology of cardiovascular disease and stroke,” said Sacco, the past president of the American Heart Association. “We will be harnessing the power of next generation sequencing to address less frequent genetic determinants of carotid disease and stroke risk with the hope of uncovering novel pathways and potential future treatment options.”

Among the risk factors for stroke is the thickness of the blood vessel walls along the neck. As co-investigator Tatjana Rundek, M.D., Ph.D., Vice Chair for Clinical Translational Research in the Department of Neurology, said, “The atherosclerotic processes leading to overt disease manifest as preclinical changes in arterial walls, which we can now easily and reliably detect by high-definition ultrasound technologies.”

These methods, Rundek noted, turned out to be extremely useful for investigations of the relative roles of genetic and environmental factors on subclinical atherosclerosis before occurrence of vascular events. They can detect early changes in arterial wall thickness and morphology and, therefore, create quantitative phenotypes of early atherosclerotic process, amendable for further genetic investigations.

“The genetic factors associated with atherosclerosis seem to be much more diverse than originally suggested and only detailed investigations as proposed in this project will be able to explain some of the genetic pathways responsible for accelerated atherosclerosis linked to certain high-risk individuals and families,” Rundek said. “These investigations will ultimately lead to targeted prevention and interventions that act on causes rather than the consequences of atherosclerosis.”

The research will be conducted in collaboration with the Hussman Institute for Human Genomics (HIHG), and co-investigator Susan Blanton, Ph.D., associate professor in the Dr. John T. Macdonald Foundation Department of Human Genetics and HIHG’s Associate Director of Communications and Compliance.

“The focus on family-based data is a unique strength of this project,” Blanton said. “The family study design allows us to address issues not possible in a traditional cohort study.”

In addition to Sacco, Rundek and Blanton, the other members of the grant team are Eugene Roberts, Ph.D., associate professor of neurology, Ashley Beecham, M.S., senior research analyst for the Department of Human Genetics, Liyong Wang, Ph.D., research assistant professor of human genetics, and Chuanhui Dong, Ph.D., research assistant professor of neurology.

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